WO2023011358A1 - Novel pharmaceutical salts and polymorphic forms of an erbb and btk inhibitor - Google Patents

Novel pharmaceutical salts and polymorphic forms of an erbb and btk inhibitor Download PDF

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WO2023011358A1
WO2023011358A1 PCT/CN2022/109065 CN2022109065W WO2023011358A1 WO 2023011358 A1 WO2023011358 A1 WO 2023011358A1 CN 2022109065 W CN2022109065 W CN 2022109065W WO 2023011358 A1 WO2023011358 A1 WO 2023011358A1
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crystalline form
compound
egfr
acid salt
xrpd pattern
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French (fr)
Inventor
Jun-Cheng Zheng
Jianan JIANG
Qinghai GUO
Shih-Ying Chang
Qingbei Zeng
Honchung TSUI
Zhenfan YANG
Xiaolin Zhang
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Dizal Jiangsu Pharmaceutical Co Ltd
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Dizal Jiangsu Pharmaceutical Co Ltd
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Priority to JP2024506641A priority Critical patent/JP2024529533A/ja
Priority to KR1020247007187A priority patent/KR20240042640A/ko
Priority to CA3224748A priority patent/CA3224748A1/en
Priority to US18/293,778 priority patent/US20250197377A1/en
Priority to AU2022324410A priority patent/AU2022324410A1/en
Priority to CN202280053629.5A priority patent/CN117794902A/zh
Priority to EP22852071.4A priority patent/EP4380924A4/en
Priority to MX2024001367A priority patent/MX2024001367A/es
Publication of WO2023011358A1 publication Critical patent/WO2023011358A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/185—Saturated compounds having only one carboxyl group and containing keto groups
    • C07C59/225—Saturated compounds having only one carboxyl group and containing keto groups containing —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the 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, “Compound I” , having a structure as shown below) ) :
  • ErbB family receptor tyrosine kinases act to transmit signals from the outside of a cell to the inside by activating secondary messaging effectors via a phosphorylation event at their tyrosine phosphorylation residues.
  • a variety of cellular processes are modulated by these signals, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival.
  • Deregulation of ErbB family signalling modulates proliferation, invasion, metastasis, angiogenesis, and tumour cell survival and may be associated with many human cancers, including those of the lung, head and neck and breast cancers.
  • Various ErbB receptors such as EGFR, and HER2 have been demonstrated to relate to disorders such as cancer. Different mutations of EGFR and HER2 have also been proved to relate to certain cancer type or to the non-responsiveness/resistance to existing drugs for WT EGFR or HER2.
  • BTK tyrosine kinase
  • SRC-related family of cytoplasmic tyrosine kinases which are predominantly expressed in B cells, and distributed in the lymphatic system, hematopoietic and hematological systems.
  • BTK plays a key role in the B-cell receptor signaling pathway of B-cells, which is required for the development, activation and survival of B-cells.
  • BTK inhibitors have therefore been developed with the aim of treating B-cell malignancies that are dependent 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 implicated in promotion of Toll-like receptor signaling, which regulates macrophage activation and production of proinflammatory cytokines.
  • TLR Toll-like receptor signaling pathway to mediate transactivation of downstream cascades.
  • BTK is found to play a critical role in regulation of immunity. BTK has become an attractive target for the treatment of B-cell malignancies, inflammation, as well as the treatment of autoimmune diseases.
  • Crystalline polymorphs are different crystalline forms of the same compound. Different crystalline polymorphs may have different crystal structures due to a different packing of the molecules in the lattice. This results in a different crystal symmetry and/or unit cell parameters which directly influences its physical properties such as the X-ray diffraction characteristics of crystals or powders. A different polymorph, for example, will in general diffract at a different set of angles and will give different values for the intensities. Therefore, X-ray powder diffraction can be used to identify different polymorphs, or a solid form that comprises more than one polymorph, in a reproducible and reliable way.
  • Crystalline polymorphic forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms.
  • Different crystalline forms of a drug substance can have different physical properties, including melting point, solubility, dissolution rate, optical and mechanical properties, vapor pressure, hygroscopicity, particle shape, density, and flowability. These properties can have a direct effect on the ability to process and/or manufacture a compound as a drug product.
  • Different crystalline forms can also exhibit different stabilities and bioavailability. For example, if the polymorphic form is not held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another.
  • the most stable crystalline form of a drug product is often chosen during drug development based on the minimal potential for conversion to another crystalline form and on its greater chemical stability. It is also desirable to have processes for producing a compound with the selected polymorphic form in high purity when the compound is used in clinical studies or commercial products since impurities present may produce undesired toxicological effects. Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies. To ensure the quality, safety, and efficacy of a drug product, it is important to choose a crystalline form that is stable, is manufactured reproducibly, and has favorable physicochemical properties.
  • the present disclosure provides novel pharmaceutical salts of Compound I.
  • the pharmaceutical salt of Compound I provided herein is selected from: hydrochloric acid salt, methanesulfonic acid salt, sulfuric acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, citric acid salt, succinic acid salt, L-malic acid salt, L- (+) -tartaric acid salt, and hydrochloric acid salt of Compound I.
  • the pharmaceutical salt of Compound I is hydrochloric acid salt, L- (+) -tartaric acid salt, fumaric acid salt, sulfuric acid salt, and maleic acid salt of Compound I.
  • the pharmaceutical salt of Compound I is in amorphous form.
  • the pharmaceutical salt of Compound I is in crystalline form.
  • the pharmaceutical salt of Compound I is hydrochloric acid salt, L- (+) -tartaric acid salt, fumaric acid salt, sulfuric acid salt, and maleic acid salt of Compound I in crystalline form.
  • the present disclosure also provides crystalline form of Compound I or pharmaceutically acceptable salts thereof.
  • the crystalline form is Form A of Compound I, Form B of Compound I, crystalline form of hydrochloric acid salt, L- (+) -tartaric acid salt, fumaric acid salt, sulfuric acid salt, or maleic acid salt of Compound I.
  • compositions each comprising one or more pharmaceutical salts or crystalline forms of Compound I, as disclosed herein.
  • the present disclosure provides methods of treating an ErbB associated disease or BTK associated disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical salts or crystalline forms of Compound I, or pharmaceutical composition provided herein.
  • the present disclosure provides use of the pharmaceutical salts or crystalline forms of Compound I, or pharmaceutical composition provided herein in inhibiting ErbB or BTK, or in the manufacture of a medicament for inhibiting ErbB or BTK.
  • the present disclosure also provides process for production of the pharmaceutical salts or the crystalline form of Compound I.
  • the present disclosure also provides process for preparing Compound I on tens of kilogram scale with high yield.
  • FIG. 1 is the XRPD data for the crystalline Form A of the free base of Compound I.
  • FIG. 2 is the DSC data for the crystalline Form A of the free base of Compound I.
  • FIG. 3 is the TGA data for the crystalline Form A of the free base of Compound I.
  • FIG. 4 is the DVS data for the crystalline Form A of the free base of Compound I.
  • FIG. 5 is the XRPD data for the crystalline Form B of the free base of Compound I.
  • FIG. 6 is the DSC data for the crystalline Form B of the free base of Compound I.
  • FIG. 7 is the TGA data for the crystalline Form B of the free base of Compound I.
  • FIG. 8 is the DVS data for the crystalline Form B of the free base of Compound I.
  • FIG. 9 is the XRPD data for the (+) -L-tartaric acid salt of Compound I (pattern I) .
  • FIG. 10 is the XRPD data for the fumaric acid salt of Compound I.
  • FIG. 11 is the XRPD data for the sulfuric acid salt of Compound I.
  • FIG. 12 is the XRPD data for the maleic acid salt of Compound I.
  • FIG. 13 is the XRPD data for the hydrochloric acid salt of Compound I.
  • FIG. 14 is the XRPD data for the (+) -L-tartaric acid salt of Compound I (pattern II) .
  • FIG. 15 is the TGA/DSC overlay data for the (+) -L-tartaric acid salt of Compound I (pattern I, prepared in acetone) .
  • FIG. 16 is the TGA/DSC overlay data for the (+) -L-tartaric acid salt of Compound I (pattern II, prepared in ethanol) .
  • FIG. 17 is the TGA/DSC overlay data for the fumaric acid salt of Compound I (prepared in ethanol) .
  • FIG. 18 is the TGA/DSC overlay data for the sulfuric acid salt of Compound I.
  • FIG. 19 is the TGA/DSC overlay data for the maleic acid salt of Compound I.
  • FIG. 20 is the TGA/DSC overlay data for the hydrochloric acid salt of Compound I.
  • FIG. 21 is the DVS data for crystalline form of the Compound I- (+) -L-tartaric acid salt. (pattern II) .
  • FIG. 22 is the DVS data for crystalline form of the Compound I-fumaric acid salt.
  • FIG. 23 is the DVS data for crystalline form of the Compound I-hydrochloric acid salt.
  • FIG. 24 is the XRPD profiles of Compound I-Form B before and after jet milling.
  • FIG. 25 is the XRPD profiles of Compound I-Form B before and after grinding.
  • FIG. 26 is the DSC profiles of Compound I-Form B before and after jet milling.
  • FIG. 27 is the XRPD profiles of Compound I-Form B after storage for 20 days at 2-8 °C.
  • FIG. 28 is the DSC profiles of Compound I-Form B after storage for 20 days at 2-8 °C.
  • FIG. 29 is the 1 H NMR for the determination of Compound I-fumaric acid salt ratio (1: 1) .
  • FIG. 30 is the 1 H NMR for the determination of Compound I-maleic acid salt ratio (1: 1) .
  • FIG. 31 is the 1 H NMR for the determination of Compound I-tartaric acid salt (pattern I) ratio (1: 1) .
  • FIG. 32 is the 1 H NMR for the determination of Compound I-tartaric acid salt (pattern II) ratio (1: 1) .
  • FIG. 33 is the single crystal X-ray diffraction ORTEP of Compound I.
  • FIG. 34 is the Dissolution profile of 200mg tablets for Compound I at pH1.2.
  • FIG. 35 is the Dissolution profile of 200mg tablets for Compound I at pH4.5.
  • the measurement error is ⁇ 0.2° for the diffraction angle 2 ⁇ in XRPD
  • the measurement error is ⁇ 0.01-10°C of the endotherms for crystal polymorph melting and ⁇ 0.01-20°C of the endotherms for polymorph dehydration/desolvation in DSC
  • the measurement error is ⁇ 5-20°C in TGA)
  • inhibitor refers to a compound or agent having the ability to inhibit a biological function of a target protein or polypeptide, such as by inhibiting the activity or expression of the target protein or polypeptide. Accordingly, the term “inhibitor” is defined in the context of the biological role of the target protein or polypeptide. While some inhibitors herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein or polypeptide by interacting with other members of the signal transduction pathway of that target protein or polypeptide are also specifically included within this definition.
  • Non-limiting examples of biological activity inhibited by an inhibitor include those associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in autoimmune disease.
  • selective inhibition or “selectively inhibit” as applied to a biologically active agent refers to the agent’s ability to selectively reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.
  • a compound that selectively inhibits mutant EGFR/Her2 over wild-type EGFR/Her2 has an activity of at least about 2x against the mutated EGFR/Her2 relative 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) .
  • the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compounds, materials, compositions, and/or dosage forms that are pharmaceutically acceptable refer to those approved by a regulatory agency (such as U.S. Food and Drug Administration, China Food and Drug Administration or European Medicines Agency) or listed in generally recognized pharmacopoeia (such as U.S. Pharmacopoeia, China Pharmacopoeia or European Pharmacopoeia) for use in animals, and more particularly in humans.
  • “pharmaceutically acceptable salts” or “pharmaceutical salts” refers to derivatives of the compounds of present disclosure wherein the parent compound is modified by converting an existing acidic moiety (e.g., carboxyl and the like) or base moiety (e.g., amine, alkali and the like) to its salt form.
  • compounds of present disclosure are capable of forming acid addition salts and/or base salts by virtue of the presence of amino, alkali and/or carboxyl groups or groups similar thereto.
  • the “pharmaceutically acceptable salt” includes acid addition salts or base salts that retain biological effectiveness and properties of the parent compound, which typically are not biologically or otherwise undesirable. Pharmaceutically acceptable salts are well known in the art.
  • Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases.
  • pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, benzoic acid, cinnamic acid, mandelic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, malonic acid, fumaric acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, or methanesulfonic acid or by using other methods used in the art such as ion
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
  • 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, and the like.
  • the pharmaceutically acceptable salt is a hydrochloric acid salt, methanesulfonic acid salt, sulfuric acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, citric acid salt, succinic acid salt, L-malic acid salt, and L- (+) -tartaric acid salt.
  • polymorphic form refers to a solid in which the constituent atoms, molecules, or ions are packed in a regularly ordered, repeating three-dimensional pattern having a highly regular chemical structure.
  • a compound or salts thereof might be produced in one or more crystalline forms.
  • Different crystalline forms can be characterized by XRPD patterns (e.g.
  • X-ray diffraction peaks position at various diffraction angles (2 ⁇ ) and/or peak intensities) , melting point onset (and onset of dehydration for hydrated forms) as illustrated by endotherms of a differential scanning calorimetry (DSC) thermogram, thermal gravimetric analysis (TGA) , solid state 1 H nuclear magnetic resonance (NMR) spectrum, aqueous solubility, high intensity light conditions, physical and chemical storage stability and any other measurements known in the art.
  • DSC differential scanning calorimetry
  • TGA thermal gravimetric analysis
  • NMR solid state 1 H nuclear magnetic resonance
  • XRPD pattern refers to the experimentally observed diffractogram or parameters derived therefrom, which is shown as an x-y graph with peak positions represented as diffraction angle (2 ⁇ ) on the x-axis and peak intensity on the y-axis. The peaks within this pattern may be used to characterize a crystalline solid form.
  • peak positions refers to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments. Peak positions are directly related to the dimensions of the unit cell. The peaks, identified by their respective peak positions, have been extracted from the diffraction patterns for the various polymorphic forms of Compound I disclosed herein.
  • peak intensities refers to relative signal intensities within a given X-ray powder diffraction pattern. Factors that can affect the relative peak intensities are sample thickness and preferred orientation (i.e., the crystalline particles are not distributed randomly) .
  • a measurement error of a diffraction angle in an XRPD is approximately 2 ⁇ ( ⁇ 0.2°) , and such degree of a measurement error should be taken into account when considering the XRPD pattern in the Figures and when reading data contained in the Tables included herein.
  • DSC measures the difference in heat energy between a solid sample and an appropriate reference with an increase in temperature.
  • DSC thermograms are characterized by endotherms (indicating energy uptake) and also by exotherms (indicating energy release) , typically as the sample is heated.
  • endotherms indicating energy uptake
  • exotherms indicating energy release
  • the endotherms exhibited by the compounds of the present disclosure may vary ( ⁇ 0.01-10°C of the endotherms for crystal polymorph melting and ⁇ 0.01-20°C of the endotherms for polymorph dehydration/desolvation) , and such degree of variation should be taken into account when considering the DSC data included herein.
  • one compound prepared in different batches may show variations in DSC thermograms, however these DSC thermograms with variations should still be considered as “substantially similar to” each other.
  • the observed endotherms may also differ from instrument to instrument; however, it will generally be within the ranges defined herein provided the instruments are calibrated similarly. Furthermore, it will be understood that removal of the residual solvent in the prepared compounds may also change the DSC onset and peak temperatures.
  • TGA is a testing procedure in which changes in weight of a specimen are recorded as the specimen is heated in air or in a controlled atmosphere such as nitrogen.
  • Thermogravimetric curves (thermograms) provide information regarding solvent and water content and the thermal stability of materials.
  • TGA thermograms show similar variations as DSC (ameasurement error of about ⁇ 5-20°C) , such that a person skilled in the art recognizes that measurement errors should be taken into account when judging substantial identity of TGA thermograms.
  • the “compound” of present disclosure can exist in solvated as well as un-solvated forms, such as, for example, hydrated forms, solid forms, and the present disclosure is intended to encompass all such solvated and unsolvated forms. It is further to be understood that the “compound” of present disclosure can exist in forms of pharmaceutically acceptable salts or esters.
  • ErbB or “wild-type ErbB” refers to normal ErbB family members.
  • the present disclosure provides inhibitory compounds of ErbB family kinase (e.g., EGFR, Her2, Her3 and/or Her4) .
  • the compounds of the present disclosure can inhibit both Wild-Type (WT) and mutant forms of ErbB family kinase.
  • the compounds of the present disclosure are selective inhibitors of at least one mutation of ErbB family kinase as compared to corresponding WT ErbB family kinase.
  • mutants refers to the any mutations to the target protein
  • mutant or mutant form refers to the protein that contains said mutation.
  • Exemplary mutations of ErbBs include but are not limited to, 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_D
  • the compounds of the present disclosure are selective inhibitors of at least one mutation of EGFR as compared to WT EGFR. In some embodiments, the compounds of the present disclosure are selective inhibitors of at least one mutation of Her2 as 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) .
  • the at least one mutation of EGFR is an insertion mutation (e.g., EGFR Exon 20 V769_D770insASV, Exon 20 H773_V774insNPH) .
  • the at least one mutation of EGFR is an activating mutation (e.g., L858R, G719S or delE746-A750) .
  • the at least one mutation of EGFR is a drug resistant mutation (e.g., Exon 20_T790M) .
  • an at least one mutation of EGFR is T790M.
  • a provided compound selectively inhibits T790M/L858R co-mutation, and is sparing as to WT EGFR inhibition.
  • the term “selectively inhibits, ” as used in comparison to inhibition of WT EGFR/Her2, means that a provided compound is more potent as an inhibitor of at least one mutation of 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 resistant mutation, or a combination of at least one deletion mutation and at least one point mutation) in at least one assay described herein (e.g., biochemical or cellular) .
  • the term “selectively inhibits, ” as used in comparison to WT EGFR/Her2 inhibition means that a provided compound is at least 100 times more potent, at least 50 times, at least 45 times, at least 40 times, at least 35 times, at least 30 times, at least 25 times, at least 20 times, at least 15 times, at least 10 times, at least 5 times, at least 4 times, at least 3 times, at least 2 times, at least 1.5 times, or at least 1.25 times more potent as an inhibitor of at least one mutation of EGFR/Her2, as defined and described herein, as compared to WT EGFR/Her2.
  • the term “selectively inhibits, ” as used in comparison to WT EGFR/Her2 inhibition means that a provided compound is up to 1500 times more potent, up to 1200 times, up to 1000 times, up to 800 times, up to 600 times, up to 400 times, up to 200 times, up to 100 times, up to 50 times, up to 10 times more potent as an inhibitor of at least one mutation of EGFR/Her2, as defined and described herein, as compared to WT EGFR/Her2.
  • the term “sparing as to WT EGFR/Her2” means that said selective inhibitor of at least one mutation of EGFR/Her2, as defined and described above and herein, cannot inhibits WT EGFR/Her2 within the upper limit of detection of at least one assay as described herein (e.g., biochemical or cellular as described in detail in Examples) .
  • the term “sparing as to WT EGFR/Her2” means that a provided compound inhibits WT EGFR/Her2 with an IC 50 of at least 10 ⁇ , at least 9 ⁇ , at least 8 ⁇ , at least 7 ⁇ , at least 6 ⁇ , at least 5 ⁇ , at least 3 ⁇ , at least 2 ⁇ , or at least 1 ⁇ .
  • compounds of the present disclosure inhibit phosphorylation of WT EGFR/Her2 and/or mutant EGFR/Her2 with an IC 50 value of 0.1-1000nM, preferably 0.1-600nM, 1-600nM, 0.1- 500nM, 1-500nM, 0.1-400nM, 1-400nM, 0.1-300nM, 1-300nM, 0.1-200nM, 1-200nM, 0.1-100nM, 1-100nM, 0.1-80nM, 0.1-50nM, 0.1-40nM, 0.1-30nM, 0.1-20nmM, 0.1-10nM, or 0.1-5nM, more preferably 0.1-20nM, 0.1-10nM, or 0.1-5nM.
  • compounds of the present disclosure inhibit proliferation of WT EGFR/Her2 and/or mutant EGFR/Her2 bearing cells with an GI 50 value of 1-1000nM, preferably 1-800nM, 1-600nM, 1-500nM, 1-400nM, 1-300nM, 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.
  • compounds of the present disclosure inhibit proliferation of BTK bearing cells with an GI 50 value of 1-1000nM, more than 1000nM, more than 2000nM, or more than 3000nM preferably 1-800nM, 1-600nM, 1-500nM, 1-400nM, 1-300nM, 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.
  • the IC 50 and/or GI 50 of the compounds to EGFR/Her2 mutant is at least 2 times, 3 times, 4 times, 5 times, preferably 10 times, 20 times, 30 times, 50 times, or 100 times higher than the IC 50 and/or GI 50 of the compounds to wild-type EGFR/Her2.
  • composition refers to a mixture of one or more physiologically/pharmaceutically acceptable salts of Compound I described herein or polymorphs of Compound I or the salts, with other chemical components, such as physiologically/pharmaceutically acceptable diluent, excipient or carrier.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to a subject.
  • sustained released form refers to release of the active agent from the pharmaceutical composition so that it becomes available for bio-absorption in the subject, primarily in the gastrointestinal tract of the subject, over a prolonged period of time (extended release) , or at a certain location (controlled release) .
  • pharmaceutically acceptable carrier 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, body fluid, tissue, organ (interior or exterior) , or portion of the body, to another location, body fluid, tissue, organ, or portion of the body.
  • Pharmaceutically acceptable carriers can be vehicles, diluents, excipients, or other materials that can be used to contact the tissues of an animal without excessive toxicity or adverse effects.
  • Non-limiting examples of pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; releasing
  • Cyclodextrins such as a-, b-, and g-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2-and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein.
  • Pharmaceutically acceptable carrier that can be employed in present disclosure includes those generally known in the art, such as those disclosed in “Remington Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) , which is incorporated herein by reference.
  • administration encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, as discussed herein.
  • a “therapeutically effective amount” refers to the amount of a compound or pharmaceutical composition described herein that is sufficient to prevent, treat, reduce and/or ameliorate the symptoms and/or underlying causes of any disorder or disease in a subject, or the amount of an agent sufficient to produce a desired effect on target cells, e.g., reduction of cell migration.
  • a “therapeutically effective amount” is an amount sufficient to reduce or eliminate a symptom of a disease.
  • a therapeutically effective amount is an amount sufficient to overcome the disease itself.
  • a “therapeutically effective amount” is an amount effective for detectable killing or inhibition of the growth or spread of cancer cells, reducing in the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer.
  • the therapeutically effective amount will vary depending upon the subject and the condition being treated, the weight and age of the subject, the severity of the condition, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • a therapeutically effective amount of an agent in the context of treating cancer, refers to an amount of the agent that alleviates, ameliorates, palliates, or eliminates one or more symptoms of cancer in the patient.
  • diseases associated with BTK or “BTK associated diseases” refers to diseases whose onset or development or both are associated with the genomic alterations or mutation, expression or activity of BTK.
  • the term “diseases associated with ErbB” or “ErbB associated diseases” refers to diseases whose onset or development or both are associated with the genomic alterations or mutation, expression or activity of ErbB (including EGFR and Her2) .
  • Examples of “diseases associated with ErbB” include “diseases associated with EGFR” or “diseases associated with Her2” .
  • the term “diseases associated with EGFR” or “EGFR associated diseases” or “diseases associated with Her2” or “Her2 associated diseases” refers to diseases whose onset or development or both are associated with the genomic alterations or mutation, expression or activity of EGFR or Her2, as the case may be. Examples include but are not limited to, immune-related diseases, proliferative disorders, cancer, and other diseases.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors) . Treatment may also be continued after symptoms have resolved, for example to present or delay their recurrence.
  • anti-cancer agent refers to any agent useful in the treatment of a neoplastic condition.
  • One class of anti-cancer agents comprises chemotherapeutic agents.
  • “Chemotherapy” means the administration of one or more chemotherapeutic drugs 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.
  • subject to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult) ) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys) ; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, rabbits, hamsters, mice, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys.
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)
  • novel pharmaceutical salts of Compound I crystalline polymorphs of Compound I or the pharmaceutical salts of the present disclosure, composition thereof, process for production of the same and the uses thereof such as inhibiting ErbB or BTK, treating an ErbB associated diseases or BTK associated diseases in a subject.
  • the present disclosure provides novel pharmaceutical salts of Compound I.
  • the pharmaceutical salt of Compound I provided herein is selected from: hydrochloric acid salt, methanesulfonic acid salt, sulfuric acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, citric acid salt, succinic acid salt, L-malic acid salt, L- (+) -tartaric acid salt, and hydrochloric acid salt of Compound I.
  • pharmaceutical salt of Compound I is a compound having the structure of Formula (I) :
  • n 1 or 2;
  • X is hydrochloric acid, L- (+) -tartaric acid, fumaric acid, sulfuric acid, or maleic acid.
  • pharmaceutical salt of Compound I is hydrochloric acid salt, L- (+) -tartaric acid salt, fumaric acid salt, sulfuric acid salt, and maleic acid salt of Compound I.
  • pharmaceutical salt of Compound I is mono-salt.
  • the pharmaceutical salt of Compound I is in amorphous form.
  • the pharmaceutical salt of Compound I is in crystalline form.
  • the pharmaceutical salt of Compound I is hydrochloric acid salt, L- (+) -tartaric acid salt, fumaric acid salt, sulfuric acid salt, and maleic acid salt of Compound I in crystalline form.
  • the present disclosure provides several polymorphic crystalline forms of Compound I or pharmaceutically acceptable salts thereof.
  • the present disclosure provides a crystalline form of Compound I, particularly, freebase Form A or Form B of Compound I.
  • the present disclosure provides a crystalline form of a pharmaceutically acceptable salt of Compound I, particularly, crystalline form of hydrochloric acid salt of Compound I, crystalline form of L- (+) -tartaric acid salt of Compound I, crystalline form of fumaric acid salt of Compound I, crystalline form of sulfuric acid salt of Compound I, or crystalline form of maleic acid salt of Compound I.
  • crystalline form of Compound I (free base) , which is Form A of Compound I.
  • Form A of Compound I has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles (2 ⁇ ) of 11.62 ⁇ 0.20, 12.48 ⁇ 0.20, 17.34 ⁇ 0.20, and 20.04 ⁇ 0.20 degrees.
  • XRPD X-ray powder diffraction
  • Form A of Compound I has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 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.
  • Form A of Compound I has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • Form A of Compound I has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 5.95 ⁇ 0.20, 14.96 ⁇ 0.20, 22.01 ⁇ 0.20, and 27.60 ⁇ 0.20 degrees.
  • Form A of Compound I has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • Form A of Compound I has a XRPD pattern substantially as shown in Table 7.
  • Form A of Compound I has a XRPD pattern substantially as shown in FIG. 1.
  • Form A of Compound I has a DSC thermogram comprising an endotherm with a desolvation onset at about 178.6 °C and a peak at about 179.6°C.
  • Form A of Compound I has a DSC thermogram substantially similar to FIG. 2.
  • Form A of Compound I has a TGA thermogram exhibiting a mass loss of about 0.23 %upon heating from about 38 °C to about 160°C.
  • Form A of Compound I has a TGA thermogram substantially similar to FIG. 3
  • Form A of Compound I has a DVS vapor sorption gram substantially similar to FIG. 4.
  • crystalline form of Compound I (free base) , which is Form B of Compound I.
  • Form B of Compound I has a XRPD pattern comprising peaks at 2 ⁇ of 9.39 ⁇ 0.20, 18.86 ⁇ 0.20, 19.50 ⁇ 0.20, and 20.06 ⁇ 0.20 degrees.
  • Form B of Compound I has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 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.
  • Form B of Compound I has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • Form B of Compound I has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 22.07 ⁇ 0.20, 22.91 ⁇ 0.20, 23.68 ⁇ 0.20, and 24.00 ⁇ 0.20 degrees.
  • Form B of Compound I has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • Form B of Compound I has a XRPD pattern substantially as shown in Table 8.
  • Form B of Compound I has a XRPD pattern substantially as shown in FIG. 5.
  • Form B of Compound I has a DSC thermogram comprising an endotherm with a desolvation onset at about 194.8 °C and a peak at about 196.7°C.
  • Form B of Compound I has a DSC thermogram substantially similar to FIG. 6.
  • Form B of Compound I has a TGA thermogram exhibiting a mass loss of less than 0.17 %upon heating from about 38 °C to about 178°C.
  • Form B of Compound I has a TGA thermogram substantially similar to FIG. 7.
  • Form B of Compound I has a DVS vapor sorption gram substantially similar to FIG. 8.
  • a crystalline form of a pharmaceutically acceptable salt of Compound I which is a crystalline form of Compound I hydrochloric acid salt.
  • the crystalline form of Compound I hydrochloric acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 9.35 ⁇ 0.20, 17.21 ⁇ 0.20, 18.21 ⁇ 0.20, 19.79 ⁇ 0.20, and 21.17 ⁇ 0.20 degrees.
  • the crystalline form of Compound I hydrochloric acid salt has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 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.
  • the crystalline form of Compound I hydrochloric acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I hydrochloric acid salt has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 7.30 ⁇ 0.20, 14.85 ⁇ 0.20, 20.91 ⁇ 0.20, 23.25 ⁇ 0.20, and 27.43 ⁇ 0.20 degrees.
  • the crystalline form of Compound I hydrochloric acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I hydrochloric acid salt has a XRPD pattern substantially as shown in Table 16.
  • the crystalline form of Compound I hydrochloric acid salt has a XRPD pattern substantially as shown in FIG. 13.
  • the crystalline form of Compound I hydrochloric acid salt has a DSC thermogram comprising an endotherm with a desolvation onset at about 207.8 °C and a peak at about 212.1 °C.
  • the crystalline form of Compound I hydrochloric acid salt has a TGA thermogram exhibiting a mass loss of about 0.76 %upon heating to about 175°C.
  • the crystalline form of Compound I hydrochloric acid salt has a TGA/DSC thermogram substantially similar to FIG. 20.
  • the crystalline form of Compound I hydrochloric acid salt has a DVS vapor sorption gram substantially similar to FIG. 23.
  • a crystalline form of a pharmaceutically acceptable salt of Compound I which is a crystalline form of Compound I L- (+) -tartaric acid salt Pattern I.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern I has a XRPD pattern comprising peaks at 2 ⁇ of 5.34 ⁇ 0.20, 5.38 ⁇ 0.20, 10.50 ⁇ 0.20, 10.92 ⁇ 0.20, and 16.37 ⁇ 0.20 degrees.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern I has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 11.84 ⁇ 0.20, 15.05 ⁇ 0.20, 17.86 ⁇ 0.20, 18.52 ⁇ 0.20, and 18.99 ⁇ 0.20 degrees.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern I has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern I has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 7.29 ⁇ 0.20, 14.40 ⁇ 0.20, 22.02 ⁇ 0.20, and 23.96 ⁇ 0.20 degrees.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern I has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern I has a XRPD pattern substantially as shown in Table 17.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern I has a XRPD pattern substantially as shown in FIG. 9.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern I has a DSC thermogram comprising an endotherm with a desolvation onset at about 207.8 °C and a peak at about 212.1 °C.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern I has a TGA thermogram exhibiting a mass loss of about 0.76 %upon heating to about 175°C.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern I has a TGA thermogram substantially similar to FIG. 15.
  • a crystalline form of a pharmaceutically acceptable salt of Compound I which is a crystalline form of Compound I L- (+) -tartaric acid salt Pattern II.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern II has a XRPD pattern comprising peaks at 2 ⁇ of 10.02 ⁇ 0.20, 18.03 ⁇ 0.20, 19.89 ⁇ 0.20, 21.15 ⁇ 0.20, and 21.26 ⁇ 0.20 degrees.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern II has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 12.70 ⁇ 0.20, 13.76 ⁇ 0.20, 16.80 ⁇ 0.20, 20.92 ⁇ 0.20, and 22.82 ⁇ 0.20 degrees.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern II has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern II has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 7.95 ⁇ 0.20, 15.91 ⁇ 0.20, 23.44 ⁇ 0.20, 25.55 ⁇ 0.20, and 29.99 ⁇ 0.20 degrees.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern II has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern II has a XRPD pattern substantially as shown in Table 21.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern II has a XRPD pattern substantially as shown in FIG. 14.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern II has a DSC thermogram comprising an endotherm with a desolvation onset at about 137.2 °C and a peak at about 140.4 °C.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern II has a TGA thermogram exhibiting a mass loss of about 3.59 %upon heating to about 100°C.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern II has a TGA/DSC thermogram substantially similar to FIG. 16.
  • the crystalline form of Compound I L- (+) -tartaric acid salt pattern II has a DVS vapor sorption gram substantially similar to FIG. 21.
  • a crystalline form of a pharmaceutically acceptable salt of Compound I which is a crystalline form of Compound I fumaric acid salt.
  • the crystalline form of Compound I fumaric acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 11.92 ⁇ 0.20, 13.71 ⁇ 0.20, 19.54 ⁇ 0.20, 20.15 ⁇ 0.20, and 24.21 ⁇ 0.20 degrees.
  • the crystalline form of Compound I fumaric acid salt has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 13.08 ⁇ 0.20, 15.79 ⁇ 0.20, 18.86 ⁇ 0.20, 20.63 ⁇ 0.20, and 22.14 ⁇ 0.20 degrees.
  • the crystalline form of Compound I fumaric acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I fumaric acid salt has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 11.63 ⁇ 0.20, 12.33 ⁇ 0.20, 17.23 ⁇ 0.20, 18.52 ⁇ 0.20, and 23.79 ⁇ 0.20 degrees.
  • the crystalline form of Compound I fumaric acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I fumaric acid salt has a XRPD pattern substantially as shown in Table 18.
  • the crystalline form of Compound I fumaric acid salt has a XRPD pattern substantially as shown in FIG. 10.
  • the crystalline form of Compound I fumaric acid salt has a DSC thermogram comprising an endotherm with a desolvation onset at about 48.9 °C and a peak at about 68.3 °C.
  • the crystalline form of Compound I fumaric acid salt has a DSC thermogram further comprising an later endotherm with a desolvation onset at about 132.79 °C and a peak at about 141.78 °C.
  • the crystalline form of Compound I fumaric acid salt has a TGA thermogram exhibiting a mass loss of about 2.86 %upon heating to about 55°C.
  • the crystalline form of Compound I fumaric acid salt has a TGA thermogram exhibiting a mass loss of about 2.42 %upon heating from about 55°C to about 140°C.
  • the crystalline form of Compound I fumaric acid salt has a TGA/DSC thermogram substantially similar to FIG. 17.
  • the crystalline form of Compound I fumaric acid salt has a DVS vapor sorption gram substantially similar to FIG. 22.
  • a crystalline form of a pharmaceutically acceptable salt of Compound I which is a crystalline form of Compound I sulfuric acid salt.
  • the crystalline form of Compound I sulfuric acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 6.00 ⁇ 0.20, 12.16 ⁇ 0.20, 17.37 ⁇ 0.20, 18.19 ⁇ 0.20, and 20.51 ⁇ 0.20 degrees.
  • the crystalline form of Compound I sulfuric acid salt has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 7.54 ⁇ 0.20, 17.16 ⁇ 0.20, 19.52 ⁇ 0.20, and 22.65 ⁇ 0.20 degrees.
  • the crystalline form of Compound I sulfuric acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I sulfuric acid salt has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 14.90 ⁇ 0.20, 22.02 ⁇ 0.20, 24.86 ⁇ 0.20, and 25.73 ⁇ 0.20 degrees.
  • the crystalline form of Compound I sulfuric acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I sulfuric acid salt has a XRPD pattern substantially as shown in Table 19.
  • the crystalline form of Compound I sulfuric acid salt has a XRPD pattern substantially as shown in FIG. 11.
  • the crystalline form of Compound I sulfuric acid salt has a DSC thermogram comprising an endotherm with a desolvation onset at about 181.2 °C and a peak at about 195.9 °C.
  • the crystalline form of Compound I sulfuric acid salt has a DSC thermogram further comprising an endotherm with a later desolvation onset at about 210.6 °C and a peak at about 226.0 °C.
  • the crystalline form of Compound I sulfuric acid salt has a TGA thermogram exhibiting a mass loss of about 4.85 %upon heating to about 120°C.
  • the crystalline form of Compound I sulfuric acid salt has a TGA thermogram substantially similar to FIG. 18.
  • a crystalline form of a pharmaceutically acceptable salt of Compound I which is a crystalline form of Compound I maleic acid salt.
  • the crystalline form of Compound I maleic acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 11.94 ⁇ 0.20, 15.64 ⁇ 0.20, 16.10 ⁇ 0.20, 20.98 ⁇ 0.20, and 22.65 ⁇ 0.20 degrees.
  • the crystalline form of Compound I maleic acid salt has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 4.90 ⁇ 0.20, 7.45 ⁇ 0.20, 24.27 ⁇ 0.20, and 25.67 ⁇ 0.20 degrees.
  • the crystalline form of Compound I maleic acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I maleic acid salt has a XRPD pattern further comprising at least one, two, three or more peaks at 2 ⁇ selected from: 9.57 ⁇ 0.20, 12.74 ⁇ 0.20, 13.19 ⁇ 0.20, and 18.46 ⁇ 0.20 degrees.
  • the crystalline form of Compound I maleic acid salt has a XRPD pattern comprising peaks at 2 ⁇ of 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.
  • the crystalline form of Compound I maleic acid salt has a XRPD pattern substantially as shown in Table 20.
  • the crystalline form of Compound I maleic acid salt has a XRPD pattern substantially as shown in FIG. 12.
  • the crystalline form of Compound I maleic acid salt has a DSC thermogram comprising an endotherm with a desolvation onset at about 64.6 °C and a peak at about 75.7 °C.
  • the crystalline form of Compound I maleic acid salt has a DSC thermogram further comprising an endotherm with a later desolvation onset at about 137.3 °C and a peak at about 140.4 °C.
  • the crystalline form of Compound I maleic acid salt has a TGA thermogram exhibiting a mass loss of about 3.59 %upon heating to about 100°C.
  • the crystalline form of Compound I maleic acid salt has a TGA thermogram substantially similar to FIG. 19.
  • the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, conveniently greater than about 90%and more conveniently greater than about 95%. Most conveniently the degree of crystallinity is greater than about 98%.
  • the polymorphic forms of the present disclosure are preferably substantially pure, meaning each polymorph form includes no more than 10%, preferably no more than 5%, and preferably no more than 1 %by weight of any one apparent impurity, including other polymorphic forms of the compound.
  • a “substantially pure” polymorphic form of the present disclosure has a purity of over 90%, over 95%, over 98%or even over 99%.
  • the polymorphic forms of the present disclosure may also exist together in a mixture.
  • Mixtures of polymorphic forms of the present disclosure will have XRPD peaks characteristic of each of the polymorphic forms present in the mixture.
  • a mixture of two polymorphs will have a XRPD pattern that is a convolution of the X-ray powder diffraction patterns corresponding to the substantially pure polymorphs.
  • the pharmaceutical salts and polymorphic forms of the present disclosure may be prepared by the methods known in the art.
  • the crystals of pharmaceutically acceptable salt of Compound I are prepared by dissolving Compound I in acetone or ethanol solution, adding corresponding acid in acetone or ethanol solution, and leaving the solution to crystallize and isolating the crystals of the pharmaceutically acceptable salt of Compound I, wherein the pharmaceutically acceptable salt is selected from hydrochloric acid salt, L- (+) -tartaric acid salt, fumaric acid salt, sulfuric acid salt, and maleic acid salt.
  • these are by no means limiting the preparation methods of the pharmaceutical salts and polymorphic forms of the present disclosure.
  • the compound of Formula (9) is selected and used for producing the compound of Formula (3) , which significantly increases 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
  • the process for preparing Compound I comprises a step of (i) contacting a compound of Formula (7) :
  • the acrylamide reagent is selected from the group consisting of: acryloyl chloride, acrylic acid, 3-chloropropionic acid and the 3-chloropropionyl chloride.
  • the acrylamide reagent is 3-chloropropionyl chloride.
  • the base reagent is selected from the group consisting of N, N, -diisopropylethylamine, Triethylamine, pyridine, DBU, K 2 CO 3 , KOH, KHCO 3 , LiOH, NaOH, Na 2 CO 3 , NaHCO 3 .
  • the base reagent is NaOH.
  • the process for preparing Compound I comprises further step of (iii) preparing the compound of Formula (7) by contacting a compound of Formula (6) :
  • the organic solvent is Tetrahydrofuran.
  • the compound of Formula (7) obtained in step (iii) is not isolated and is directly used in the step of (i) .
  • the process for preparing Compound I comprises further step of (iv) preparing the compound of Formula (6) by contacting a compound of Formula (5) :
  • the base is K 2 CO 3 and/or N, N-Diisopropylethylamine and the organic solvent is acetonitrile.
  • the process for preparing Compound I comprises further step of (v) preparing the compound of Formula (5) by contacting a compound of Formula (3) :
  • the organic solvent is isopropanol and the organic acid is trifluoroacetic acid.
  • the process for preparing Compound I comprises further step of (vi) preparing the compound of Formula (3) by contacting a compound of Formula (1) or a salt of the compound of Formula (1) :
  • the salt of the compound of Formula (1) is selected from the group consisting of hydrochloric acid salt, methanesulfonic acid salt, sulfuric acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, citric acid salt, succinic acid salt, L-malic acid salt, L- (+) -tartaric acid salt of the compound of Formula (1) .
  • the organic solvent is isopropanol and the organic base is N, N, -diisopropylethylamine.
  • the salt of the compound of Formula (1) is selected from the group consisting of: hydrochloric acid salt, methanesulfonic acid salt, sulfuric acid salt, phosphoric acid salt, maleic acid salt, fumaric acid salt, citric acid salt, succinic acid salt, L-malic acid salt, L- (+) -tartaric acid salt of the compound of Formula (1) .
  • the organic solvent is isopropanol and the organic base is N, N, -diisopropylethylamine.
  • a re-crystallization process for preparing a Form B of Compound I which comprises a step of dissolving Compound I in the Acetone/H 2 O solution, adding a Form B crystal seed into the solution, leaving the solution to crystallize and isolating the Form B of Compound I.
  • the present disclosure also provides pharmaceutical compositions comprising one or more also such crystalline polymorphic forms as discussed above, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carriers are conventional medicinal carriers in the art which can be prepared in a manner well known in the pharmaceutical art.
  • the compounds of the present disclosure may be admixed with pharmaceutically acceptable carrier for the preparation of pharmaceutical composition.
  • materials which can serve as pharmaceutically-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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • compositions depends on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.
  • the pharmaceutical compositions can be formulated for oral, nasal, rectal, percutaneous, intravenous, or intramuscular administration.
  • the pharmaceutical compositions can be formulated in the form of tablets, capsule, pill, dragee, powder, granule, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) , spray, ointment, paste, cream, lotion, gel, patches, inhalant, or suppository.
  • the pharmaceutical compositions can be formulated to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the pharmaceutical composition is formulated in a sustained released form.
  • the prolonged period of time can be about 1 hour to 24 hours, 2 hours to 12 hours, 3 hours to 8 hours, 4 hours to 6 hours, 1 to 2 days or more. In certain embodiments, the prolonged period of time 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 can be formulated in the form of tablet.
  • release rate of the active agent can not only be controlled by dissolution of the active agent in gastrointestinal fluid and subsequent diffusion out of the tablet or pills independent of pH, but can also be influenced by physical processes of disintegration and erosion of the tablet.
  • polymeric materials as 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.
  • the pharmaceutical compositions comprise about 0.0001 mg to about 5000 mg of the compounds of the present disclosure (e.g. 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, about 100 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
  • the pharmaceutical compositions can be formulated in a unit dosage form, each dosage containing from 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, about 100 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
  • the pharmaceutical compositions comprise one or more pharmaceutical salts and/or polymorphs of the present disclosure as a first active ingredient, and further comprise a second active ingredient.
  • the second active ingredient can be any anti-cancer agent known in the art, for examples, cell signal transduction inhibitors, cell signal transduction inhibitors, alkylating agents, topoisomerase inhibitors, immunotherapeutic agents, mitosis inhibitors, antihormonal agents, chemotherapy drugs, EGFR inhibitors, CTLA-4 inhibitors, MEK inhibitors, PD-L1 inhibitors; OX40 agonists, and the like.
  • anti-cancer agents for treating cancers or tumors may include, but are not limited to, 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, paclitaxel, vincristine, vinblastine, cisplatin, carboplatin, gemcitabine, tamoxifen, raloxifene, cyclopho
  • the second active agent is one or more of bevacizumab, pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, durvalumab, crizotinib.
  • the crystalline form, pharmaceutical salts, or pharmaceutical composition provided herein are for use as a medicament for inhibiting ErbB (e.g., EGFR, Her2, Her3 or Her4) or BTK.
  • ErbB e.g., EGFR, Her2, Her3 or Her4
  • the present disclosure provides use of the crystalline form, pharmaceutical salt, or pharmaceutical composition of the present disclosure in the manufacture of medicaments for treating diseases associated with ErbB or BTK.
  • the present disclosure provides a method of inhibiting ErbB or BTK by using one or more crystalline form, pharmaceutical salt, or pharmaceutical composition provided herein.
  • the present disclosure also provides a method of inhibiting ErbB or BTK by using one or more crystalline form, pharmaceutical salts, or pharmaceutical composition provided herein.
  • the present disclosure provides a method of treating an ErbB (including, for example, EGFR or Her2, especially ErbB mutant) , associated diseases or BTK associated diseases in a subject, comprising administering to the subject an effective amount of one or more crystalline form, pharmaceutical salts, or pharmaceutical composition provided herein.
  • an ErbB including, for example, EGFR or Her2, especially ErbB mutant
  • associated diseases or BTK associated diseases comprising administering to the subject an effective amount of one or more crystalline form, pharmaceutical salts, or pharmaceutical composition provided herein.
  • the subject is a warm blooded-animal such as man.
  • an ErbB associated diseases or BTK associated diseases is cancer, autoimmune diseases, or inflammation.
  • the ErbB associated diseases is cancer.
  • the ErbB associated diseases are diseases associated with the mutant ErbB.
  • the mutant ErbB is mutant EGFR.
  • the mutant ErbB is mutant Her2.
  • the diseases associated with ErbB are diseases associated with mutant ErbB, including cancers.
  • the BTK associated disease is cancer or an autoimmune disease.
  • the cancers include but are 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 cancers, mesothelioma, neuroblastoma, thyroid cancer, head and neck cancers, esophageal cancers, eye cancers, prostate cancer, nasopharyngeal cancer, or oral cancer.
  • the cancers are lung cancer, breast cancer, ovarian cancer, bladder cancer, or glioblastoma.
  • 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) .
  • the cancer is lymphoma or leukemia.
  • the cancer is metastatic lung cancer.
  • the cancer is cancer with one or more ErbB mutations (e.g., point mutations, deletion mutations, insertion mutations, activating mutations, or drug resistant mutations of EGFR or Her2) .
  • the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus or Sjogren’s syndrome.
  • the ErbB is EGFR or Her2, preferably is mutant EGFR or mutant Her2.
  • the mutant EGFR selected from 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,
  • the mutant Her2 is selected from the group consisting of Her2 A775_G776insYVMA, Her2 delG776insVC, Her2 V777_G778insCG and Her2 P780_Y781insGSP.
  • the crystalline form, pharmaceutical salt, or pharmaceutical composition in the present disclosure can be used in the prevention or treatment of the onset or development of any of the diseases or conditions associated with ErbB/BTK (expression or activities) in mammals especially in human.
  • the crystalline form, pharmaceutical salt, or pharmaceutical composition in the present disclosure can be used in the prevention or treatment of the onset or development of any of the diseases or conditions associated with mutant ErbB in mammals especially in human.
  • the present disclosure also provides a method of screening patient suitable for treating with the compounds or pharmaceutical composition of the present disclosure alone or combined with other ingredients (e.g. a second active ingredient, e.g. anti-cancer agent) .
  • the method includes sequencing the tumor samples from patients and detecting the accumulation of ErbB (e.g., EGFR or Her2) or BTK in the patient or detecting the mutations status of ErbB (e.g., EGFR or Her2) or BTK in the patient.
  • ErbB e.g., EGFR or Her2
  • BTK the mutations status of ErbB
  • the one or more crystalline form, pharmaceutical salts, or pharmaceutical composition provided herein is administered via a parenteral route or a non-parenteral route.
  • the one or more crystalline form, pharmaceutical salts, or pharmaceutical composition provided herein is administered orally, enterally, buccally, nasally, intranasally, transmucosally, epidermally, transdermally, dermally, ophthalmically, pulmonary, sublingually, rectally, vaginally, topically, subcutaneously, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardiacally, intradermally, intraperitoneally, transtracheally, subcuticularly, intra-articularly, subcapsularly, subarachnoidly, intraspinally, or intrasternally.
  • the crystalline forms or pharmaceutical salts provided herein can be administrated in pure form, or in the form of pharmaceutically compositions of the present disclosure.
  • the one or more crystalline form, pharmaceutical salts, or pharmaceutical composition provided herein is used in combination with a second active ingredient, preferably an anti-cancer agent.
  • the crystalline form, pharmaceutical salts, or pharmaceutical composition provided herein can be administered to a subject in need concurrently or sequentially in a combination with a second active ingredient (e.g. one or more anti-cancer agent (s) known in the art) .
  • the administration is conducted 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, once a week.
  • the one or more crystalline form, pharmaceutical salts, or pharmaceutical composition provided herein is administered orally.
  • any dose is appropriate that achieves the desired goals.
  • suitable daily dosages are between about 0.001-5000mg, preferably between 0.1mg and 5g, more preferably between 5mg and 1g, more preferably between 10mg and 500mg, and the administration is conducted once a day, twice a day, three times a day, every day, or 3-5 days a week.
  • the dose of the one or more compounds, pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers thereof or the pharmaceutical composition provided herein ranges between about 0.0001mg, preferably, 0.001mg, 0.01mg, 0.1mg, 1mg, 10mg, 50mg, 100mg, 200mg, 250mg, 500mg, 750mg, 1000mg, 2000mg, 3000mg, 4000mg or up to about 5000mg per day.
  • Solid samples were examined using D8 advance or D2 X-ray diffractometer (Bruker) .
  • the system was equipped with LynxEye detector. Samples were scanned from 3 to 40° 2 ⁇ , at a step of 0.02° 2 ⁇ .
  • the tube voltage and current were 40 KV and 40 mA (D8 ADVANCE) , 30 KV and 10 mA, respectively.
  • PLM analysis was conducted with a Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN) . Put the sample on a piece of glass slide, dispersed with cedar oil and observed with suitable magnification.
  • TGA was carried out on TGA Q5000IR, Q500, Discovery TGA 55 (TA Instruments, US) or Mettler Toledo TGA 2.
  • the sample was placed in an open tarred aluminum pan, automatically weighed, and inserted into the TGA furnace. The sample was heated at 10 °C/min to the final temperature.
  • DSC Differential scanning calorimeter
  • DSC analysis was conducted with DSC Q2000, Q200, Discovery DSC 250 (TA Instruments, US) or Mettler Toledo DSC 3+. A weighed sample was placed into a DSC pinhole pan, and the weight was accurately recorded. The sample was heated at 10 °C/min to the final temperature.
  • DVS DVS was determined using DVS Advantage-1 or Intrinsic (SMS, UK) .
  • SMS DVS Advantage-1 or Intrinsic
  • the sample was tested at a targeted RH of 10 to 90%full cycle in step mode. The analysis was performed in 10%RH increments.
  • Equilibrium 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.
  • Step 1 To a solution of compound (7) (5.0 g, 9.43 mmol) in CH 2 Cl 2 (150 mL) was added 3-chloropropanoyl chloride (1.3 g, 10.37 mmol) in ice water bath. The resulting mixture was stirred at 0-5 °C for 30 min (little un-dissolved oil was precipitated out) . The reaction mixture was poured into saturated NaHCO 3 (50 mL) and stirred at 12-17 °C for 2 h, and extracted with CH 2 Cl 2 (150 mL ⁇ 2) .
  • Step 2 To a solution of the yellow solid from step 1 (3.4 g, 5.48 mmol) in CH 3 CN (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 about 35 mL CH 3 CN, and then poured onto 500 mL H 2 O and stirred for 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.
  • H 2 O (576 kg) was charged into the reactor followed by the wet cake. The mixture was stirred at 15-25°C for 4h and filtered. The wet cake was washed with H 2 O (164 kg) and with ACN (148 kg) . The wet cake was dried at 45°C for 20h. 88.91 kg of Compound (6) was obtained with 99.8%HPLC purity, 89.2%isolated yield by assay.
  • the organic solution was filtered by silica gel (235 kg) , and the silica gel pad was washed with THF (2695 kg) .
  • the solution was concentrated to 340 ⁇ 350L and swapped with acetone (1008 kg) twice in total. Acetone (448 kg) was charged into the system and IPC sample was taken to control residual THF ⁇ 5.0%.
  • Purified water (95 kg) was charged into reactor, the temperature was adjusted to 56°C (52 ⁇ 59°C) and the reaction system was stirred for 2h to a clear solution.
  • Purified water (103 kg) was charged in 3h and the solution was cooled to 40 ⁇ 44°C. Seed (68 g) was charged into the solution and stirred for 14 ⁇ 18h.
  • Purified water (1118 kg) was charged dropwise at 40 ⁇ 44°C in a constant flow rate. The mixture was stirred for 2 ⁇ 6h at 40 ⁇ 44°C, adjusted to 15 ⁇ 25°C in 4h and stirred for 4h (2 ⁇ 6h) then filtered and dried to obtain 76.71 kg solid Compound I in 84.5%yield with 99.63%HPLC purity by 98.9%assay.
  • reaction system was filtered and washed by acetone/purified water (103 kg, 2v/3v) twice.
  • the wet cake was dried at 45°C for 20h.
  • 54.58 kg of Compound I was obtained with 99.83%HPLC purity, 96.7%isolated yield by 99.8%assay.
  • the single crystal X-ray diffraction ORTEP for compound I was shown in FIG. 33.
  • Form A or Form B was suspended separately in different water activity systems (Table 4) .
  • About 20 mg Form A or Form B was suspended in 3 mL mixture of acetone and water at room temperature for 7 days. Residual solids were filtered and then dried in the vacuum oven at 45 °C for 8-24 hours. Dry solids were characterized by XRPD.
  • the DSC data for crystalline Form-Aof the free base Compound I is shown in FIG. 2.
  • the DSC profile for crystalline Form-Aof the free base Compound I shows an endothermic transition with an onset temperature of about 178.63 °C with a peak temperature of about 179.64 °C, an associated enthalpy of 104.20 J/g.
  • the TGA data for crystalline Form-Aof the free base Compound I is shown in FIG. 3.
  • the TGA profile of Compound I-maleic acid salt shows a weight loss of about 0.232%before temperature reaching 160.00°C.
  • API crude (15 kg) was dissolved in acetone/purified water (258 L, 9/1, v/v) at 48-55 °C to a clear solution.
  • Water (51 L) was charged 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 14h.
  • Water (268 L) was charged dropwise at 38-42 °C and stirred for at least 2h.
  • 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 the mixture of acetone/purified water.
  • the wet cake was dried at 45-50 °C for at least 16h to give to give crystalline Compound I-Form B (14.1kg, 94%yield)
  • the DSC data for crystalline Form-B of the free base Compound I is shown in FIG. 6.
  • the DSC profile for crystalline Form-Aof the free base Compound I shows an endothermic transition with an onset temperature of about 194.84 °C with a peak temperature of about 195.74 °C, an associated enthalpy of 111.60 J/g.
  • the TGA data for crystalline Form-B of the free base Compound I is shown in FIG. 7.
  • the TGA profile of Compound I-maleic acid salt shows a weight loss of about 0.166%before temperature reaching 177.60°C.
  • the dried solid was characterized by XRPD, TGA, DSC, and DVS.
  • Salt ratio of hydrochloride to Compound I was determined by IC-test. The measured chloride content was 5.78%, compared to 5.72%-theoretical content of chloride in a 1: 1 salt ratio.
  • the TGA data for crystalline form of the Compound I-hydrochloric acid salt is shown in FIG. 20.
  • the TGA profile of Compound I-hydrochloric acid salt shows a weight loss of about 0.759%before temperature reaching 175°C.
  • the DSC data for crystalline form of the Compound I-hydrochloric acid salt is shown in FIG. 20.
  • the DSC profile for crystalline form of the Compound I-hydrochloric acid salt shows an endothermic transition with an onset temperature of about 207.77 °C with a peak temperature of about 212.14 °C, an associated enthalpy of 75.60 J/g.
  • the DVS data for crystalline form of the Compound I-hydrochloric acid salt is shown in FIG. 23.
  • the TGA data for crystalline form of the Compound I-L- (+) -tartaric acid salt (pattern I) is shown in FIG. 15.
  • the TGA profile of Compound I-L- (+) -tartaric acid salt (pattern I) shows a weight loss of about 2.52%before temperature reaching 100°C.
  • the DSC profile for crystalline form of the (+) -L-tartaric acid salt of Compound I shows the first endothermic transition with an onset temperature of about 36.91 °C with a peak temperature of about 56.29 °C, an associated enthalpy of 44.43 J/g and The second endothermic transition with an onset temperature of about 136.73 °C with a peak temperature of about 140.18 °C, an associated enthalpy of 19.53 J/g.
  • the XRPD data for crystalline of the Compound I-fumaric acid salt is shown in FIG. 10 and in Table 18.
  • the TGA data for crystalline form of the Compound I-fumaric acid salt is shown in FIG. 17.
  • the TGA profile of Compound I-fumaric acid salt shows a weight loss of about 2.857%before temperature reaching 55°C and a further weight loss of about 2.424%between temperature range 55-140 °C.
  • the DSC data for crystalline form of the Compound I-fumaric acid salt is shown in FIG. 17.
  • the DSC profile for crystalline form of the Compound I-fumaric acid salt shows an endothermic transition with an onset temperature of about 48.86 °C with a peak temperature of about 68.34 °C, an associated enthalpy of 28.63 J/g and a later endothermic transition with an onset temperature of about 132.79 °C with a peak temperature of about 141.78 °C, an associated enthalpy of 27.78 J/g.
  • the DVS data for crystalline form of the Compound I-fumaric acid salt is shown in FIG. 22.
  • the TGA data for crystalline form of the Compound I-sulfuric acid salt is shown in FIG. 18.
  • the TGA profile of Compound I-sulfuric acid salt shows a weight loss of about 4.85%before temperature reaching 120°C.
  • the DSC data for crystalline form of the Compound I-sulfuric acid salt is shown in FIG. 18.
  • the DSC profile for crystalline form of the Compound I-sulfuric acid salt shows an endothermic transition with an onset temperature of about 181.24 °C with a peak temperature of about 195.93 °C, an associated enthalpy of 11.87 J/g and a later endothermic transition with an onset temperature of about 210.59 °C with a peak temperature of about 226.02 °C, an associated enthalpy of 26.76 J/g.
  • the XRPD data for crystalline form of the Compound I-maleic acid salt is shown in FIG. 12 and in Table 20.
  • the TGA data for crystalline form of the Compound I-maleic acid salt is shown in FIG. 19.
  • the TGA profile of Compound I-maleic acid salt shows a weight loss of about 5.25%before temperature reaching 100°C.
  • the DSC data for crystalline form of the Compound I-maleic acid salt is shown in FIG. 19.
  • the TGA data for crystalline form of the Compound I-L- (+) -tartaric acid salt (pattern II) is shown in FIG. 16.
  • the TGA profile of Compound I-L- (+) -tartaric acid salt (pattern II) shows a weight loss of about 3.587%before temperature reaching 100°C.
  • the DSC data for crystalline form of the Compound I-L- (+) -tartaric acid salt (pattern II) is shown in FIG. 16.
  • the DSC profile for crystalline form of the Compound I-L- (+) -tartaric acid salt (pattern II) shows an endothermic transition with an onset temperature of about 64.62 °C with a peak temperature of about 75.67 °C, an associated enthalpy of 34.23 J/g and a later endothermic transition with an onset temperature of about 137.25 °C with a peak temperature of about 140.39 °C, an associated enthalpy of 17.53 J/g.
  • the tablets were manufactured in accordance with the following manufacturing process:
  • 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.
  • Coating material was 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 is 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%.
  • Compound I freebase, form B
  • lactose monohydrate, colloidal silicon dioxide Microcrystalline cellulose, Microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose and magnesium stearate.
  • the hydroxypropyl cellulose, microcrystalline cellulose and colloidal silicon dioxide were passed through a screen together.
  • Compound I, lactose monohydrate, croscarmellose sodium, microcrystalline cellulose and magnesium stearate were passed through a screen.
  • the screened excipients, except for the extra-granular phases (microcrystalline cellulose, croscarmellose sodium and magnesium stearate) were charged into a high shear wet granulator bowl and blend.
  • the purified water was sprayed onto the blended powders. If necessary, additional purified water was sprayed.
  • the wet materials was continued to granulate after spraying.
  • the wet materials were charged through a screen.
  • the materials from above were charged into a fluid bed and dried, the drying process was monitored by loss-on-drying.
  • the dried granule was charged through a screen.
  • the milled granule, extra croscarmellose sodium and microcrystalline cellulose were charged into the bin blender and blended. Then magnesium stearate was charged into the bin blender.
  • the lubricated blend was compressed into tablets.
  • a 12% (w/w) suspension was prepared.
  • the core tablets were preheated until the exhaust temperature reaches about 40-50 °C and then coating was started.
  • Coating solution was sprayed until the coating weight gain reached the target range. Heating was stopped after spraying has finished, then the coated tablets were dried and discharged.

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JP2024506641A JP2024529533A (ja) 2021-08-02 2022-07-29 Ｅｒｂｂおよびｂｔｋ阻害剤の新規な医薬塩および多形形態
KR1020247007187A KR20240042640A (ko) 2021-08-02 2022-07-29 Erbb 및 btk 억제제의 신규한 약제학적 염 및 다형체 형태
CA3224748A CA3224748A1 (en) 2021-08-02 2022-07-29 Novel pharmaceutical salts and polymorphic forms of an erbb and btk inhibitor
US18/293,778 US20250197377A1 (en) 2021-08-02 2022-07-29 Novel pharmaceutical salts and polymorphic forms of an erbb and btk inhibitor
AU2022324410A AU2022324410A1 (en) 2021-08-02 2022-07-29 Novel pharmaceutical salts and polymorphic forms of an erbb and btk inhibitor
CN202280053629.5A CN117794902A (zh) 2021-08-02 2022-07-29 ErbB和BTK抑制剂的新型药用盐和多晶型形式
EP22852071.4A EP4380924A4 (en) 2021-08-02 2022-07-29 NEW PHARMACEUTICAL SALTS AND POLYMORPHIC FORMS OF AN ERBB AND BTK INHIBITOR
MX2024001367A MX2024001367A (es) 2021-08-02 2022-07-29 Nuevas sales farmaceuticas y formas polimorficas de un inhibidor de erbb y btk.

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CN106905245A (zh) * 2015-12-23 2017-06-30 正大天晴药业集团股份有限公司 2,4-二取代的嘧啶类化合物
WO2019177375A1 (ko) * 2018-03-13 2019-09-19 포로노이바이오 주식회사 2, 4, 5-치환된 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물
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CN105384694A (zh) * 2014-08-22 2016-03-09 四川海思科制药有限公司 一种取代的氨基嘧啶衍生物及其制备方法和药物用途
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WO2019177375A1 (ko) * 2018-03-13 2019-09-19 포로노이바이오 주식회사 2, 4, 5-치환된 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물

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WO2024261740A1 (en) 2023-06-23 2024-12-26 Assia Chemical Industries, Ltd. Solid state forms of sunvozertinib

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