Process for the preparation of (S)-N-(3-((2-((4-((1-acetylpyrrolidin-3-yl)(methyl)amino)phenyl)amino)-5-methoxypyrimidin-4-yl)oxy)phenyl)acrylamide and formulation thereof

Abstract

The present invention relates to a solid form of certain N-(pyrimidinyloxy)acrylamide derivatives useful for treating proliferative and immunological disorders, as well as other diseases related to kinase dysregulation, including EGFR (including HER), Alk, PDGFR, BLK, BMX / ETK, BTK, FLT3 (D835Y), ITK, JAK1, JAK2, JAK3, TEC, and TXK. The present invention provides these materials, as well as methods for producing their salts and polymorphs, intermediates for preparing these materials, and pharmaceutical compositions comprising these materials. The solid forms and pharmaceutical compositions comprising them are useful for treating conditions including proliferative disorders, tumors, inflammatory diseases, autoimmune diseases, psoriasis, dry eye, rheumatoid arthritis, or lupus.

Description

[Technical field]

[0001] Technical Field The present disclosure relates to solid forms of N-(pyrimidinophenyl)-acrylamide compounds useful for treating proliferative disorders and immunological conditions associated with dysregulation of kinases, such as, but not limited to, EGFR (including HER), Alk, PDGFR, BLK, BMX / ETK, BTK, FLT3(D835Y), ITK, JAK1, JAK2, JAK3, TEC and TXK. Methods of making and using these compounds and solid forms thereof are further disclosed. Also disclosed are certain salt forms and physical forms of the compounds, pharmaceutical compositions comprising these compounds, and methods of using these compounds, solid forms and pharmaceutical compositions to modulate kinase activity and treat certain proliferative and immunological conditions. [Background technology]

[0002] Background technology Certain N-(pyrimidinophenyl)acrylamide compounds of general formula (I) [ka] (In the formula, R 3 may be alkoxy, R c can be alkyl, cycloalkyl or heterocycloalkyl; Y can be N, CH or C-halo; R d can be H or alkyl) are described as potent modulators of certain protein kinases known to be important pharmaceutical targets. WO2015 / 0067654. These compounds are useful for the treatment of certain diseases mediated by protein kinases, including cancer, immunological conditions and chronic inflammation.

[0003] Of particular interest is the inhibition of Bruton's tyrosine kinase (BTK) by compounds of formula (I), which plays a pivotal role in B cell maturation and mast cell activation. Inhibitors of BTK are in clinical trials for B cell-related proliferative disorders (chronic lymphocytic leukemia, non-Hodgkin's lymphoma) and autoimmune disorders (e.g., X-linked agammaglobulinemia (XLA)).

[0004] Compound A [ka] Certain compounds of general formula (I), including and pharma- ceutically acceptable salts thereof, are of particular interest because they potently inhibit protein kinases, including EGFR and BTK, and may therefore be suitable for clinical trials for treating conditions associated with EGFR and / or BTK. Improved forms and formulations of these compounds are needed and have been developed to enhance their clinical usefulness.

[0005] Efficient methods for making these compounds are needed to enable their use in clinical trials and commercial use. Such methods and intermediates useful for the preparation of these compounds are described herein. Certain salt forms and polymorphs of these compounds and their preparation methods are also described. In general, drug stability is an important consideration in the design, manufacture and storage of pharmaceutical compositions.Drug products that lack stability can form degradation products that can cause undesirable side effects or can sometimes reduce the efficacy and bioavailability of the drug substance itself, making it difficult for doctors to prescribe consistent and effective doses.In order to develop compound A for widespread pharmaceutical use, there is a need for solid forms that can be stably produced with high purity, as the dosage forms and preparations of these solid forms are stable during long-term storage.The present invention provides such solid forms of compound A, as well as pharmaceutical compositions and treatment methods using these solid forms. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2015 / 0067654 Summary of the Invention [Means for solving the problem]

[0007] overview The present invention relates to methods for preparing certain N-(pyrimidinyloxy)phenylacrylamide compounds and their solid forms, as well as intermediates useful in their preparation. Certain solid forms, salts and polymorphs of Compound A are also described that are particularly useful in pharmaceutical development and manufacturing. Particularly useful solid forms of Compound A are described, including the 1:1 salt of Compound A with L-(+)-tartaric acid (Compound A-TA). In addition, pharmaceutical compositions that include these novel solid forms, as well as methods for preparing and using them, are also described.

[0008] The present disclosure relates to compound A [ka] and a method for making the tartrate salt thereof, and a method for producing a novel solid form of said tartrate salt, which can be stably produced and is highly stable during formulation and storage.Stable polymorphs of salts of Compound A are also disclosed, along with methods of using said polymorphs or other solid forms to prepare pharmaceutical compositions and dosage forms.

[0009] Compound A is highly potent as a kinase inhibitor, but exhibits low water solubility that reduces its suitability for oral administration. The neutral compound, referred to as the free base of Compound A, is weakly basic and therefore poorly soluble at high pH. Since increasing water solubility is expected to significantly improve oral bioavailability, preparation of an acid addition salt of Compound A was attempted to increase water solubility. Surprisingly, of the 12 acids used in the initial test [HCl, HBr, H3PO4, maleic acid, hydroxybutanedioic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, fumaric acid, L-(+)-tartaric acid, and D-(-)-tartaric acid], only (L)-(+)-tartaric acid produced a stable crystalline solid. Thus, the L-(+)-tartrate salt of Compound A, hereinafter referred to as Compound A L-(+)-tartrate salt or Compound A-TA, is particularly suitable for development and is used in many of the compositions and methods herein.

[0010] In one embodiment, the present invention provides compound A, which is a tartrate salt: [ka] In some embodiments, it is a 1:1 salt of Compound A and L-(+)-tartaric acid. In some embodiments, it is a crystalline dihydrate.

[0011] In another aspect, the present invention provides stable, and particularly useful, polymorphs of the tartrate salt of Compound A (as described further herein) and methods for preparing these salts.

[0012] The present invention also provides pharmaceutical compositions comprising the solid forms described herein, and methods of using those pharmaceutical compositions to make highly stable drug products and dosage units. The present invention provides dosage units in various forms (including capsules and tablets) with solid forms of Compound A and formulations thereof in amounts suitable for treating conditions characterized by undesirable levels of activity of EGFR and / or BTK.

[0013] In some embodiments, the pharmaceutical compositions of the present invention are packaged with at least one protective agent, which may be one or more materials selected from desiccants, antioxidants, oxygen scavengers, and inert gases. The protective agent may reduce the rate of formation of trace impurities when the pharmaceutical composition is exposed to heat or humidity, or both.

[0014] The invention also provides dosage units containing the pharmaceutical compounds of the invention, and packaged pharmaceutical products containing these compounds.

[0015] In another embodiment, the present invention provides a method of using the compounds, solid forms, pharmaceutical compositions and dosage units of the present invention to treat proliferation disorder, cancer, tumor, inflammatory disease, psoriasis, dry eye or autoimmune disease in subjects, such as rheumatoid arthritis or lupus.Exemplary proliferation disorders suitable for treatment include sarcoma, epidermoid carcinoma, fibrosarcoma, cervical cancer, gastric cancer, skin cancer, leukemia, lymphoma, lung cancer, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, liver cancer, head and neck cancer and pancreatic cancer.Of particular interest are lymphomas or leukemias related to B cells, such as chronic myelogenous leukemia and chronic lymphocytic leukemia.

[0016] The present invention also provides improved methods of synthesizing compounds such as Compound A, or a pharma- ceutically acceptable salt thereof.

[0017] Other aspects and advantages of the present invention will become apparent from the embodiments and examples provided herein.

[0018] For the sake of brevity, the disclosures of the publications (including patents) cited in this specification are hereby incorporated by reference. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 is an X-ray powder diffraction pattern of polymorphic Form I of compound A-TA.

[0020] [Diagram 2] FIG. 2 is an infrared spectrum of compound A-TA.

[0021] [Diagram 3] FIG. 3 shows the UV spectrum of compound A-TA in methanol.

[0022] [Figure 4] FIG. 4 shows the UV spectrum of compound A-TA in acidic medium.

[0023] [Diagram 5] FIG. 5 is an ultraviolet spectrum of compound A-TA in basic aqueous medium.

[0024] [Figure 6] FIG. 6 is a proton nuclear magnetic resonance (H NMR) spectrum of compound A-TA in d6-DMSO.

[0025] [Figure 7] FIG. 7 shows the thermogravimetric analysis of polymorphic Form I of compound A-TA.

[0026] [Figure 8] FIG. 8 shows the differential scanning calorimetry curve of polymorphic Form I of compound A-TA.

[0027] [Figure 9] FIG. 9 is a process flow diagram for a wet granulation process for preparing capsules filled with Compound A-TA.

[0028] [Figure 10] FIG. 10 is a process flow diagram for a wet granulation process for preparing tablets of Compounds A-TA.

[0029] [Figure 11]FIG. 11 is a process flow diagram for a direct blend process for preparing capsules filled with Compound A-TA.

[0030] [Figure 12] FIG. 12 is a process flow diagram for a direct blend process for preparing tablets of Compounds A-TA. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Detailed Description The present invention encompasses an improved method for making certain N-(pyrimidinyloxy)phenylacrylamide derivatives, which are useful in pharmaceutical compositions and in the method of treating certain proliferative and immunological disorders.The general method for making the compounds or precursors related to the present invention, as well as the biochemical and biological data related to the present invention, can be found in WO2015 / 0067654 and US Patent No. 9,464,089.

[0032] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. The scope of the present invention will be limited only by the appended claims, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0033] It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. Accordingly, this statement is intended to serve as a basis for using exclusive terminology such as "solely," "only," and the like in connection with the recitation of claim elements or for using a "negative" limitation.

[0034] In order to provide a more concise description, some of the quantitative expressions given herein are not modified with the term "about". Regardless of whether the term "about" is expressly used or not, all numerical quantities given herein are intended to refer to given actual values ​​and to be within the scope of the experimental and / or measurement conditions for such given values. Equal It is understood that the term also includes approximations of such a given value that would be reasonably expected based on ordinary skill in the art, including and approximations. For example, when a peak in an XRPD is described as "about" a particular value, the value includes a range of ±0.2°. Amounts of material set forth in claims are understood to include a range that allows at least a reasonable variation associated with the precision normally achieved in the context, and unless otherwise specified, should generally be interpreted to include a range of ±10% around the specified value. When a temperature for DSC is specified, it should be understood to include a range of ±3°C.

[0035] Whenever a yield is given as a percentage, such yield refers to the mass of the entity for which the yield is given, based on the maximum amount of that entity obtainable under the specified stoichiometric conditions. Concentrations given as percentages refer to mass ratios, unless otherwise indicated.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs.Although any method and material similar or equivalent to those described herein can be used in the practice or testing of this invention, preferred methods and materials are described herein.All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials for which they are cited.

[0037] Unless otherwise stated, the methods and techniques of the present embodiment are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification.See, for example, Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0038] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense. When an embodiment is described as "comprising" certain materials, steps, or features, it is understood that the invention also includes corresponding embodiments "consisting essentially of" and "consisting of" those materials, steps, or features.

[0039] It should be appreciated that certain features of the invention that are described in the context of separate embodiments for clarity may be provided in combination in a single embodiment. Conversely, various features of the invention that are described in the context of a single embodiment for brevity may be provided separately or in any suitable subcombination. All combinations of the embodiments relating to the chemical groups represented by the variables are expressly encompassed by the present invention and are disclosed herein to the extent that such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity) as if each and every combination were individually and explicitly disclosed herein. Furthermore, all subcombinations of the chemical groups listed in the embodiments describing such variables are also expressly encompassed by the present invention and are disclosed herein as if each and every subcombination of such chemical groups were individually and explicitly disclosed herein.

[0040] The term "alkyl" refers to a straight or branched chain alkyl group having 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that would be considered equivalent to any one of the foregoing examples given one of ordinary skill in the art and the teachings provided herein.

[0041] The term "alkoxy" refers to an alkyl group, as defined above, attached to an oxygen atom. An alkoxy group is connected to the parent structure through an oxygen atom.

[0042] The term "amino" refers to the group -NH2 or a mono- or dialkylamino group.

[0043] The term "halogen" refers to chlorine, fluorine, bromine or iodine. The term "halo" refers to chloro, fluoro, bromo or iodo. The term "haloalkyl" refers to alkyl as defined above substituted with one or more halogen atoms. The term "haloalkoxy" refers to alkoxy as defined above substituted with one or more halogen atoms.

[0044] The term "acyl" refers to the group RC(O)-, where R is an acyl group of 1 to 10 carbon atoms (C 1-10 ) in a linear, branched or cyclic arrangement or combinations thereof. Such R groups can be saturated or unsaturated, and can be aliphatic or aromatic.

[0045] The term "cyano" refers to the group --CN.

[0046] The term "nitro" refers to the group --NO.sub.2.

[0047] The term "hydroxyl" refers to the group --OH.

[0048] One of ordinary skill in the art will recognize that the species listed or exemplified above are not exhaustive and that additional species may be selected that fall within the scope of these defined terms.

[0049] Any formula drawn herein is intended to represent each compound that is not inconsistent with its structural formula drawn.For example, any formula given herein that does not explicitly describe the stereochemistry at one or more chiral centers is intended to include racemic form, or one or more enantiomers, diastereoisomers or geometric isomers, or mixtures thereof.Furthermore, any formula given herein is also intended to refer to the hydrate, solvate, or polymorph of such compound, or mixtures thereof.

[0050] The structures and names of compounds depicted herein as specific enantiomers refer to the designated enantiomer, but it is understood that such compounds may nevertheless contain small amounts, i.e., less than 10%, usually less than 5%, of the opposite enantiomer.

[0051] Any formula given herein is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms.Isotopically labeled compounds have the structure depicted by the formula given herein, except that one or more atoms are replaced by atoms with selected atomic masses or mass numbers.Examples of isotopes that can be incorporated into the compounds of these embodiments include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Cl and 125 Such isotopically labeled compounds are useful in metabolic studies, preferably 14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques including drug or substrate tissue distribution assays (e.g., positron emission tomography (PET) or single photon emission computed tomography (SPECT)), or radiation treatment of patients. 18 F or 11 C labeled compounds may be particularly preferred for PET or SPECT studies. Additionally, deuterium (i.e. 2Substitution with heavier isotopes such as H) may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of these embodiments and their prodrugs can be prepared by carrying out the procedures disclosed in the schemes or examples and preparation methods described below, typically by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0052] "Pharmaceutically acceptable salts" is intended to mean salts of free acids or free bases of the compounds represented herein that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally, SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a subject without undue toxicity, irritation, or allergic reaction. The compounds described herein may have sufficiently acidic groups, sufficiently basic groups, both types of functional groups, or more than one of each type, and thus react with a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0053] Examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-diol, hexylate-1,5-diol, hexylate-2 ... Examples of suitable salts include phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate and mandelate salts. Representative Embodiments

[0054] The embodiments listed below represent certain aspects of the present invention.

[0055] 1. Compound A, which is a tartrate salt [ka] A solid form of.

[0056] 2. The solid form of embodiment 1, which is a 1:1 salt of Compound A and L-(+)-tartaric acid.

[0057] 3. The solid form of embodiment 1 or 2, which is a hydrate of the L-(+)-tartrate salt of Compound A.

[0058] 4. The solid form of embodiment 3, which is a dihydrate.

[0059] 5. A solid form according to any one of the preceding embodiments, which is crystalline.

[0060] The solid form of any one of the preceding embodiments, wherein the solid form is a crystalline form having an X-ray powder diffraction pattern including at least two peaks selected from about 5.7°, about 9.8°, about 11.6°, about 14.7°, about 15.4°, about 16.1°, about 17.1°, about 19.3°, about 23.8°, about 24.5°, and about 25.4°, calculated at 6.2θ.

[0061] 7. The solid form of embodiment 6, wherein the powder X-ray diffraction pattern comprises at least 3 peaks, or at least 4 peaks, or at least 5 peaks, or at least 6 peaks, or at least 7 peaks, or at least 8 peaks, or at least 9 peaks, or at least 10 peaks, wherein the peaks are selected from about 5.7°, about 9.8°, about 11.6°, about 14.7°, about 15.4°, about 16.1°, about 17.1°, about 19.3°, about 23.8°, about 24.5°, and about 25.4° in terms of 2θ. In certain examples, the XRPD pattern is substantially identical to the XRPD in FIG.

[0062] 8. The solid form of any one of the previous embodiments, having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 74 °C.

[0063] 9. A solid form of any one of the preceding embodiments, having a thermogravimetric analysis (TGA) substantially as shown in FIG. 7.

[0064] 10. A pharmaceutical composition comprising a solid form of compound A according to any one of the preceding embodiments, mixed with at least one pharma- ceutically acceptable excipient.

[0065] 11. The pharmaceutical composition according to embodiment 10, comprising at least two pharma- ceutically acceptable excipients.

[0066] 12. The pharmaceutical composition according to embodiment 10 or 11, comprising at least one pharma- ceutically acceptable excipient selected from fillers, disintegrants, glidants, adhesives, lubricants and antioxidants, such as sodium bisulfite, sodium sulfite, sodium thiosulfate, butylated hydroxytoluene (antioxidant-264), butylated hydroxyanisole, citric acid and vitamin E.

[0067] 13. The pharmaceutical composition of embodiment 12, comprising at least one pharma- ceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, mannitol, polyvinylpyrrolidone (PVP) and sodium stearyl fumarate. In some embodiments, the microcrystalline cellulose comprises or consists of silicified microcrystalline cellulose, such as silicified microcrystalline cellulose 50 (SMCC50) and / or silicified microcrystalline cellulose 90 (SMCC90).

[0068] 14. A weight of Compound A in the form of a free base selected from the group consisting of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, and 400 mg. Equivalent A dosage unit comprising a solid form of compound A according to any one of embodiments 1 to 9 in an amount of

[0069] 15. The dosage unit according to embodiment 14, which is a tablet or capsule.

[0070] 16. The dosage unit according to embodiment 14 or embodiment 15, comprising compound A-TA and one or more pharma- ceutically acceptable excipients.

[0071] 17. The dosage unit of embodiment 16, wherein the one or more pharma-ceutically acceptable excipients comprise one or more excipients selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, mannitol, polyvinylpyrrolidone (PVP) and sodium stearyl fumarate.

[0072] 18. The dosage unit according to any of embodiments 14-17, comprising at least one pharma- ceutically acceptable excipient selected from silicified microcrystalline cellulose 50, silicified microcrystalline cellulose 90, pregelatinized starch, mannitol, croscarmellose sodium, povidone and sodium stearyl fumarate.

[0073] 19. The dosage unit according to any one of embodiments 14 to 18, comprising an antioxidant, such as sodium bisulfite, sodium sulfite, sodium thiosulfate, butylated hydroxytoluene (antioxidant-264), butylated hydroxyanisole, citric acid and vitamin E.

[0074] 20. A packaged pharmaceutical product comprising a pharmaceutical composition comprising compound A and a protective agent as two separate materials in a closed container.

[0075] 21. The packaged pharmaceutical product of embodiment 20, wherein the pharmaceutical composition comprises a dosage unit of any of embodiments 14 to 18.

[0076] 22. The packaged pharmaceutical of any one of embodiments 21-22, wherein the protective agent comprises at least one material selected from a desiccant, an antioxidant, an oxygen scavenger, and an inert gas.

[0077] 23. The packaged pharmaceutical of any one of embodiments 20-22, wherein the protective agent comprises at least one material selected from molecular sieves, silica gel, and fibrous desiccants.

[0078] 24. The packaged pharmaceutical of any one of embodiments 20-23, wherein the protective agent and the pharmaceutical composition are contained in an airtight container.

[0079] 25. The packaged pharmaceutical product of embodiment 24, wherein the airtight container is a sealed bottle.

[0080] 26. A method for preparing a pharmaceutical composition according to any one of embodiments 10 to 13, comprising combining said L-(+)-tartrate salt of compound A with at least one pharma- ceutically acceptable excipient.

[0081] 27. The method of embodiment 26, wherein the at least one pharma- ceutically acceptable excipient comprises a filler, optionally selected from mannitol and microcrystalline cellulose.

[0082] 28. The method of embodiment 26 or 27, wherein the at least one pharma- ceutically acceptable excipient comprises a disintegrant, optionally comprising croscarmellose sodium.

[0083] 29. The method of any one of embodiments 26-28, wherein the at least one pharma-ceutically acceptable excipient comprises an adhesive, which is optionally polyvinylpyrrolidone (PVP).

[0084] 30. The method of any one of embodiments 26-29, wherein the at least one pharma-ceutically acceptable excipient comprises a lubricant, which optionally is sodium stearyl fumarate.

[0085] 31. The method of embodiment 26, comprising combining said L-(+)-tartrate salt of Compound A with microcrystalline cellulose, sodium stearyl fumarate and PVP, and optionally mannitol to form a mixture.

[0086] 32. The method of embodiment 31, comprising combining said L-(+)-tartrate salt of Compound A with microcrystalline cellulose, sodium stearyl fumarate and PVP, and optionally mannitol, to form a mixture, and adding PVP and optionally water to form a wet granule mixture.

[0087] 33. A pharmaceutical composition comprising compound A-TA, prepared by the method according to embodiment 26.

[0088] 34. The method of embodiment 31 or embodiment 32, wherein the mixture is blended in a wet granulator.

[0089] 35. A process for preparing the L-(+)-tartrate salt of compound A, comprising contacting compound A with L-(+)-tartaric acid in the presence of a solvent.

[0090] 36. A process for preparing a solid form of Compound A, comprising contacting Compound A with tartaric acid in a solvent.

[0091] 37. The process of embodiment 36, comprising contacting compound A with L-(+)-tartaric acid in the presence of a solvent under conditions such that the L-(+)-tartrate salt of compound A precipitates from the solvent as a solid.

[0092] 38. The process of embodiment 37, wherein the solvent comprises water and an organic co-solvent.

[0093] 39. The process of embodiment 38, wherein the organic co-solvent is selected from acetone, isopropanol, ethanol, and tetrahydrofuran.

[0094] 40. The process of embodiment 39, wherein the solid form of Compound A comprises Form I of the L-(+)-tartrate salt of Compound A.

[0095] 41. A process for synthesizing compound A or a pharma- ceutically acceptable salt thereof, comprising reductive hydrogenation of compound 1 to obtain compound 2. [ka] The process includes: In this embodiment, the catalyst typically comprises palladium, platinum or nickel. Suitably, the catalyst may be a palladium catalyst, optionally on a carbon support.

[0096] 42. Reacting compound 2 with compound 3 to obtain compound A: [ka] 42. The process of embodiment 41, further comprising:

[0097] 43. The method of embodiment 42, further comprising contacting compound A with L-(+)-tartaric acid to obtain said L-(+)-tartrate salt of compound A.

[0098] 44. A method for treating an immunological or cell proliferation disorder, comprising administering to a subject in need thereof a solid form of compound A as described in any one of embodiments 1-9 or a pharmaceutical composition thereof.

[0099] In embodiment 12, the pharmaceutical composition may include one or more excipients selected from fillers, disintegrants, adhesives, lubricants, and antioxidants. Some examples of embodiment 12 include a filler that may be selected from mannitol, dextrose, and microcrystalline cellulose. In some such embodiments, the pharmaceutical composition includes about 50-80% by weight of the filler. In one of these embodiments, the filler is a mixture of mannitol and microcrystalline cellulose. Some examples of embodiment 12 include a disintegrant that may be croscarmellose sodium. In some such embodiments, the pharmaceutical composition includes about 1-8% by weight of the disintegrant, and in a preferred embodiment, it includes 2-5% by weight of the disintegrant. Some examples of embodiment 12 include a lubricant, which may be selected from salts of stearic acid and salts of stearyl fumarate, particularly sodium stearyl fumarate. In some such embodiments, the pharmaceutical composition includes about 0.5-2% by weight of the lubricant. In one of these embodiments, the lubricant is sodium stearyl fumarate. Some examples of embodiment 12 include an adhesive that can be PVP or cross-linked PVP. In some such embodiments, the pharmaceutical composition includes about 0-5 wt% of the adhesive. In one of these embodiments, the adhesive is Povidone K30 and the pharmaceutical composition includes about 3 wt% of the adhesive. A preferred embodiment is a composition that includes the ratio (wt%) of ingredients listed in Table 4. Another preferred embodiment is a composition that includes the ratio (wt%) of ingredients listed in Table 5 in the formulated material. These preferred embodiments include compositions in which the amount of any of the ingredients listed in Tables 4 or 5 is within ±10% of the specified value.

[0100] In embodiments 26-32, the method of preparing the pharmaceutical composition may be a wet granulation process. In certain of these embodiments, the pharmaceutical composition comprises about 35% Compound A-TA, about 25% Mannitol 25C, about 30% Microcrystalline cellulose, about 5% Croscarmellose sodium, about 3% PVP and about 2% Sodium Stearyl Fumarate, expressed as weight % of the composition. In this embodiment, "about" means that the weight percentage of each component is plus or minus 1 wt% of the specified wt%. In certain embodiments, the method of any one of embodiments 26-32 is carried out using ratios of ingredients in the formulation expressed in wt%, preferably using ratios of ingredients listed in Table 4 or Table 5, where each ratio listed may vary from the listed value by up to ±10% of the specified value, as appropriate. In certain examples, the process of any one of embodiments 26-32 includes the following steps: (a) combining Compound A-TA, mannitol 25C, microcrystalline cellulose, and a percentage of croscarmellose sodium to form a first mixture; (b) blending the first mixture in a wet granulator; (c) adding PVP dissolved in water to form a second mixture and mixing in a wet granulator; (d) drying the second mixture to obtain a third mixture; (e) adding and mixing the remaining croscarmellose sodium and sodium stearyl fumarate to the third mixture to form a final mixture suitable for filling capsules to form the dosage units of the present invention.

[0101] Preferred embodiments of the method according to claim 26 are presented in Examples 9 and 10 using the materials listed in Table 4.

[0102] In some embodiments, the solid form of compound A-TA is a crystalline polymorph of Form I. Form I is characterized by an XRPD spectrum that includes one or more peaks at 2θ values ​​(within experimental error) selected from the group consisting of about 5.7°, about 9.8°, about 11.6°, about 14.7°, about 15.4°, about 16.1°, about 17.1°, about 19.3°, about 23.8°, about 24.5°, and about 25.4°. In some embodiments, Form I is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more peaks selected from the specifically recited peaks or within the error range of the recited peaks. In some embodiments, Form I is characterized by an XRPD pattern that substantially corresponds to the XRPD pattern in FIG. 1. The peaks may be described as "about" a particular value to allow for normal experimental variation, and the included variation may be ±0.2 2θ or ±0.1 2θ.

[0103] In some embodiments, the L-(+)-tartrate salt of compound A-TA in Form I is crystallized from a mixture of ethanol and water, or a mixture of propanol and water, or a mixture of methanol and water, or a mixture of acetone and water. In some embodiments, Form I is crystallized from ethanol / water in a ratio of 1:1 to 9:1 (v / v). In some embodiments, the ratio of ethanol / water is 1:1, or 4:6, or 9:1. In some embodiments, Form I is crystallized from methanol / water in a ratio of 7:3 (v / v). In some embodiments, Form I is crystallized from acetone / water in a ratio of 1:1, or 4:6, or 9:1. Pharmaceutical Compositions

[0104] In one embodiment, the present invention provides pharmaceutical compositions and dosage units for oral administration. Apart from the pharmacological activity of the active pharmaceutical ingredient (API), the active substance has some physical or physicochemical characteristics that are relevant for preparation of solid oral dosage forms (including oral powders, granules, pellets, tablets, capsules, chewable tablets, dispersible tablets, troches or lozenges). In order to achieve suitable formulation characteristics (e.g., accurate assay, content and mass uniformity, chemical and physical stability of drug product and suitable dissolution rate), the characteristics of drug product intermediates must also support a robust manufacturing process.

[0105] Thus, in some embodiments, how to achieve suitable and adequate formulation characteristics depends on the creation and manufacturing process for a solid form of Compound A or a pharma- ceutically acceptable salt thereof, or a stable pharmaceutical composition comprising a pharma- ceutically acceptable salt thereof.

[0106] In some embodiments, the pharmaceutical compositions described herein exhibit high stability of the solid form of Compound A or a pharma- ceutically acceptable salt thereof upon storage or under the stability testing conditions described herein.

[0107] In some embodiments, the present invention also relates to a method of making a pharmaceutical composition. Such a method may include a wet granulation process. In some embodiments, the wet granulation process includes the steps of: (a) combining Compound A-TA, mannitol 25C, microcrystalline cellulose, and a percentage of croscarmellose sodium (e.g., 80% of the total amount of the ingredients listed) to form a first mixture; (b) blending the first mixture in a wet granulator; (c) adding PVP dissolved in water to form a second mixture and mixing in a wet granulator; (d) drying the second mixture to obtain a third mixture and, optionally, grinding the mixture in a Comil; and (e) adding and mixing the remaining croscarmellose sodium and sodium stearyl fumarate to the third mixture to form a final mixture suitable for filling capsules to form the dosage units of the present invention.

[0108] In some embodiments, the pharmaceutical composition may contain any suitable type of pharmaceutically acceptable additives to make it into a unit dosage form.Thus, in some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable additive.Suitable additives include, but are not limited to, diluents, binders, vehicles, carriers, excipients, binders, disintegrants, lubricants, swelling agents, solubilizers, wicking agents, cooling agents, preservatives, stabilizers, sweeteners, flavoring agents and polymers.While any pharmaceutically acceptable additives are contemplated by the present disclosure, it should be understood that the additives selected for compounding with compound A or its pharmaceutically acceptable salt should not defeat the stability goal of the present disclosure.

[0109] Examples of disintegrants include, but are not limited to, cross-linked sodium carboxymethylcellulose, croscarmellose sodium (e.g., VIVASOL®), crospovidone, and mixtures thereof. In some embodiments, the pharmaceutical composition comprises about 0.1% (w / w) to about 10% (w / w) or about 5% (w / w) of croscarmellose sodium (e.g., VIVASOL®).

[0110] Examples of lubricants include, but are not limited to, magnesium stearate, stearic acid or its pharma- ceutically acceptable alkali metal salts, sodium stearyl fumarate, polyethylene glycol (e.g., macrogol 6000) (especially in granule or flake formulations to reduce friction with the mold), glyceryl behenate, talc, colloidal or fumed silicon dioxide and silica derivatives (e.g., Cab-O-Sil, Syloid® products, etc.), calcium stearate, sodium stearate, sodium lauryl sulfate, sodium chloride, magnesium lauryl sulfate, talc, and mixtures thereof. A portion of the lubricant may be used as an internal solid lubricant that is blended and granulated with other components of the granulation. Another portion of the lubricant may be added to the final blend material just before compression or encapsulation, and coats the outside of the granules in the final formulation. In some embodiments, the pharmaceutical composition further comprises a disintegrant and a lubricant. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the pharmaceutical composition comprises from about 0.05% (w / w) to about 5% (w / w) sodium stearyl fumarate.

[0111] Oral pharmaceutical compositions as described herein may generally be in the form of individualized doses or multiple unit doses (e.g., tablets, caplets, powders, suspension tablets, chewable tablets, fast dissolving tablets, capsules, such as single or double shell gelatin capsules, tablet-filled capsules, effervescent powders, effervescent tablets, pellets, granules, liquids, solutions or suspensions, respectively). In some embodiments, the pharmaceutical composition is formulated as an oral dosage form or solid oral dosage form. In some embodiments, the oral dosage form is an oral powder, granules, pellets, tablet, capsule, lozenge or lozenge. In some embodiments, the tablet is a chewable tablet, dispersible tablet or lozenge. In some embodiments, the pharmaceutical composition is formulated to include a single dose or multiple doses. In some embodiments, each pharmaceutical composition dosage form (e.g., each tablet or capsule) contains 25 mg or 50 mg or 100 mg or 150 mg or 200 mg or 250 mg or 300 mg or 350 mg or 400 mg or 450 mg or 500 mg of free base equivalent of Compound A. In some embodiments, the active ingredient (e.g., Compound A or a pharma- ceutically acceptable salt thereof, e.g., Compound A-TA) is present in the pharmaceutical composition at a concentration of about 10 to about 70% (w / w), or about 15 to about 60% (w / w), or about 20% (w / w) to about 50% (w / w), or about 30 to 40% (w / w). In the case of a salt form, the concentration is stated as the free base equivalent of the salt form.

[0112] Although the disclosed solid forms of Compound A-TA exhibit high chemical and polymorphic stability, pharmaceutical compositions containing Compound A or Compound A-TA may be subject to oxidation under prolonged storage conditions in the presence of humidity and / or oxygen. Data on the stability of selected pharmaceutical compositions of Compound A-TA are provided in the following table, which shows that the formation of the oxidation product, impurity B, is slow upon storage at elevated temperatures, and that the formation rate of this impurity is reduced in the presence of an oxygen scavenger (PharmaKeep® CD20, also known as Deoxidizer CD20). [Table 1]

[0113] Formulation 4 in Table 1 refers to a formulated material made with the ingredients and ratios shown in Table 4, and was tested both with and without an oxygen scavenger (oxygen scavenger) present in the storage container along with the formulated pharmaceutical composition. Formulation 5 is a formulated material made with the ingredients and ratios shown in Table 5. To test stability, the material was stored at 60°C or 40°C for up to 6 months as shown in Table 1 above. Both formulations (Formulation 4 and Formulation 5) were prepared with the same batch of Compound A-TA. When the formulated pharmaceutical composition was stored in a container in the presence of an oxygen scavenger (oxygen scavenger CD20), a minimal amount of impurity B, an oxidized derivative of Compound A, was found. Thus, packaging a pharmaceutical composition containing Compound A-TA in the presence of an oxygen scavenger reduces the formation of at least one impurity during long-term storage.

[0114] Thus, in some embodiments, the pharmaceutical composition comprising compound A-TA is stored under conditions that reduce exposure to oxygen, humidity, or both.In some embodiments, the pharmaceutical composition can be stored in the presence of a protective agent, or packaged with a protective agent, or stored in an inert atmosphere, or coated with a film.Protective agents suitable for this purpose include the following desiccants and oxygen scavengers:

[0115] Desiccants, including but not limited to the following representative desiccants: 1) Silica gel desiccant, for example, activated silica gel; 2) Molecular sieve desiccants, i.e. synthetic zeolites with high absorptivity for water molecules. The pore size of the molecular sieve material can be controlled by various processing methods, so that in addition to adsorbing water vapor, it can also adsorb other gases. 3) Fiber desiccant.

[0116] Oxygen absorber products known in the art, such as iron-containing oxygen absorber canisters, and oxygen absorbers designed for use with pharmaceuticals, including commercially available oxygen-absorbing PharmaKeep® canisters (including CD20, CD10, KD10 and KD20) manufactured by Mitsubishi Gas Chemicals Company.

[0117] As is known in the art, certain of the above oxygen absorbents can be used in combination with a desiccant (eg, molecular sieves and / or activated silica gel).

[0118] Other methods of reducing oxidation of compound A-TA in the pharmaceutical compositions of the present disclosure include adding one or more antioxidants, such as sodium bisulfite, sodium sulfite, sodium thiosulfate, sodium pyrosulfite, butylated hydroxyanisole (BHA), antioxidant-264 (BHT), vitamin E, and the like, to the formulated pharmaceutical composition; or maintaining the pharmaceutical composition in an atmosphere of an inert gas, such as dry nitrogen or argon, that is substantially free of oxygen and / or moisture.

[0119] Separately packaged oxygen absorbers can effectively reduce the amount of oxygen (or) in the package and protect the product from oxidation during long-term storage. Many suitable oxygen absorber products are known in the art; for example, iron-containing oxygen scavenging canisters can be used. Other examples include oxygen absorbing PharmaKeep® canisters manufactured by Mitsubishi Gas Chemicals Company, including CD20, CD10, KD10 and KD20, which are designed for use with pharmaceuticals. These oxygen absorbers can be used in combination with desiccants, such as molecular sieves and / or activated silica gel. Table 2 shows that in a stability test at high temperature (40° C.), the impurity profile is improved by including PharmaKeep® CD20 oxygen absorber in the container along with a pharmaceutical composition containing compound A-TA.

[0120] When encapsulated as described herein and stored in an opaque HDPE bottle with a conventional LDPE cap in the presence of an effective oxygen scavenger (e.g., PharmaKeep® CD20), compound A-TA is highly stable when stored at 40° C. and 75% relative humidity for up to 6 months or at 25° C. and 60% relative humidity for up to 24 months.

[0121] Thus, in some embodiments, capsules or tablets containing compound A-TA are packaged in opaque high density polyethylene (HDPE) bottles and capped with opaque high density polyethylene (HDPE) or low density polyethylene (LDPE) caps. Optionally, the bottles also contain a protective agent, such as silica gel or activated charcoal or activated zeolite (molecular sieve) desiccant, and optionally, the bottles also contain an oxygen scavenger, such as PharmaKeep® CD10, CD20, KD10 or KD20 oxygen scavenger canister products. In some embodiments, the protective agent is placed in a canister, sachet, envelope or similar container within the bottle to prevent the protective agent from coming into direct contact with the pharmaceutical composition while allowing the protective agent to be exposed to oxygen within the bottle.

[0122] In some embodiments, the bottle containing the capsule or tablet containing compound A-TA contains an oxygen scavenger (e.g., iron powder, catechol, calcium, ascorbic acid, or calcium oxide) in a container such as a vented plastic canister using methods and products known in the art for protecting pharmaceutical products. In some embodiments, the oxygen scavenger is a PharmaKeep® product or a StabilOx product, which may be a pouch or canister containing a proprietary oxygen scavenging material and, optionally, a desiccant. Thus, in some embodiments, the present invention provides a packaged pharmaceutical product containing a pharmaceutical composition containing compound A-TA and a protectant, which may be a desiccant, antioxidant, oxygen scavenger, or opaque coating, or an inert gas used to replace the air in the bottle or other container used to package the pharmaceutical product. In some embodiments, the pharmaceutical composition, which may be in the form of a dosage unit of compound A-TA, e.g., a capsule or tablet, is packaged in a bottle, and the protectant is packaged separately in the same bottle, preferably the same bottle that is substantially airtight. In some of these embodiments, the oxygen scavenger in the canister is added to the bottle with the pharmaceutical composition. Optionally, the oxygen scavenger is selected from Mitsubishi's CD and KD products in the PharmaKeep® product line, e.g., CD10 and KD10 and CD20 and KD20, which are designed for use with pharmaceutical products to provide protection to the composition.

[0123] In some embodiments, a pharmaceutical composition comprising compound A-TA, optionally in the form of a dosage unit of compound A-TA, is packaged in a sealed bag, box, canister or other container and protected by an atmosphere of an inert gas, e.g., dry nitrogen or argon.

[0124] The method can be used for any suitable purpose. In some embodiments, the method can be used to treat and / or prevent proliferation disorders, cancer, tumors, inflammatory diseases, autoimmune diseases, psoriasis, dry eye or immunologically related diseases, or lupus in a subject. The method can be used to treat and / or prevent any suitable proliferation disorder. Exemplary proliferation disorders include sarcoma, epidermoid carcinoma, fibrosarcoma, cervical cancer, gastric cancer, skin cancer, leukemia, lymphoma, lung cancer, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, liver cancer, head and neck cancer, and pancreatic cancer. Of particular interest are methods of using solid forms of compound A-TA, pharmaceutical compositions and dosage units comprising these solid forms to treat conditions selected from lupus, rheumatoid arthritis, chronic myelogenous leukemia, and chronic lymphocytic leukemia. EXAMPLES

[0125] Exemplary chemical entities, pharmaceutical compositions, and methods of making such compounds and compositions are illustrated by reference to the following specific examples. Those skilled in the art will recognize that in the case of chemical synthesis, starting materials may be appropriately selected so that the ultimately desired substituents are retained throughout the reaction scheme, with or without appropriate protection, to obtain the desired product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that may be retained throughout the reaction scheme and replaced with the desired substituent as appropriate. Furthermore, those skilled in the art will recognize that the transformations shown in the examples below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each reaction shown in the general scheme is preferably performed at a temperature from about 0° C. to the reflux temperature of the organic solvent used. Some of the reactions described in the examples provided below are performed at temperatures from about −10° C. to about 100° C. With respect to the example pharmaceutical compositions, those skilled in the art will recognize that variations of the following examples may be appropriate.

[0126] The examples described herein are provided only to illustrate representative embodiments of the present invention. It should therefore be understood that the present invention is not limited to the specific conditions or details described in these or any other examples discussed herein, and such examples should not be construed as limiting the scope of the present invention in any way. Throughout this specification, any and all references are expressly incorporated herein by reference in their entirety.

[0127] The following abbreviations may be used in the specification and examples: DCM = dichloromethane; DIEA = DIPEA = N,N-diisopropylethylamine; DMF = N,N-dimethylformamide; EtOH = ethanol; EtOAc = ethyl acetate; MeOH = methanol; t-BuOH = tert-butyl alcohol; and THF = tetrahydrofuran. Abbreviations used herein have the meanings commonly understood in the art unless otherwise indicated.

[0128] Compound A was synthesized by three different methods. Strategy / Pathway 1: [ka]

[0129] This synthetic strategy / route 1 is acceptable for small-scale synthesis (e.g., SAR studies / focused library synthesis), especially in early drug discovery, since structural diversity can be obtained by using various 2-Cl-pyrimidines 2 and aromatic amines 3 in the synthesis. In this strategy, key intermediates 2 and 3 are coupled by Pd-catalyzed CN coupling reaction, followed by reduction and acylation to obtain the target compound 6. The drawback of this synthesis is that the acylation reaction in the final step is often influenced by other NH groups in the molecule, resulting in unwanted by-products (impurities). To overcome this shortcoming, we decided to modify this synthetic strategy / route by performing acylation before the coupling reaction (see strategy / route 2). Strategy / Pathway 2: [ka]

[0130] In strategy / route 2, the acylation reaction is carried out prior to the coupling reaction, ensuring that there are no other NH groups present in the molecule and avoiding the possible acylation side reaction in synthetic strategy / route 1. Also, the acrylamide group has been found to be very stable in the final coupling reaction. Strategy / Pathway 3: [ka]

[0131] In strategy / route 3, the synthetic efficiency is further improved by shortening the synthesis of 2-Cl-pyrimidine 4 (omitting the reduction reaction) by using the inexpensive starting material 3-aminophenol instead of 3-nitrophenol. The acylation reaction between 3-aminophenol and acryloyl chloride is found to be highly selective.

[0132] Furthermore, during process development, starting material 2-Cl-pyrimidine 4 of various purities was examined and the results showed that different batches of 2-Cl-pyrimidine 4 with purity ranges of 97.8–99.2% all yielded product 9 (compound A) that met the acceptance criteria.

[0133] Based on the results of testing the above three synthetic strategies, Route 3 was used as the final synthetic strategy / route for synthesizing Compound A free base to prepare batches of Compound A for the compositions and experiments described herein.

[0134] The synthetic route starts from commercially available (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate 1 with an ee% (enantiomeric purity) of at least 98.5%. All reactions are carried out under mild conditions with moderate to excellent yields. Most importantly, the entire process leads to the retention of stereochemistry of the final product, compound A free base. Therefore, this synthetic route is selected for further development and scale-up production.

[0135] After completing the synthetic route, we began to optimize the reaction conditions for each step of the synthesis, and gradually expanded the production scale to over 5 kg. Example 1. Synthesis of starting material (8) [ka] Step 1: Synthesis of N-(3-hydroxyphenyl)acrylamide (12)

[0136] A 30 L jacketed reaction vessel was equipped with a cooling system set at -20°C. 3-aminophenol 11 (2.3 kg, 21.1 mol), THF (15 L) and K2CO3 (4.5 kg, 32.6 mol) were added to the reaction vessel with mechanical stirring. When the temperature in the reaction vessel reached about -10°C, acryloyl chloride (2 kg, 22.1 mol) was added dropwise to the reaction vessel. The internal temperature was maintained below 0°C during the addition. After the addition of acryloyl chloride, the reaction was stirred for 1 h. At the end of the stirring, an in-process TLC analysis (ethyl acetate / petroleum ether / HOAc = 2 / 1 / 0.1 as mobile phase) was performed to confirm the completion of the reaction. The reaction was then quenched by slow addition of water (10 L). The mixture was concentrated and the THF was removed under reduced pressure. Ethyl acetate (10 L) was added and the batch was stirred for 30 min. The aqueous layer was separated and extracted with ethyl acetate (10 L x 4) until no compound 12 was present in the aqueous layer (by TLC). The organic layers were combined and washed with water (3 L x 3).

[0137] To maximize the recovery of compound 12 from the above aqueous layer, the extraction-washing process was repeated two more times. All ethyl acetate layers were combined, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to a volume of about 5 L. The concentrated solution was allowed to stand at room temperature overnight and the precipitate was collected to give crude compound 12, which was further purified by mixing with cold ethyl acetate (4 L) under vigorous stirring for 30 minutes. The solid product was collected and dried under vacuum to give compound 12 (2.1 kg, 60% yield) as a white solid.

[0138] Step 2: Synthesis of N-(3-((2-chloro-5-methoxypyrimidin-4-yl)oxy)phenyl)acrylamide (8)

[0139] DMF (15 L) was charged into a reaction vessel equipped with a heater set at 75°C. Compound 12 (3.05 kg, 18.7 mol), 2,4-dichloro-5-methoxypyrimidine (3.3 kg, 18.4 mol) and K2CO3 (3.85 kg, 27.9 mol) were then added with mechanical stirring. When the internal temperature reached 70°C, the mixture was stirred for an additional 4-4.5 h. At the end of the stirring period, in-process TLC analysis (ethyl acetate / petroleum ether / Et3N=2 / 2 / 0.1 as mobile phase) indicated the reaction was complete. The mixture was then cooled to room temperature, filtered and washed with DMF (1 L). The resulting DMF solution (filtrate) was slowly poured into water (10 times the volume of DMF). The precipitate was collected and washed with water (about 4 L) until the aqueous layer was neutral, and then dried to obtain crude 8.

[0140] The crude product was further purified by mixing with ethyl acetate (about 45 L, 8 times the weight of crude compound 8). The resulting suspension was heated to reflux and stirred for 1 h. After cooling, the solid was collected, washed with ethyl acetate (1 L x 2), and dried to give compound 8 (4.79 kg, 85% yield) as a white solid. Example 2. Synthesis of Compound A

[0141] Step 1: Synthesis of (S)-tert-butyl 3-((4-nitrophenyl)amino)pyrrolidine-1-carboxylate (3) [ka]

[0142] (S)-tert-Butyl 3-aminopyrrolidine-1-carboxylate 1 (5.996 kg, 32.19 mol), 1-fluoro-4-nitrobenzene 2 (4.622 kg, 32.75 mol), DMSO (19.8 L) and Et3N (4.840 kg, 47.83 mol) were charged into a 50 L reaction vessel equipped with a condenser. The reaction mixture was then heated using a water bath (90-95 °C) and stirred for 12 h (during this time the internal temperature was maintained at 85-95 °C). At the end of the stirring, in-process TLC analysis (ethyl acetate / petroleum ether = 1 / 2 as mobile phase) showed that the reaction was complete. The reaction mixture was then cooled to room temperature. The resulting solution was slowly transferred to a reaction vessel containing ice water (60 L) whereupon a thick precipitate formed. The resulting slurry was vigorously stirred for 2 h. The yellow precipitate was then filtered, washed with water (12 L×2), and dried at 40-45°C to obtain compound 3 (9.6 kg, 97.09% purity by HPLC, 96.96% yield) as a yellow solid, which was used in the next step reaction without further purification. Step 2: (S)-tert-butyl 3-(methyl(4-nitrophenyl)amino)pyrrolidine-1-carboxylate (4) [ka]

[0143] A 100 L reaction vessel was charged with compound 3 (9.6 kg, 31.23 mol) and DMF (48 L) and stirred. After compound 3 was completely dissolved, the resulting yellow solution was cooled to 0-5°C and NaH (60%, 1.876 kg, 46.90 mol) was added slowly (in small portions while maintaining the temperature inside the reaction vessel at 0-5°C). The reaction mixture was stirred for 15 min and then CH3I (5.326 kg, 37.52 mol) was added slowly while maintaining the internal temperature at 0-5°C. Once the addition was complete, cooling was removed and the mixture was stirred for 1 h. At the end of the stirring, in-process TLC analysis (ethyl acetate / petroleum ether = 1 / 6 as mobile phase) showed the reaction was complete. The reaction was then quenched by adding cold water (12 L) and the reaction mixture was stirred for an additional 1 h.

[0144] Extraction with ethyl acetate: The reaction mixture was roughly divided into three equal parts. To one portion of the reaction mixture in a 100 L reaction vessel, water (42 L) was added. The resulting solution was extracted with ethyl acetate (24 L). The aqueous layer was removed. The organic layer was washed with water (18 L x 2) and then filtered through a Celite® layer. The same procedure was repeated for the other two portions of the reaction mixture. The combined filtrate (organic layer) was concentrated under reduced pressure. The resulting solid was further dried to give compound 4 (10.080 kg, 97.17% purity by HPLC, 100.12% yield) as a brown solid, which was used in the next step reaction without further purification. Step 3: Synthesis of (S)-N-methyl-N-(4-nitrophenyl)pyrrolidin-3-amine hydrochloride (5) [ka]

[0145] A 100 L reaction vessel was charged with compound 4 (10.045 kg, 31.26 mol), methanol (10 L) and dichloromethane (10 L). The reaction mixture was stirred at 120-150 rpm until compound 4 was completely dissolved. The resulting yellow solution was cooled to 0-5°C and HCl / MeOH (8 M, 20 L) was added slowly with stirring. Once the addition was complete, the reaction mixture was stirred at this temperature for an additional 0.5 h. The cooling system was removed and the reaction mixture was allowed to warm to room temperature and continued to stir for an additional 16.5 h (a precipitate formed). At the end of the stirring, in-process TLC analysis (ethyl acetate / petroleum ether = 1 / 1 as mobile phase) indicated the reaction was complete. The suspension was then re-cooled to 0-5°C. The resulting precipitate was collected, washed with ethyl acetate (3 L × 2), and dried at 40-45 °C to give compound 5 (7.060 kg, 99.93% purity by HPLC, 88.05% yield) as a yellow solid, which was used in the next step reaction without further purification. Step 4: Synthesis of (S)-1-(3-(methyl(4-nitrophenyl)amino)pyrrolidin-1-yl)ethenone (6) [ka]

[0146] Et3N (6.940 kg, 68.65 mol) was added to a solution of compound 5 (7.052 kg, 27.58 mol) in methanol (41 L) and dichloromethane (32 L). The resulting yellow solution was cooled to 0-5 °C, and then acetyl chloride (2.590 kg, 32.99 mol) was added dropwise with stirring while maintaining the reaction temperature below 5 °C. Upon completion of the addition, the reaction mixture was stirred at this temperature for an additional 0.5 h. At the end of the stirring, in-process TLC analysis (ethyl acetate as mobile phase) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was redissolved in ethyl acetate (72 L) and washed with water (36 L x 1, 18 L x 2). The organic phase was concentrated under reduced pressure. The crude product was suspended in heptane / ethyl acetate (v / v=1:1, 24 L) with vigorous stirring for 1 h. The resulting suspension was filtered. The solid was collected, washed with heptane (6 L) and dried to give compound 6 (6.430 kg, 99.84% purity by HPLC, 89.25% yield) as a yellow powder, which was used in the next step reaction without further purification. Step 5: Synthesis of (S)-1-(3-((4-aminophenyl)(methyl)amino)pyrrolidin-1-yl)ethanone (7) [ka]

[0147] Pd / C (10% on activated carbon, 257.00 g, 0.241 mol), THF (51.3 L), methanol (12.8 L) and compound 6 (6.420 kg, 24.39 mol) were charged into a 100 L reaction vessel. The air in the reaction vessel was removed by nitrogen flow. Hydrogen pressure was applied by bubbling at normal atmosphere. The hydrogen flow was controlled to maintain the internal temperature at 25-35°C. The reaction mixture was stirred for 48 h. At the end of the stirring, in-process TLC analysis (dichloromethane / methanol = 15:1 as mobile phase) showed that the reaction was complete. The reaction mixture was filtered through Celite® to remove the catalyst. The filtrate was concentrated under reduced pressure to give compound 7 (5.498 kg, 98.00% purity by HPLC, 96.6% yield) as a black oil, which was used in the next step reaction without further purification. Step 6: Synthesis of (S)-N-(3-((2-((4-((1-acetylpyrrolidin-3-yl)(methyl)amino)phenyl)amino)-5-methoxypyrimidin-4-yl)oxy)phenyl)acrylamide (9: Compound A) [ka]

[0148] To a jacketed 30 L reaction vessel, t-BuOH (16 L) was added with mechanical stirring at 110 rpm. Compound 7 (975.0 g, 4.18 mol) and compound 8 were added. 1(1277.5 g, 4.18 mol, synthesized separately) was added. The reaction mixture was stirred for 5-10 min. Potassium carbonate (805.6 g, 5.82 mol), tris(dibenzylideneacetone)dipalladium (76.5 g, 0.084 mol) and dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (74 g, 0.155 mol) were then added with stirring. Air was removed from the reaction vessel with a stream of nitrogen. The reaction vessel was heated by applying hot water (95-97 °C) through the jacket. The reaction mixture was stirred for 7 h, during which the reaction temperature was maintained at 82-85 °C. At the end of the stirring period, in-process HPLC analysis indicated that less than 5% of compound 7 was unreacted. The mixture was then cooled to 50° C. and filtered through a mixture of silica gel (ca. 300 mesh, 2 kg) and Celite® (2 kg), washing with ethyl acetate (8 L). The combined filtrate was concentrated under reduced pressure to give crude 9.

[0149] The crude product was redissolved in ethyl acetate (20 L) and transferred to a 50 L reaction vessel. The resulting solution was washed with brine (12 L x 3). The bottom layer was removed. The organic layer was dried over anhydrous Na2SO4 (2 kg), filtered, and concentrated under reduced pressure until the residual volume was about 5 L. The resulting solution was cooled to room temperature and left to stand overnight with stirring. A precipitate formed as an off-white solid. The precipitate was collected and dried by vacuum to give the second crude product (1300 g, 96.4% purity by HPLC, 61.9% yield), which was sealed away from light and stored in a dry place at room temperature for the next step of removing heavy metal palladium.

[0150] The three crops of the second crude product of compound 9 were combined for further treatment to remove the palladium heavy metal. Palladium removal process using TMT (s-triazine-2,4,6-trithiol; 1,3,5-triazine-2,4,6-trithiol)

[0151] The second crude product (2950 g, 5.88 mol) was charged into a 100 L reaction vessel containing THF (29.5 L) and dichloromethane (29.5 L) and then stirred at room temperature until compound 9 was completely dissolved. TMT (100 g, 0.85 mol), activated carbon (295 g) and silica gel (300-400 mesh, 295 g) were then added. The resulting suspension was stirred at room temperature for 48 h and then filtered through Celite® and washed with EtOH (5.4 L). The combined filtrate was concentrated under reduced pressure. The resulting residue was redissolved in dichloromethane (29.5 L). The solution was washed with dilute aqueous ammonia solution (1.5-2.0%, 5.4 L) and water (13 L x 2). The organic layer was separated, dried over Na2SO4 (1.34 kg), filtered, and concentrated under reduced pressure to remove most of the dichloromethane (no precipitate, about 4.5 L remained). Ethyl acetate (27 L) was added slowly. The precipitate (similar to recrystallization) was collected and dried under vacuum to give the desired final product 9 (2398 g, 98.91% purity by HPLC, 81.3% yield from the second crude crop of compound 9) as an off-white solid. Example 3. Synthesis of Compound A-TA as a Crystalline Dihydrate

[0152] Synthesis of (S)-N-(3-((2-((4-((1-acetylpyrrolidin-3-yl)(methyl)amino)phenyl)amino)-5-methoxypyrimidin-4-yl)oxy)phenyl)acrylamide L-(+)-tartrate dihydrate (10, compound A-TA) [ka]

[0153] For this process step, three batches of compound 9 (compound A) were combined.

[0154] Compound 9 (5918 g, about 98.7% purity) was dissolved in dichloromethane (60 L) at 25° C. The solution was concentrated under reduced pressure at 40° C. to remove about 55 L of dichloromethane. Ethyl acetate (30 L) was added slowly with stirring. The mixture was cooled to about 20° C. for crystallization. The resulting crystals were collected, washed with cold ethyl acetate (10 L), and dried overnight under vacuum at 45° C. to give compound 9 (4950 g) as an off-white powder with a purity of 99.19% by HPLC, which was used in the salt formation step.

[0155] A 100 L reaction vessel was charged with acetone (30 L) and water (3.5 L). A purified sample of compound 9 (free base, 4.7 kg, 9.36 mol) was added with stirring followed by rinsing with acetone (12.3 L). The resulting suspension was vigorously stirred at 45° C. until compound 9 was completely dissolved (approximately 1.5 h). A solution of L-(+)-tartaric acid (1.471 kg, 9.8 mol) in water (1.2 L) was then added slowly with stirring. The solution was cooled to room temperature and continued to stir for 5 h. The resulting precipitate was collected, washed with acetone (1 L) and dried at 45° C. for 24 h. The solid was then crushed, sieved to 60 mesh size and air-dried at room temperature to give the desired product 10 (compound A-TA) as an orange powder (5.8 kg, 99.3% HPLC purity, 90.0% yield). Infrared Spectrum (IR)

[0156] The successive hydroxyls are at 3420 cm -1 Successive amines give rise to absorption peaks in the 3302 cm -1 Successive alkyls give rise to absorption peaks in the region of 2822, 2892, 2953, 3047 and 3117 cm -1 The successive ammonium (NH + ) at 2310 and 2345 cm -1 Ammonium (NH + ) group bending is 1956 cm -1Successive carbonyl groups in the carboxylic acid moiety result in absorption peaks at 1723 and 1610 cm -1 Successive carbonyl groups in the amide moiety result in an absorption peak in the 1660 cm -1 The bending of the amine group in the amide moiety results in an absorption peak in the 1520 cm -1 The successive C-N bonds in the amide moiety result in an absorption peak in the 1266 cm -1 The vibrations of the benzene skeleton then produce absorption peaks at 1433, 1461 and 1539 cm -1 Successive alkyl aryl ethers give rise to absorption peaks in the 1227 cm -1 Successive biaryl ethers give rise to absorption peaks in the 1203 cm -1 This results in an absorption peak in the region.

[0157] ultraviolet spectroscopy

[0158] See table for UV absorption data and analysis.

[0159] (1) Sample preparation: A sample was prepared in a solution of a specific concentration and placed in a 1.00 cm cell. (2) Wavelength: 200~400nm. (3) Solvent: methanol, 0.1 M HCl aqueous solution, 0.1 M NaOH aqueous solution. (4) Concentration: 3.3×10 -5 M.

[0160] UV spectrum: Samples in methanol, 0.1M HCl aqueous solution, and 0.1M NaOH aqueous solution were measured. The measurement range was 200-400 nm. [Table 2] The UV spectrum (F, Figures 4 and 5) is shown below.

[0161] The two absorption maxima (λ) of the sample in a neutral solvent (methanol) max) are 204.6 nm (ε = 4.62 × 10 4 ) and 280.2 nm (ε = 3.58 × 10 4 The absorption at 204.6 nm occurs at the n-σ * The absorption at 280.2 nm is identified as the π-π transition of the conjugated double bond in the benzene ring. * The K absorption band of the sample caused by the transition is identified as 268.6 nm (ε = 3.00 × 10 4 ) to λ max In basic solvents, the K absorption band of the conjugated system is at 277.0 nm (ε = 3.20 × 10 4 ) to λ max has. NMR

[0162] Solvent: DMSO-d6; Internal standard: trimethylsilyl propionate (TSP) 1 The H-NMR spectrum is shown in Figure 6. Powder X-ray diffraction

[0163] Test conditions: Power 40kV x 250mA, CuKα rays

[0164] Scanning mode: linear scanning, step size: 0.02°, scanning range (2θ): 3°~40°, scanning speed: 5° / min.

[0165] The powder X-ray diffraction pattern is shown in F. thermogravimetric analysis Sweep gas: N2 120mL / min, heating rate: 10℃ / min Temperature range: from room temperature to 280℃ The TGA trace is shown in FIG. Differential thermal analysis Sweep gas: N250mL / min, heating rate: 10℃ / min Temperature range: from room temperature to 200℃ The DSC trace is shown in FIG.

[0166] A variety of conditions were tested to generate crystalline forms and attempt to identify useful polymorphic forms of compound A-TA. The table briefly summarizes the conditions used for the preparation of the polymorphs and the results obtained. [Table 3]

[0167] Dosage form selection: oral immediate release capsule formulations are disclosed herein. One embodiment of this is 25mg / capsule (free base equivalent) in HPMC#2 capsule shell. If necessary, the drug load can be increased by using larger capsules, so that each dosage unit can contain, for example, 50mg / capsule or 100mg / capsule (free base equivalent).

[0168] Process selection: Compound A-TA is a drug substance with two molecules of water. To prevent dehydration that may occur during higher temperature manufacturing processes (e.g., drying process for wet granulation in tablet making), a direct blend capsule filling manufacturing process is used. To protect the stability of the pharmaceutical composition before and after capsule formation, the process including capsule filling and storage steps is preferably carried out under moderate conditions, such as a temperature of less than about 30° C. and a relative humidity of less than about 60%, preferably less than about 45%.

[0169] Excipient Selection: The excipients used in Compound A-TA capsules are commonly used excipients and can be found in the FDA's Inactive Ingredient Database (IID). Physicochemical and biological properties

[0170] The drug substance free base is a weakly basic compound with a pKa of approximately 5.3. The aqueous solubility of the free base is pH dependent. It becomes nearly insoluble as the pH increases, and its solubility increases dramatically as the pH decreases. To enhance absorption and bioavailability, a tartrate salt (compound A-TA) was made to increase the dissolution of the molecule in compositions intended for oral administration. In a dog PK study using HPMC capsules, capsules containing compound A-TA showed a good dissolution profile (>85% release after 30 minutes) and achieved a bioavailability of 20% to 39%. Example 4. Capsules containing Compound A-TA prepared by wet granulation

[0171] The drug product of Compound A-TA was diluted to 34.26 mg of the tartrate salt (Compound A-TA). Equivalent A capsule containing 25 mg of Compound A free base was prepared for oral administration. The capsule also contains 32.00 mg of Prosolv® SMCC50 (silicified microcrystalline cellulose), 89.74 mg of Prosolv® SMCC90 (silicified microcrystalline cellulose), 3.20 mg of croscarmellose sodium (VIVASOL®) and 0.80 mg of sodium stearyl fumarate (PRUV®). The total weight of the contents in one capsule is 160 mg. A size #2 HPMC capsule shell with a light blue opaque cap and a white opaque body was used. The Compound A-TA capsule was packaged in a high density polyethylene (HDPE) bottle and capped with a low density polyethylene (LDPE) cap with molecular sieves.

[0172] A flow diagram summarizing the above process is shown in FIG. [Table 4]

[0173] The following steps were followed to wet granulate compound A-TA according to the ingredients list in Table 4: a. Weigh out the intragranular materials (Compound A-TA, Mannitol 25C, Microcrystalline Cellulose PH101) and sieve through a 40 mesh sieve. b. Blend the inner granule materials (except Povidone K30) in the wet granulator for 5-10 minutes to obtain Blend #1 in the wet granulator. c. Add Povidone PK 30 dissolved in water to Blend #1 in the wet granulator and process for 5-10 minutes to obtain Blend #2. d. Mixture #2 is dried in a fluidized bed at about 60° C. for 30-60 minutes to obtain Mixture #3. e. Dry mill Blend #3 in Comil for 10 minutes to obtain Blend #4. f. Weigh out the outer granule materials, croscarmellose sodium and sodium stearyl fumarate, and sieve them through a 40 mesh sieve. Add them to Blend #4 and mix for 10-20 minutes to obtain Blend #5. g. Fill capsules with Mixture #5. The capsule shells were Vcap plus made of HPMC. h. Package in HDPE bottles (containing molecular sieve desiccant and oxygen scavenger). Example 5. Preparation of tablets containing compounds A-TA via wet granulation

[0174] Using the same ingredients and proportions as shown in Table 4 above, tablets were made as dosage units of Compound A-TA by the following process steps: a. Intragranular materials (Compound A-TA, Mannitol 25C, Microcrystalline Cellulose PH101) are weighed and sieved through a 40 mesh sieve. b. Blend the inner granule materials (except Povidone PK30) in the wet granulator for 5-10 minutes to obtain Blend #1 in the wet granulator. c. Add PvpK30 dissolved in water to mixture #1 in the wet granulator for 5-10 minutes to obtain mixture #2. d. Mixture #2 is dried in a fluid bed at about 60° C. for 30-60 minutes to obtain Mixture #3. e. Dry mill Blend #3 in Comil for 10 minutes to obtain Blend #4. f. Weigh out the outer granule materials, croscarmellose sodium and sodium stearyl fumarate, and sieve them through a 40 mesh sieve. Add them to Blend #4 and mix for 10-20 minutes to obtain Blend #5. g. Compress mixture #5 in a tablet press to obtain uncoated tablets #1. h. Coat tablet #1 with OPADRY 03B120001. i. Packaged in HDPE bottles (containing molecular sieve desiccant and oxygen scavenger). Figure 10 shows a flow diagram of this process. Example 6. Preparation of capsules containing compounds A-TA via direct mixing [Table 5]

[0175] The amounts of excipients and ingredients for different formulation products containing Compound A-TA are shown in Table 5. Using the ingredients in Table 5 and the direct blending process, capsules were prepared by the following steps: a. Prepare and weigh out the drug substance and all excipients. b. Compound A-TA drug substance is mixed with SMCC 90 and SMCC 50. The blend is sieved through a 40 mesh sieve to obtain Blend #1. c. Mixture #1 is combined with croscarmellose sodium (Vivasol) and mixed for 18-22 minutes to obtain Mixture #2. d. Sift together Blend #2 and Sodium Stearyl Fumarate (Pruv) and mix for 3-7 minutes to obtain the final granulated product. e. Filling into capsules. f.Package in HDPE bottles. Figure 11 provides a flow diagram of this process. Example 7. Preparation of tablets containing Compound A-TA via direct mixing

[0176] Using the excipients and amounts of ingredients shown in Table 5, tablets were made by the following process: (a) Prepare and weigh the drug substance and all excipients. (b) Compound A-TA drug substance and SMCC 90, SMCC 50 are mixed together. The blend is sieved through a 40 mesh sieve to obtain Blend #1. (c) Mixture #1 is combined with croscarmellose sodium (Vivasol) and mixed for 18-22 minutes to obtain mixture #2. (d) Sift together Blend #2 and Sodium Stearyl Fumarate (Pruv) and mix for 3-7 minutes to obtain the final granulation. (e) Compress in a tablet press to obtain uncoated tablet #1. (f) Coat tablet #1 with OPADRY 03B120001.

[0177] Packaged in HDPE bottles (containing molecular sieve desiccant and oxygen scavenger). Figure 12 provides a flow diagram of this process. The present invention provides, for example, the following items. (Item 1) Compound A, which is a tartrate salt [ka] A solid form of. (Item 2) 2. The solid form according to item 1, which is a 1:1 salt of Compound A and L-(+)-tartaric acid. (Item 3) 3. The solid form according to item 1 or 2, which is a hydrate of the L-(+)-tartrate salt of Compound A. (Item 4) 4. The solid form according to item 3, which is a dihydrate. (Item 5) The solid form of any one of the preceding items, which is crystalline. (Item 6) The solid form of any one of the preceding items, which is a crystalline form having a powder X-ray diffraction pattern including at least two peaks selected from about 5.7°, about 9.8°, about 11.6°, about 14.7°, about 15.4°, about 16.1°, about 17.1°, about 19.3°, about 23.8°, about 24.5° and about 25.4° in terms of 2θ. (Item 7) 7. The solid form according to item 6, wherein the powder X-ray diffraction pattern comprises at least three peaks, or at least four peaks, or at least five peaks, or at least six peaks, or at least seven peaks, or at least eight peaks, or at least nine peaks, or at least ten peaks, the peaks being selected from about 5.7°, about 9.8°, about 11.6°, about 14.7°, about 15.4°, about 16.1°, about 17.1°, about 19.3°, about 23.8°, about 24.5°, about 25.4° in terms of 2θ. (Item 8) The solid form of any one of the preceding items, having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 74° C. (Item 9) The solid form of any one of the preceding items, having a thermogravimetric analysis (TGA) substantially as shown in FIG. (Item 10) A pharmaceutical composition comprising a solid form of compound A according to any one of the preceding paragraphs, mixed with at least one pharma- ceutically acceptable excipient. (Item 11) Item 12. The pharmaceutical composition according to item 10, comprising at least two pharma- ceutically acceptable excipients. 12. The pharmaceutical composition according to item 10 or 11, comprising at least one pharma- ceutically acceptable excipient selected from fillers, disintegrants, glidants, adhesives, lubricants and antioxidants, such as sodium bisulfite, sodium sulfite, sodium thiosulfate, butylated hydroxytoluene (antioxidant-264), butylated hydroxyanisole, citric acid and vitamin E. (Item 13) 13. The pharmaceutical composition according to item 12, comprising at least one pharma- ceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, mannitol, polyvinylpyrrolidone (PVP) and sodium stearyl fumarate. (Item 14) 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, and 400 mg of Compound A in free base form. Equivalent A dosage unit comprising a solid form of compound A according to any one of items 1 to 9 in an amount of (Item 15) 15. The dosage unit according to item 14, which is a tablet or capsule. (Item 16) 16. The dosage unit according to item 14 or item 15, comprising compound A-TA and one or more pharma- ceutically acceptable excipients. (Item 17) Item 17. The dosage unit of item 16, wherein the one or more pharma- ceutically acceptable excipients comprise one or more excipients selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, mannitol, polyvinylpyrrolidone (PVP) and sodium stearyl fumarate. (Item 18) 18. The dosage unit according to any of items 14 to 17, comprising at least one pharma- ceutically acceptable excipient selected from silicified microcrystalline cellulose 50, silicified microcrystalline cellulose 90, pregelatinized starch, mannitol, croscarmellose sodium, povidone and sodium stearyl fumarate. (Item 19) 19. The dosage unit according to any one of items 14 to 18, comprising an antioxidant such as sodium bisulfite, sodium sulfite, sodium thiosulfate, butylated hydroxytoluene (antioxidant-264), butylated hydroxyanisole, citric acid and vitamin E. (Item 20) A packaged pharmaceutical product comprising a pharmaceutical composition comprising compound A and a protective agent as two separate materials in a closed container. (Item 21) 20. The packaged pharmaceutical according to item 19, wherein the pharmaceutical composition comprises a dosage unit according to any one of items 14 to 18. (Item 22) 21. The packaged pharmaceutical of any one of items 19 to 20, wherein the protective agent comprises at least one material selected from a desiccant, an antioxidant, an oxygen scavenger, and an inert gas. (Item 23) 22. The packaged pharmaceutical of any one of items 19 to 21, wherein the protective agent comprises at least one material selected from molecular sieves, silica gel, and fibrous desiccants. (Item 24) 22. The packaged pharmaceutical of any one of items 19 to 21, wherein the protective agent and the pharmaceutical composition are contained in an airtight container. (Item 25) 25. The packaged pharmaceutical product of item 24, wherein the airtight container is a sealed bottle. (Item 26) 14. A method for preparing a pharmaceutical composition according to any one of items 10 to 13, comprising combining the L-(+)-tartrate salt of compound A with at least one pharma- ceutically acceptable excipient. (Item 27) 27. The method of claim 26, wherein the at least one pharma- ceutically acceptable excipient comprises a filler, optionally selected from mannitol, starch, microcrystalline cellulose (including SMCC50, SMCC90), lactose, gelatin, pregelatinized starch, sucrose, calcium phosphate, maltodextrin, sorbitol, calcium carbonate, and calcium phosphate. (Item 28) 28. The method according to claim 26 or 27, wherein the at least one pharma- ceutically acceptable excipient comprises a disintegrant, optionally comprising croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and sodium starch glycolate. (Item 29) The method according to any one of items 26 to 28, wherein the at least one pharma- ceutically acceptable excipient comprises an adhesive, and the adhesive is, as appropriate, polyvinylpyrrolidone (PVP), cross-linked PVP, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, or sodium carboxymethylcellulose (CMC-Na). 30. The method according to any one of items 26 to 29, wherein the at least one pharma- ceutically acceptable excipient comprises a lubricant, optionally selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, colloidal silicon dioxide, talc, stearic acid, glyceryl monostearate, isopropyl myristate. (Item 31) 27. The method of claim 26, comprising combining the L-(+)-tartrate salt of Compound A with microcrystalline cellulose, sodium stearyl fumarate and PVP, and optionally mannitol to form a mixture. (Item 32) 32. The method of claim 31, comprising combining the L-(+)-tartrate salt of Compound A with microcrystalline cellulose, sodium stearyl fumarate and PVP, and optionally mannitol, to form a mixture, and adding PVP and optionally water to form a wet granule mixture. (Item 33) 27. A pharmaceutical composition comprising compound A-TA, prepared by the method according to item 26. (Item 34) 33. The method of claim 31 or 32, wherein the mixture is blended in a wet granulator. (Item 35) A process for preparing the L-(+)-tartrate salt of compound A, comprising contacting compound A with L-(+)-tartaric acid in the presence of a solvent. (Item 36) 1. A process for preparing a solid form of Compound A, comprising contacting Compound A with tartaric acid in a solvent. (Item 37) 37. The process according to item 36, comprising contacting compound A with L-(+)-tartaric acid in the presence of a solvent under conditions whereby the L-(+)-tartrate salt of compound A precipitates from the solvent as a solid. (Item 38) 38. The process of claim 37, wherein the solvent comprises water and an organic co-solvent. (Item 39) 39. The process of claim 38, wherein the organic co-solvent is selected from acetone, isopropanol, ethanol and tetrahydrofuran. (Item 40) 40. The process of claim 39, wherein the solid form of compound A comprises Form I of the L-(+)-tartrate salt of compound A. (Item 41) A process for synthesizing compound A or a pharma- ceutically acceptable salt thereof, comprising reductive hydrogenation of compound 1 to obtain compound 2. [ka] The process includes: (Item 42) reacting compound 2 with compound 3 to obtain compound A: [ka] Item 42. The process of item 41, further comprising: (Item 43) Item 43. The method of item 42, further comprising contacting compound A with L-(+)-tartaric acid to obtain the L-(+)-tartrate salt of compound A. (Item 44) 10. A method for treating a condition selected from a proliferation disorder, a proliferative disorder, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye, rheumatoid arthritis or lupus in a subject, said method comprising administering to a subject in need thereof a solid form of compound A according to any one of items 1 to 9 or a pharmaceutical composition thereof. (Item 45) 45. The method of claim 44, wherein the condition is selected from chronic lupus, rheumatoid arthritis, chronic lymphocytic leukemia and chronic myelogenous leukemia.

Claims

1. Compound A: 【Chemistry 1】 and L-(+)-tartrate, and crystalline form I having an X-ray powder diffraction pattern including at least 10 peaks selected from 5.7°±0.2°, 9.8°±0.2°, 11.6°±0.2°, 14.7°±0.2°, 15.4°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 19.3°±0.2°, 23.8°±0.2°, 24.5°±0.2°, and 25.4°±0.2°, calculated in degrees 2θ. Dihydrate crystals.

2. The dihydrate crystal according to claim 1, which is a hydrate of the L-(+)-tartrate salt of Compound A.

3. 3. The dihydrate crystal according to claim 1 or 2, having a differential scanning calorimetry (DSC) thermogram including an endothermic peak at 74°C ± 3°C.

4. below: 【Chemistry 7】 The dihydrate crystal according to any one of claims 1 to 3, having a thermogravimetric analysis (TGA) as shown in:

5. A pharmaceutical composition comprising a crystalline dihydrate of the L-(+)-tartrate salt of Compound A according to any one of claims 1 to 4, in admixture with at least one pharma- ceutically acceptable excipient.

6. 6. The pharmaceutical composition of claim 5, wherein the crystalline dihydrate of the L-(+)-tartrate salt of Compound A is present in the dosage unit in an amount equivalent to the weight of Compound A as a free base selected from 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, and 400 mg.

7. 7. The pharmaceutical composition of claim 6, comprising at least one pharma- ceutically acceptable excipient selected from silicified microcrystalline cellulose 50, silicified microcrystalline cellulose 90, pregelatinized starch, mannitol, croscarmellose sodium, povidone, and sodium stearyl fumarate.

8. 8. The pharmaceutical composition of claim 6 or 7, further comprising an antioxidant.

9. A packaged pharmaceutical product comprising a pharmaceutical composition comprising the L-(+)-tartrate salt of Compound A and a protective agent as two separate materials in a closed container, wherein Compound A is 【Chemistry 9】 Represented by, medicines.

10. A method for preparing a pharmaceutical composition according to any one of claims 5 to 8, comprising combining said L-(+)-tartrate salt of Compound A with at least one pharma- ceutically acceptable excipient.

11. 11. The method of claim 10, wherein the at least one pharma- ceutically acceptable excipient comprises a filler, optionally selected from mannitol, starch, microcrystalline cellulose (including SMCC50, SMCC90), lactose, gelatin, pregelatinized starch, sucrose, calcium phosphate, maltodextrin, sorbitol, calcium carbonate, and calcium phosphate.

12. 12. The method of claim 11, comprising combining the L-(+)-tartrate salt of Compound A with microcrystalline cellulose, sodium stearyl fumarate and PVP, and optionally mannitol to form a mixture.

13. The method of claim 12, wherein the mixture is blended in a wet granulator.

14. Compound A 【Chemistry 14】 23. A process for preparing the L-(+)-tartrate salt of formula (I), comprising contacting compound A with L-(+)-tartaric acid in the presence of a solvent.

15. Reacting compound 2 with compound 3 to obtain compound A: 【Chemistry 21】 15. The process of claim 14, further comprising:

16. 16. The process of claim 15, comprising reductive hydrogenation of compound 1 to give compound 2. 【Chemistry 20】 The process includes:

17. A pharmaceutical composition comprising a crystalline dihydrate of the L-(+)-tartrate salt of compound A according to any one of claims 1 to 4 for treating a condition selected from a proliferation disorder, a proliferative disorder, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye, rheumatoid arthritis or lupus in a subject.

18. 18. The pharmaceutical composition of claim 17, wherein the condition is selected from chronic lupus, rheumatoid arthritis, chronic lymphocytic leukemia and chronic myelogenous leukemia.

19. 9. The composition of claim 8, wherein the antioxidant is sodium bisulfite, sodium sulfite, sodium thiosulfate, butylated hydroxytoluene (antioxidant-264), butylated hydroxyanisole, citric acid, or vitamin E.

Images