Solid forms of n-(pyrimidinylphenyl)-acrylamide compounds and uses thereof

Abstract

The present invention relates to certain solid forms of N-(pyrimidinyloxy)acrylamide derivatives useful in the treatment of proliferative and immunological diseases and other diseases associated with 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 methods of making these materials and salts and polymorphs thereof, as well as intermediates in the preparation of these materials, and methods of pharmaceutical compositions comprising these materials. These solid forms and pharmaceutical compositions comprising them are useful in the treatment of conditions including proliferative diseases, tumors, inflammatory diseases, autoimmune diseases, psoriasis, dry eye, rheumatoid arthritis, or lupus.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to solid forms of N-(pyrimidinylphenyl)-acrylamide compounds useful in the treatment of proliferative disorders and immunological conditions associated with kinase dysregulation, 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 the compounds and solid forms thereof are also disclosed. Certain salt forms and physical forms of the compounds are also disclosed, as are pharmaceutical compositions containing these compounds, and methods of using these compounds, solid forms and pharmaceutical compositions to modulate kinase activity and treat certain proliferative and immunological diseases. BACKGROUND

[0002] Certain N-(pyrimidinylphenyl)acrylamide compounds of general formula (I)

[0003]

[0004] wherein R 3 may be alkoxy, R c may be alkyl, cycloalkyl or heterocycloalkyl; Y can be N, CH or C halo (C-halo); R d may be H or alkyl;

[0005] are described as potent modulators of certain protein kinases known to be important drug targets.

[0006] WO2015 / 0067654. These compounds are useful in the treatment of certain protein kinase mediated diseases, including cancer, immune diseases and chronic inflammation.

[0007] Of particular interest is the inhibition of Bruton's tyrosine kinase (BTK) by compounds of formula (I), which plays a crucial role in the maturation of B-cells and activation of mast cells. Inhibitors of BTK are in clinical trials for B-cell related proliferative diseases (chronic lymphocytic leukemia, non-Hodgkin's lymphoma) and autoimmune diseases such as X-linked agammaglobulinemia (XLA).

[0008] Certain compounds of general formula (I), including Compound A

[0009]

[0010] (S)-N-(3-(2-(4-((1-acetylpiperazin-3-yl)(methyl)amino)anilino)-5- methoxy pyrimidin-4-yloxy)phenyl)acrylamide and pharmaceutically acceptable salts thereof are of particular interest due to their potent inhibition of protein kinases including EGFR and BTK, and thus can be suitable for use in clinical trials for the treatment of EGFR and / or BTK related diseases. In order to enhance their clinical utility, improved forms and formulations of these compounds are needed, and have now been developed.

[0011] An efficient process is needed to prepare these compounds for clinical testing and commercial use. Such processes, as well as intermediates useful in the preparation of these compounds, are described herein; certain salt forms and polymorphs of these compounds, and methods of their preparation, are also described.

[0012] Generally, drug stability is an important consideration in the design, manufacture, and storage of pharmaceutical compositions. Drugs that lack stability can form degradation products, causing adverse side effects, or in some cases, a decrease in efficacy and bioavailability of the drug itself, making it difficult for physicians to prescribe consistent and effective doses. In order to develop Compound A for widespread use in pharmaceutical applications, solid forms that can be consistently produced and in high purity are needed, as are dosage forms and formulations of these solid forms that are stable for long term storage. The present invention provides such solid forms of Compound A, as well as pharmaceutical compositions and methods of treatment utilizing these solid forms.

[0013] SUMMARY

[0014] The present invention relates to methods of preparing certain N-(pyrimidinyloxy)phenyl acrylamide compounds and solid forms thereof, as well as intermediates useful in their preparation. Certain solid forms, salts, and polymorphs of Compound A, which is particularly useful in the development and production of pharmaceutical products, are also described. The present invention describes particularly useful solid forms of Compound A, including a 1 : 1 salt of Compound A with L-(+)-tartaric acid (Compound A-TA). In addition, the present invention describes pharmaceutical compositions comprising these novel solid forms, and methods of their preparation and use.

[0015] The present disclosure provides methods of preparing Compound A

[0016]

[0017] and its tartrate salt, as well as methods of producing novel solid forms of the tartrate salt that can be consistently produced and are highly stable for formulation and storage. Also disclosed herein are stable polymorphs of the salt of Compound A, as well as methods of using the polymorphs or other solid forms to prepare pharmaceutical compositions and dosage forms.

[0018] Compound A is very effective as a kinase inhibitor, but has low water solubility, which reduces its suitability for oral administration. The neutral compound, which is referred to as the free base of Compound A, is practically insoluble at higher pH values due to its weak basicity. To improve water solubility, which is expected to greatly improve oral bioavailability, attempts have been made to prepare acid addition salts of Compound A. Surprisingly, of twelve acids [HCl, HBr, H3PO4, maleic acid, hydroxybutanedioic acid, citric acid, methanesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, fumaric acid, L-(+)-tartaric acid and D-(-)-tartaric acid] used in initial testing, only (L)-(+)-tartaric acid produced a stable crystalline solid. Thus, the L-(+)-tartaric acid salt of Compound A, referred to hereinafter as Compound A L-(+)-tartaric acid salt, or Compound A-TA, is particularly suitable for development and use in the many compositions and methods herein.

[0019] In one aspect, the present application provides a solid form of Compound A:

[0020]

[0021] which is a tartrate salt. In some embodiments, it is a 1:1 salt of Compound A and L-(+)-tartaric acid. In some embodiments, it is a crystalline dihydrate.

[0022] In another aspect, the present application provides stable and particularly useful polymorphs of the tartrate salt of Compound A, which are further described herein, as well as methods of making these salts.

[0023] The present application also provides pharmaceutical compositions comprising the solid forms described herein, as well as methods of using the pharmaceutical compositions to make highly stable pharmaceutical products and dosage units. It provides various forms of dosage units, including capsules and tablets, having suitable amounts of the solid forms of Compound A and formulations thereof for treating diseases characterized by abnormal levels of EGFR and / or BTK activity.

[0024] In some embodiments, the pharmaceutical compositions of the present application are packaged with at least one protective agent, which can be one or more materials selected from the group consisting of desiccants, antioxidants, oxygen scavengers, and inert gases. The protective agent can reduce the rate of formation of trace impurities when the pharmaceutical composition is exposed to heat or moisture or both.

[0025] The present application also provides dosage units comprising the pharmaceutical compounds of the present application and packaged pharmaceutical products comprising these compounds.

[0026] In another aspect, the present invention provides a method for treating proliferative diseases, cancers, tumors, inflammatory diseases, psoriasis, dry eye syndrome, or autoimmune diseases such as rheumatoid arthritis or lupus in subjects using the compounds, solid forms, pharmaceutical compositions, and dosage units of the present invention. Exemplary proliferative diseases for treatment include sarcomas, epidermoid carcinomas, fibrosarcomas, cervical cancer, gastric cancer, skin cancer, leukemia, lymphoma, lung cancer, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, breast cancer, liver cancer, head and neck cancer, and pancreatic cancer. Of particular interest are B-cell-related forms of lymphoma or leukemia, such as chronic myeloid leukemia and chronic lymphocytic leukemia.

[0027] The present invention also provides an improved method for synthesizing compounds such as compound A or pharmaceutically acceptable salts thereof.

[0028] Other aspects and beneficial effects of the present invention will become apparent from the implementation schemes and embodiments provided herein.

[0029] For the sake of brevity, the disclosures of publications including those containing patents cited in this specification are incorporated herein by reference. Attached Figure Description

[0030] Figure 1 This is the X-ray powder diffraction pattern of polymorph I of compound A-TA.

[0031] Figure 2 This is the infrared spectrum of compound A-TA.

[0032] Figure 3 The ultraviolet spectrum of compound A-TA in methanol is shown.

[0033] Figure 4 The ultraviolet spectrum of compound A-TA in acidic medium is shown.

[0034] Figure 5 It is the ultraviolet spectrum of compound A-TA in alkaline water medium.

[0035] Figure 6 It is in d 6 -Proton NMR spectrum of compound A-TA in DMSO ( 1 H NMR).

[0036] Figure 7 Thermogravimetric analysis of polymorph I of compound A-TA is shown.

[0037] Figure 8 Differential scanning calorimetry (DSC) curves of polymorph I of compound A-TA are shown.

[0038] Figure 9is a process flow diagram for a wet granulation process to prepare capsules filled with Compound A-TA.

[0039] Figure 10 is a process flow diagram for a wet granulation process to prepare tablets of Compound A-TA.

[0040] Figure 11 is a process flow diagram for a direct mixing process to prepare capsules filled with Compound A-TA.

[0041] Figure 12 is a process flow diagram for a direct mixing process to prepare tablets of Compound A-TA.

[0042] DETAILED DESCRIPTION

[0043] The present invention includes improved methods of making certain N-(pyrimidinyloxy)phenylpropenamide derivatives, which are useful in pharmaceutical compositions and methods of treating certain proliferative and immunological diseases. General methods of making compounds or precursors related to the present invention, as well as biochemical and biological data related to the present invention, can be found in WO 2015 / 0067654 and U.S. Patent No. 9,464,089.

[0044] Before further description of the present invention, it should be understood that the present invention is not limited to the particular embodiments described, as such can of course vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, as the scope of the present invention will be limited only by the appended claims.

[0045] It must be noted that, as used herein and in the appended claims, singular articles "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the claims can be drafted to exclude any optional element. Thus, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in

[0046] For the sake of providing a more concise description, some quantitative expressions given herein do not conform to the qualification of the term "about." It should be understood that each quantity given herein, whether or not expressly stated to be approximate, is intended to refer to an actual given value, and is also intended to include values that are reasonably approximated given the value. Such equivalents and approximations are within the knowledge of those of ordinary skill in the art, including due to experimental and / or measurement conditions. For example, when a peak in an XRPD is described as being "about" a particular value, the value includes a range of ±0.2°. The amounts of materials recited in the claims should be understood to include ranges that allow for at least a reasonable variation around the precision with which the context allows, and if not otherwise specified, should generally be interpreted as including a range of ±10% around the specified value. Where temperatures are specified for DSC, it should be understood to include a range of ±3°C.

[0047] Whenever yields are given in percentages, such yields refer to the amount of an entity relative to the maximum amount of the same entity obtainable under the particular stoichiometric conditions. Concentrations given in percentages refer to mass ratios, unless otherwise specified.

[0048] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which this application belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present application, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0049] The methods and techniques of the present embodiments are generally performed according to conventional methods well-known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., 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.

[0050] As used herein, the terms "comprises," "comprising," and "including" are used in their open, non-limiting sense. In the case of describing embodiments as "comprising" specified elements, the application also contemplates embodiments "consisting essentially of and "consisting of the same specified elements.

[0051] It should be understood that certain features of the application described in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, various features of the application described in the context of a single embodiment can also be provided separately or in any appropriate

[0052] The term "alkyl" refers to a straight or branched chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, i-propyl, butyl, i-butyl, sec-butyl, t-butyl (tBu), pentyl, i-pentyl, t-pentyl, hexyl, i-hexyl, and equivalents to any of the foregoing groups that would be recognized by one of ordinary skill in the art and by the teachings provided herein.

[0053] The term "alkoxy" refers to an alkyl group as defined above bonded to an oxygen atom. The alkoxy group is attached to the parent structure through the oxygen atom.

[0054] The term "amino" refers to a -NH2 group, or mono- or dialkylamino.

[0055] The term "halogen" denotes chlorine, fluorine, bromine, or iodine. The term "halo" denotes chlorine, fluorine, bromine, or iodine.

[0056] The term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halogen atoms. The term "haloalkoxy" refers to an alkoxy group as defined above substituted with one or more halogen atoms.

[0057] The term "acyl" refers to the group R-C(O)-, where R is a straight chain, branched, or cyclic configuration of 1 to 10 carbon atoms (C 1-10 ) attached to the parent structure through the carbonyl functionality. The R group can be saturated or unsaturated, and aliphatic or aromatic.

[0058] The term "cyano" refers to the group -CN.

[0059] The term "nitro" refers to the group -NO2.

[0060] The term "hydroxy" refers to the group -OH.

[0061] Those skilled in the art will recognize that the categories listed or described above are not exhaustive and that other categories within the scope of these defined terms can also be selected.

[0062] Any formula given herein is intended to represent each and every compound structurally similar to the described structure. For example, unless otherwise specified, the formulas given herein are intended to include the racemic mixture, or one or more of the enantiomeric, diastereomeric, or geometric isomers, or mixtures thereof, of the compounds. Additionally, any formula given herein is also intended to represent hydrates, solvates, or polymorphs of such compounds or mixtures thereof.

[0063] Compounds described herein as specific enantiomers refer to the indicated enantiomer.

[0064] It is understood that such compounds can still contain minor amounts of, i.e., less than 10%, typically less than 5%, of the opposite enantiomer.

[0065] Any formula given herein is also intended to represent unlabelled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be found in embodiments of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 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 I. Such isotopically labeled compounds are useful in metabolic studies (e.g., with 14 C), reaction kinetic studies (with 2 H or 3 H), detection or imaging techniques [e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] and for use in radiotherapy. In particular, for PET or SPECT studies, the 18 F or 11 C labeled compounds are particularly preferred. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) Substitution can provide certain therapeutic advantages due to greater metabolic stability, for example, longer half-life in vivo or lower dosage requirements. Isotopically-labeled compounds of embodiments and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes or Examples and Preparations below, by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent.

[0066] "Pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base represented herein which is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. Commonly, for example, S. M. 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 subjects without undue toxicity, irritation, or allergic response. Compounds described herein can have sufficiently acidic, sufficiently basic, both types of functional groups, or more than one of each, and thus react with inorganic or organic bases, and inorganic and organic acids to form pharmaceutically acceptable salts.

[0067] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1- sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates.

[0068] REPRESENTATIVE EMBODIMENTS

[0069] The following enumerated embodiments represent some aspects of the present invention.

[0070] 1. A solid form of Compound A:

[0071]

[0072] which is a tartrate salt.

[0073] 2. The solid form of embodiment 1, which is a 1:1 salt of Compound A and L-(+)-tartaric acid.

[0074] 3. The solid form of embodiment 1 or 2, which is a hydrate of the L-(+)-tartaric acid salt of Compound A.

[0075] 4. The solid form of embodiment 3, which is a dihydrate.

[0076] 5. The solid form of any one of the preceding embodiments, which is crystalline.

[0077] 6. The solid form of any one of the preceding embodiments, which is a crystalline form having an X-ray powder diffraction pattern comprising at least two peaks selected from the group consisting of, in terms of 2-theta, 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°.

[0078] 7. The solid form of embodiment 6, wherein the X-ray powder 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, wherein the peaks are selected from the group consisting of, in terms of 2-theta, 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 particular examples, the XRPD pattern substantially matches the XRPD in Figure 1

[0079] 8. The solid form of any one of the preceding embodiments, which differential scanning calorimetry (DSC) thermogram comprises an endothermic peak at about 74 °C.

[0080] 9. The solid form of any one of the preceding embodiments, which has a thermogravimetric analysis (TGA) substantially as shown in Figure 7 .

[0081] 10. A pharmaceutical composition comprising a solid form of Compound A according to any one of the preceding embodiments, in admixture with at least one pharmaceutically acceptable excipient.

[0082] 11. The pharmaceutical composition of embodiment 10, comprising at least two pharmaceutically acceptable excipients.

[0083] ​12. The pharmaceutical composition of embodiment 10 or 11, comprising at least one pharmaceutically acceptable excipient selected from the group consisting of fillers, disintegrants, glidants, binders, lubricants, and antioxidants, such as sodium bisulfite, sodium sulfite, sodium thiosulfate, butylated hydroxytoluene (antioxidant-264), butylated hydroxyanisole, citric acid, and vitamin E.

[0084] 13. The pharmaceutical composition of embodiment 12, comprising at least one pharmaceutically 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 siliconized microcrystalline cellulose, such as siliconized microcrystalline cellulose 50 (SMCC 50) and / or siliconized microcrystalline cellulose 90 (SMCC 90).

[0085] 14. A dosage unit comprising a solid form of Compound A of any one of embodiments 1-9 in an amount equal to the weight of the free base of Compound A 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.

[0086] 15. The dosage unit of embodiment 14, which is a tablet or a capsule.

[0087] 16. The dosage unit of embodiment 14 or embodiment 15, comprising Compound A-TA and one or more pharmaceutically acceptable excipients.

[0088] 17. The dosage unit of embodiment 16, wherein the one or more pharmaceutically acceptable excipients comprise one or more excipients selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, mannitol, polyvinylpyrrolidone (PVP), and sodium stearyl fumarate.

[0089] 18. The dosage unit of any one of embodiments 14-17, comprising at least one pharmaceutically acceptable excipient selected from the group consisting of siliconized microcrystalline cellulose 50, siliconized microcrystalline cellulose 90, pregelatinized starch, mannitol, croscarmellose sodium, polyvinylpyridone, and sodium stearyl fumarate.

[0090] 19. The dosage unit of 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.

[0091] 20. A packaged pharmaceutical product comprising a pharmaceutical composition comprising Compound A and a protective agent as two separate materials in a closed container.

[0092] 21. The packaged pharmaceutical product of embodiment 20, wherein the pharmaceutical composition comprises a dosage unit according to any one of embodiments 14-18.

[0093] 22. The packaged pharmaceutical product according to any one of embodiments 21-22, wherein the protective agent comprises at least one material selected from the group consisting of a desiccant, an antioxidant, an oxygen scavenger, and an inert gas.

[0094] 23. The packaged pharmaceutical product according to any one of embodiments 20-22, wherein the protective agent comprises at least one material selected from the group consisting of a molecular sieve, silica gel, and a fibrous desiccant.

[0095] 24. The packaged pharmaceutical product according to any one of embodiments 20-23, wherein the protective agent and the pharmaceutical composition are contained in a gas-tight container.

[0096] 25. The packaged pharmaceutical product according to embodiment 24, wherein the gas-tight container is a sealed bottle.

[0097] 26. A method of preparing the pharmaceutical composition of any one of embodiments 10-13, comprising combining the L-(+)-tartrate salt of Compound A with at least one pharmaceutically acceptable excipient.

[0098] 27. The method of embodiment 26, wherein the at least one pharmaceutically acceptable excipient comprises a filler, which is optionally selected from the group consisting of mannitol and microcrystalline cellulose.

[0099] 28. The method of embodiment 26 or 27, wherein the at least one pharmaceutically acceptable excipient comprises a disintegrant, which is optionally croscarmellose sodium.

[0100] 29. The method of any one of embodiments 26-28, wherein the at least one pharmaceutically acceptable excipient comprises a binder, which is optionally polyvinylpyrrolidone (PVP).

[0101] 30. The method of any one of embodiments 26-29, wherein the at least one pharmaceutically acceptable excipient comprises a lubricant, which is optionally sodium stearyl fumarate.

[0102] 31. The method of embodiment 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.

[0103] 32. The method of embodiment 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 granular mixture.

[0104] 33. A pharmaceutical composition comprising Compound A-TA prepared by the method of embodiment 26.

[0105] 34. The method of embodiment 31 or embodiment 32, wherein the mixture is blended in a wet granulator.

[0106] 35. A method of preparing the L-(+)-tartrate salt of Compound A, the method comprising contacting Compound A with L-(+)-tartaric acid in the presence of a solvent.

[0107] 36. A method of preparing a solid form of Compound A, the method comprising contacting Compound A with tartaric acid in a solvent.

[0108] 37. The method of embodiment 36, comprising contacting Compound A with L-(+)-tartaric acid in the presence of a solvent, under conditions in which the L-(+)-tartrate salt of Compound A precipitates from the solvent as a solid.

[0109] 38. The method of embodiment 37, wherein the solvent comprises water and an organic co-solvent.

[0110] 39. The method of embodiment 38, wherein the organic co-solvent is selected from the group consisting of acetone, isopropyl alcohol, ethanol and tetrahydrofuran.

[0111] 40. The method of embodiment 39, wherein the solid form of Compound A comprises Form I of the L-(+)-tartrate salt of Compound A.

[0112] 41. A method of synthesizing Compound A, or a pharmaceutically acceptable salt thereof, comprising reductive hydrogenation of Compound 1 to provide Compound 2:

[0113]

[0114] In this embodiment, the catalyst typically comprises palladium, platinum or nickel. Suitably, the catalyst can be a palladium catalyst, optionally on a carbon support.

[0115] 42. The method of embodiment 41, further comprising reacting Compound 2 with Compound 3 to provide Compound A:

[0116]

[0117] 43. The method of embodiment 42, further comprising contacting Compound A with L-(+)-tartaric acid to provide an L-(+)-tartaric acid salt of Compound A.

[0118] 44. A method of treating an immunological or cell proliferative disease, wherein the method comprises administering to a subject in need thereof a solid form of Compound A according to any one of embodiments 1-9, or a pharmaceutical composition thereof.

[0119] In embodiment 12, the pharmaceutical composition can comprise one or more excipients selected from the group consisting of fillers, disintegrants, binders, lubricants, and antioxidants. Some examples of embodiment 12 include fillers, which can be selected from the group consisting of mannitol, dextrose, and microcrystalline cellulose. In some such embodiments, the pharmaceutical composition comprises about 50-80% by weight of a filler. In one of these embodiments, the filler is a mixture of mannitol and microcrystalline cellulose. Some examples of embodiment 12 include disintegrants, which can be croscarmellose sodium. In some such embodiments, the pharmaceutical composition comprises about 1-8% by weight of a disintegrant, and in a preferred embodiment, it comprises about 2-5% by weight of a disintegrant. Some examples of embodiment 12 include lubricants, which can be selected from the group consisting of a salt of stearic acid and a salt of stearyl fumarate, particularly sodium stearyl fumarate. In some such embodiments, the pharmaceutical composition comprises about 0.5% to 2% by weight of a lubricant. In one of these embodiments, the lubricant is sodium stearyl fumarate. Some examples of embodiment 12 include binders, which can be PVP or cross-linked PVP. In some such embodiments, the pharmaceutical composition comprises about 0-5% by weight of a binder. In one of these embodiments, the binder is povidone K30, and the pharmaceutical composition comprises about 3% by weight of a binder. Compositions comprising the proportions (wt-%) of the materials listed in Table 4 are preferred embodiments. Compositions comprising the proportions (wt-%) of the materials listed in Table 5 are another preferred embodiment. These preferred embodiments include compositions in which the amount of any of the materials listed in Table 4 or Table 5 is within ±10% of the stated value.

[0120] In embodiments 26-32, the method of making the pharmaceutical composition can be a wet granulation method. 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 a percentage by weight of the composition. In this embodiment, "about" means that the percentage by weight of each component is the specified wt-% plus or minus 1 wt-%. In certain embodiments, the method of any one of embodiments 26-32 is performed using the proportions of materials in wt-% as set forth in the above formulation, and preferably using the proportions of materials in Table 4 or Table 5, wherein each listed proportion can optionally differ from the listed value by ±10% of the specified value. In one particular example, the process of any one of embodiments 26-32 comprises the following steps:

[0121] (a) mixing Compound A-TA, mannitol 25C, microcrystalline cellulose, and a portion of the croscarmellose sodium to form a first mixture;

[0122] (b) mixing the first mixture in a wet granulator;

[0123] (c) adding PVP dissolved in water to form a second mixture and mixing in the wet granulator;

[0124] (d) drying the second mixture to provide a third mixture;

[0125] (e) adding the remaining croscarmellose sodium and sodium stearyl fumarate to the third mixture and mixing to form a final mixture. The final mixture is suitable for filling into capsules to form a dosage unit of the application.

[0126] Preferred examples of the method of embodiment 26 are set forth in Examples 9 and 10, using the materials listed in Table 4.

[0127] In some embodiments, the solid form of Compound A-TA is crystalline polymorph Form I. Form I is characterized by an XRPD spectrum comprising one or more peaks (within experimental error) at 2Θ values 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 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 listed ones or within the error range of the listed ones. In some embodiments, polymorph I is characterized by an XRPD pattern substantially corresponding to Figure 1The XRPD pattern in Table 1. In view of common experimental variation, these peaks can be described as "about" a certain value, and the included variation can be ±0.2 2theta or ±0.12 2theta.

[0128] In some embodiments, polymorph Form I of the L-(+)-tartaric acid salt of Compound A-TA is extracted from a mixture of ethanol and water, or from a mixture of propanol and water, or from a mixture of methanol and water, or from a mixture of acetone and water. In some embodiments, polymorph 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 is 4:6, or is 9:1. In some embodiments, polymorph Form I is crystallized from methanol / water in a ratio of 7:3 (v / v). In some embodiments, polymorph Form I is crystallized from acetone / water in a ratio of 1:1, or 4:6, or 9:1.

[0129] Pharmaceutical ingredients

[0130] In one aspect, the present application provides pharmaceutical compositions and dosage units for oral administration. In addition to the pharmacological activity of the active pharmaceutical ingredient (API), several physical or physicochemical properties of the active substance are also relevant for the preparation of solid oral dosage forms (including oral powders, granules, pellets, tablets, capsules, chewable tablets, dispersible tablets, lozenges or troches). In order to achieve adequate formulation properties, such as correct assay, content and mass uniformity, chemical and physical stability of the drug product, and appropriate dissolution rates, the properties of the drug substance intermediate must also support robust manufacturing processes.

[0131] Thus, in some aspects, how suitable adequate formulation properties are achieved depends on the preparation and manufacturing process of the stable pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof in solid form.

[0132] In some embodiments, the pharmaceutical compositions described herein exhibit high stability of the solid form of Compound A or a pharmaceutically acceptable salt thereof under storage or under the stability test conditions described herein.

[0133] In some embodiments, the present application also relates to methods of preparing the pharmaceutical compositions. Such methods can include a wet granulation process. In some embodiments, the wet granulation process includes the following steps:

[0134] (a) mixing Compound A-TA, mannitol 25C, microcrystalline cellulose, and a portion of croscarmellose sodium (e.g., 80% of the total amount of the substance indicated) to form a first mixture;

[0135] (b) mixing the first mixture in a wet granulator;

[0136] (c) Add PVP dissolved in water to form a second mixture and mix in a wet granulator;

[0137] (d) The second mixture is dried to provide a third mixture, and optionally this mixture is ground into powder;

[0138] (e) The remaining croscarmellose sodium and stearoyl fumarate sodium are added to the third mixture and mixed to form the final mixture. The final mixture is suitable for filling capsules to form the dosage unit of the present invention.

[0139] In some embodiments, the pharmaceutical compositions of the present invention may include pharmaceutically acceptable additives in any suitable type of unit dosage form. Therefore, in some embodiments, the pharmaceutical compositions further comprise at least one pharmaceutically acceptable additive. Suitable additives include, but are not limited to, diluents, binders, mediators, carriers, excipients, adhesives, disintegrants, lubricants, swelling agents, solubilizers, wicking agents, coolants, preservatives, stabilizers, sweeteners, flavorings, and polymers. Although this disclosure contemplates any pharmaceutically acceptable additive, it should be understood that the selection of additives for use in combination with compound A or its pharmaceutically acceptable salts should not compromise the stability objectives of the present invention.

[0140] Examples of disintegrants include, but are not limited to, cross-linked sodium carboxymethyl cellulose, and cross-linked sodium carboxymethyl cellulose (e.g., sodium carboxymethyl cellulose). ), 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 crospovidone sodium (e.g., crospovidone). ).

[0141] Examples of lubricants include, but are not limited to, magnesium stearate, stearic acid or its pharmaceutically acceptable alkali metal salt, sodium stearoyl fumarate, polyethylene glycol (e.g., Macrogol 6000) (particularly in granular or sheet formulations to reduce friction with molds), glyceryl docosanoate, talc, colloidal or fumed silica and silica derivatives (e.g., Cab-O-Sil, ...). 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, which is mixed with other components in the granulation and granulation. Another portion of the lubricant may be added to the final blend material prior to compression or encapsulation, encapsulating the external coating of particles in the final formulation. In some embodiments, the pharmaceutical composition further comprises a disintegrant and a lubricant. In some embodiments, the lubricant is sodium stearoyl fumarate. In some embodiments, the pharmaceutical composition comprises about 0.05% (w / w) to about 5% (w / w) of sodium stearoyl fumarate.

[0142] The oral pharmaceutical compositions described herein can generally be present in the form of single or multiple unit dosage forms, such as tablets, caplets, powders, suspensions, chewable tablets, fast-dissolving tablets, capsules, such as single or double shell gelatin capsules, tablet- filled capsules, effervescent powders, effervescent tablets, pills, granules, liquids, solutions or suspensions. In some embodiments, the pharmaceutical compositions are formulated into oral dosage forms or solid oral dosage forms. In some embodiments, the oral dosage form is an oral powder, granule, pill, tablet, capsule, lozenge or troche. In some embodiments, the tablet is a chewable tablet, dispersible tablet or lozenge. In some embodiments, the pharmaceutical compositions are formulated to contain 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 the free base equivalent of Compound A. In some embodiments, the active ingredient (e.g., Compound A or a pharmaceutically acceptable salt thereof, such as 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 30-40% (w / w). For salt forms, the concentration is expressed as the free base equivalent of the salt form.

[0143] While the disclosed solid forms of Compound A-TA exhibit high chemical and polymorphic stability, pharmaceutical compositions comprising Compound A or Compound A-TA can undergo oxidation upon storage in the presence of moisture and / or oxygen, under prolonged storage conditions. Data on the stability of selected pharmaceutical compositions of Compound A-TA are provided in the table below, which shows the slow formation of Impurity B, an oxidation product, during storage at high temperature, and a reduced rate of formation of this impurity when an oxygen scavenger (Deoxidizer CD20) is present. CD20, also known as Deoxidizer CD20.

[0144] Table 1. Comparison of impurity profiles for formulations in Table 4 (see below) and Table 5 (see below) stored with and without oxygen scavenger:

[0145]

[0146] *Both formulations used the same batch of Compound A-TA, the stability of which is compared in Table 1.

[0147] Formulation 4 in Table 1 refers to the formulation material prepared from the ingredients and proportions shown in Table 4, and was tested together with the formulated pharmaceutical composition in and without an oxygen absorber in the storage container. Formulation 5 is the formulation material prepared using the ingredients and proportions shown in Table 5. As shown in Table 1 above, the materials were stored at 60°C or 40°C for 6 months to test stability. Two formulations (Formulation 4 and Formulation 5) were prepared using the same batch of compounds A-TA. It was found that the content of impurity B, an oxidized derivative of compound A, was lowest when the formulated pharmaceutical composition was stored in a container in the presence of an oxygen absorber (oxygen absorber CD20). Therefore, packaging pharmaceutical compositions containing compounds A-TA in the presence of an oxygen absorber reduces the formation of at least one impurity during long-term storage.

[0148] Therefore, in some embodiments, the pharmaceutical composition comprising compound A-TA is stored under conditions that minimize exposure to oxygen, moisture, or both. In some embodiments, the pharmaceutical composition is stored in the presence of a protective agent, or packaged with a protective agent, or may be stored in an inert atmosphere, or may be film-coated. Suitable protective agents for this purpose include the following desiccants and oxygen absorbers:

[0149] Desiccants, including but not limited to typical desiccants, such as:

[0150] 1) Silica gel desiccant, such as activated silica gel;

[0151] 2) Molecular sieve desiccant - a synthetic zeolite with strong absorption of water molecules. The pore size of the molecular sieve material allows for the passage of water molecules.

[0152] They can be controlled by different processing techniques, so in addition to adsorbing water vapor, they can also adsorb other gases.

[0153] 3) Fiber desiccant.

[0154] Oxygen absorbers, including oxygen absorption products known in the art, such as iron-containing oxygen absorber canisters, and commercially available oxygen absorbers. The cans, manufactured by Mitsubishi Gas Chemical Co., Ltd., include CD20, CD10, KD10, and KD20, which are designed for use in pharmaceuticals.

[0155] As is known in the art, some oxygen absorbents can be used in combination with desiccants, such as molecular sieves and / or activated silica gel.

[0156] Other methods of reducing oxidation of Compound A-TA in the pharmaceutical compositions of the disclosure include adding one or more antioxidants to the formulated pharmaceutical composition, such as sodium bisulfite, sodium sulfite, sodium thiosulfate, sodium metabisulfite, butylated hydroxyanisole (BHA), antioxidant-264 (BHT), vitamin E, and the like; or maintaining the pharmaceutical composition in an inert gas atmosphere that is substantially free of oxygen and / or moisture, such as dry nitrogen or argon.

[0157] Separately packaged oxygen absorbers can be effective in reducing the amount of oxygen in the package and preventing the product from being oxidized during long-term storage. Many suitable oxygen absorber products are known in the art, for example, iron-containing deoxidizing cans can be used. Other examples include oxygen-absorbing cans manufactured by Mitsubishi Gas Chemical Company, including CD20, CD10, KD10, and KD20, which are designed for pharmaceuticals. Oxygen absorbers can be used in combination with desiccants, such as molecular sieves and / or activated silica gel. Table 2 shows that the impurity profile can be improved by placing CD20 oxygen absorbers in containers containing pharmaceutical compositions comprising Compound A-TA during stability testing at high temperature (40°C).

[0158] After encapsulation as described herein, Compound A-TA has high stability when stored in opaque HDPE bottles with conventional LDPE caps in the presence of an effective deoxidizer, such as CD20, when stored for up to 6 months at 40°C and 75% relative humidity, or for up to 24 months at 25°C and 60% relative humidity.

[0159] Accordingly, in some embodiments, capsules or tablets comprising Compound A-TA are packaged within an opaque high-density polyethylene (HDPE) bottle and capped with an opaque high-density polyethylene (HDPE) or low-density polyethylene (LDPE) cap. Optionally, the bottle further comprises a protective agent, such as silica gel or activated charcoal or activated zeolite desiccant; and optionally, the bottle further comprises a deoxidizer, such as a deoxidizing can product such as CD10, CD20, KD10, or KD20. In some embodiments, the protective agent is contained within a can, pouch, envelope, or similar container within the bottle to prevent direct contact of the protective agent with the pharmaceutical composition, while allowing the protective agent to be exposed to any oxygen within the interior of the bottle.

[0160] In some embodiments, the bottle containing capsules or tablets comprising Compound A-TA comprises an oxygen-capturing agent, such as iron powder, catechol, calcium, ascorbic acid, or calcium oxide in a container such as a vented plastic can, using methods and products known in the art to protect the drug. In some embodiments, the oxygen-capturing agent is​ A product or StabilOx product, which can be a sachet or a canister containing proprietary oxygen-capturing material and optionally further comprising a desiccant. Thus, in some embodiments, the present application provides a packaged pharmaceutical product comprising a pharmaceutical composition comprising Compound A-TA and a protective agent, which can be a desiccant, an antioxidant, an oxygen scavenger or an opaque coating, and also an inert gas for displacing air in a vial or other container used for packaging the pharmaceutical product. In some embodiments, the pharmaceutical composition, e.g., a capsule or tablet, in dosage unit form of Compound A-TA, is packaged in a vial and the protective agent is packaged separately in the same vial, preferably substantially air-tight. In some of these embodiments, a deoxidizing agent within a canister is added to the vial along with the pharmaceutical composition. Alternatively, the deoxidizing agent is selected from the group consisting of CD and KD products, e.g., CD10 and KD10 and CD20 and KD20, manufactured by Mitsubishi A product in the StabilOx® product line, which products are designed for pharmaceutical use and provide protection for the composition.

[0161] In some embodiments, a pharmaceutical composition comprising Compound A-TA, optionally in dosage unit form of Compound A-TA, is packaged in a sealed bag, box, tub or other container and is protected by an inert gas, e.g., dry nitrogen or argon.

[0162] The present methods can be used for any suitable purpose. In some embodiments, the methods of the present application are used to treat and / or prevent a proliferative disease, a cancer, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye or an immunologically related disease or lupus in a subject. The present methods can be used to treat and / or prevent any suitable proliferative disease. Exemplary proliferative diseases 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 the solid forms of Compound A-TA, pharmaceutical compositions and dosage units comprising these solid forms for treating a disorder selected from the group consisting of lupus, rheumatoid arthritis, chronic myelogenous leukemia and chronic lymphocytic leukemia.

[0163] Examples

[0164] Exemplary chemical entities, pharmaceutical compositions, and methods of making such compounds and compositions will now be described with reference to the following specific examples. The skilled artisan will recognize that, for chemical synthesis, starting materials can be appropriately selected so as to carry the ultimately desired substituents through the reaction scheme, with or without appropriate protection as necessary. Alternatively, it can be necessary or desirable to employ appropriate functional group interconversions in order to carry the ultimately desired substituents through the reaction scheme. In addition, the skilled artisan will recognize that the transformations shown in the following examples can be performed in any order that is compatible with the functionality of particular side groups. Each reaction in the general scheme is preferably conducted at a temperature from about 0 °C to the reflux temperature of the organic solvent(s) used. Some of the reactions described in the examples provided below are conducted at a temperature from about -10 °C to about 100 °C. With respect to the pharmaceutical composition examples, the skilled artisan will recognize that variations of the following examples can be appropriate.

[0165] The embodiments described herein are provided only to illustrate representative embodiments of the application. Thus, it should be understood that the application is not limited to the particular conditions or details described in these or any other examples discussed herein, and that the examples should not be construed as limiting the scope of the application in any way. Throughout this specification, any and all references to a patent or application, or patent or application publication are hereby incorporated by reference in their entirety.

[0166] The following abbreviations can 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-butanol; THF = tetrahydrofuran. The abbreviations used herein have their normally understood meaning in the art, unless otherwise indicated.

[0167] Compound A was synthesized by three different methods.

[0168] Strategy / Routel: 1

[0169]

[0170] This synthetic strategy / route 1 is acceptable for small-scale synthesis, especially in the early stages of drug discovery (e.g., SAR studies / targeted library synthesis) because structural diversity can be achieved through the use of various 2-Cl-pyrimidines 2 and aromatic amines 3 in the synthesis. In this strategy, key intermediates 2 and 3 are coupled via a Pd-catalyzed CN coupling reaction, followed by reduction and acylation to obtain the target compound 6. A drawback of this synthesis is that the acylation reaction in the final step is often affected by other NH groups in the molecule, leading to undesirable byproducts (impurities). To overcome this drawback, we decided to modify this synthetic strategy / route by performing an acylation reaction prior to the coupling reaction (see Strategy / Route 2).

[0171] Strategy / Routel: 2

[0172]

[0173] In strategy / route 2, we perform the acylation reaction prior to the coupling reaction, and there are no other NH groups in the molecule, which avoids the side acylation reaction that might occur in synthetic strategy / route 1. Furthermore, the acrylamide group was found to be very stable in the final coupling reaction.

[0174] Strategy / Routel: 3

[0175]

[0176] In strategy / route 3, the synthesis efficiency of 2-Cl-pyrimidine 4 was further improved by using the inexpensive starting material 3-aminophenol instead of 3-nitrophenol (eliminating the reduction reaction). The acylation reaction between 3-aminophenol and acryloyl chloride was found to be a highly preferred option.

[0177] In addition, during the process development, starting materials 2-Cl-pyrimidine 4 with different purities were explored. The results showed that different batches of 2-Cl-pyrimidine 4 with a purity range of 97.8–99.2% could all yield product 9 (compound A) that met the acceptance criteria.

[0178] Based on the test results of the three synthetic strategies, route 3 was used to prepare batches of compound A for the compositions and experiments described herein, as the final synthetic strategy / pathway for synthesizing the free base of compound A.

[0179] The synthetic route starts with commercially available (S) tert-butyl 3- aminopyrrolidine-1 -carboxylate 1 with an ee% (enantiomeric purity) of at least 98.5%. All reactions were performed under mild conditions with moderate to excellent yields. Most importantly, the entire process resulted in the preservation of the stereochemistry in the final product Compound A free base. Therefore, this synthetic route was chosen for further development and scale-up.

[0180] After finalizing the synthetic route, the reaction conditions were optimized for each step of the synthesis and the production scale was gradually expanded to more than 5 kg.

[0181] Example 1. Synthesis of starting material (8).

[0182]

[0183] Step 1: Synthesis of N-(3-hydroxyphenyl)acrylamide (12)

[0184] A set of 30 L jacketed reactors 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 reactor under mechanical stirring. When the internal temperature of the reactor reached about -10 °C, acryloyl chloride (2 kg, 22.1 mol) was added dropwise to the reactor. 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 this point, a TLC analysis (ethyl acetate / petroleum ether / acetic acid = 2 / 1 / 0.1 as mobile phase) of the reaction in progress was performed to confirm the completion of the reaction. Water (10 L) was then slowly added to quench the reaction. The mixture was concentrated under reduced pressure to remove THF. 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 there was no compound 12 in the aqueous layer (by TLC). The organic layers were combined and washed with water (3 L x 3).

[0185] The extraction-washing process was repeated twice more to maximize the recovery of compound 12 from the upper aqueous layer. 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 left 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 min. The solid product was collected and dried under vacuum to give compound 12 (2.1 kg, 60% yield) as a white solid.

[0186] Step 2: Synthesis of N-(3-((2-chloro-5-methoxy pyrimidin-4-yl)oxy)phenyl)acrylamide (8)

[0187] DMF (15 L) was charged in a reactor fitted with a heater set at 75 °C. Compound 12 (3.05 kg, 18.7 mol), 2,4-dichloro-5-methoxymidazole (3.3 kg, 18.4 mol) and K2CO3 (3.85 kg, 27.9 mol) were then added under mechanical stirring. When the internal temperature reached 70 °C, the mixture was stirred for a further 4-4.5 h. At this point, TLC analysis in progress (ethyl acetate / petroleum ether / triethylamine = 2 / 2 / 0.1 as mobile phase) indicated that 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, washed with water (about 4 L) until the aqueous layer was neutral, and then dried to obtain crude 8.

[0188] Further purification was carried out by mixing the crude product 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 obtain compound 8 (4.79 kg, yield 85%) as a white solid.

[0189] Example 2. Synthesis of Compound A

[0190] Step 1: Synthesis of (S)-tert-butyl 3-((4-nitrophenyl)amino)pyrrolidine-1-carboxylate

[0191]

[0192] (S)-3-Aminopyrrolidine-1-carboxylic acid tert-butyl ester 1 (5.996 kg, 32.19 mol), 1-fluoro-4-nitrobenzene 2 (4.622 kg, 32.75 mol), DMSO (19.8 L) and triethylamine (4.840 kg, 47.83 mol) were charged in a 50 L reactor fitted with a condenser. The reaction mixture was then heated with a water bath (90-95 °C) and stirred for 12 h (during which the internal temperature was maintained between 85-95 °C). At this point, TLC analysis in progress (ethyl acetate / petroleum ether = 1 / 2 as mobile phase) indicated that the reaction was complete. The reaction mixture was then cooled to room temperature. The resulting solution was slowly transferred to a reactor containing ice water (60 L), forming a dense precipitate. The resulting slurry was vigorously stirred for 2 h. The yellow precipitate was then filtered, washed with water (12 L x 2) and dried at 40-45 °C to obtain compound 3 (9.6 kg, HPLC purity 97.09%, yield 96.96%) as a yellow solid, which was used in the next reaction without further purification.

[0193] Step 2: (S)-tert-butyl 3-(methyl(4-nitrophenyl)amino)pyrrolidine-1-carboxylate (4)

[0194]

[0195] Compound 3 (9.6 kg, 31.23 mol) and DMF (48 L) were charged in a 100 L reactor and stirred. After complete dissolution of compound 3, the resulting yellow solution was cooled to and NaH (60%, 1.876 kg, 46.90 mol) was added slowly (in portions, maintaining the internal temperature of the reactor between The reaction mixture was stirred for 15 min and then CH3I (5.326 kg, 37.52 mol) was added slowly, maintaining the internal temperature between Once the addition was complete, the cooling was removed and the mixture was stirred for 1 h. At this point, the ongoing TLC analysis (ethyl acetate / petroleum ether = 1 / 6 as mobile phase) indicated that the reaction was complete. Then, cold water (12 L) was added to quench the reaction and the reaction mixture was stirred for another 1 h.

[0196] Extraction with ethyl acetate: The reaction mixture was divided into three approximately equal portions. To one portion of the reaction mixture in a 100 L reactor, 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 For the other two portions of the reaction mixture, the same procedure was repeated. The combined filtrates (organic layer) were concentrated under reduced pressure. The resulting solid was further dried to obtain compound 4 (10.080 kg, HPLC purity 97.17%, yield 100.12%) as a brown solid, which was used for the next reaction without further purification.

[0197] Step 3: Synthesis of (S)-N-methyl-N-(4-nitrophenyl)pyrrolidin-3-amine hydrochloride (5)

[0198]

[0199] Compound 4 (10.045 kg, 31.26 mol), methanol (10 L) and dichloromethane (10 L) were charged in a 100 L reactor. The reaction mixture was stirred at a rate of until compound 4 was completely dissolved. The resulting yellow solution was cooled to HCl / MeOH (8 M, 20 L) was added slowly under stirring. Once the addition was complete, the reaction mixture was stirred at this temperature for another 0.5 h. The cooling system was removed, the reaction mixture was allowed to warm up to room temperature and stirring was continued for another 16.5 h (precipitate formed). At this point, the ongoing TLC analysis (ethyl acetate / petroleum ether = 1 / 1 as mobile phase) indicated that the reaction was complete. Then, the suspension was re-cooled to The resulting precipitate was collected, washed with ethyl acetate (3 L x 2) and dried at The reaction mixture was stirred for 1 hour at 25 °C. The reaction mixture was concentrated under reduced pressure. The residue was dissolved 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 was stirred vigorously for 1 hour, suspended in heptane / ethyl acetate (v / v = 1 : 1, 24 L). 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% HPLC purity, 89.25% yield) as a yellow powder, which was used in the next step without further purification.

[0200] Step 4: Synthesis of (S)-1-(3-(methyl(4-nitrophenyl)amino)pyrrolidin-1-yl)ethanone (6)

[0201]

[0202] Et3N triethylamine (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 °C. Acetyl chloride (2.590 kg, 32.99 mol) was then added dropwise while maintaining the reaction temperature below 5 °C with stirring. Once the addition was complete, the reaction mixture was stirred at this temperature for a further 0.5 hours. At this point, in-process TLC analysis (ethyl acetate as the mobile phase) indicated that the reaction had gone to completion. 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 was stirred vigorously for 1 hour, suspended in heptane / ethyl acetate (v / v = 1 : 1, 24 L). 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% HPLC purity, 89.25% yield) as a yellow powder, which was used in the next step without further purification.

[0203] Step 5: Synthesis of (S)-1-(3-((4-aminophenyl)(methyl)amino)pyrrolidin-1-yl)ethanone (7)

[0204]

[0205] 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 added to a 100 L reactor. The reactor was purged of air by a stream of nitrogen. Hydrogen pressure was applied at atmospheric pressure by bubbling. The hydrogen flow was controlled to maintain the internal temperature between 20 and 25 °C. The reaction mixture was stirred for 48 hours. At this point, in-process TLC analysis (dichloromethane / methanol = 15:1 as the mobile phase) indicated that the reaction had gone to completion. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to give compound 7 (5.498 kg, 98.00% HPLC purity, 96.6% yield) as a black oil, which was used in the next step without further purification. ​

[0206] Step 6: Synthesis of (S)-N-(3-((2-((4-((1-acetylpiperidin-3-yl)(methyl)amino)phenyl)amino)-5- methoxypyrimidin-4-yl)oxy)phenyl)acrylamide (9: Compound A-TA) Process for removing palladium with TMT (s-triazine-2,4,6-trithiol; 1,3,5-triazine-2,4,6-trithiol).

[0207]

[0208] Tert-butanol (16 L) was added to a 30 L jacketed reactor under mechanical stirring at 110 rpm. Compound 7 (975.0 g, 4.18 mol) and compound 8 1 (1277.5 g, 4.18 mol, synthesized separately) were added. The reaction mixture was stirred for 5-10 minutes. 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 under stirring. The air in the reactor was removed by a stream of nitrogen. Hot water was applied through the jacket The reactor was heated. The reaction mixture was stirred for 7 hours, during which the reaction temperature was maintained between At this time, ongoing HPLC analysis indicated less than 5% of compound 7 unreacted. The mixture was then cooled to 50 °C, filtered through a mixture of silica gel (2 kg) and (2 kg) and washed with ethyl acetate (8 L). The combined filtrates were concentrated under reduced pressure to give crude 9.

[0209] The crude product was re-dissolved in ethyl acetate (20 L) and transferred to a 50 L reactor. The resulting solution was washed with brine (12 L x 3). The lower layer was removed. The organic layer was dried over anhydrous Na2S04(2 kg), filtered and concentrated under reduced pressure to a residual volume of about 5 L. The resulting solution was cooled to room temperature and left under stirring overnight. A precipitate formed, which was an off-white solid. The precipitate was collected and vacuum dried to give a second crude product (1300 g, HPLC purity of 96.4%, yield of 61.9%), which was sealed to avoid light and stored in a dry place at room temperature for the next step to remove the heavy metal palladium.

[0210] Three portions of the second crude product of compound 9 synthesized were combined for further treatment to remove the palladium heavy metal.

[0211] Example 3. Synthesis of Compound A-TA as crystalline dihydrate

[0212] The second crude product (2950 g, 5.88 mol) was added to a 100 L reactor 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 ( (295g). The resulting suspension was stirred at room temperature for 48 hours, and then... Filter and wash with ethanol (5.4 L). The combined filtrates were concentrated under reduced pressure. The resulting residue was redissolved in dichloromethane (29.5 L). The solution was washed with dilute ammonia (1.5–2.0%, 5.4 L) and water (13 L × 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, approximately 4.5 L remaining). Ethyl acetate (27 L) was slowly added. The precipitate was collected (similar to recrystallization) and dried under vacuum to give the final desired product 9 (2398 g, HPLC purity 98.91%, yield of the second crude product from compound 9, 81.3%) as a grayish-white solid.

[0213] Synthesis of (S)-N-(3-((2-((4-((1-acetylpiperidin-3-yl)(methyl)amino)phenyl)amino)-5- methoxypyrimidin-4-yl)oxy)phenyl)acrylamide L-(+)-tartaric acid dihydrate (10, Compound A-TA).

[0214] Figure 4 Figure 5

[0215]

[0216] Three batches of compound 9 (compound A) were combined for this process step.

[0217] Compound 9 (5918 g, approximately 98.7% purity) was dissolved in dichloromethane (60 L) at 25 °C. The solution was concentrated under reduced pressure at 40 °C to remove approximately 55 L of dichloromethane. Ethyl acetate (30 L) was slowly added with stirring. The mixture was cooled to approximately 20 °C to crystallize. The resulting crystals were collected, washed with cold ethyl acetate (10 L), and dried overnight under vacuum at 45 °C to obtain a grayish-white powder of compound 9 (4950 g) with an HPLC purity of 99.19%, which was used in the salt formation step.

[0218] A 100-liter reactor was charged with acetone (30 liters) and water (3.5 liters). A purified sample of compound 9 (free base, 4.7 kg, 9.36 mol) was added with stirring, followed by washing with acetone (12.3 L). The resulting suspension was stirred vigorously at 45 °C until compound 9 was completely dissolved (approximately 1.5 h). Then, a solution of L-(+)-tartaric acid (1.471 kg, 9.8 mol) in water (1.2 L) was slowly added with stirring. The solution was cooled to room temperature, and stirring was continued 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 ground and sieved to a size of 60 mesh and air-dried at room temperature to provide the desired product 10 (compound A-TA) as an orange powder (5.8 kg, 99.3% HPLC purity, 90.0% yield).

[0219] Infrared spectrum (IR)

[0220] Hydroxyl stretching vibration absorption peaks appear at 3420 cm -1 -1. Amines stretching vibration absorption peaks appear at 3302 cm -1 -1. Alkyl stretching vibration absorption peaks appear at 2822, 2892, 2953, 3047 and 3117 cm -1 -1. Stretching vibration absorption peaks of the ammonium group (NH + ) appear at 2310 and 2345 cm -1 -1. Bending vibration absorption peaks of the ammonium group (NH + ) appear at 1956 cm -1 -1. Stretching vibration absorption peaks of the carbonyl in the carboxylic acid moiety appear at 1723 and 1610 cm -1 -1. Stretching vibration absorption peaks of the carbonyl in the amide moiety appear at 1660 cm -1 -1. Bending vibration absorption peaks of the amine group in the amide moiety appear at 1520 cm -1 -1. Stretching vibration absorption peaks of the C-N bond in the amide moiety appear at 1266 cm -1 -1. Skeleton vibration absorption peaks of benzene appear at 1433, 1461 and 1539 cm -1 -1. Stretching vibration absorption peaks of the alkyl aryl ether appear at 1227 cm -1 -1. Stretching vibration absorption peaks of the diaryl ether appear at 1203 cm -1

[0221] Ultraviolet spectrum

[0222] See the table of ultraviolet absorption data and analysis.

[0223] (1) Sample preparation: Prepare the sample in solution at the specified concentration and place in a 1.00-cm cell.

[0224] (2) Wavelength:

[0225] (3) Solvent: Methanol, 0.1 M aqueous HC1, 0.1 M aqueous NaOH.

[0226] (4) Concentration: 3.3 x 10 -5 M.

[0227] Ultraviolet spectrum: Measure the sample in methanol, 0.1 M aqueous HC1, and 0.1 M aqueous NaOH. The measurement range is 200-400 nm.

[0228] Table 2: Ultraviolet absorption data and analysis. ​

[0229]

[0230] The UV spectrum (F, NMR and Figure 6 ) is shown below.

[0231] The two maximum absorption values (λ max ) of the sample in neutral solvent (methanol) were 204.6 nm (ε = 4.62 x 10 4 ) and 280.2 nm (ε = 3.58 x 10 4 ). The absorption at 204.6 nm was identified as n-σ* transition of heteroatom, while the absorption at 280.2 nm was identified as K absorption band of the sample caused by π-π* transition of conjugated double bonds in benzene ring. In acidic solvent, λ max of K absorption band of conjugated system was at 268.6 nm (ε = 3.00 x 10 4 ). In basic solvent, λ max of K absorption band of conjugated system was at 277.0 nm (ε = 3.20 x 10 4 ).

[0232] X-ray powder diffraction

[0233] Solvent: DMSO-d6; Internal standard: trimethylsilyl propionate (TSP). 1 The H-NMR spectrum is shown in Figure 7 .

[0234] Figure 8

[0235] Test conditions: power 40 kV x 250 mA, Cu Kα radiation

[0236] Scanning mode: straight line scanning, step: 0.02°, scanning area (2θ): 3°-40°, scanning speed: 5° / min.

[0237] The X-ray powder diffraction pattern is shown in the figure.

[0238] Thermogravimetric analysis

[0239] Purge gas: N2 120 mL / min, temperature rise rate: 10°C / min

[0240] Temperature range: from room temperature to 280°C

[0241] The TGA curve is shown in Dosage form selection .

[0242] Differential thermal analysis

[0243] Purge gas: N2 50 mL / min, Temperature ramp rate: 10 °C / min

[0244] Temperature range: from room temperature to 200 °C

[0245] DSC curve is shown in Process selection

[0246] Various conditions were tested in an attempt to produce a crystalline form and to identify a useful polymorph of Compound A-TA. Table 3 briefly summarizes the conditions for preparing polymorphs and the results obtained.

[0247] Table 3: Summary of conditions for polymorph formation of Compound A-TA.

[0248]

[0249]

[0250] Physico-chemical properties : An oral immediate release capsule formulation is disclosed herein. One embodiment is 25 mg / capsule (equivalent free base) in a HPMC #2 capsule shell. Alternatively, the drug load can be increased by using larger capsules, such that each dosage unit can contain, for example, 50 mg / capsule or 100 mg / capsule (equivalent free base).

[0251] Example 4. Capsules containing Compound A-TA prepared by wet granulation. : Compound A-TA is a drug associated with two water molecules. To prevent dehydration that can occur at higher manufacturing process temperatures (e.g., drying process used for wet granulation in tablet manufacturing), a direct mix capsule fill manufacturing process is employed. To protect the stability of the drug composition before and after capsule formation, the process including the capsule fill and storage steps is preferably conducted under mild conditions, e.g., temperature less than about 30 °C, relative humidity less than about 60%, preferably less than about 45%.

[0252] Excipient selection: The excipients used in Compound A-TA capsules are common excipients that can be found in the FDA's Inactive Ingredient Database (IID).

[0253] Figure 9

[0254] ​The drug 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 is almost insoluble at higher pH and the solubility increases dramatically at lower pH. To enhance absorption and bioavailability, the tartrate salt (Compound A-TA) was prepared to enhance the solubility of the molecule in the compositions intended for oral administration. Capsules containing Compound A-TA have good dissolution (release >85% in 30 minutes) and bioavailability of 20-39% in dog PK testing using HPMC capsules.

[0255] Example 5. Tablets containing Compound A-TA prepared by wet granulation.

[0256] Compound A-TA drug product was prepared as an oral capsule containing 25 mg of Compound A free base, which is equivalent to 34.26 mg of the tartrate salt (Compound A-TA). The capsule also contains 32.00 mg SMCC50 (Silicified Microcrystalline Cellulose), 89.74 mg SMCC90 (Silicified Microcrystalline Cellulose), 3.20 mg croscarmellose sodium and 0.80 mg sodium stearyl fumarate The total weight of one capsule is 160 mg, using HPMC capsule shells of size #2 with light blue opaque cap and white opaque body. Compound A-TA capsules are packaged in high density polyethylene (HDPE) bottles with a low density polyethylene (LDPE) bottle cap with a desiccant.

[0257] A flow chart summarizing the process is shown in Figure 10 .

[0258] Table 4. Materials used for the wet granulation process

[0259]

[0260] Compound A-TA was wet granulated according to the ingredient list in Table 4, following the steps below:

[0261] a. The internal granulation materials (Compound A-TA, mannitol 25C, microcrystalline cellulose PH101) were weighed and sieved through a 40 mesh sieve.

[0262] b. The internal granulation materials (excluding povidone K30) were mixed in the wet granulator for 5-10 minutes to obtain a #1 mix in the wet granulator.

[0263] c. Povidone PK30 dissolved in water was added to the #1 mix in the wet granulator and processed for 5-10 minutes to obtain a #2 mix.

[0264] d. Dry #2 mixture in fluid bed at about 60 °C for 30-60 minutes to obtain #3 mixture.

[0265] e. Dry #3 mixture in a comminuter for 10 minutes to obtain #4 mixture.

[0266] f. Weigh additional granulating materials, sodium croscarmellose and sodium stearyl fumarate, and sieve them through a 40 mesh sieve. Add them to #4 mixture and mix for 10-20 minutes to obtain #5 mixture.

[0267] g. Fill #5 mixture into capsules, the capsule shells are made of HPMC, Vcap plus.

[0268] h. Pack in HDPE bottles (with molecular sieve drier and deoxidizer).

[0269] Example 6. Capsules containing Compound A-TA prepared by direct mixing.

[0270] Prepare tablets of dosage unit of Compound A-TA using the same ingredients and proportions shown in Table 4 by following the processing steps:

[0271] a. Weigh the internal granulating materials (Compound A-TA, mannitol 25C, microcrystalline cellulose PH101) and sieve them through a 40 mesh sieve.

[0272] b. Mix the internal granulating materials (excluding povidone K30) in a wet granulator for 5-10 minutes to obtain #1 mixture in the wet granulator.

[0273] c. Add povidone PK30 dissolved in water to #1 mixture in the wet granulator and process for 5-10 minutes to obtain #2 mixture.

[0274] d. Dry #2 mixture in fluid bed at about 60 °C for 30-60 minutes to obtain #3 mixture.

[0275] e. Dry #3 mixture in a comminuter for 10 minutes to obtain #4 mixture.

[0276] f. Weigh additional granulating materials, sodium croscarmellose and sodium stearyl fumarate, and sieve them through a 40 mesh sieve. Add them to #4 mixture and mix for 10-20 minutes to obtain #5 mixture.

[0277] g. Compress #5 mixture in a tablet press to obtain uncoated #1 tablets.

[0278] h. Coat #1 tablets with OPADRY 03B120001.

[0279] i. Packaged in HDPE bottles (with molecular sieve desiccant and deoxidizer).

[0280] Figure 11 A flow diagram of the process is shown.

[0281] Example 7. Tablets containing Compound A-TA prepared by direct mixing.

[0282]

[0283] Table 5. Ingredients and amounts used to prepare capsules by direct mixing.

[0284] Table 5 lists the excipients and amounts of materials for another formulation containing Compound A-TA. Using the materials in Table 5 and the direct mixing process, capsules are prepared by the following steps:

[0285] a. Prepare and weigh the drug substance and all excipients.

[0286] b. Mix the Compound A-TA drug substance with SMCC90 and SMCC50. Sieve the mixture through a 40 mesh sieve to obtain a #1 mixture.

[0287] c. Mix the #1 mixture with crosscarmellose sodium (Vivasol) and mix for 18-22 minutes to obtain a #2 mixture.

[0288] d. Sieve the #2 mixture and sodium stearyl fumarate (Pruv) together and mix for 3-7 minutes to obtain the final granular product.

[0289] e. Capsule fill.

[0290] f. Packaged in HDPE bottles.

[0291] Figure 12 A flow diagram of the process is provided.

[0292] ​

[0293] Tablets are produced using the excipients and amounts of materials shown in Table 5 by the following steps:

[0294] (a) Preparation and weighing of the drug substance and all excipients.

[0295] (b) Mix the Compound A-TA drug substance with SMCC90, SMCC50. Sieve the mixture through a 40 mesh sieve to obtain a #1 mixture.

[0296] (c) Mix the #1 mixture with crosscarmellose sodium (Vivasol) and mix for 18-22 minutes to obtain a #2 mixture.

[0297] (d) Sieve #2 mixture and sodium stearyl fumarate (Pruv) together and mix for 3-7 minutes to obtain final granules.

[0298] (e) Compress in a tablet press to obtain uncoated #1 tablets.

[0299] (f) Coat #1 tablets with OPADRY 03B120001.

[0300] Packaged in HDPE bottles containing molecular sieve desiccant and oxygen absorber.

[0301] ​ A flow diagram of the process is provided.

Claims

1. A solid form of Compound A: which is a dihydrate crystal of a 1 : 1 salt of Compound A and L-(+)-tartaric acid, characterized by its X-ray powder diffraction pattern comprising the following characteristic peaks, in terms of 2 theta, 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°; wherein the "about" indicates a variation of ± 0.2° in 2 theta.

2. The solid form according to claim 1, having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 74 °C.

3. The solid form according to claim 1, having a thermogravimetric analysis (TGA) substantially as shown in Figure 7.

4. A pharmaceutical composition comprising the solid form of Compound A according to any one of claims 1 to 3, in admixture with at least one pharmaceutically acceptable excipient.

5. The pharmaceutical composition according to claim 4, comprising at least two pharmaceutically acceptable excipients.

6. The pharmaceutical composition according to claim 4 or 5, comprising at least one pharmaceutically acceptable excipient selected from the group consisting of fillers, disintegrants, glidants, binders, lubricants and antioxidants selected from the group consisting of sodium bisulfite, sodium sulfite, sodium thiosulfate, butylated hydroxytoluene, butylated hydroxyanisole, citric acid and vitamin E.

7. The pharmaceutical composition according to claim 6, comprising at least one pharmaceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, mannitol, polyvinylpyrrolidone (PVP) and sodium stearyl fumarate.

8. A dosage unit comprising the solid form of Compound A according to any one of claims 1 to 3, in an amount equivalent to the weight of the free base of Compound A, 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.

9. The dosage unit according to claim 8, which is a tablet or a capsule.

10. The dosage unit according to claim 9, comprising the solid form of Compound A according to any one of claims 1 to 3 and one or more pharmaceutically acceptable excipients.

11. The dosage unit according to claim 10, wherein the one or more pharmaceutically acceptable excipients comprise one or more excipients selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, mannitol, polyvinylpyrrolidone and sodium stearyl fumarate.

12. The dosage unit according to any one of claims 8 to 11, comprising at least one pharmaceutically acceptable excipient selected from the group consisting of silicified microcrystalline cellulose 50, silicified microcrystalline cellulose 90, pregelatinized starch, mannitol, croscarmellose sodium, polyvinylpyrrolidone and sodium stearyl fumarate.

13. The dosage unit according to any one of claims 8-11, comprising an antioxidant selected from the group consisting of sodium bisulfite, sodium sulfite, sodium thiosulfate, butylated hydroxytoluene, butylated hydroxyanisole, citric acid, and vitamin E.

14. A packaged pharmaceutical product comprising a pharmaceutical composition comprising a solid form of Compound A according to claim 1 and a protective agent as two separate materials in a closed container.

15. The packaged pharmaceutical product according to claim 14, wherein the pharmaceutical composition comprises a dosage unit according to any one of claims 8-11.

16. The packaged pharmaceutical product according to claim 14 or 15, wherein the protective agent comprises at least one material selected from the group consisting of a desiccant, an antioxidant, an oxygen scavenger, and an inert gas.

17. The packaged pharmaceutical product according to claim 14 or 15, wherein the protective agent comprises at least one material selected from the group consisting of a molecular sieve, silica gel, and a fibrous desiccant.

18. The packaged pharmaceutical product according to claim 14 or 15, wherein the protective agent and the pharmaceutical composition are contained in a gas-tight container.

19. The packaged pharmaceutical product of claim 18, wherein, The gas-tight container is a sealed bottle.

20. A method of making a pharmaceutical composition according to any one of claims 4-6, comprising combining a solid form of Compound A according to claim 1 with at least one pharmaceutically acceptable excipient.

21. The method according to claim 20, wherein the at least one pharmaceutically acceptable excipient comprises a filler selected from the group consisting of mannitol, starch, microcrystalline cellulose, lactose, gelatin, pregelatinized starch, sucrose, calcium phosphate, maltodextrin, sorbitol, calcium carbonate, and calcium phosphate.

22. The method according to claim 20, wherein the at least one pharmaceutically acceptable excipient comprises a disintegrant comprising sodium croscarmellose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and sodium starch glycolate.

23. The method according to claim 20, wherein the at least one pharmaceutically acceptable excipient comprises a binder selected from the group consisting of polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, or sodium carboxymethyl cellulose.

24. The method according to any one of claims 20-23, wherein the at least one pharmaceutically acceptable excipient comprises a lubricant selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, colloidal silicon dioxide, talc, stearic acid, glyceryl monostearate, isopropyl myristate.

25. The method according to claim 20, comprising combining a solid form of Compound A according to claim 1 with microcrystalline cellulose, sodium stearyl fumarate, and polyvinylpyrrolidone, and optionally mannitol, to form a mixture.

26. The method of claim 25, comprising combining the solid form of Compound A of claim 1 with microcrystalline cellulose, sodium stearyl fumarate, and polyvinylpyrrolidone, and optionally mannitol, to form a mixture, and adding polyvinylpyrrolidone and optionally water to form a wet granular mixture.

27. A pharmaceutical composition comprising the solid form of Compound A of claim 1, prepared by the method of claim 24.

28. The method of claim 25 or 26, wherein the mixture is blended in a wet granulator.

29. A process for preparing the solid form of Compound A of claim 1, comprising contacting Compound A with L-(+)-tartaric acid in the presence of a solvent, wherein the solvent comprises water and an organic co-solvent.

30. The process of claim 29, wherein the organic co-solvent is selected from the group consisting of acetone, isopropyl alcohol, ethanol, and tetrahydrofuran.

31. Use of the solid form of Compound A of any one of claims 1-3 for the manufacture of a medicament for the treatment of a condition that is a proliferative disease.

32. Use of the solid form of Compound A of any one of claims 1-3 for the manufacture of a medicament for the treatment of a condition selected from the group consisting of a tumor, psoriasis, dry eye, rheumatoid arthritis, or lupus.

33. Use of the solid form of Compound A of any one of claims 1-3 for the manufacture of a medicament for the treatment of a condition that is an inflammatory disease.

34. Use of the solid form of Compound A of any one of claims 1-3 for the manufacture of a medicament for the treatment of a condition that is an autoimmune disease.

35. Use of the solid form of Compound A of any one of claims 1-3 for the manufacture of a medicament for the treatment of a condition selected from the group consisting of chronic lupus, rheumatoid arthritis, chronic lymphocytic leukemia, and chronic myelogenous leukemia.

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