FGFR inhibitors, and methods for producing and using the same.

Abstract

To provide N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide, its salts, its cocrystals, and crystalline forms of its variants. [Solution] This disclosure generally covers compounds of formulas I to IV and their solvates, as well as their crystalline forms. In another embodiment, pharmaceutical compositions comprising the compounds or their solvates or crystalline forms described herein, and pharmaceutically acceptable additives are provided herein.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the benefit of U.S. Provisional Application No. 63 / 115,319, filed November 18, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] background Fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3, and FGFR4) are receptor tyrosine kinases consisting of an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. Binding of FGF ligands leads to dimerization and conformational changes in the intracellular domain, resulting in intermolecular phosphate transfer between the kinase domain and the intracellular tail. Phosphorylated residues act as docking sites for adapter proteins that facilitate downstream signaling cascades, leading to cellular behaviors including proliferation, survival, differentiation, migration, and angiogenesis. Deregulated FGFR signaling can occur via FGFR gene amplification or fusion, FGFR missense mutations, receptor overexpression resulting from dysregulation of epigenic and / or transcription factors, or upregulation of FGF ligands in the tumor microenvironment. FGFRs are expressed in numerous cell types. Thus, abnormal FGFR signaling is involved in tumorigenesis, tumor progression, and resistance to treatment across numerous tumor types (for a review of FGFR signaling, see N. Turner and R. Grose, Nat. Rev. Cancer 2010, 10:116-129 and the references cited therein).

[0003] In cancers altered by multiple FGFRs, pan-FGFR1-FGFR3 inhibitors elicit clinical responses, but their use is limited due to on-target toxicity. One of the most common adverse effects of pan-FGFR inhibition is hyperphosphatemia. The regulation of phosphate reabsorption is mediated by FGFR3 and FGFR1. Therefore, FGFR-selective inhibitors that preserve FGFR1 are needed (J. Gattineni et al., Am. J. Physiol. Renal Physiol. 2014, 306:F351-F358; X. Han et al., PLoS One 2016, 11:e0147845). Cancers containing FGFR2 gene fusions, as well as those with FGFR2 amplification and / or FGFR2 activating mutations, have been shown to respond to pan-FGFR inhibition, but low response rates and short response durations suggest that they are limited by toxicity. Therefore, there is a need for FGFR2-selective inhibitor compounds, as well as methods for treating cancer and other disorders with these compounds. (For a review of pan-FGFR1-3 inhibitors and their clinical responses, see IS Babina and NC Turner, Nat. Rev.) See Cancer 2017, 17:318-332; M. Katoh, Nat. Rev. Clin. Oncol. 2019, 16:105-122 and the references cited therein). Polymorphism is the ability of a substance to crystallize in more than one crystalline lattice arrangement. Crystallization, or polymorphism, can affect numerous aspects of the solid-state properties of a drug substance. Crystallized forms can differ considerably from amorphous forms, and different crystalline forms of a substance can differ considerably from one another in many respects, including solubility, dissolution rate, and / or bioavailability. In general, it is difficult to predict whether a given compound will form various crystalline solid-state forms. Predicting the physical properties of these crystalline solid-state forms is even more difficult. Furthermore, having a crystalline form of a therapeutic agent can be advantageous for a particular formulation, for example, a formulation suitable for subcutaneous use. [Prior art documents]

Non-Patent Literature

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Summary of the Invention

Means for Solving the Problems

[0005] Summary of the Invention The present disclosure generally relates to compounds of Formulas I-IV and their solvates, as well as their crystalline forms.

[0006] In one aspect, a compound of formula (I)

Chemical Formula

[0007] In another embodiment, the compound of formula (II) [ka] Or the solvates thereof are provided herein (wherein X, p, and q are each independently defined and described in the embodiments herein). In some embodiments, the compound of formula (II) or its solvates is the crystalline form described herein.

[0008] In another embodiment, the compound of formula (III) [ka] Or the solvates thereof are provided herein (wherein X, r, and s are each independently defined and described in the embodiments herein). In some embodiments, the compound of formula (III) or its solvates is the crystalline form described herein.

[0009] In another embodiment, the compound of formula (IV) [ka] Or the solvates thereof are provided herein (wherein X, t, and u are each independently defined and described in the embodiments herein). In some embodiments, the compound of formula (IV) or its solvates is the crystalline form described herein.

[0010] In another embodiment, pharmaceutical compositions comprising a compound or solvate thereof described herein, or a crystalline form thereof, and a pharmaceutically acceptable additive are provided herein.

[0011] In another embodiment, methods are provided herein for using the compounds or solvates thereof, or their crystalline forms or pharmaceutical compositions, described herein for inhibiting FGFR2 activity and for treating the disorders, diseases and / or conditions described herein. [Brief explanation of the drawing]

[0012] [Figure 1A] Figure 1A illustrates the X-ray diffraction pattern of compound I-1 in form A.

[0013] [Figure 1B] Figure 1B illustrates the characterization of morphology A of compound I-1 by differential scanning calorimetry (DSC).

[0014] [Figure 1C] Figure 1C illustrates the characterization of morphology A of compound I-1 by thermogravimetric analysis (TGA).

[0015] [Figure 1D] Figure 1D illustrates the characterization of morphology A of compound I-1 by dynamic water vapor sorption (DVS).

[0016] [Figure 2A] Figure 2A illustrates the X-ray diffraction pattern of compound I-1 in form B.

[0017] [Figure 2B] Figure 2B illustrates the characterization of morphology B of compound I-1 by differential scanning calorimetry (DSC).

[0018] [Figure 2C] Figure 2C illustrates the characterization of morphology B of compound I-1 by thermogravimetric analysis (TGA).

[0019] [Figure 2D] Figure 2D illustrates the characterization of morphology B of compound I-1 by dynamic water vapor sorption (DVS).

[0020] [Figure 3A] Figure 3A illustrates the X-ray diffraction pattern of compound I-1 in form C.

[0021] [Figure 3B] Figure 3B illustrates the characterization of morphology C of compound I-1 by differential scanning calorimetry (DSC).

[0022] [Figure 3C] Figure 3C illustrates the characterization of morphology C of compound I-1 by thermogravimetric analysis (TGA).

[0023] [Figure 3D] Figure 3D illustrates the characterization of morphology C of compound I-1 by dynamic water vapor sorption (DVS).

[0024] [Figure 4A] Figure 4A illustrates the X-ray diffraction pattern of compound I-1 in morphology D.

[0025] [Figure 4B] Figure 4B illustrates the characterization of morphology D of compound I-1 by differential scanning calorimetry (DSC).

[0026] [Figure 4C] Figure 4C illustrates the characterization of morphology D of compound I-1 by thermogravimetric analysis (TGA).

[0027] [Figure 4D] Figure 4D illustrates the characterization of morphology D of compound I-1 by dynamic water vapor sorption (DVS).

[0028] [Figure 4E] Figure 4E illustrates the characterization of morphology D of compound I-1 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0029] [Figure 5A] Figure 5A illustrates the X-ray diffraction pattern of compound I-1 in form E.

[0030] [Figure 5B] Figure 5B illustrates the characterization of morphology E of compound I-1 by differential scanning calorimetry (DSC).

[0031] [Figure 6A] Figure 6A illustrates the X-ray diffraction pattern of compound I-1 in form F.

[0032] [Figure 6B] Figure 6B illustrates the characterization of morphology F of compound I-1 by differential scanning calorimetry (DSC).

[0033] [Figure 6C] Figure 6C illustrates the characterization of morphology F of compound I-1 by thermogravimetric analysis (TGA).

[0034] [Figure 6D] Figure 6D illustrates the characterization of morphology F of compound I-1 by dynamic water vapor sorption (DVS).

[0035] [Figure 7A] Figure 7A illustrates the X-ray diffraction pattern of compound I-1 in morphology G.

[0036] [Figure 7B] Figure 7B illustrates the characterization of morphology G of compound I-1 by differential scanning calorimetry (DSC).

[0037] [Figure 7C] Figure 7C illustrates the characterization of morphology G of compound I-1 by thermogravimetric analysis (TGA).

[0038] [Figure 7D] Figure 7D illustrates the characterization of morphology G of compound I-1 by dynamic water vapor sorption (DVS).

[0039] [Figure 8A] Figure 8A illustrates the X-ray diffraction pattern of compound I-1 in form H.

[0040] [Figure 8B] Figure 8B illustrates the characterization of morphology H of compound I-1 by differential scanning calorimetry (DSC).

[0041] [Figure 8C] Figure 8C illustrates the characterization of morphology H of compound I-1 by thermogravimetric analysis (TGA).

[0042] [Figure 8D] Figure 8D illustrates the characterization of morphology H of compound I-1 by dynamic water vapor sorption (DVS).

[0043] [Figure 9A] Figure 9A illustrates the X-ray diffraction pattern of compound I-1 in form I.

[0044] [Figure 9B] Figure 9B illustrates the characterization of morphology I of compound I-1 by differential scanning calorimetry (DSC).

[0045] [Figure 9C] Figure 9C illustrates the characterization of morphology I of compound I-1 by thermogravimetric analysis (TGA).

[0046] [Figure 9D] Figure 9D illustrates the characterization of morphology I of compound I-1 by dynamic water vapor sorption (DVS).

[0047] [Figure 9E] Figure 9E illustrates the characterization of morphology I of compound I-1 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0048] [Figure 10A] Figure 10A illustrates the X-ray diffraction pattern of compound I-1 in form J.

[0049] [Figure 10B] Figure 10B illustrates the characterization of morphology J of compound I-1 by differential scanning calorimetry (DSC).

[0050] [Figure 10C] Figure 10C illustrates the characterization of morphology J of compound I-1 by thermogravimetric analysis (TGA).

[0051] [Figure 10D] Figure 10D illustrates the characterization of morphology J of compound I-1 by dynamic water vapor sorption (DVS).

[0052] [Figure 11A] Figure 11A illustrates the X-ray diffraction pattern of compound I-1 in morphology K.

[0053] [Figure 11B] Figure 11B illustrates the characterization of morphology K of compound I-1 by differential scanning calorimetry (DSC).

[0054] [Figure 11C] Figure 11C illustrates the characterization of morphology K of compound I-1 by thermogravimetric analysis (TGA).

[0055] [Figure 11D] Figure 11D illustrates the characterization of morphology K of compound I-1 by dynamic water vapor sorption (DVS).

[0056] [Figure 12]Figure 12 illustrates the procedure for generating patterns 1 to 11, which correspond to forms A to K of compound I-1. Pattern 1 corresponds to form A. Pattern 2 corresponds to form B. Pattern 3 corresponds to form C. Pattern 4 corresponds to form D. Pattern 5 corresponds to form E. Pattern 6 corresponds to form F. Pattern 7 corresponds to form G. Pattern 8 corresponds to form H. Pattern 9 corresponds to form I. Pattern 10 corresponds to form J. Pattern 11 corresponds to form K.

[0057] [Figure 13A] Figure 13A illustrates the X-ray diffraction patterns 1-5 (morphologies A-E) of compound I-2 (free form).

[0058] [Figure 13B] Figure 13B illustrates the X-ray diffraction pattern of compound I-2 (free form) in form B.

[0059] [Figure 13C] Figure 13C illustrates the characterization of morphology B of compound I-2 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0060] [Figure 13D] Figure 13D illustrates the characterization of morphology B of compound I-2 by thermogravimetric analysis (bottom) and differential scanning calorimetry (top).

[0061] [Figure 13E] Figure 13E illustrates the X-ray diffraction patterns of compound I-2, form B, before and after static storage at 40°C, 75% relative humidity and 25°C, 97% relative humidity.

[0062] [Figure 14A] Figure 14A illustrates the X-ray diffraction patterns of compound I-3 (HBr salt) morph A before storage and after one week of storage at 40°C and 75% relative humidity.

[0063] [Figure 14B] Figure 14B illustrates the characterization of morphology A of compound I-3 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0064] [Figure 14C] Figure 14C illustrates the characterization of morphology A of compound I-3 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0065] [Figure 15A] Figure 15A illustrates the X-ray diffraction patterns of compound I-4 (sulfate) morph B before storage and after one week of storage at 40°C and 75% relative humidity.

[0066] [Figure 15B] Figure 15B illustrates the characterization of morphology B of compound I-4 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0067] [Figure 15C] Figure 15C illustrates the characterization of morphology B of compound I-4 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0068] [Figure 16A] Figure 16A illustrates the X-ray diffraction patterns of compound I-5 (p-tosylate) in form A before storage and after one week of storage at 40°C and 75% relative humidity.

[0069] [Figure 16B] Figure 16B illustrates the characterization of morphology A of compound I-5 by 1H nuclear magnetic resonance (1H NMR) in D6-DMSO at 400 MHz.

[0070] [Figure 16C] Figure 16C illustrates the characterization of morphology A of compound I-5 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0071] [Figure 17A] Figure 17A illustrates the X-ray diffraction patterns of compound I-6 (mesylate) in form A before storage and after one week of storage at 40°C and 75% relative humidity.

[0072] [Figure 17B] Figure 17B illustrates the characterization of morphology A of compound I-6 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0073] [Figure 17C] Figure 17C illustrates the characterization of morphology A of compound I-6 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0074] [Figure 18A] Figure 18A illustrates the X-ray diffraction patterns of compound I-7 (besylate) in form A before storage and after one week of storage at 40°C and 75% relative humidity.

[0075] [Figure 18B] Figure 18B illustrates the characterization of morphology A of compound I-7 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0076] [Figure 18C] Figure 18C illustrates the characterization of morphology A of compound I-7 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0077] [Figure 19A] Figure 19A illustrates the X-ray diffraction patterns of compound I-8 (maleate) in form A before storage and after one week of storage at 40°C and 75% relative humidity.

[0078] [Figure 19B]Figure 19B illustrates the characterization of morphology A of compound I-8 by 1H nuclear magnetic resonance (1H NMR) in D6-DMSO at 400 MHz.

[0079] [Figure 19C] Figure 19C illustrates the characterization of morphology A of compound I-8 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0080] [Figure 20] Figure 20 illustrates the X-ray diffraction pattern of morphology A of the fumarate cocrystal of compound I-2.

[0081] [Figure 21] Figure 21 illustrates the X-ray diffraction pattern of morphology A of the malonic acid cocrystal of compound I-2.

[0082] [Figure 22] Figure 22 illustrates the X-ray diffraction pattern of morphology A of the benzoic acid cocrystal of compound I-2.

[0083] [Figure 23] Figure 23 illustrates the X-ray diffraction pattern of morphology A of the benzamide cocrystal of compound I-2.

[0084] [Figure 24A] Figure 24A illustrates the X-ray diffraction pattern of compound II-1 (free form) in form A.

[0085] [Figure 24B] Figure 24B illustrates the characterization of morphology A of compound II-1 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0086] [Figure 24C] Figure 24C illustrates the characterization of morphology A of compound II-1 by differential scanning calorimetry (DSC).

[0087] [Figure 24D] Figure 24D illustrates the characterization of morphology A of compound II-1 by thermogravimetric analysis (TGA).

[0088] [Figure 24E] Figure 24E shows the XRPD diffractogram of compound II-1, form A (bottom), after storage at 40°C / 75%RH for 7 days (top).

[0089] [Figure 25A] Figure 25A illustrates the X-ray diffraction pattern of compound II-1 (free form) in form B.

[0090] [Figure 25B] Figure 25B illustrates the characterization of morphology B of compound II-1 in D6-DMSO at 400 MHz, based on 1H nuclear magnetic resonance (1H NMR).

[0091] [Figure 25C] Figure 25C illustrates the characterization of morphology B of compound II-1 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0092] [Figure 25D] Figure 25D shows the XRPD diffractogram of compound II-1, form B (bottom), after storage at 40°C / 75%RH for 7 days (top).

[0093] [Figure 26A] Figure 26A illustrates the X-ray diffraction pattern of compound II-2 (hydrochloride salt) in form A.

[0094] [Figure 26B] Figure 26B illustrates the characterization of morphology A of compound II-2 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0095] [Figure 26C]Figure 26C illustrates the characterization of morphology A of compound II-2 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0096] [Figure 26D] Figure 26D shows the XRPD diffractogram of compound II-2, form A (bottom), after storage at 40°C / 75%RH for 7 days (top).

[0097] [Figure 27A] Figure 27A illustrates the X-ray diffraction pattern of compound II-3 (hydrobromide) in form A.

[0098] [Figure 27B] Figure 27B illustrates the characterization of morphology A of compound II-3 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0099] [Figure 27C] Figure 27C illustrates the characterization of morphology A of compound II-3 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0100] [Figure 27D] Figure 27D shows the XRPD diffractogram of compound II-3 in form A (bottom) after storage at 40°C / 75%RH for 7 days (top).

[0101] [Figure 28A] Figure 28A illustrates the X-ray diffraction pattern of compound II-4 (tosylate) in form A.

[0102] [Figure 28B] Figure 28B illustrates the characterization of morphology A of compound II-4 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0103] [Figure 28C]Figure 28C illustrates the characterization of morphology A of compound II-4 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0104] [Figure 28D] Figure 28D shows the XRPD diffractogram of compound II-4 in form A (bottom) after storage at 40°C / 75%RH for 7 days (top).

[0105] [Figure 29A] Figure 29A illustrates the X-ray diffraction pattern of compound II-5 (mesylate) in form A.

[0106] [Figure 29B] Figure 29B illustrates the characterization of morphology A of compound II-5 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0107] [Figure 29C] Figure 29C illustrates the characterization of morphology A of compound II-5 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0108] [Figure 30A] Figure 30A shows the X-ray diffraction pattern of compound II-6 (besylate) in form A.

[0109] [Figure 30B] Figure 30B illustrates the characterization of morphology A of compound II-6 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0110] [Figure 30C-1] Figure 30C illustrates the characterization of morphology A of compound II-6 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom). [Figure 30C-2] Same as above.

[0111] [Figure 30D]Figure 30D shows the XRPD diffractogram of compound II-6 in form A (bottom) after storage at 40°C / 75%RH for 7 days (top).

[0112] [Figure 31A] Figure 31A illustrates the X-ray diffraction pattern of compound II-7 (fumarate) in form A.

[0113] [Figure 31B] Figure 31B illustrates the characterization of morphology A of compound II-7 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0114] [Figure 31C] Figure 31C illustrates the characterization of morphology A of compound II-7 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0115] [Figure 31D] Figure 31D shows the XRPD diffractogram of compound II-7 in form A (bottom) after storage at 40°C / 75%RH for 7 days (top).

[0116] [Figure 32A] Figure 32A illustrates the X-ray diffraction pattern of compound III-1 (free form) in form A.

[0117] [Figure 32B] Figure 32B illustrates the characterization of morphology A of compound III-1 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0118] [Figure 32C] Figure 32C illustrates the characterization of morphology A of compound III-1 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0119] [Figure 32D]Figure 32D shows the XRPD diffractogram of compound III-1, form A (top), after storage at 40°C / 75%RH for 7 days (bottom).

[0120] [Figure 33A] Figure 33A illustrates the X-ray diffraction pattern of compound III-1 (free form) in form B.

[0121] [Figure 33B] Figure 33B illustrates the characterization of morphology B of compound III-1 in D6-DMSO at 400 MHz, based on 1H nuclear magnetic resonance (1H NMR).

[0122] [Figure 33C] Figure 33C illustrates the characterization of morphology B of compound III-1 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0123] [Figure 33D] Figure 33D shows the XRPD diffractogram of compound III-1, form B (top), after storage at 40°C / 75%RH for 7 days (bottom).

[0124] [Figure 34A] Figure 34A illustrates the X-ray diffraction pattern of compound III-1 (free form) in form C.

[0125] [Figure 34B] Figure 34B illustrates the characterization of morphology C of compound III-1 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0126] [Figure 34C] Figure 34C illustrates the characterization of morphology C of compound III-1 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0127] [Figure 34D]Figure 34D shows the XRPD diffractogram of compound III-1, form C (top), after storage at 40°C / 75%RH for 7 days (bottom).

[0128] [Figure 35A] Figure 35A illustrates the X-ray diffraction pattern of compound III-2 (hydrochloride salt) in form A.

[0129] [Figure 35B] Figure 35B illustrates the characterization of morphology A of compound III-2 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0130] [Figure 35C] Figure 35C illustrates the characterization of morphology A of compound III-2 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0131] [Figure 35D] Figure 35D shows the XRPD diffractogram of compound III-2, form A (top), after storage at 40°C / 75%RH for 7 days (bottom).

[0132] [Figure 36A] Figure 36A illustrates the X-ray diffraction pattern of compound III-2 (hydrochloride salt) in form B.

[0133] [Figure 36B] Figure 36B illustrates the characterization of morphology B of compound III-2 in D6-DMSO at 400 MHz, based on 1H nuclear magnetic resonance (1H NMR).

[0134] [Figure 36C] Figure 36C illustrates the characterization of morphology B of compound III-2 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0135] [Figure 36D]Figure 36D shows the XRPD diffractogram of compound III-2, form B (top), after storage at 40°C / 75%RH for 7 days (bottom).

[0136] [Figure 37A] Figure 37A illustrates the X-ray diffraction patterns of a mixture of form C and form E of compound III-2 (hydrochloride) (top), and form C (bottom).

[0137] [Figure 37B] Figure 37B illustrates the characterization of a mixture of compound III-2 in forms C and E, as determined by 1H nuclear magnetic resonance (1H NMR) in D6-DMSO at 400 MHz.

[0138] [Figure 37C] Figure 37C illustrates the characterization of a mixture of compound III-2 in forms C and E, based on thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0139] [Figure 37D] Figure 37D shows the XRPD diffractogram of a mixture of form C and form E of compound III-2 (top) after storage at 40°C / 75%RH for 7 days (bottom).

[0140] [Figure 38A] Figure 38A illustrates the X-ray diffraction pattern of compound III-2 (hydrochloride salt) in form D.

[0141] [Figure 38B] Figure 38B illustrates the characterization of morphology D of compound III-2 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0142] [Figure 38C] Figure 38C illustrates the characterization of morphology D of compound III-2 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0143] [Figure 38D] Figure 38D shows the XRPD diffractogram of compound III-2, form D (top), after storage at 40°C / 75%RH for 7 days (bottom).

[0144] [Figure 39A] Figure 39A illustrates the X-ray diffraction pattern of compound III-3 (hydrobromide) in form A.

[0145] [Figure 39B] Figure 39B illustrates the characterization of morphology A of compound III-3 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0146] [Figure 39C] Figure 39C illustrates the characterization of morphology A of compound III-3 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0147] [Figure 39D] Figure 39D shows the XRPD diffractogram of compound III-3, form A (top), after storage at 40°C / 75%RH for 7 days (bottom).

[0148] [Figure 40A] Figure 40A illustrates the X-ray diffraction pattern of compound III-4 (sulfate) in form A.

[0149] [Figure 40B] Figure 40B illustrates the characterization of morphology A of compound III-4 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0150] [Figure 40C] Figure 40C illustrates the characterization of morphology A of compound III-4 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0151] [Figure 40D]Figure 40D shows the XRPD diffractogram of compound III-4 in form A (top) after storage at 40°C / 75%RH for 7 days (bottom).

[0152] [Figure 41A] Figure 41A shows the X-ray diffraction patterns of compound III-4 (sulfate) in form B (bottom) and form A (top).

[0153] [Figure 41B] Figure 41B illustrates the characterization of morphology A of compound III-4 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0154] [Figure 41C] Figure 41C illustrates the characterization of morphology A of compound III-4 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0155] [Figure 41D] Figure 41D shows the XRPD diffractogram of compound III-4 in form A (top) after storage at 40°C / 75%RH for 7 days (bottom).

[0156] [Figure 42A] Figure 42A illustrates the X-ray diffraction pattern of compound III-5 (mesylate) in form A.

[0157] [Figure 42B] Figure 42B illustrates the characterization of morphology A of compound III-5 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0158] [Figure 42C] Figure 42C illustrates the characterization of morphology A of compound III-5 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0159] [Figure 42D]Figure 42D shows the XRPD diffractogram of Form A (top) of Compound III-5 after storage at 40 °C / 75% RH for 7 days (bottom).

[0160] [Figure 43A] Figure 43A shows the X-ray diffraction pattern of Form A of Compound III-6 (tartrate).

[0161] [Figure 43B] Figure 43B shows the characterization of Form A of Compound III-6 by 1H nuclear magnetic resonance (1H NMR) in D6-DMSO at 400 MHz.

[0162] [Figure 43C] Figure 43C shows the characterization of Form A of Compound III-6 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0163] [Figure 43D] Figure 43D shows the XRPD diffractogram of Form A (top) of Compound III-6 after storage at 40 °C / 75% RH for 7 days (bottom).

[0164] [Figure 44A] Figure 44A shows the X-ray diffraction pattern of Form A of Compound IV-1 (free form).

[0165] [Figure 44B] Figure 44B shows the characterization of Form A of Compound IV-1 by 1H nuclear magnetic resonance (1H NMR) in D6-DMSO at 400 MHz.

[0166] [Figure 44C] Figure 44C shows the characterization of Form A of Compound IV-1 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0167] [Figure 44D]Figure 44D shows the XRPD diffractogram of compound IV-1, form A (top), after storage at 40°C / 75%RH for 7 days (bottom).

[0168] [Figure 45A] Figure 45A illustrates the X-ray diffraction pattern of compound IV-2 (hydrochloride salt) in form A.

[0169] [Figure 45B] Figure 45B illustrates the characterization of morphology A of compound IV-2 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0170] [Figure 45C] Figure 45C illustrates the characterization of morphology A of compound IV-2 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0171] [Figure 45D] Figure 45D shows the XRPD diffractogram of compound IV-2 in form A (top) after storage at 40°C / 75%RH for 7 days (bottom).

[0172] [Figure 46A] Figure 46A illustrates the X-ray diffraction pattern of compound IV-3 (tosylate) in form A.

[0173] [Figure 46B] Figure 46B illustrates the characterization of morphology A of compound IV-3 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0174] [Figure 46C] Figure 46C illustrates the characterization of morphology A of compound IV-3 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0175] [Figure 46D]Figure 46D shows the XRPD diffractogram of Form A of Compound IV-3 (top) after storage at 40 °C / 75% RH for 7 days (bottom).

[0176] [Figure 47A] Figure 47A shows the X-ray diffraction pattern of Form B of Compound IV-3 (tosylate).

[0177] [Figure 47B] Figure 47B shows the characterization of Form B of Compound IV-3 by 1H nuclear magnetic resonance (1H NMR) in D6-DMSO at 400 MHz.

[0178] [Figure 48A] Figure 48A shows the X-ray diffraction pattern of Form A of Compound IV-4 (mesylate).

[0179] [Figure 48B] Figure 48B shows the characterization of Form A of Compound IV-4 by 1H nuclear magnetic resonance (1H NMR) in D6-DMSO at 400 MHz.

[0180] [Figure 48C] Figure 48C shows the characterization of Form A of Compound IV-4 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0181] [Figure 48D] Figure 48D shows the XRPD diffractogram of Form A of Compound IV-4 (top) after storage at 40 °C / 75% RH for 7 days (bottom).

[0182] [Figure 49A] Figure 49A shows the X-ray diffraction pattern of Form A of Compound IV-5 (besylate).

[0183] [Figure 49B]Figure 49B illustrates the characterization of morphology A of compound IV-5 in D6-DMSO at 400 MHz by 1H nuclear magnetic resonance (1H NMR).

[0184] [Figure 49C] Figure 49C illustrates the characterization of morphology A of compound IV-5 by thermogravimetric analysis (top) and differential scanning calorimetry (bottom).

[0185] [Figure 49D] Figure 49D shows the XRPD diffractogram of compound IV-5 in form A (top) after storage at 40°C / 75%RH for 7 days (bottom). [Modes for carrying out the invention]

[0186] Detailed description of the invention Compounds of the formula: [ka] It has been found that the FGFR inhibitor is useful for treating disorders, diseases, and / or conditions, such as the “FGFR2-mediated” disorders, diseases, and / or conditions described herein. It is desirable to provide a solid form of the compound (e.g., a free base or salt or solvate) that results in features such as improved water solubility, stability, and ease of formulation.

[0187] Through the optimization process, the compound [ka] The purity of can be significantly improved, and as shown in Examples 1 and 2, impurity compound 6: [ka] It was also found that the liquid chromatography area percentage (LCAP) can be reduced to less than approximately 0.15. Therefore, the compounds provided herein [ka] It is substantially free of impurities, such as compound 6. Compound of formula (I)

[0188] In some embodiments, the compound of formula (I) [ka] or its solvate is provided herein (wherein, m is 1, 2, 3, 4, 5, 6, 7, 8 or 9. n is 0, 0.5, 1, 1.5, 2, 2.5, or 3. X is hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, or maleic acid.

[0189] It will be recognized by those skilled in the art that the acid moiety indicated as "X" and N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide ionically bond to form the compound of formula (I). It will also be recognized that when n is 0, X is absent, and the compound of formula (I) exists as a "free base," i.e., in a "free form."

[0190] The compound of formula (I) is intended to exist in various physical forms. For example, the compound of formula (I) may be in solution, suspension or solid form. In certain embodiments, the compound of formula (I) is in solid form. When the compound of formula (I) is in solid form, it may be amorphous, crystalline or a mixture thereof. Exemplary solid forms are described in more detail below.

[0191] In some embodiments, the compound of formula (I) may be in hydrate form. In some embodiments, the compound of formula (I) may be in hemihydrate form.

[0192] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9.

[0193] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 0.5. In some embodiments, n is 1.5. In some embodiments, n is 2.5.

[0194] In some embodiments, X is hydrochloric acid. In some embodiments, X is hydrobromic acid. In some embodiments, X is sulfuric acid. In some embodiments, X is p-toluenesulfonic acid. In some embodiments, X is methanesulfonic acid. In some embodiments, X is benzenesulfonic acid. In some embodiments, X is maleic acid.

[0195] In some embodiments, the present invention provides a form of compound I that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound I, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound I.

[0196] In some embodiments, the compound of formula (I) or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, the compound of formula (I) or its solvate, or its crystalline form, contains any single impurity in an amount of less than about 0.40% by weight, less than about 0.35% by weight, less than about 0.3% by weight, less than about 0.25% by weight, less than about 0.2% by weight, less than about 0.15% by weight, less than about 0.10% by weight, or less than about 0.05% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, the compound of formula (I) or its solvate, or its crystalline form, contains impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in amounts of about 0.40% by weight or less, about 0.35% by weight or less, about 0.3% by weight or less, about 0.25% by weight or less, about 0.2% by weight or less, about 0.15% by weight or less, about 0.10% by weight or less, or about 0.05% by weight or less, where the percentage is relative to the total weight of the composition.

[0197] In some embodiments, the compound of formula (I) or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9 HPLC area% relative to the total area of ​​the HPLC chromatogram. In some embodiments, the compound of formula (I) or its solvate, or its crystalline form, contains no single impurity in any amount of HPLC area% or less than about 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, or 0.05 relative to the total area of ​​the HPLC chromatogram. In some embodiments, the compound of formula (I) or its solvate, or its crystalline form, contains impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in an HPLC area % of about 0.40, about 0.35, about 0.3, about 0.25, about 0.2, about 0.15, about 0.10, or about 0.05 of the total area of ​​the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0198] The structures illustrated for the compound of formula (I) are also intended to include all tautomers. Furthermore, the structures illustrated here are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms, for example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon substitution with carbon-rich carbon, fall within the scope of the present invention.

[0199] In some embodiments, N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide hydrochloride is provided herein. In some embodiments, N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide hydrochloride is monohydrochloride. In some embodiments, N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide hydrochloride is dihydrochloride. In some embodiments, N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide hydrochloride is a trihydrochloride salt. Compound I-1

[0200] In some embodiments, the compound of formula (I) is compound I-1 [ka] or its solvate.

[0201] In some embodiments, compound I-1 is an anhydrous solid.

[0202] In some embodiments, compound I-1 is an amorphous solid. In other embodiments, compound I-1 is a crystalline solid. In some embodiments, compound I-1 is a mixture of amorphous and crystalline solid forms.

[0203] In some embodiments, the present invention provides a form of compound I-1 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound I-1, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound I-1.

[0204] In some embodiments, compound I-1 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-1 or its solvate, or its crystalline form, contains any single impurity in amounts of less than about 0.40% by weight, less than about 0.35% by weight, less than about 0.3% by weight, less than about 0.25% by weight, less than about 0.2% by weight, less than about 0.15% by weight, less than about 0.10% by weight, or less than about 0.05% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-1 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in amounts of about 0.40% by weight or less, about 0.35% by weight or less, about 0.3% by weight or less, about 0.25% by weight or less, about 0.2% by weight or less, about 0.15% by weight or less, about 0.10% by weight or less, or about 0.05% by weight or less, where the percentages are relative to the total weight of the composition.

[0205] In some embodiments, compound I-1 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-1 or its solvate, or its crystalline form, contains no more than about 0.4% of the total area of ​​the HPLC chromatogram of any single impurity, about 0.35% of the total area of ​​the HPLC chromatogram, about 0.3% of the total area of ​​the HPLC chromatogram, about 0.25% of the total area of ​​the HPLC chromatogram, about 0.2% of the total area of ​​the HPLC chromatogram, about 0.15% of the total area of ​​the HPLC chromatogram, about 0.10% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-1 or its solvate, or its crystalline form, contains impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in an HPLC area % of about 0.40, about 0.35, about 0.3, about 0.25, about 0.2, about 0.15, about 0.10, or about 0.05 of the total area of ​​the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0206] The structures illustrated with respect to compound I-1 are also intended to include all tautomers of compound I-1. Furthermore, the structures illustrated here are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon substitution with carbon-rich carbon, fall within the scope of the present invention.

[0207] In certain embodiments, compound I-1 is a crystalline solid. In other embodiments, compound I-1 is a crystalline solid substantially free of amorphous compound I-1. As used herein, the term "substantially free of amorphous compound I-1" means that the compound does not contain a significant amount of amorphous compound I-1. In certain embodiments, at least about 95% by weight of crystalline compound I-1 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound I-1 is present.

[0208] Compound I-1 has been found to exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0209] In some embodiments, the solid crystal form of compound I-1 is form A. In some embodiments, form A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group consisting of about 12.3 2θ, about 24.0 2θ, and about 15.6 2θ. In some embodiments, form A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group consisting of about 12.3 2θ, about 24.0 2θ, about 15.6 2θ, about 12.7 2θ, about 10.4 2θ, about 11.1 2θ, and about 15.2 2θ. In some embodiments, morphology A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group consisting of approximately 12.3 2θ, approximately 24.0 2θ, approximately 15.6 2θ, approximately 12.7 2θ, approximately 10.4 2θ, approximately 11.1 2θ, and approximately 15.2 2θ. In some embodiments, morphology A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group consisting of approximately 12.3 2θ, approximately 24.0 2θ, approximately 15.6 2θ, and approximately 12.7 The peaks are selected from the group consisting of 2θ, about 10.4 2θ, about 11.1 2θ, and about 15.2 2θ. In some embodiments, morphology A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group consisting of about 12.3 2θ, about 24.0 2θ, about 15.6 2θ, about 12.7 2θ, about 10.4 2θ, about 11.1 2θ, and about 15.2 2θ. In some embodiments, morphology A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group consisting of about 12.3 2θ, about 24.0 2θ, about 15.6 2θ, about 12.7 2θ, about 10.4 2θ, about 11.1 2θ, and about 15.2 2θ. In some embodiments, morphology A of compound I-1 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 1A. In some embodiments, morphology A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.1. In some embodiments, morphology A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.1. In some embodiments, morphology A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.1. In some embodiments, morphology A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.1. In some embodiments, form A of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.1.

[0210] As used herein, the term “approximately” in the context of a peak at 2θ degrees means that the peak can be at a given 2θ value ± 0.2, a given 2θ value ± 0.1, or a given value. For example, a peak at “approximately 23.8 2θ” means that the peak could be at 23.6 2θ, 23.7 2θ, 23.8 2θ, 23.9 2θ, or 24.0 2θ.

[0211] In some embodiments, form A of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 1B. In some embodiments, form A of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 1C. In some embodiments, form A of compound I-1 may be characterized by substantial similarity to two or more of these figures simultaneously.

[0212] In some embodiments, the solid crystal form of compound I-1 is form B. In some embodiments, form B of compound II has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 2A. In some embodiments, form B of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.2. In some embodiments, form B of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.2. In some embodiments, form B of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.2. In some embodiments, form B of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.2. In some embodiments, form B of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.2.

[0213] In some embodiments, form B of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 2B. In some embodiments, form B of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 2C. In some embodiments, form B of compound I-1 may be characterized by substantial similarity to two or more of these figures simultaneously.

[0214] In some embodiments, the solid crystal form of compound I-1 is form C. In some embodiments, form C of compound II has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 3A. In some embodiments, form C of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.3. In some embodiments, form C of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.3. In some embodiments, form C of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.3. In some embodiments, form C of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.3. In some embodiments, form C of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.3.

[0215] In some embodiments, form C of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 3B. In some embodiments, form C of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 3C. In some embodiments, form C of compound I-1 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0216] In some embodiments, the solid crystal form of compound I-1 is form D. In some embodiments, form D of compound II has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 4A. In some embodiments, form D of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.4. In some embodiments, form D of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.4. In some embodiments, form D of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.4. In some embodiments, form D of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.4. In some embodiments, form D of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.4.

[0217] In some embodiments, morphology D of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 4B. In some embodiments, morphology D of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 4C. In some embodiments, morphology D of compound I-1 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0218] In some embodiments, the solid crystal form of compound I-1 is form E. In some embodiments, form E of compound II has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 5A. In some embodiments, form E of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.5. In some embodiments, form E of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.5. In some embodiments, form E of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.5. In some embodiments, form E of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.5. In some embodiments, morphology E of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.5.

[0219] In some embodiments, form E of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 5B. In some embodiments, form E of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 5C. In some embodiments, form E of compound I-1 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0220] In some embodiments, the solid crystal form of compound I-1 is form F. In some embodiments, form F of compound II has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 6A. In some embodiments, form F of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.6. In some embodiments, form F of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.6. In some embodiments, form F of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.6. In some embodiments, form F of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.6. In some embodiments, morphology F of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.6.

[0221] In some embodiments, morphology F of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 6B. In some embodiments, morphology F of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 6C. In some embodiments, morphology F of compound I-1 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0222] In some embodiments, the solid crystal form of compound I-1 is form G. In some embodiments, form G of compound II has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 7A. In some embodiments, form G of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.7. In some embodiments, form G of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.7. In some embodiments, form G of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.7. In some embodiments, form G of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.7. In some embodiments, morphology G of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.7.

[0223] In some embodiments, morphology G of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 7B. In some embodiments, morphology G of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 7C. In some embodiments, morphology G of compound I-1 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0224] In some embodiments, the solid crystal form of compound I-1 is form H. In some embodiments, form H of compound II has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 8A. In some embodiments, form H of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.8. In some embodiments, form H of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.8. In some embodiments, form H of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.8. In some embodiments, form H of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.8. In some embodiments, form H of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.8.

[0225] In some embodiments, form H of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 8B. In some embodiments, form H of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 8C. In some embodiments, form H of compound I-1 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0226] In some embodiments, the solid crystal form of compound I-1 is form I. In some embodiments, form I of compound II has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 9A. In some embodiments, form I of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.9. In some embodiments, form I of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.9. In some embodiments, form I of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.9. In some embodiments, form I of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.9. In some embodiments, morphology I of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.9. In some embodiments, morphology I of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 9B. In some embodiments, morphology I of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 9C. In some embodiments, morphology I of compound I-1 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0227] In some embodiments, the solid crystal form of compound I-1 is form J. In some embodiments, form J of compound II has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 10A. In some embodiments, form J of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.10. In some embodiments, form J of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.10. In some embodiments, form J of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.10. In some embodiments, form J of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.10. In some embodiments, morphology J of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.10.

[0228] In some embodiments, form J of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 10B. In some embodiments, form J of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 10C. In some embodiments, form J of compound I-1 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0229] In some embodiments, the solid crystal form of compound I-1 is form K. In some embodiments, form K of compound II has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 11A. In some embodiments, form K of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.11. In some embodiments, form K of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.11. In some embodiments, form K of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.11. In some embodiments, form K of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.11. In some embodiments, form K of compound I-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 2.11.

[0230] In some embodiments, form K of compound I-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 11B. In some embodiments, form K of compound I-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 11C. In other embodiments, form K of compound I-1 may be characterized by substantial similarities to two or more of these figures simultaneously. Compound I-2

[0231] In another embodiment, the compound of formula (I) is compound I-2, where compound I-2 is a free base (or "free form").

[0232] In some embodiments, compound I-2 is an amorphous solid. In some embodiments, compound I-2 is a crystalline solid. In some embodiments, compound I-2 is a mixture of amorphous and crystalline solid forms.

[0233] In some embodiments, the present invention provides a form of compound I-2 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound I-2, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound I-2.

[0234] In some embodiments, compound I-2 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-2 or its solvate, or its crystalline form, contains any single impurity in amounts of less than or equal to about 0.40% by weight, less than or equal to about 0.35% by weight, less than or equal to about 0.3% by weight, less than or equal to about 0.25% by weight, less than or equal to about 0.2% by weight, less than or equal to about 0.15% by weight, less than or equal to about 0.10% by weight, or less than or equal to about 0.05% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-2 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in amounts of about 0.40% by weight or less, about 0.35% by weight or less, about 0.3% by weight or less, about 0.25% by weight or less, about 0.2% by weight or less, about 0.15% by weight or less, about 0.10% by weight or less, or about 0.05% by weight or less, where the percentages are relative to the total weight of the composition.

[0235] In some embodiments, compound I-2 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-2 or its solvate, or its crystalline form, contains no single impurity in any amount of HPLC area of ​​less than or equal to about 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, or 0.05% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-2 or its solvate, or its crystalline form, contains impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in an HPLC area % of about 0.40, about 0.35, about 0.3, about 0.25, about 0.2, about 0.15, about 0.10, or about 0.05 of the total area of ​​the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0236] The structures illustrated with respect to compound I-2 are also intended to include all tautomers of compound I-2. Furthermore, the structures illustrated here are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon substitution with carbon-rich carbon, fall within the scope of the present invention.

[0237] In other embodiments, compound I-2 is a crystalline solid substantially free of amorphous compound I-2. As used herein, the term "substantially free of amorphous compound I-2" means that the compound does not contain a significant amount of amorphous compound I-2. In certain embodiments, at least about 95% by weight of crystalline compound I-2 is present. In certain embodiments, at least about 99% by weight of crystalline compound I-2 is present.

[0238] Compound I-2 has been found to exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0239] In certain embodiments, the solid crystal form of compound I-2 is form A. In some embodiments, form A of compound I-2 has an X-ray diffraction pattern substantially similar to pattern 1 illustrated in Figure 13A.

[0240] In certain embodiments, the solid crystal form of compound I-2 is form B. In some embodiments, form B of compound I-2 has an X-ray diffraction pattern substantially similar to pattern 2 illustrated in Figure 13A. In certain embodiments, form B of compound I-2 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 13B. In certain embodiments, form B of compound I-2 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 13D. In certain embodiments, form B of compound I-2 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 13E before and after static storage at 40C, 75% relative humidity and 25C, 97% relative humidity. In certain embodiments, form B of compound I-2 may be characterized by substantial similarity to two or more of these figures simultaneously.

[0241] In certain embodiments, the solid crystal form of compound I-2 is form C. In some embodiments, form C of compound I-2 has an X-ray diffraction pattern substantially similar to pattern 3 illustrated in Figure 13A.

[0242] In certain embodiments, the solid crystal form of compound I-2 is form D. In some embodiments, form D of compound I-2 has an X-ray diffraction pattern substantially similar to pattern 4 illustrated in Figure 13A.

[0243] In certain embodiments, the solid crystal form of compound I-2 is form E. In some embodiments, form E of compound I-2 has an X-ray diffraction pattern substantially similar to pattern 5 illustrated in Figure 13A. Compound I-3 [ka]

[0244] In another embodiment, the compound of formula (I) is compound I-3, which is a hydrobromide salt. In some embodiments, compound I-3 is a monobromide salt. In some embodiments, compound I-3 is a dibromide salt. In some embodiments, compound I-3 is a tribromide salt.

[0245] In some embodiments, compound I-3 is an amorphous solid. In some embodiments, compound I-3 is a crystalline solid. In some embodiments, compound I-3 is a mixture of amorphous and crystalline solid forms.

[0246] In some embodiments, the present invention provides a form of compound I-3 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound I-3, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound I-3.

[0247] In some embodiments, compound I-3 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-3 or its solvate, or its crystalline form, contains any single impurity in amounts of less than or equal to about 0.40% by weight, less than or equal to about 0.35% by weight, less than or equal to about 0.3% by weight, less than or equal to about 0.25% by weight, less than or equal to about 0.2% by weight, less than or equal to about 0.15% by weight, less than or equal to about 0.10% by weight, or less than or equal to about 0.05% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-3 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in amounts of about 0.40% by weight or less, about 0.35% by weight or less, about 0.3% by weight or less, about 0.25% by weight or less, about 0.2% by weight or less, about 0.15% by weight or less, about 0.10% by weight or less, or about 0.05% by weight or less, where the percentages are relative to the total weight of the composition.

[0248] In some embodiments, compound I-3 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-3 or its solvate, or its crystalline form, contains no more than about 0.4% of the total area of ​​the HPLC chromatogram of any single impurity, about 0.35% of the total area of ​​the HPLC chromatogram, about 0.3% of the total area of ​​the HPLC chromatogram, about 0.25% of the total area of ​​the HPLC chromatogram, about 0.2% of the total area of ​​the HPLC chromatogram, about 0.15% of the total area of ​​the HPLC chromatogram, about 0.10% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-3 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in an HPLC area % of about 0.40, about 0.35, about 0.3, about 0.25, about 0.2, about 0.15, about 0.10, or about 0.05 of the total area of ​​the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0249] The structures illustrated with respect to compound I-3 are also intended to include all tautomers of compound I-3. Furthermore, the structures illustrated here are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon substitution with carbon-rich carbon, fall within the scope of the present invention.

[0250] In other embodiments, compound I-3 is a crystalline solid substantially free of amorphous compound I-3. As used herein, the term "substantially free of amorphous compound I-3" means that the compound does not contain a significant amount of amorphous compound I-3. In certain embodiments, at least about 95% by weight of crystalline compound I-3 is present. In certain embodiments, at least about 99% by weight of crystalline compound I-3 is present.

[0251] In certain embodiments, the solid crystal morphology of compound I-3 has an X-ray diffraction pattern substantially similar to one of the patterns illustrated in Figure 14A. In certain embodiments, the solid crystal morphology of compound I-3 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 14C. In certain embodiments, the solid crystal morphology of compound I-3 may be characterized by substantial similarity to two or more of these figures simultaneously. Compound I-4 [ka]

[0252] In another embodiment, the compound of formula (I) is compound I-4, which is a sulfate (or sulfate ester).

[0253] In some embodiments, compound I-4 is an amorphous solid. In some embodiments, compound I-4 is a crystalline solid. In some embodiments, compound I-4 is a mixture of amorphous and crystalline solid forms.

[0254] In some embodiments, the present invention provides a form of compound I-4 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound I-4, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound I-4.

[0255] In some embodiments, compound I-4 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-4 or its solvate, or its crystalline form, contains no single impurity in amounts of less than about 0.40% by weight, less than about 0.35% by weight, less than about 0.3% by weight, less than about 0.25% by weight, less than about 0.2% by weight, less than about 0.15% by weight, less than about 0.10% by weight, or less than about 0.05% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-4 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in amounts of about 0.40% by weight or less, about 0.35% by weight or less, about 0.3% by weight or less, about 0.25% by weight or less, about 0.2% by weight or less, about 0.15% by weight or less, about 0.10% by weight or less, or about 0.05% by weight or less, where the percentages are relative to the total weight of the composition.

[0256] In some embodiments, compound I-4 or a solvate thereof, or a crystalline form thereof, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 HPLC area % relative to the total area of the HPLC chromatogram. In some embodiments, compound I-4 or a solvate thereof, or a crystalline form thereof, contains any single impurity in an HPLC area % of about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of the HPLC chromatogram. In some embodiments, compound I-4 or a solvate thereof, or a crystalline form thereof, contains impurity compound 6 (including the free base and salts of compound 6 or solvates thereof, or solid forms thereof) in an HPLC area % of about 0.40 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.10 or less, or about 0.05 or less relative to the total area of the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0257] The structures depicted with respect to compound I-4 are also intended to include all tautomeric forms of compound I-4. Further, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or replacement of carbon by carbon enriched in 13 C or 14 C, compounds having the present structure are within the scope of the present invention.

[0258] In other embodiments, compound I-4 is a crystalline solid substantially free of amorphous compound I-4. As used herein, the term "substantially free of amorphous compound I-4" means that the compound does not contain a significant amount of amorphous compound I-4. In certain embodiments, at least about 95% by weight of crystalline compound I-4 is present. In certain embodiments, at least about 99% by weight of crystalline compound I-4 is present.

[0259] In certain embodiments, the solid crystal morphology of compound I-4 has an X-ray diffraction pattern substantially similar to one of the patterns illustrated in Figure 15A. In certain embodiments, the solid crystal morphology of compound I-4 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 15C. In certain embodiments, the solid crystal morphology of compound I-4 may be characterized by substantial similarity to two of these figures simultaneously. Compound I-5 [ka]

[0260] In another embodiment, the compound of formula (I) is compound I-5, which is a p-toluenesulfonate.

[0261] In some embodiments, compound I-5 is an amorphous solid. In some embodiments, compound I-5 is a crystalline solid. In some embodiments, compound I-5 is a mixture of amorphous and crystalline solid forms.

[0262] In some embodiments, the present invention provides a form of compound I-5 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound I-5, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound I-5.

[0263] In some embodiments, compound I-5 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-5 or its solvate, or its crystalline form, contains any single impurity in amounts of less than or equal to about 0.40% by weight, less than or equal to about 0.35% by weight, less than or equal to about 0.3% by weight, less than or equal to about 0.25% by weight, less than or equal to about 0.2% by weight, less than or equal to about 0.15% by weight, less than or equal to about 0.10% by weight, or less than or equal to about 0.05% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-5 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in amounts of about 0.40% by weight or less, about 0.35% by weight or less, about 0.3% by weight or less, about 0.25% by weight or less, about 0.2% by weight or less, about 0.15% by weight or less, about 0.10% by weight or less, or about 0.05% by weight or less, where the percentages are relative to the total weight of the composition.

[0264] In some embodiments, compound I-5 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-5 or its solvate, or its crystalline form, contains no single impurity in any amount of HPLC area of ​​less than or equal to about 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, or 0.05% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-5 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in an HPLC area % of about 0.40, about 0.35, about 0.3, about 0.25, about 0.2, about 0.15, about 0.10, or about 0.05 of the total area of ​​the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0265] The structures illustrated with respect to compound I-5 are also intended to include all tautomers of compound I-5. Furthermore, the structures illustrated here are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon substitution with carbon-rich carbon, fall within the scope of the present invention.

[0266] In other embodiments, compound I-5 is a crystalline solid substantially free of amorphous compound I-5. As used herein, the term "substantially free of amorphous compound I-5" means that the compound does not contain a significant amount of amorphous compound I-5. In certain embodiments, at least about 95% by weight of crystalline compound I-5 is present. In certain embodiments, at least about 99% by weight of crystalline compound I-5 is present.

[0267] In certain embodiments, the solid crystal morphology of compound I-5 has an X-ray diffraction pattern substantially similar to one of the patterns illustrated in Figure 16A. In certain embodiments, the solid crystal morphology of compound I-5 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 16C. In certain embodiments, the solid crystal morphology of compound I-5 may be characterized by substantial similarity to two or more of these figures simultaneously. Compound I-6 [ka]

[0268] In another embodiment, the compound of formula (I) is compound I-6, which is a methanesulfonate.

[0269] In some embodiments, compound I-6 is an amorphous solid. In some embodiments, compound I-6 is a crystalline solid. In some embodiments, compound I-6 is a mixture of amorphous and crystalline solid forms.

[0270] In some embodiments, the present invention provides a form of compound I-6 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound I-6, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound I-6.

[0271] In some embodiments, compound I-6 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-6 or its solvate, or its crystalline form, contains any single impurity in amounts of less than about 0.40% by weight, less than about 0.35% by weight, less than about 0.3% by weight, less than about 0.25% by weight, less than about 0.2% by weight, less than about 0.15% by weight, less than about 0.10% by weight, or less than about 0.05% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-6 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in amounts of about 0.40% by weight or less, about 0.35% by weight or less, about 0.3% by weight or less, about 0.25% by weight or less, about 0.2% by weight or less, about 0.15% by weight or less, about 0.10% by weight or less, or about 0.05% by weight or less, where the percentages are relative to the total weight of the composition.

[0272] In some embodiments, compound I-6 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-6 or its solvate, or its crystalline form, contains no single impurity in any amount of HPLC area of ​​less than or equal to about 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, or 0.05% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-6 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in an HPLC area % of about 0.40, about 0.35, about 0.3, about 0.25, about 0.2, about 0.15, about 0.10, or about 0.05 of the total area of ​​the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0273] The structures illustrated with respect to compound I-6 are also intended to include all tautomers of compound I-6. Furthermore, the structures illustrated here are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon substitution with carbon-rich carbon, fall within the scope of the present invention.

[0274] In other embodiments, compound I-6 is a crystalline solid substantially free of amorphous compound I-6. As used herein, the term "substantially free of amorphous compound I-6" means that the compound does not contain a significant amount of amorphous compound I-6. In certain embodiments, at least about 95% by weight of crystalline compound I-6 is present. In certain embodiments, at least about 99% by weight of crystalline compound I-6 is present.

[0275] In certain embodiments, the solid crystalline form of compound I-6 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 17A. In certain embodiments, the solid crystalline form of compound I-6 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 17C. In certain embodiments, the solid crystalline form of compound I-6 may be characterized by substantial similarity to two of these figures simultaneously. Compound I-7 [ka]

[0276] In another embodiment, the compound of formula (I) is compound I-7, which is a benzenesulfonate.

[0277] In some embodiments, compound I-7 is an amorphous solid. In some embodiments, compound I-7 is a crystalline solid. In some embodiments, compound I-7 is a mixture of amorphous and crystalline solid forms.

[0278] In some embodiments, the present invention provides a form of compound I-7 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound I-7, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound I-7.

[0279] In some embodiments, compound I-7 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-7 or its solvate, or its crystalline form, contains any single impurity in amounts of less than about 0.40% by weight, less than about 0.35% by weight, less than about 0.3% by weight, less than about 0.25% by weight, less than about 0.2% by weight, less than about 0.15% by weight, less than about 0.10% by weight, or less than about 0.05% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-7 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in amounts of about 0.40% by weight or less, about 0.35% by weight or less, about 0.3% by weight or less, about 0.25% by weight or less, about 0.2% by weight or less, about 0.15% by weight or less, about 0.10% by weight or less, or about 0.05% by weight or less, where the percentages are relative to the total weight of the composition.

[0280] In some embodiments, compound I-7 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-7 or its solvate, or its crystalline form, contains no single impurity in any amount of HPLC area of ​​less than or equal to about 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, or 0.05% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-7 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in an HPLC area % of about 0.40, about 0.35, about 0.3, about 0.25, about 0.2, about 0.15, about 0.10, or about 0.05 of the total area of ​​the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0281] The structures illustrated with respect to compound I-7 are also intended to include all tautomers of compound I-7. Furthermore, the structures illustrated here are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon substitution with carbon-rich carbon, fall within the scope of the present invention.

[0282] In other embodiments, compound I-7 is a crystalline solid substantially free of amorphous compound I-7. As used herein, the term "substantially free of amorphous compound I-7" means that the compound does not contain a significant amount of amorphous compound I-7. In certain embodiments, at least about 95% by weight of crystalline compound I-7 is present. In certain embodiments, at least about 99% by weight of crystalline compound I-7 is present.

[0283] In certain embodiments, the solid crystal morphology of compound I-7 has an X-ray diffraction pattern substantially similar to one of the patterns illustrated in Figure 18A. In certain embodiments, the solid crystal morphology of compound I-7 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 18C. In certain embodiments, the solid crystal morphology of compound I-7 may be characterized by substantial similarity to two of these figures simultaneously. Compound I-8 [ka]

[0284] In another embodiment, the compound of formula (I) is compound I-8, which is a maleate salt.

[0285] In some embodiments, compound I-8 is an amorphous solid. In some embodiments, compound I-8 is a crystalline solid. In some embodiments, compound I-8 is a mixture of amorphous and crystalline solid forms.

[0286] In some embodiments, the present invention provides a form of compound I-8 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound I-8, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound I-8.

[0287] In some embodiments, compound I-8 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-8 or its solvate, or its crystalline form, contains any single impurity in amounts of less than or equal to about 0.40% by weight, less than or equal to about 0.35% by weight, less than or equal to about 0.3% by weight, less than or equal to about 0.25% by weight, less than or equal to about 0.2% by weight, less than or equal to about 0.15% by weight, less than or equal to about 0.10% by weight, or less than or equal to about 0.05% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, compound I-8 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in amounts of about 0.40% by weight or less, about 0.35% by weight or less, about 0.3% by weight or less, about 0.25% by weight or less, about 0.2% by weight or less, about 0.15% by weight or less, about 0.10% by weight or less, or about 0.05% by weight or less, where the percentages are relative to the total weight of the composition.

[0288] In some embodiments, compound I-8 or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-8 or its solvate, or its crystalline form, contains no single impurity in any amount of HPLC area of ​​less than or equal to about 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, or 0.05% of the total area of ​​the HPLC chromatogram. In some embodiments, compound I-8 or its solvates, or their crystalline forms, contain impurity compound 6 (including the free base and salts of compound 6 or their solvates, or their solid forms) in an HPLC area % of about 0.40, about 0.35, about 0.3, about 0.25, about 0.2, about 0.15, about 0.10, or about 0.05 of the total area of ​​the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0289] The structures illustrated with respect to compound I-8 are also intended to include all tautomers of compound I-8. Furthermore, the structures illustrated here are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon substitution with carbon-rich carbon, fall within the scope of the present invention.

[0290] In other embodiments, compound I-8 is a crystalline solid substantially free of amorphous compound I-8. As used herein, the term "substantially free of amorphous compound I-8" means that the compound does not contain a significant amount of amorphous compound I-8. In certain embodiments, at least about 95% by weight of crystalline compound I-8 is present. In certain embodiments, at least about 99% by weight of crystalline compound I-8 is present.

[0291] In certain embodiments, the solid crystal morphology of compound I-8 has an X-ray diffraction pattern substantially similar to one of the patterns illustrated in Figure 19A. In certain embodiments, the solid crystal morphology of compound I-8 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 19C. In certain embodiments, the solid crystal morphology of compound I-8 may be characterized by substantial similarity to two of these figures simultaneously. Compound of formula (II)

[0292] In one embodiment, the compound of formula (II) [ka] or its solvate is provided herein (wherein, p is 1, 2, 3, 4, 5, 6, 7, 8 or 9. q is 0, 0.5, 1, 1.5, 2, 2.5, or 3. X is hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, or fumaric acid.

[0293] It will be recognized by those skilled in the art that the acid moiety indicated as "X" and (R)-N-(4-(4-amino-7-methyl-5-(4-(pyrroridine-1-carbonyl)cyclohexa-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-methylphenyl)methacrylamide ionically bond to form the compound of formula (II). It will also be recognized that when q is 0, X is absent, and the compound of formula (II) exists as a "free base," i.e., in a "free form."

[0294] The compound of formula (II) is intended to exist in various physical forms. For example, the compound of formula (II) may be in solution, suspension or solid form. In certain embodiments, the compound of formula (II) is in solid form. When the compound of formula (II) is in solid form, it may be amorphous, crystalline or a mixture thereof. Exemplary solid forms are described in more detail below.

[0295] In some embodiments, the compound of formula (II) may be in hydrate form. In some embodiments, the compound of formula (II) may be in hemihydrate form.

[0296] In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9.

[0297] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 0.5. In some embodiments, q is 1.5. In some embodiments, q is 2.5.

[0298] In some embodiments, X is hydrochloric acid. In some embodiments, X is hydrobromic acid. In some embodiments, X is p-toluenesulfonic acid. In some embodiments, X is methanesulfonic acid. In some embodiments, X is benzenesulfonic acid. In some embodiments, X is fumaric acid.

[0299] In some embodiments, the present invention provides a form of the compound of formula (II) that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of the compound of formula (II), residual solvents, or any other impurities that may result from the preparation and / or isolation of the compound of formula (II).

[0300] In some embodiments, the compound of formula (II) or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, the compound of formula (II) or its solvate, or its crystalline form, contains any single impurity in an amount of less than about 0.40% by weight, less than about 0.35% by weight, less than about 0.3% by weight, less than about 0.25% by weight, less than about 0.2% by weight, less than about 0.15% by weight, less than about 0.10% by weight, or less than about 0.05% by weight, where the percentage is relative to the total weight of the composition.

[0301] In some embodiments, the compound of formula (II) or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% of the total area of ​​the HPLC chromatogram. In some embodiments, the compound of formula (II) or its solvate, or its crystalline form, contains no single impurity in an amount of less than or equal to about 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, or 0.05% of the total area of ​​the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0302] The structures illustrated for the compound of formula (II) are also intended to include all tautomers. Furthermore, the structures illustrated here are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms, for example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon substitution with carbon-rich carbon, fall within the scope of the present invention.

[0303] In some embodiments, the compound of formula (II) is compound II-1, which is a free base (or "free form"). In some embodiments, compound II-1 is an amorphous solid. In some embodiments, compound II-1 is a crystalline solid. In some embodiments, compound II-1 is a mixture of an amorphous solid form and a crystalline solid form.

[0304] In some embodiments, the present invention provides a form of compound II-1 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound II-1, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound II-1. In certain embodiments, at least about 95% by weight of compound II-1 is present. In certain embodiments, at least about 99% by weight of compound II-1 is present.

[0305] In other embodiments, compound II-1 is a crystalline solid substantially free of amorphous compound II-1. As used herein, the term "substantially free of amorphous compound II-1" means that the compound does not contain a significant amount of amorphous compound II-1. In certain embodiments, at least about 95% by weight of crystalline compound II-1 is present. In certain embodiments, at least about 99% by weight of crystalline compound II-1 is present.

[0306] Compound II-1 has been found to exist in various solid forms. Exemplary such forms include polymorphisms, such as those described herein.

[0307] In some embodiments, the solid crystal form of compound II-1 is form A. In certain embodiments, form A of compound II-1 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 24A. In some embodiments, form A of compound II-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 8. In some embodiments, form A of compound II-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 8. In some embodiments, form A of compound II-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 8. In some embodiments, form A of compound II-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 8. In some embodiments, form A of compound II-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 8.

[0308] In certain embodiments, form A of compound II-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 24C. In certain embodiments, form A of compound II-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 24D. In certain embodiments, form A of compound II-1 may be characterized by substantial similarity to two or more of these figures simultaneously.

[0309] In some embodiments, the solid crystal form of compound II-1 is form B. In certain embodiments, form B of compound II-1 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 25A. In some embodiments, form B of compound II-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 9. In some embodiments, form B of compound II-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 9. In some embodiments, form B of compound II-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 9. In some embodiments, form B of compound II-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 9. In some embodiments, form B of compound II-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 9.

[0310] In certain embodiments, form B of compound II-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 25C. In certain embodiments, form B of compound II-1 has a thermogravimetric analysis (TGA) pattern substantially similar to the thermogravimetric analysis (TGA) pattern illustrated in Figure 25D. In certain embodiments, form B of compound II-1 may simultaneously be characterized by substantial similarities to two or more of these figures.

[0311] In another embodiment, the compound of formula (II) is compound II-2, and compound II-2 is a hydrochloride salt. In some embodiments, compound II-2 is a monohydrochloride salt. In some embodiments, compound II-2 is a dihydrochloride salt. In some embodiments, compound II-2 is a trihydrochloride salt.

[0312] In some embodiments, compound II-2 is an amorphous solid. In some embodiments, compound II-2 is a crystalline solid. In some embodiments, compound II-2 is a mixture of amorphous and crystalline solid forms.

[0313] In some embodiments, the present invention provides a form of compound II-2 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound II-2, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound II-2. In certain embodiments, at least about 95% by weight of compound II-2 is present. In certain embodiments, at least about 99% by weight of compound II-2 is present.

[0314] In certain embodiments, compound II-2 is a crystalline solid. In other embodiments, compound II-2 is a crystalline solid substantially free of amorphous compound II-2. As used herein, the term "substantially free of amorphous compound II-2" means that the compound does not contain a significant amount of amorphous compound II-2. In certain embodiments, at least about 95% by weight of crystalline compound II-2 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound II-2 is present.

[0315] In some embodiments, the solid crystal form of compound II-2 is form A. In some embodiments, form A of compound II-2 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 26A. In some embodiments, form A of compound II-2 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 14. In some embodiments, form A of compound II-2 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 14. In some embodiments, form A of compound II-2 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 14. In some embodiments, form A of compound II-2 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 14. In some embodiments, form A of compound II-2 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 14.

[0316] In some embodiments, form A of compound II-2 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 26C. In some embodiments, form A of compound II-2 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 26C. In some embodiments, form A of compound II-2 may be characterized by substantial similarity to two or more of these figures simultaneously.

[0317] In another embodiment, the compound of formula (II) is compound II-3, and compound II-3 is a hydrobromide salt. In some embodiments, compound II-3 is a monobromide salt. In some embodiments, compound II-3 is a dibromide salt. In some embodiments, compound II-3 is a tribromide salt.

[0318] In some embodiments, compound II-3 is an amorphous solid. In some embodiments, compound II-3 is a crystalline solid. In some embodiments, compound II-3 is a mixture of amorphous and crystalline solid forms.

[0319] In some embodiments, the present invention provides a form of compound II-3 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound II-3, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound II-3. In certain embodiments, at least about 95% by weight of compound II-3 is present. In certain embodiments, at least about 99% by weight of compound II-3 is present.

[0320] In certain embodiments, compound II-3 is a crystalline solid. In other embodiments, compound II-3 is a crystalline solid substantially free of amorphous compound II-3. As used herein, the term "substantially free of amorphous compound II-3" means that the compound does not contain a significant amount of amorphous compound II-3. In certain embodiments, at least about 95% by weight of crystalline compound II-3 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound II-3 is present.

[0321] In some embodiments, the solid crystal form of compound II-3 is form A. In some embodiments, form A of compound II-3 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern in Figure 27A. In some embodiments, form A of compound II-3 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 15. In some embodiments, form A of compound II-3 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 15. In some embodiments, form A of compound II-3 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 15. In some embodiments, form A of compound II-3 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 15. In some embodiments, form A of compound II-3 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 15.

[0322] In some embodiments, form A of compound II-3 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 27C. In some embodiments, form A of compound II-3 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 27C. In some embodiments, form A of compound II-3 may be characterized by substantial similarity to two or more of these figures simultaneously.

[0323] In another embodiment, the compound of formula (II) is compound II-4, and compound II-4 is p-toluenesulfonate.

[0324] In some embodiments, compound II-4 is an amorphous solid. In some embodiments, compound II-4 is a crystalline solid. In some embodiments, compound II-4 is a mixture of amorphous and crystalline solid forms.

[0325] In some embodiments, the present invention provides a form of compound II-4 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound II-4, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound II-4. In certain embodiments, at least about 95% by weight of compound II-4 is present. In certain embodiments, at least about 99% by weight of compound II-4 is present.

[0326] In certain embodiments, compound II-4 is a crystalline solid. In other embodiments, compound II-4 is a crystalline solid substantially free of amorphous compound II-4. As used herein, the term "substantially free of amorphous compound II-4" means that the compound does not contain a significant amount of amorphous compound II-4. In certain embodiments, at least about 95% by weight of crystalline compound II-4 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound II-4 is present.

[0327] In some embodiments, the solid crystal form of compound II-4 is form A. In some embodiments, form A of compound II-4 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern of Figure 28A. In some embodiments, form A of compound II-4 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 16. In some embodiments, form A of compound II-4 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 16. In some embodiments, form A of compound II-4 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 16. In some embodiments, form A of compound II-4 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 16. In some embodiments, form A of compound II-4 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 16.

[0328] In some embodiments, form A of compound II-4 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 28C. In some embodiments, form A of compound II-4 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 28C. In some embodiments, form A of compound II-4 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0329] In another embodiment, the compound of formula (II) is compound II-5, and compound II-5 is a methanesulfonate.

[0330] In some embodiments, compound II-5 is an amorphous solid. In some embodiments, compound II-5 is a crystalline solid. In some embodiments, compound II-5 is a mixture of amorphous and crystalline solid forms.

[0331] In some embodiments, the present invention provides a form of compound II-5 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound II-5, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound II-5. In certain embodiments, at least about 95% by weight of compound II-5 is present. In certain embodiments, at least about 99% by weight of compound II-5 is present.

[0332] In certain embodiments, compound II-5 is a crystalline solid. In other embodiments, compound II-5 is a crystalline solid substantially free of amorphous compound II-5. As used herein, the term "substantially free of amorphous compound II-5" means that the compound does not contain a significant amount of amorphous compound II-5. In certain embodiments, at least about 95% by weight of crystalline compound II-5 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound II-5 is present.

[0333] In some embodiments, the solid crystal form of compound II-5 is form A. In certain embodiments, form A of compound II-5 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 29A. In some embodiments, form A of compound II-5 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 17. In some embodiments, form A of compound II-5 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 17. In some embodiments, form A of compound II-5 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 17. In some embodiments, form A of compound II-5 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 17. In some embodiments, form A of compound II-5 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 17.

[0334] In certain embodiments, form A of compound II-5 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 29C. In certain embodiments, form A of compound II-5 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 29C. In certain embodiments, form A of compound II-5 may be characterized by substantial similarity to two or more of these figures simultaneously.

[0335] In another embodiment, the compound of formula (II) is compound II-6, which is a benzenesulfonate.

[0336] In some embodiments, compound II-6 is an amorphous solid. In some embodiments, compound II-6 is a crystalline solid. In some embodiments, compound II-6 is a mixture of amorphous and crystalline solid forms.

[0337] In some embodiments, the present invention provides a form of compound II-6 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound II-6, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound II-6. In certain embodiments, at least about 95% by weight of compound II-6 is present. In certain embodiments, at least about 99% by weight of compound II-6 is present.

[0338] In certain embodiments, compound II-6 is a crystalline solid. In other embodiments, compound II-6 is a crystalline solid substantially free of amorphous compound II-6. As used herein, the term "substantially free of amorphous compound II-6" means that the compound does not contain a significant amount of amorphous compound II-6. In certain embodiments, at least about 95% by weight of crystalline compound II-6 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound II-6 is present.

[0339] In some embodiments, the solid crystal form of compound II-6 is form A. In certain embodiments, form A of compound II-6 has an X-ray diffraction pattern substantially similar to one of the patterns illustrated in Figure 30A. In some embodiments, form A of compound II-6 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 18. In some embodiments, form A of compound II-6 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 18. In some embodiments, form A of compound II-6 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 18. In some embodiments, form A of compound II-6 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 18. In some embodiments, form A of compound II-6 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 18.

[0340] In certain embodiments, form A of compound II-6 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 30C. In certain embodiments, form A of compound II-6 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 30C. In certain embodiments, form A of compound II-6 may be characterized by substantial similarity to two of these figures simultaneously.

[0341] In another embodiment, the compound of formula (II) is compound II-7, and compound II-7 is a fumarate.

[0342] In some embodiments, compound II-7 is an amorphous solid. In some embodiments, compound II-7 is a crystalline solid. In some embodiments, compound II-7 is a mixture of amorphous and crystalline solid forms.

[0343] In some embodiments, the present invention provides a form of compound II-7 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound II-7, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound II-7. In certain embodiments, at least about 95% by weight of compound II-7 is present. In certain embodiments, at least about 99% by weight of compound II-7 is present.

[0344] In certain embodiments, compound II-7 is a crystalline solid. In other embodiments, compound II-7 is a crystalline solid substantially free of amorphous compound II-7. As used herein, the term "substantially free of amorphous compound II-7" means that the compound does not contain a significant amount of amorphous compound II-7. In certain embodiments, at least about 95% by weight of crystalline compound II-7 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound II-7 is present.

[0345] In some embodiments, the solid crystal form of compound II-7 is form A. In certain embodiments, form A of compound II-7 has an X-ray diffraction pattern substantially similar to one of the patterns illustrated in Figure 31A. In some embodiments, form A of compound II-7 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 19. In some embodiments, form A of compound II-7 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 19. In some embodiments, form A of compound II-7 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 19. In some embodiments, form A of compound II-7 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 19. In some embodiments, form A of compound II-7 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 19.

[0346] In certain embodiments, form A of compound II-7 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 31C. In certain embodiments, form A of compound II-7 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 31C. In certain embodiments, form A of compound II-7 may be characterized by substantial similarity to two or more of these figures simultaneously. Compound of formula (III)

[0347] In one embodiment, the compound of formula (III) [ka] or its solvate is provided herein (wherein, r is 1, 2, 3, 4, 5, 6, 7, 8 or 9. s is 0, 0.5, 1, 1.5, 2, 2.5, or 3. X is hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, or tartaric acid.

[0348] It will be recognized by those skilled in the art that the acid moiety indicated as "X" and 6-(6-ethynyl-4-methoxypyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine ionically bond to form the compound of formula (III). It will also be recognized that when s is 0, X is absent, indicating that the compound of formula (III) exists as a "free base," i.e., in a "free form."

[0349] The compound of formula (III) is intended to exist in various physical forms. For example, the compound of formula (III) may be in solution, suspension or solid form. In certain embodiments, the compound of formula (III) is in solid form. When the compound of formula (III) is in solid form, it may be amorphous, crystalline or a mixture thereof. Exemplary solid forms are described in more detail below.

[0350] In some embodiments, the compound of formula (III) may be in hydrate form. In some embodiments, the compound of formula (III) may be in hemihydrate form.

[0351] In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9.

[0352] In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 0.5. In some embodiments, s is 1.5. In some embodiments, s is 2.5.

[0353] In some embodiments, X is hydrochloric acid. In some embodiments, X is hydrobromic acid. In some embodiments, X is sulfuric acid. In some embodiments, X is methanesulfonic acid. In some embodiments, X is tartaric acid.

[0354] In some embodiments, the present invention provides a form of the compound of formula (III) that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of the compound of formula (III), residual solvents, or any other impurities that may result from the preparation and / or isolation of the compound of formula (III).

[0355] In some embodiments, the compound of formula (III) or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, the compound of formula (III) or its solvate, or its crystalline form, contains any single impurity in an amount of less than about 0.40% by weight, less than about 0.35% by weight, less than about 0.3% by weight, less than about 0.25% by weight, less than about 0.2% by weight, less than about 0.15% by weight, less than about 0.10% by weight, or less than about 0.05% by weight, where the percentage is relative to the total weight of the composition.

[0356] In some embodiments, the compound of formula (III) or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% of the total area of ​​the HPLC chromatogram. In some embodiments, the compound of formula (III) or its solvate, or its crystalline form, contains no single impurity in an amount of less than or equal to about 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, or 0.05% of the total area of ​​the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0357] The structures illustrated for the compound of formula (III) are also intended to include all tautomers. Furthermore, the structures illustrated here are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms, for example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon substitution with carbon-rich carbon, fall within the scope of the present invention.

[0358] In some embodiments, the compound of formula (III) is compound III-1, and compound III-1 is a free base (or "free form"). In some embodiments, compound III-1 is an amorphous solid. In some embodiments, compound III-1 is a crystalline solid. In some embodiments, compound III-1 is a mixture of amorphous and crystalline solid forms.

[0359] In some embodiments, the present invention provides a form of compound III-1 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound III-1, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound III-1. In certain embodiments, at least about 95% by weight of compound III-1 is present. In certain embodiments, at least about 99% by weight of compound III-1 is present.

[0360] In other embodiments, compound III-1 is a crystalline solid substantially free of amorphous compound III-1. As used herein, the term "substantially free of amorphous compound III-1" means that the compound does not contain a significant amount of amorphous compound III-1. In certain embodiments, at least about 95% by weight of crystalline compound III-1 is present. In certain embodiments, at least about 99% by weight of crystalline compound III-1 is present.

[0361] Compound III-1 has been found to exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0362] In some embodiments, the solid crystal form of compound III-1 is form A. In some embodiments, form A of compound III-1 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 32A. In some embodiments, form A of compound III-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 23. In some embodiments, form A of compound III-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 23. In some embodiments, form A of compound III-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 23. In some embodiments, form A of compound III-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 23. In some embodiments, form A of compound III-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 23.

[0363] In some embodiments, form A of compound III-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 32C. In some embodiments, form A of compound III-1 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 32C. In some embodiments, form A of compound III-1 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0364] In some embodiments, the solid crystal form of compound III-1 is form B. In some embodiments, form B of compound III-1 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 33A. In some embodiments, form B of compound III-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 33C. In some embodiments, form A of compound III-1 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 33C. In some embodiments, form B of compound III-1 may simultaneously be characterized by substantial similarities to two or more of these figures.

[0365] In some embodiments, the solid crystal form of compound III-1 is form C. In some embodiments, form C of compound III-1 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 34A. In some embodiments, form C of compound III-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 34C. In some embodiments, form C of compound III-1 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 34C. In some embodiments, form C of compound III-1 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0366] In another embodiment, the compound of formula (III) is compound III-2, and compound III-2 is a hydrochloride salt. In some embodiments, compound III-2 is a monohydrochloride salt. In some embodiments, compound III-2 is a dihydrochloride salt. In some embodiments, compound III-2 is a trihydrochloride salt.

[0367] In some embodiments, compound III-2 is an amorphous solid. In some embodiments, compound III-2 is a crystalline solid. In some embodiments, compound III-2 is a mixture of amorphous and crystalline solid forms.

[0368] In some embodiments, the present invention provides a form of compound III-2 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound III-2, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound III-2. In certain embodiments, at least about 95% by weight of compound III-2 is present. In certain embodiments, at least about 99% by weight of compound III-2 is present.

[0369] In other embodiments, compound III-2 is a crystalline solid substantially free of amorphous compound III-2. As used herein, the term "substantially free of amorphous compound III-2" means that the compound does not contain a significant amount of amorphous compound III-2. In certain embodiments, at least about 95% by weight of crystalline compound III-2 is present. In certain embodiments, at least about 99% by weight of crystalline compound III-2 is present.

[0370] Compound III-2 has been found to exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0371] In some embodiments, the solid crystal form of compound III-2 is form A. In certain embodiments, form A of compound III-2 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 35A. In some embodiments, form A of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 31. In some embodiments, form A of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 31. In some embodiments, form A of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 31. In some embodiments, form A of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 31. In some embodiments, form A of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 31.

[0372] In some embodiments, form A of compound III-2 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 35C. In some embodiments, form A of compound III-2 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 35C. In some embodiments, form A of compound III-2 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0373] In some embodiments, the solid crystal form of compound III-2 is form B. In some embodiments, form B of compound III-2 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 36A. In some embodiments, form B of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 32. In some embodiments, form B of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 32. In some embodiments, form B of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 32. In some embodiments, form B of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 32. In some embodiments, form B of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 32.

[0374] In some embodiments, form B of compound III-2 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 36C. In some embodiments, form B of compound III-2 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 36C. In some embodiments, form B of compound III-2 may be characterized by substantial similarity to two or more of these figures simultaneously.

[0375] In some embodiments, the solid crystal form of compound III-2 is form C. In some embodiments, form C of compound III-2 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 37A. In some embodiments, form C of compound III-2 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 37C. In some embodiments, form C of compound III-2 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 37C. In some embodiments, form C of compound III-2 may be characterized by substantial similarity to two or more of these figures simultaneously.

[0376] In some embodiments, the solid crystal form of compound III-2 is form D. In some embodiments, form D of compound III-2 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 38A. In some embodiments, form D of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 33. In some embodiments, form D of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 33. In some embodiments, form D of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 33. In some embodiments, form D of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 33. In some embodiments, form D of compound III-2 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 33.

[0377] In some embodiments, form D of compound III-2 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 38C. In some embodiments, form D of compound III-2 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 38C. In some embodiments, form D of compound III-2 may be characterized by substantial similarities to two or more of these figures simultaneously.

[0378] In another embodiment, the compound of formula (III) is compound III-3, and compound III-3 is a hydrobromide salt. In some embodiments, compound III-3 is a monobromide salt. In some embodiments, compound III-3 is a dibromide salt. In some embodiments, compound III-3 is a tribromide salt.

[0379] In some embodiments, compound III-3 is an amorphous solid. In some embodiments, compound III-3 is a crystalline solid. In some embodiments, compound III-3 is a mixture of amorphous and crystalline solid forms.

[0380] In some embodiments, the present invention provides a form of compound III-3 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound III-3, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound III-3. In certain embodiments, at least about 95% by weight of compound III-3 is present. In certain embodiments, at least about 99% by weight of compound III-3 is present.

[0381] In certain embodiments, compound III-3 is a crystalline solid. In other embodiments, compound III-3 is a crystalline solid substantially free of amorphous compound III-3. As used herein, the term "substantially free of amorphous compound III-3" means that the compound does not contain a significant amount of amorphous compound III-3. In certain embodiments, at least about 95% by weight of crystalline compound III-3 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound III-3 is present.

[0382] In some embodiments, the solid crystal form of compound III-3 is form A. In some embodiments, form A of compound III-3 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 39A. In some embodiments, form A of compound III-3 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 34. In some embodiments, form A of compound III-3 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 34. In some embodiments, form A of compound III-3 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 34. In some embodiments, form A of compound III-3 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 34. In some embodiments, form A of compound III-3 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 34.

[0383] In some embodiments, form A of compound III-3 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 39C. In some embodiments, form A of compound III-3 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 39C. In some embodiments, form A of compound III-3 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0384] In another embodiment, the compound of formula (III) is compound III-4, and compound III-4 is a sulfate (or sulfate ester).

[0385] In some embodiments, compound III-4 is an amorphous solid. In some embodiments, compound III-4 is a crystalline solid. In some embodiments, compound III-4 is a mixture of amorphous and crystalline solid forms.

[0386] In some embodiments, the present invention provides a form of compound III-4 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound III-4, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound III-4. In certain embodiments, at least about 95% by weight of compound III-4 is present. In certain embodiments, at least about 99% by weight of compound III-4 is present.

[0387] In certain embodiments, compound III-4 is a crystalline solid. In other embodiments, compound III-4 is a crystalline solid substantially free of amorphous compound III-4. As used herein, the term "substantially free of amorphous compound III-4" means that the compound does not contain a significant amount of amorphous compound III-4. In certain embodiments, at least about 95% by weight of crystalline compound III-4 is present. In yet another embodiment of the present invention, at least about 99% by weight of crystalline compound III-4 is present.

[0388] Compound III-4 has been found to exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0389] In some embodiments, the solid crystal form of compound III-4 is form A. In some embodiments, form A of compound III-4 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 40A. In some embodiments, form A of compound III-4 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 35. In some embodiments, form A of compound III-4 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 35. In some embodiments, form A of compound III-4 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 35. In some embodiments, form A of compound III-4 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 35. In some embodiments, form A of compound III-4 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 35.

[0390] In some embodiments, form A of compound III-4 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 40C. In some embodiments, form A of compound III-4 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 40C. In some embodiments, form A of compound III-4 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0391] In some embodiments, the solid crystal form of compound III-4 is form B. In some embodiments, form B of compound III-4 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 41A. In some embodiments, form B of compound III-4 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 41C. In some embodiments, form B of compound III-4 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 41C. In some embodiments, form B of compound III-4 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0392] In another embodiment, the compound of formula (III) is compound III-5, and compound III-5 is a methanesulfonate.

[0393] In some embodiments, compound III-5 is an amorphous solid. In some embodiments, compound III-5 is a crystalline solid. In some embodiments, compound III-5 is a mixture of amorphous and crystalline solid forms.

[0394] In some embodiments, the present invention provides a form of compound III-5 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound III-5, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound III-5. In certain embodiments, at least about 95% by weight of compound III-5 is present. In certain embodiments, at least about 99% by weight of compound III-5 is present.

[0395] In other embodiments, compound III-5 is a crystalline solid substantially free of amorphous compound III-5. As used herein, the term "substantially free of amorphous compound III-5" means that the compound does not contain a significant amount of amorphous compound III-5. In certain embodiments, at least about 95% by weight of crystalline compound III-5 is present. In certain embodiments, at least about 99% by weight of crystalline compound III-5 is present.

[0396] In some embodiments, the solid crystal form of compound III-5 is form A. In some embodiments, form A of compound III-5 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 42A. In some embodiments, form A of compound III-5 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 36. In some embodiments, form A of compound III-5 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 36. In some embodiments, form A of compound III-5 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 36. In some embodiments, form A of compound III-5 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 36. In some embodiments, form A of compound III-5 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 36.

[0397] In some embodiments, form A of compound III-5 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 42C. In some embodiments, form A of compound III-5 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 42C. In some embodiments, form A of compound III-5 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0398] In another embodiment, the compound of formula (III) is compound III-6, which is a tartaric acid (or tartaric acid salt) salt.

[0399] In some embodiments, compound III-6 is an amorphous solid. In some embodiments, compound III-6 is a crystalline solid. In some embodiments, compound III-6 is a mixture of amorphous and crystalline solid forms.

[0400] In some embodiments, the present invention provides a form of compound III-6 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound III-6, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound III-6. In certain embodiments, at least about 95% by weight of compound III-6 is present. In certain embodiments, at least about 99% by weight of compound III-6 is present.

[0401] In other embodiments, compound III-6 is a crystalline solid substantially free of amorphous compound III-6. As used herein, the term "substantially free of amorphous compound III-6" means that the compound does not contain a significant amount of amorphous compound III-6. In certain embodiments, at least about 95% by weight of crystalline compound III-6 is present. In certain embodiments, at least about 99% by weight of crystalline compound III-6 is present.

[0402] In some embodiments, the solid crystal form of compound III-6 is form A. In some embodiments, form A of compound III-6 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 43A. In some embodiments, form A of compound III-6 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 43C. In some embodiments, form A of compound III-6 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 43C. In some embodiments, form A of compound III-6 may be characterized by substantial similarity to two or more of these figures simultaneously. Compound of formula (IV)

[0403] In one embodiment, the compound of formula (IV) [ka] or its solvate is provided herein (wherein, t is 1, 2, 3, 4, 5, 6, 7, 8 or 9, u is 0, 0.5, 1, 1.5, 2, 2.5, or 3. X is hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, or benzenesulfonic acid.

[0404] It will be recognized by those skilled in the art that the acid moiety indicated as "X" and 6-(6-ethynyl-2,4-dimethylpyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine can ionically bond to form the compound of formula (IV). It will also be recognized that when u is 0, X is absent, indicating that the compound of formula (IV) exists as a "free base," i.e., a "free form." It will be further recognized that the compound of formula (IV) can exist as specific rotational isomers or as mixtures of rotational isomers.

[0405] The compound of formula (IV) is intended to exist in various physical forms. For example, the compound of formula (IV) may be in solution, suspension or solid form. In certain embodiments, the compound of formula (IV) is in solid form. When the compound of formula (IV) is in solid form, it may be amorphous, crystalline or a mixture thereof. Exemplary solid forms are described in more detail below.

[0406] In some embodiments, the compound of formula (IV) may be in hydrate form. In some embodiments, the compound of formula (IV) may be in hemihydrate form.

[0407] In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 5. In some embodiments, t is 6. In some embodiments, t is 7. In some embodiments, t is 8. In some embodiments, t is 9.

[0408] In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 0.5. In some embodiments, u is 1.5. In some embodiments, u is 2.5.

[0409] In some embodiments, X is hydrochloric acid. In some embodiments, X is p-toluenesulfonic acid. In some embodiments, X is methanesulfonic acid. In some embodiments, X is benzenesulfonic acid.

[0410] In some embodiments, the present invention provides a form of the compound of formula (IV) that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of the compound of formula (IV), residual solvents, or any other impurities that may result from the preparation and / or isolation of the compound of formula (IV).

[0411] In some embodiments, the compound of formula (IV) or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight, where the percentage is relative to the total weight of the composition. In some embodiments, the compound of formula (IV) or its solvate, or its crystalline form, contains any single impurity in an amount of about 0.40% by weight or less, about 0.35% by weight or less, about 0.3% by weight or less, about 0.25% by weight or less, about 0.2% by weight or less, about 0.15% by weight or less, about 0.10% by weight or less, or about 0.05% by weight or less, where the percentage is relative to the total weight of the composition.

[0412] In some embodiments, the compound of formula (IV) or its solvate, or its crystalline form, is present in an amount of at least about 95, 95.5, 96, 96.5, 97, 97.5, 98.0, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% of the total area of ​​the HPLC chromatogram. In some embodiments, the compound of formula (IV) or its solvate, or its crystalline form, contains no single impurity in an amount of less than or equal to about 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, or 0.05% of the total area of ​​the HPLC chromatogram. In some embodiments, the HPLC method is the HPLC method described in Example 1.

[0413] The structures illustrated for the compound of formula (IV) are also intended to include all tautomers. Furthermore, the structures illustrated here are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms, for example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon substitution with carbon-rich carbon, fall within the scope of the present invention.

[0414] In some embodiments, the compound of formula (IV) is compound IV-1, and compound IV-1 is a free base (or "free form"). In some embodiments, compound IV-1 is an amorphous solid. In some embodiments, compound IV-1 is a crystalline solid. In some embodiments, compound IV-1 is a mixture of amorphous and crystalline solid forms.

[0415] In some embodiments, the present invention provides a form of compound IV-1 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound IV-1, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound IV-1. In certain embodiments, at least about 95% by weight of compound IV-1 is present. In certain embodiments, at least about 99% by weight of compound IV-1 is present.

[0416] In other embodiments, compound IV-1 is a crystalline solid substantially free of amorphous compound IV-1. As used herein, the term "substantially free of amorphous compound IV-1" means that the compound does not contain a significant amount of amorphous compound IV-1. In certain embodiments, at least about 95% by weight of crystalline compound IV-1 is present. In certain embodiments, at least about 99% by weight of crystalline compound IV-1 is present.

[0417] In some embodiments, the solid crystal form of compound IV-1 is form A. In some embodiments, form A of compound IV-1 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 44A. In some embodiments, form A of compound IV-1 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 39. In some embodiments, form A of compound IV-1 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 39. In some embodiments, form A of compound IV-1 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 39. In some embodiments, form A of compound IV-1 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 39. In some embodiments, form A of compound IV-1 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 39.

[0418] In some embodiments, form A of compound IV-1 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 44C. In some embodiments, form A of compound IV-1 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 44C. In some embodiments, form A of compound IV-1 may be characterized by substantial similarities to two or more of these figures simultaneously.

[0419] In another embodiment, the compound of formula (IV) is compound IV-2, and compound IV-2 is a hydrochloride salt. In some embodiments, compound IV-2 is a monohydrochloride salt. In some embodiments, compound IV-2 is a dihydrochloride salt. In some embodiments, compound IV-2 is a trihydrochloride salt. In some embodiments, compound IV-2 is an amorphous solid. In some embodiments, compound IV-2 is a crystalline solid. In some embodiments, compound IV-2 is a mixture of amorphous and crystalline solid forms.

[0420] In some embodiments, the present invention provides a form of compound IV-2 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound IV-2, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound IV-2. In certain embodiments, at least about 95% by weight of compound IV-2 is present. In certain embodiments, at least about 99% by weight of compound IV-2 is present.

[0421] In other embodiments, compound IV-2 is a crystalline solid substantially free of amorphous compound IV-2. As used herein, the term "substantially free of amorphous compound IV-2" means that the compound does not contain a significant amount of amorphous compound IV-2. In certain embodiments, at least about 95% by weight of crystalline compound IV-2 is present. In certain embodiments, at least about 99% by weight of crystalline compound IV-2 is present.

[0422] In some embodiments, the solid crystal form of compound IV-2 is form A. In some embodiments, form A of compound IV-2 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 45A. In some embodiments, form A of compound IV-2 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 44. In some embodiments, form A of compound IV-2 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 44. In some embodiments, form A of compound IV-2 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 44. In some embodiments, form A of compound IV-2 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 44. In some embodiments, form A of compound IV-2 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 44.

[0423] In some embodiments, form A of compound IV-2 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 45C. In some embodiments, form A of compound IV-2 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 45C. In some embodiments, form A of compound IV-2 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0424] In another embodiment, the compound of formula (IV) is compound IV-3, which is p-toluenesulfonate. In some embodiments, compound IV-3 is an amorphous solid. In some embodiments, compound IV-3 is a crystalline solid. In some embodiments, compound IV-3 is a mixture of amorphous and crystalline solid forms.

[0425] In some embodiments, the present invention provides a form of compound IV-3 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound IV-3, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound IV-3. In certain embodiments, at least about 95% by weight of compound IV-3 is present. In certain embodiments, at least about 99% by weight of compound IV-3 is present.

[0426] In other embodiments, compound IV-3 is a crystalline solid substantially free of amorphous compound IV-3. As used herein, the term "substantially free of amorphous compound IV-3" means that the compound does not contain a significant amount of amorphous compound IV-3. In certain embodiments, at least about 95% by weight of crystalline compound IV-3 is present. In certain embodiments, at least about 99% by weight of crystalline compound IV-3 is present.

[0427] Compound IV-3 has been found to exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0428] In some embodiments, the solid crystal form of compound IV-3 is form A. In some embodiments, form A of compound IV-3 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 46A. In some embodiments, form A of compound IV-3 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 45. In some embodiments, form A of compound IV-3 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 45. In some embodiments, form A of compound IV-3 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 45. In some embodiments, form A of compound IV-3 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 45. In some embodiments, form A of compound IV-3 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 45.

[0429] In some embodiments, form A of compound IV-3 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 46C. In some embodiments, form A of compound IV-3 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 46C. In some embodiments, form A of compound IV-3 may be characterized simultaneously by substantial similarities to two or more of these figures.

[0430] In some embodiments, the solid crystal form of compound IV-3 is form B. In some embodiments, form B of compound IV-3 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 47A. In some embodiments, form B of compound IV-3 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 46. In some embodiments, form B of compound IV-3 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 46. In some embodiments, form B of compound IV-3 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 46. In some embodiments, form B of compound IV-3 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 46. In some embodiments, form B of compound IV-3 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 46.

[0431] In some embodiments, form B of compound IV-3 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 47C. In some embodiments, form B of compound IV-3 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 47C. In some embodiments, form B of compound IV-3 may be characterized by substantial similarities to two or more of these figures simultaneously.

[0432] In another embodiment, the compound of formula (IV) is compound IV-4, which is a methanesulfonate. In some embodiments, compound IV-4 is an amorphous solid. In some embodiments, compound IV-4 is a crystalline solid. In some embodiments, compound IV-4 is a mixture of amorphous and crystalline solid forms.

[0433] In some embodiments, the present invention provides a form of compound IV-4 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound IV-4, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound IV-4. In certain embodiments, at least about 95% by weight of compound IV-4 is present. In certain embodiments, at least about 99% by weight of compound IV-4 is present.

[0434] In other embodiments, compound IV-4 is a crystalline solid substantially free of amorphous compound IV-4. As used herein, the term "substantially free of amorphous compound IV-4" means that the compound does not contain a significant amount of amorphous compound IV-4. In certain embodiments, at least about 95% by weight of crystalline compound IV-4 is present. In certain embodiments, at least about 99% by weight of crystalline compound IV-4 is present.

[0435] In some embodiments, the solid crystal form of compound IV-4 is form A. In some embodiments, form A of compound IV-4 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 48A. In some embodiments, form A of compound IV-4 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 47. In some embodiments, form A of compound IV-4 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 47. In some embodiments, form A of compound IV-4 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 47. In some embodiments, form A of compound IV-4 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 47. In some embodiments, form A of compound IV-4 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 47.

[0436] In some embodiments, form A of compound IV-4 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 48C. In some embodiments, form A of compound IV-4 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 48C. In some embodiments, form A of compound IV-4 may be characterized by substantial similarities to two or more of these figures simultaneously.

[0437] In another embodiment, the compound of formula (IV) is compound IV-5, which is a benzenesulfonate. In some embodiments, compound IV-5 is an amorphous solid. In some embodiments, compound IV-5 is a crystalline solid. In some embodiments, compound IV-5 is a mixture of amorphous and crystalline solid forms.

[0438] In some embodiments, the present invention provides a form of compound IV-5 that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include different forms of compound IV-5, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound IV-5. In certain embodiments, at least about 95% by weight of compound IV-5 is present. In certain embodiments, at least about 99% by weight of compound IV-5 is present.

[0439] In other embodiments, compound IV-5 is a crystalline solid substantially free of amorphous compound IV-5. As used herein, the term "substantially free of amorphous compound IV-5" means that the compound does not contain a significant amount of amorphous compound IV-5. In certain embodiments, at least about 95% by weight of crystalline compound IV-5 is present. In certain embodiments, at least about 99% by weight of crystalline compound IV-5 is present.

[0440] In some embodiments, the solid crystal form of compound IV-5 is form A. In some embodiments, form A of compound IV-5 has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern illustrated in Figure 49A. In some embodiments, form A of compound IV-5 may be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 48. In some embodiments, form A of compound IV-5 may be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 48. In some embodiments, form A of compound IV-5 may be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 48. In some embodiments, form A of compound IV-5 may be characterized by a powder X-ray diffraction pattern having at least five characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 48. In some embodiments, form A of compound IV-5 may be characterized by a powder X-ray diffraction pattern having at least six characteristic peaks at 2θ degrees, each selected from the group of peaks listed in Table 48.

[0441] In some embodiments, form A of compound IV-5 has a differential scanning calorimetry (DSC) pattern substantially similar to the differential scanning calorimetry (DSC) pattern illustrated in Figure 49C. In some embodiments, form A of compound IV-5 has a thermogravimetric analysis pattern substantially similar to the thermogravimetric analysis pattern illustrated in Figure 49C. In some embodiments, form A of compound IV-5 may be characterized simultaneously by substantial similarities to two or more of these figures. method

[0442] In some embodiments, methods for treating patients with intrahepatic cholangiocarcinoma (ICC) and / or other progressive solid tumors are provided herein, using compounds or solvates thereof described herein, or their solid forms, or pharmaceutical compositions thereof. In some embodiments, the patient has a progressive, unresectable solid tumor with FGFR2 alteration. In some embodiments, the patient has a measurable or evaluable disease according to RECIST v1.1.

[0443] In some embodiments, methods for treating patients with intrahepatic cholangiocarcinoma (ICC) and / or other advanced solid tumors are provided herein, using compound I-1 or its solvates, or their solid forms, or their pharmaceutical compositions. In some embodiments, compound I-1 or its solvates, or their solid forms, or their pharmaceutical compositions are administered orally twice daily. In some embodiments, compound I-1 or its solvates, or their solid forms, or their pharmaceutical compositions are administered orally twice daily at a dose of 50 mg / dose.

[0444] In some embodiments, the patient is 18 years of age or older. In some embodiments, the patient has a disease that is refractory to standard treatment. In some embodiments, the patient has a disease that does not respond adequately to standard treatment. In some embodiments, the patient has a disease for which no standard or curative treatment exists. In some embodiments, the patient is intolerant of or refuses standard treatment.

[0445] In some embodiments, the patient has a US East Coast Cancer Clinical Trials Group (ECOG) Performance Status (PS) of 0 disease and FGFR2 status. In some embodiments, the patient shows FGFR2 changes in the blood and / or tumor by local assessment, as defined by one or more of the following: • The FGFR2 fusion includes genomic translocations that are expected to create oncogenic FGFR2 fusion proteins detectable by DNA or RNA sequencing, or to cause FISH splitting. FGFR2 amplification includes amplified FGFR2 loci with copy number ≥ 8 in tumor tissue [e.g., FGFR2 amplification factor ≥ 4 per next-generation sequencing (NGS) or FGFR2 probe; reference ratio ≥ 4 per fluorescence in situ hybridization (FISH)]. The FGFR2 mutation includes one or more of the following primary oncogenic FGFR2 mutations or acquired FGFR2 resistance mutations: H167_N173del, S252X, P253X, Y375X, C382X, M537X, N549X, V564X, E565X, L617X, K641X, K659X, and R664X (numbered based on mesenchymal isoform IIIc; X represents any amino acid change).

[0446] In some embodiments, the patient has a histologically or cytologically confirmed diagnosis of unresectable ICC or other progressive unresectable solid tumor. In some embodiments, the patient exhibits FGFR2 genomic alterations (fusion, amplification, or mutation) in the blood and / or tumor tissue by local evaluation. In some embodiments, the patient has the potential for oncogenic FGFR2 alterations (e.g., FGFR2 protein or mRNA overexpression).

[0447] In some embodiments, the patient has a confirmed diagnosis of unresectable incisional carcinoma (ICC) with FGFR2 fusion (as determined by local evaluation of the blood and / or tumor) and has received prior treatment with a pan-FGFR inhibitor (e.g., pemigatinib, erdafitinib, infiglatinib, TAS-120).

[0448] In some embodiments, the patient has a confirmed diagnosis of unresectable incisional carcinoma (ICC) with FGFR2 fusion (as determined by local evaluation of blood and / or tumor) and has not received prior treatment with a pan-FGFR inhibitor (e.g., pemigatinib, erdafitinib, infiglatinib, TAS-120).

[0449] In some embodiments, the patient has a progressive, unresectable solid tumor with FGFR2 fusions other than ICC (as determined by local evaluation of the blood and / or tumor).

[0450] In some embodiments, the patient has a progressive, unresectable solid tumor with FGFR2 amplification (as determined by local assessment of the blood and / or tumor).

[0451] In some embodiments, the patient has a progressive, unresectable solid tumor with an oncogenic FGFR2 mutation (as determined by local evaluation of the blood and / or tumor).

[0452] In some embodiments, the patient has a known primary driver alteration other than FGFR2 (e.g., EGFR, ALK, ROS, RET, PI3K, HER2, BRAF) that is suitable for approved targeted therapies, rather than a patented alteration.

[0453] In some embodiments, the patient has no history of clinically significant corneal or retinal disorders, nor are they currently progressing.

[0454] In some embodiments, the patient does not have any of the following within 14 days prior to the first dose of compound I-1: a. Platelet count < 75 × 10⁻⁶ 9 / L; b. Absolute neutrophil count (ANC) < 1 × 10⁻⁶ 9 / L; c. Hemoglobin < 8 g / dL (Red blood cell transfusions and erythropoietin may be used to reach 8 g / dL, but these must have been administered at least two weeks prior to the first dose of compound I-1); d. If liver metastases are absent, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × upper limit of normal (ULN); if liver metastases are present, > 5 × ULN; e. Total bilirubin > 1.5 × ULN, and in the presence of Gilbert's disease, direct bilirubin > 3 × ULN accompanied by > 1.5 × ULN; f. Estimated (Cockroft-Gault formula) or measured creatinine clearance <50 mL / min.

[0455] In some embodiments, the patient does not have a known active human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) and / or hepatitis C virus (HCV).

[0456] In some embodiments, the patient does not have a QTcF > 480 msec. In some embodiments, the patient has no history of QT longevity syndrome or Torsades de Pointes. In some embodiments, the patient has no family history of QT longevity syndrome.

[0457] In some embodiments, the patient does not have clinically significant uncontrolled cardiovascular disease, including congestive heart failure grade III or IV, as classified by the New York Heart Association (NYHA); or clinically significant uncontrolled arrhythmias (e.g., type II second-degree or third-degree atrioventricular block), including myocardial infarction or unstable angina, uncontrolled hypertension (grade 3 or higher), or bradyarrythmias that could cause prolonged QT intervals within the preceding six months.

[0458] In some embodiments, the patient has neither central nervous system (CNS) tumor metastases nor primary CNS tumors with progressive neurological symptoms, or requires increased doses of corticosteroids to control CNS disease. In some embodiments, the patient is a patient who requires corticosteroids to manage CNS disease, and the dose is stable for two weeks prior to day 1 of cycle 1 (C1D1). In some embodiments, the patient has stable or asymptomatic CNS tumor metastases or primary CNS.

[0459] In some embodiments, the patient has not received systemic antineoplasm therapy or radiation therapy within 14 days or 5 half-lives prior to the first dose of compound I-1.

[0460] In some embodiments, the patient has not received local hepatic treatment (e.g., TACE or Y90) within four weeks prior to C1D1. In some embodiments, the patient has not received neutrophil growth factor support therapy within 14 days of the first dose of compound I-1. In some embodiments, the patient is not a patient who requires treatment involving prohibited drugs or herbal therapies that cannot be interrupted for at least two weeks prior to the initiation of compound I-1 administration.

[0461] In some embodiments, the patient has not undergone a major surgical procedure (such as central venous catheter placement or tumor needle biopsy, but feeding tube placement is not considered a major surgical procedure) within 14 days of the first dose of compound I-1.

[0462] In some embodiments, the patient has no history of another primary malignancy diagnosed or requiring treatment within the past year, in which case the primary malignancy is not a completely excised basal cell or squamous cell carcinoma, a curatively treated localized prostate cancer, a curatively treated localized thyroid cancer, or a completely excised in-situ cancer of any site.

[0463] In some embodiments, the methods provided herein include monitoring serum phosphorus and / or calcium levels before and / or after administration of a compound (e.g., compound I-1) or its solvate, or their solid form, or their pharmaceutical composition. In some embodiments, the methods provided herein do not significantly increase serum phosphorus and / or calcium levels. In some embodiments, the methods provided herein include an increase in serum phosphorus and / or calcium levels of about 2% or less, about 5% or less, about 10% or less, about 15% or less, about 20% or less, about 25% or less, or about 30% or less compared to before administration, after administration of a compound (e.g., compound I-1) or its solvate, or their solid form, or their pharmaceutical composition.

[0464] In some embodiments, the methods provided herein include a step of limiting the patient's direct exposure to sunlight to avoid potential phototoxicity. In some embodiments, the methods provided herein include a step of applying a sunscreen to the patient. In some embodiments, the methods provided herein include a step of advising the patient to use a sunscreen and / or wear sunglasses.

[0465] In some embodiments, methods for inhibiting FGFR2 activity, and therefore useful for treating one or more disorders related to the activity of FGFR2 or its variants, are disclosed herein. Accordingly, in certain embodiments, the present invention provides a method for treating an FGFR2-mediated disorder in a subject, comprising the step of administering a therapeutically effective amount of a solid form disclosed herein or a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition, to the subject. In some embodiments, the subject is human.

[0466] As used herein, the terms “FGFR2-mediated” disorder, disease, and / or condition mean any disease or other adverse condition in which FGFR2 or its variants are known to play a predetermined role. Therefore, another embodiment of the present invention relates to treating or mitigating the severity of one or more diseases in which FGFR2 or its variants are known to play a certain role. Such FGFR2-mediated disorders include, but are not limited to, proliferative disorders (e.g., cancer) and craniosynostosis syndrome.

[0467] In some embodiments, the present invention provides a method for treating one or more disorders, wherein the disorder is selected from proliferative disorders and craniosynostosis syndrome, and the method comprises administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or any of the pharmaceutically acceptable compositions described above, to a patient who requires treatment for one or more disorders. In some embodiments, the present invention provides a method for treating one or more disorders, wherein the disorder is selected from proliferative disorders and craniosynostosis syndrome, and the method comprises administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable composition thereof to a patient who requires treatment for one or more disorders.

[0468] In some embodiments, the impairment is related to FGFR2 signaling. FGFR2 and other receptor tyrosine kinases (RTKs) are known to have multiple upstream and downstream signaling pathways (see Turner and Grose, Nat. Rev. Cancer (2010)10, 116), and inhibition of FGFR2 can be used to disrupt abnormal signaling within those pathways. The disorders related to these can be addressed. In some embodiments, the disorders are related to FGF signaling, JAK-STAT signaling, PI3K-Akt signaling, PLC-gamma signaling, or MAPK signaling.

[0469] In some embodiments, the treatment method includes the steps of: i) identifying a subject requiring such treatment; (ii) preparing a disclosed compound or a pharmaceutically acceptable salt thereof; and (iii) administering the prepared compound in a therapeutically effective dose to treat, suppress and / or prevent a disease condition or state in the subject requiring such treatment.

[0470] In some embodiments, the treatment method includes the steps of: i) identifying a subject requiring such treatment; (ii) preparing a composition comprising the disclosed compound or a pharmaceutically acceptable salt thereof; and (iii) administering the composition in a therapeutically effective dose to treat, suppress and / or prevent a disease condition or state in the subject requiring such treatment.

[0471] Another aspect of the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof, or any of the above-described pharmaceutical compositions, for use in the treatment of the disorders described herein. Another aspect of the present invention provides the use of a compound as defined herein or a pharmaceutically acceptable salt thereof, or any of the above-described pharmaceutical compositions, for use in the treatment of the disorders described herein. Similarly, the present invention provides the use of a compound as defined herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of the disorders described herein.

[0472] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the proliferative disorder is leukemia, breast cancer, lung cancer, colorectal cancer, or a combination thereof. In some embodiments, the proliferative disorder is leukemia. In some embodiments, the proliferative disorder is breast cancer. In some embodiments, the proliferative disorder is lung cancer. In some embodiments, the proliferative disorder is colorectal cancer.

[0473] In some embodiments, the proliferative disorder is intrahepatic cholangiocarcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, squamous cell carcinoma of the lung, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, or urothelial carcinoma. In some embodiments, the proliferative disorder is intrahepatic cholangiocarcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, squamous cell carcinoma of the lung, thyroid cancer, gastric cancer, or ovarian cancer. In some embodiments, the proliferative disorder is gastric cancer, breast cancer, triple-negative breast cancer, or rectal cancer. In some embodiments, the proliferative disorder is endometrial cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, gastric cancer, breast cancer, or urothelial carcinoma.

[0474] In some embodiments, proliferative disorders are associated with one or more activating mutations in FGFR2. In some embodiments, the activating mutation in FGFR2 is a mutation in one or more of the intracellular kinase domain and / or extracellular domain. In some embodiments, the activating mutation in FGFR2 is a mutation in the intracellular kinase domain. In some embodiments, the activating mutation in FGFR2 is a mutation in the extracellular domain. In some embodiments, the activating mutation in FGFR2 is selected from N549K, K659N / M, S252W, P253R, and combinations thereof. In some embodiments, the activating mutation in FGFR2 is N549K or K659N / M. In some embodiments, the activating mutation in FGFR2 is N549K. In some embodiments, the activating mutation in FGFR2 is K659N / M. In some embodiments, the activating mutation in FGFR2 is S252W or P253R. In some embodiments, the activating mutation in FGFR2 is S252W. In some embodiments, the activating mutation in FGFR2 is P253R.

[0475] In some embodiments, proliferative impairment is associated with one or more resistance mutations in FGFR2. In some embodiments, the resistance mutations in FGFR2 are selected from V564F, E565A, N549K / H / T, and L617V, as well as combinations thereof. In some embodiments, the resistance mutation in FGFR2 is V564F. In some embodiments, the resistance mutation in FGFR2 is E565A. In some embodiments, the resistance mutation in FGFR2 is N549K / H / T. In some embodiments, the resistance mutation in FGFR2 is L617V.

[0476] In some embodiments, the compounds or compositions of the Disclosure may be useful in inhibiting tumor cell growth. In some embodiments, the compounds or compositions of the Disclosure may be useful in relieving the pathogenesis of systemic lupus erythematosus. In some embodiments, the compounds or compositions of the Disclosure may be useful in treating a variety of other disorders, including Noonan syndrome (NS), Leopard syndrome (Noonan syndrome including lentigo multifocals), diabetes mellitus, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia (JMML), chronic myelomonocytic leukemia, acute myeloid leukemia, HER2-positive breast cancer, triple-negative breast cancer, thoracic tubal carcinoma, invasive thoracic tubal carcinoma, non-small cell lung cancer (including adenocarcinoma of the lung), colorectal cancer (SW480, SW620, CACO2, HCT116, HT29 colon cancer cell lines), esophageal cancer, gastric cancer, head and neck squamous cell carcinoma (SCCHN), and neutropenia (Kostmann syndrome).

[0477] In some embodiments, the compounds or compositions of the Disclosure may be used in combination with other treatments and / or cancer therapies. For example, the compounds or compositions of the Disclosure may be used in combination with antibodies, antibody-drug conjugates, kinase inhibitors, immunomodulators, and histone deacetylase inhibitors, but are not limited to the following. The compounds or compositions of the Disclosure may also be used in combination with other treatments and / or cancer therapies disclosed in WO2018 / 057884, WO2015 / 107495, WO2018 / 172984, and WO2018 / 136265, each of which is incorporated in whole by reference in this specification; and in references cited therein, such as SHP099, RLY1971, RMC-4550, RMC4630, JAB3068, JAB3312, or TNO155.

[0478] In some embodiments, the compounds or compositions of the present disclosure are compounds of the formula: [ka] Alternatively, it can be used in combination with a pharmaceutically acceptable salt thereof.

[0479] For example, the compounds disclosed herein (or pharmaceutical compositions containing them) can be used alone or in combination with other therapeutic agents to treat one or more of the diseases specified herein. For example, the compound of formula (I) can be used in combination with the following agents: BCR-ABL inhibitors: imatinib mesylate; inilotinib hydrochloride; nilotinib; dasatinib; bosutinib; ponatinib; bafetinib; danucertib; salakatinib; N-[2-[(1S,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl))-2 -Pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalene-1,4-imine-9-yl]-2-oxoethyl]acetamide. ALK inhibitors: crizotinib; 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)phenyl)pyrimidin-2,4-diamine, ceritinib, alectinib, brigatinib, entrecinib. BRAF inhibitors: vemurafenib and dabrafenib. FGFR inhibitors: infiglatinib, dovitinib, erdafitinib, BLU-554, AZD4547. FLT3 inhibitors: sunitinib malate; midostaurin; tanutinib; sorafenib, restaurtinib, quizartinib, and klenolanib. KRAS inhibitors: MRTX849, AMG510. MEK inhibitors: trametinib, combimetinib, binimetinib, selumetinib. VEGF receptor inhibitors: bevacizumab, axitinib, aflibercept, (N-methyl-2-[[3-[(E)-2-pyridine-2-ylethenyl]-1H-indazole-6-yl]sulfanil]benzamide, brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indole-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-yloxy)propan-2-yl)2-aminopropanoate, motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indole-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecal Boxamide, pasireotide, sorafenib. Tyrosine kinase inhibitors: erlotinib hydrochloride, linifanib, sunitinib malate, pazopanib. Epidermal growth factor receptor (EGFR) inhibitors: gefitonib, osimertinib, cetuximab, panitumumab. HER2 receptor inhibitors: trastuzumab, neratinib, lapatinib or lapatinib nitosylate. MET inhibitors: crizotinib, cabozantinib. CD20 antibodies: rituximab, tocitumomab, ofatumumab. DNA synthesis inhibitors: capecitabine, gemcitabine hydrochloride, nelarabine, hydroxycarbamide. Antineoplastic agents: oxaliplatin. HER dimerization inhibitors: pertuzumab.Human granulocyte colony-stimulating factor (G-CSF) modulator: filgrastim. Immunomodulators: aftuzumab, lenalidomide, thalidomide. CD40 inhibitor: dasetuzumab. Apoptosis-inducing receptor agonist (PARA): duranermin. Heat shock protein (HSP) inhibitor: tanespimycin (17-allylamino-17-demethoxygeldanamycin). Hedgehog antagonist: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)-benzamide. Proteasome inhibitor: bortezomib. PI3K inhibitor: 4-[2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)piperazine-1-yl]methyl]thieno[3,2-d]pyrimidine-4-yl]mocholine, 2. -Methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4,5-c]quinoline-1-yl]phenyl]propiocyano, buparlicib, tasericib, idelalisib, duvelicib, TGR1202. Phospholipase A2 inhibitor: Anagrelide. BCL-2 inhibitor: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide. Fission-promoting factor-activated protein kinase (MEK) inhibitor: XL-518. Aromatase inhibitors: exemestane, letrozole, anastrozole, faslodex, tamoxifen. Topoisomerase I inhibitors: irinotecan, topotecan hydrochloride. Topoisomerase II inhibitors: etoposide, teniposide. mTOR inhibitors: temsirolimus, ridafololimus, everolimus. Osteoclast bone resorption inhibitors: 1-hydroxy-2-imidazole-1-ylphosphonoethyl)phosphonic acid monohydrate. CD33 antibody drug conjugate: gemtuzumab ozogamicin. CD22 antibody drug conjugate: inotuzumab ozogamicin. CD20 antibody drug conjugate: ibritumomab tiuxetan. Somatostatin analog: octreotide. Synthetic interleukin-11 (IL-11): oprelbequin. Synthetic erythropoietin: darbepoetin alfa. Receptor activator for nuclear factor-κB (RANK) inhibitors: denosumab. Thrombopoietin mimetic peptide: romiplostim. Cell proliferation promoter: palifermin. Anti-insulin-like growth factor-1 receptor (IGF-1R) antibody: figtumumab. Anti-CSl antibody: elotuzumab. CD52 antibody: alemtuzumab. CTLA-4 inhibitors: tremelimumab, ipilimumab. PD1 inhibitors: nivolumab; pembrolizumab; immunoadhesin; pizilizumab; and AMP-224. PDL1 inhibitors: MSB0010718C; YW243.55.S70, MPDL3280A; MEDI-4736, MSB-0010718C or MDX-1105. LAG-3 inhibitor: BMS-986016.GITR agonists: GITR fusion proteins and anti-GITR antibodies. Histone deacetylase inhibitors (HDIs): Voninostat. Anti-CTLA4 antibodies: Tremelimumab and ipilimumab. Alkylating agents: Temozolomide, dactinomycin, melphalan, altoretamine, carmustine, bendamustine, busulfan, carboplatin, lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, altoretamine, ifosamide, procarbazine, mechloretamine, mustine and mechloroetamine hydrochloride, streptozocin, thiotepa. Bio-response modifiers: Calmet-Guéran bacilli, Denileukin difuticox. Antitumor antibiotics: Doxorubicin, bleomycin, daunorubicin, daunorubicin liposome, mitoxantrone, epirubicin, idarubicin, mitomycin C. Antimicrotubule agents: Estramustine. Cathepsin K inhibitors: Odanacatib. Epothyron B analog: Ixabepyrone. TpoR agonists: Eltrombopag. Antimitotic agents: Docetaxel. Adrenal steroid inhibitors: Aminoglutethimide. Antiandrogen drugs: Nilutamide, androgen receptor inhibitors: Enzalutamide, abiraterone acetate, orteronel, galeterone and ceviteronel, bicalutamide, flutamide. Androgens: Fluoxymesterone. CDK inhibitors: Arbocidib, palbociclib, ribociclib, trilaciclib, abemaciclib. TRK inhibitors: Entrectinib, larotrectinib. RET inhibitors: BLU-667, LOXO-292. Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or Leuprolide acetate.Taxane antineoplastic agents: Cabazitaxel (1-hydroxy,10-dimethoxy-9-oxo-5,20-epoxytaxa-11-en-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate), Larotaxel ((2α,5β,7β,10β,13α)-4,10-diacetoxy-1-hydroxy-13-{[(2R,3S)-2-hydroxy-3-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-3-phenylpropanoyl]oxy}-9-oxo-5,20-epoxy-7,19-cyclotaxa-11-en-2-ylbenzoate). 5HTla receptor agonist: xaliproden (also known as SR57746, 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine).

[0480] HPC vaccines: Cervarix®, marketed by GlaxoSmithKline; Gardasil®, marketed by Merck;

[0481] Iron chelating agent: Deferasirox. Antimetabolites: Claribine (2-chlorodeoxyadenosine), 5-fluorouracil, 6-thioguanine, pemetrexed, cytarabine, cytarabine liposome, decitabine, hydroxyurea, fludarabine, phloxuridine, cladribine, methotrexate, pentostatin. Bisphosphonate: Pamidronate. Demethylating agent: 5-azacitidine, decitabine.

[0482] Plant alkaloids: Paclitaxel protein binding; vinblastine, vincristine, vinorelbine, paclitaxel.

[0483] Retinoids: Alitretinoin (sold under the trademark name Panretin®), Tretinoin (also known as ATRA, all-trans retinoic acid, sold under the trademark name Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the trademark names Accutane®, Amnesteem®, Claravis®, Claras®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), Bexarotene (sold under the trademark name Targretin®).Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort) Dexamethasone ((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one), prednisolone (marketed under the trademarks Delta-Cortel(registered trademark), Orapred(registered trademark), Pediapred(registered trademark), and Prelone(registered trademark)), prednisone (Deltasone(registered trademark), Liquid Medicinal herbs (marketed under the trademarks Red (registered trademark), Meticorten (registered trademark), and Orasone (registered trademark)), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, and sodium methylprednisolone succinate, marketed under the trademarks Duralone (registered trademark), Medralone (registered trademark), Medrol (registered trademark), M-Prednisol (registered trademark), and Solu-Medrol (registered trademark)). Cytokines: Interleukin-2 (also known as aldesleukin and IL-2, marketed under the trademark Proleukin (registered trademark)), interleukin-11 (also known as opleukin, marketed under the trademark Neumega (registered trademark)), alpha-interferon alpha (also known as IFN-alpha, marketed under the trademarks Intron (registered trademark) A and Roferon-A (registered trademark)). Estrogen receptor downmodulators: fulvestrant (marketed under the trademark Faslodex (registered trademark)). Anti-estrogen agent: Tamoxifen (sold under the trademark name Novaldex®).Toremifene (sold under the trademark name Fareston®). Selective estrogen receptor modulator (SERM): Raloxifene (sold under the trademark name Evista®). Luteinizing hormone-releasing hormone (LHRH) agonist: Goserelin (sold under the trademark name Zoladex®).

[0484] Progesterone: Megestrol (also known as megestrol acetate, marketed under the trademark name Megace®); various cytotoxic agents: arsenic trioxide (marketed under the trademark name Trizenox®), asparaginase (L-asparaginase, also known as Elwinia-derived L-asparaginase, marketed under the trademark names Elspar® and Kidrolase®). Antiemetics: NK-1 receptor antagonists: Casopitant (marketed by GlaxoSmithKline under the trademark names Rezonic® and Zunrisa®); and

[0485] Cytoprotective agents: Amiphostin (marketed under the trademark name Ethyol®), leucovorin (also known as leucovorin calcium, citroboram factor, and folinic acid). Immune checkpoint inhibitors: The term “immune checkpoint” refers to a group of molecules on the cell surface of CD4 and CD8 T cells. Immune checkpoint molecules include, but are not limited to, programmed death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40, and LAG3. Immunotherapy agents that can act as immune checkpoint inhibitors useful in the methods of this disclosure include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and / or TGFR beta.

[0486] In certain embodiments, the compounds described herein function as allosteric inhibitors and can block the activation of FGFR2 by targeting the autoinhibitory conformation of FGFR2.

[0487] The compounds described herein can be ligated to one end of the variable chain, while the other end of the variable chain can be bound to the E3 ligase. Thus, recruitment of FGFR2 to the ligase results in the disruption of the FGFR2 protein.

[0488] In some embodiments, the compounds or compositions of the Disclosure may be used in combination with an antibody. In some embodiments, the compounds or compositions of the Disclosure may be used in combination with an antibody-drug conjugate. In some embodiments, the compounds or compositions of the Disclosure may be used in combination with a kinase inhibitor. In some embodiments, the compounds or compositions of the Disclosure may be used in combination with an immunomodulator. In some embodiments, the compounds or compositions of the Disclosure may be used in combination with a histone deacetylase inhibitor.

[0489] In some embodiments, the disclosed compounds may be administered to subjects requiring treatment at dosages ranging from about 0.0001 mg to about 100 mg / kg body weight per day, for example, about 1.0 to 10 mg / kg. However, additional variability is within the scope of this disclosure.

[0490] The disclosed compounds may be administered alone or in combination with pharmaceutically acceptable carriers such as diluents, fillers, aqueous solutions, and even organic solvents. The compounds and / or compositions of this disclosure may be administered as tablets, powders, lozenges, syrups, injectable solutions, etc. Additional components such as flavorings, binders, and additives are within the scope of this disclosure.

[0491] In some embodiments, the Disclosure provides pharmaceutical compositions and / or pharmaceutical uses comprising compounds disclosed herein or pharmaceutically acceptable salts thereof in methods for treating disease conditions and / or states caused by or associated with FGFR2 kinase. For example, methods are provided herein for treating subjects in need of treatment (e.g., subjects suffering from cancer (e.g., leukemia, breast cancer, lung cancer and / or colorectal cancer)) with an effective amount of a disclosed compound and, optionally, an effective amount of additional compounds (e.g., therapeutic agents), such as those disclosed herein.

[0492] In some embodiments, the treatment method includes the steps of: i) identifying a subject requiring such treatment; (ii) preparing a compound disclosed herein or a pharmaceutically acceptable salt thereof; and (iii) administering the compound in a therapeutically effective dose to treat, suppress and / or prevent a disease condition or state in the subject requiring such treatment.

[0493] In some embodiments, the treatment method includes the steps of: i) identifying a subject requiring such treatment; (ii) preparing a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and (iii) administering the composition in a therapeutically effective dose to treat, suppress and / or prevent a disease condition or state in the subject requiring such treatment.

[0494] In some embodiments, the subject is an animal. The animal includes all members of the animal kingdom, but is not limited to humans, mice, rats, cats, monkeys, dogs, horses, and pigs. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, rat, cat, monkey, dog, horse, or pig.

[0495] In some embodiments, methods for treating, preventing and / or suppressing FGFR2-related conditions include: (i) identifying a subject requiring such treatment; (ii) preparing a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a compound disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and (iii) administering the compound or composition in a therapeutically effective dose to treat, prevent and / or suppress an FGFR2-related disease condition or condition in a subject requiring such treatment.

[0496] According to the method of this disclosure, the compounds of this disclosure are administered to a subject in a therapeutically effective dose, for example, to reduce or alleviate symptoms associated with FGFR2 kinase activity in the subject. This dose can be readily determined by those skilled in the art based on known procedures, including the analysis of titration curves established in vivo, as well as the methods and assays disclosed herein.

[0497] In some embodiments, the method comprises administering a therapeutically effective dose of the compound of the present disclosure. In some embodiments, the therapeutically effective dose is at least about 0.0001 mg / kg body weight, at least about 0.001 mg / kg body weight, at least about 0.01 mg / kg body weight, at least about 0.05 mg / kg body weight, at least about 0.1 mg / kg body weight, at least about 0.25 mg / kg body weight, at least about 0.3 mg / kg body weight, at least about 0.5 mg / kg body weight, at least about 0.75 mg / kg body weight, at least about 1 mg / kg body weight, at least about 2 mg / kg body weight, at least about 3 mg / kg body weight, at least about 4 mg / kg body weight, at least about 5 mg / kg body weight, at least about 6 mg / kg body weight, at least about 7 mg / kg body weight, at least about 8 mg / kg body weight, at least about 9 mg / kg body weight, at least about 10 mg / kg body weight, at least about 15 mg / kg body weight, at least about 20 mg / kg Body weight, at least approximately 25 mg / kg body weight, at least approximately 30 mg / kg body weight, at least approximately 40 mg / kg body weight, at least approximately 50 mg / kg body weight, at least approximately 75 mg / kg body weight, at least approximately 100 mg / kg body weight, at least approximately 200 mg / kg body weight, at least approximately 250 mg / kg body weight, at least approximately 300 mg / kg body weight, at least approximately 350 mg / kg body weight, at least approximately 400 mg / kg body weight, at least approximately 450 mg / kg body weight, at least approximately 500 mg / kg body weight, at least approximately 550 mg / kg body weight, at least approximately 600 mg / kg body weight, at least approximately 650 mg / kg body weight, at least approximately 700 mg / kg body weight, at least approximately 750 mg / kg body weight, at least approximately 800 mg / kg body weight, at least approximately 900 mg / kg body weight, or at least approximately 1000 mg / kg body weight. It will be recognized that any of the dosages listed herein may constitute an upper or lower limit of the dosage range, and may be combined with any other dosages that constitute a dosage range including the upper and lower limits.

[0498] In some embodiments, the therapeutically effective dose is in the range of approximately 0.1 mg to approximately 10 mg / kg body weight, approximately 0.1 mg to approximately 6 mg / kg body weight, approximately 0.1 mg to approximately 4 mg / kg body weight, or approximately 0.1 mg to approximately 2 mg / kg body weight.

[0499] In some embodiments, the therapeutically effective dose is in the range of approximately 1-500 mg, approximately 2-150 mg, approximately 2-120 mg, approximately 2-80 mg, approximately 2-40 mg, approximately 5-150 mg, approximately 5-120 mg, approximately 5-80 mg, approximately 10-150 mg, approximately 10-120 mg, approximately 10-80 mg, approximately 10-40 mg, approximately 20-150 mg, approximately 20-120 mg, approximately 20-80 mg, approximately 20-40 mg, approximately 40-150 mg, approximately 40-120 mg, or approximately 40-80 mg.

[0500] In some embodiments, the method includes a single dose or administration (e.g., as a single injection or deposit). Alternatively, the method includes administration once, twice, three or four times daily to a subject needing it for about 2 to about 28 days, or about 7 to about 10 days, or about 7 to about 15 days, or longer. In some embodiments, the method includes long-term administration. In yet another embodiment, the method includes administration over several weeks, months, years, or decades. In yet another embodiment, the method includes administration over several weeks. In yet another embodiment, the method includes administration over several months. In yet another embodiment, the method includes administration over several years. In yet another embodiment, the method includes administration over several decades.

[0501] The dosage administered may vary depending on known factors such as the pharmacodynamic characteristics of the active ingredient, as well as its mode and route of administration; the timing of administration of the active ingredient; the recipient's age, sex, health, and weight; the nature and severity of symptoms; the type of concurrent treatment, the frequency of treatment, and the desired effect; and the rate of elimination. All of these can be easily determined and used by those skilled in the art to adjust or titrate the dosage and / or administration regimen.

[0502] The precise dose used in the composition also depends on the route of administration and should be determined according to the physician's judgment and the circumstances of each individual. In specific embodiments of this disclosure, the suitable dose range for oral administration of the compounds of this disclosure is generally about 1 mg / day to about 1000 mg / day. In some embodiments, the oral dose is about 1 mg / day to about 800 mg / day. In some embodiments, the oral dose is about 1 mg / day to about 500 mg / day. In some embodiments, the oral dose is about 1 mg / day to about 250 mg / day. In some embodiments, the oral dose is about 1 mg / day to about 100 mg / day. In some embodiments, the oral dose is about 5 mg / day to about 50 mg / day. In some embodiments, the oral dose is about 5 mg / day. In some embodiments, the oral dose is about 10 mg / day. In some embodiments, the oral dose is about 20 mg / day. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 40 mg / day. In some embodiments, the oral dose is approximately 50 mg / day. In some embodiments, the oral dose is approximately 60 mg / day. In some embodiments, the oral dose is approximately 70 mg / day. In some embodiments, the oral dose is approximately 100 mg / day. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range, and may be combined with any other dosages that constitute a dosage range including the upper and lower limits. composition

[0503] Another aspect of this disclosure provides pharmaceutical compositions comprising compounds disclosed herein, formulated with a pharmaceutically acceptable carrier. In particular, this disclosure provides pharmaceutical compositions comprising compounds disclosed herein, formulated with one or more pharmaceutically acceptable carriers. These formulations include formulations suitable for oral, topical, oral, intraocular, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, but the most preferred form of administration in any given case depends on the degree and severity of the condition being treated, as well as the properties of the specific compounds used. For example, the disclosed compositions may be formulated as unit doses and / or for oral, subcutaneous, or intravenous administration.

[0504] The exemplary pharmaceutical compositions of this disclosure may be used, for example, in the form of pharmaceutical preparations in solid, semi-solid, or liquid form, which contain one or more of the compounds of this disclosure as active ingredients in mixture with organic or inorganic carriers or additives suitable for external, enteral, or parenteral use. The active ingredients may be compounded with, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other forms suitable for use, which are common non-toxic and pharmaceutically acceptable carriers. The active compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of a disease.

[0505] In some embodiments, pharmaceutically acceptable compositions may contain the disclosed compound and / or a pharmaceutically acceptable salt thereof in concentrations ranging from about 0.01 to about 2.0% by weight, such as 0.01 to about 1% by weight or about 0.05 to about 0.5% by weight. The compositions may be formulated as solutions, suspensions, ointments, or capsules. Pharmaceutical compositions may be prepared as aqueous solutions and may contain additional components, such as preservatives, buffers, isotonic agents, antioxidants, stabilizers, and viscosity modifiers.

[0506] To prepare solid compositions such as tablets, the main active ingredient can be mixed with conventional tableting components, such as a pharmaceutical carrier (e.g., corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other pharmaceutical diluents (e.g., water), to form a solid pre-formulated composition containing a homogeneous mixture of the compound of this disclosure or a non-toxic, pharmaceutically acceptable salt thereof. When these pre-formulated compositions are referred to as homogeneous, it means that the active ingredient is evenly dispersed throughout the composition, and as a result, the composition can be easily divided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0507] Pharmacopoeially acceptable carriers are well known to those skilled in the art and include, for example, adjuvants, diluents, additives, fillers, lubricants, and vehicles. In some embodiments, the carrier is a diluent, adjuvant, additive, or vehicle. In some embodiments, the carrier is a diluent, adjuvant, or additive. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an additive. Often, pharmaceutically acceptable carriers are chemically inert to the active compound and non-toxic under the conditions of use. Examples of pharmaceutically acceptable carriers may include, for example, water or saline solution, polymers such as polyethylene glycol, carbohydrates and their derivatives, oils, fatty acids, or alcohols. Non-limiting examples of oils as pharmaceutical carriers include, for example, oils of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Pharmaceutical carriers can also be physiological saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Furthermore, auxiliary agents, stabilizers, thickeners, lubricants, and colorants may be used. Other examples of suitable pharmaceutical carriers are, for example, Remington's: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5 th Ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7 th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)) (each of these in its entirety is incorporated herein by reference) It is being done.

[0508] In some embodiments, the compounds of the Disclosure are formulated into pharmaceutical compositions for administration to a subject in a biocompatible form suitable for in vivo administration. In another embodiment, the Disclosure provides a pharmaceutical composition comprising the disclosed compounds in a mixture with a pharmaceutically acceptable diluent and / or carrier. A pharmaceutically acceptable carrier is "acceptable" in the sense that it is compatible with other components of the composition and is not harmful to its recipient. The pharmaceutically acceptable carriers used herein may be selected from organic or inorganic materials used as materials for pharmaceutical formulations and formulated as analgesics, buffers, binders, disintegrants, diluents, emulsifiers, additives, bulking agents, flow enhancers, solubilizers, stabilizers, suspending agents, isotonic agents, vehicles, and viscosity improvers. Pharmaceutical additives such as antioxidants, fragrances, colorants, flavor enhancers, preservatives, and sweeteners may also be added. Examples of acceptable pharmaceutical carriers include, among others, carboxymethylcellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powders, saline, sodium alginate, sucrose, starch, talc, and water. In some embodiments, the term “pharmaceutically acceptable” means that it is approved by a state or central government regulatory agency or is listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more specifically in humans.

[0509] For example, surfactants such as detergents are also suitable for use in formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylene esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives such as methacrylate; anionic surfactants, such as alkaline stearates, especially sodium stearate, potassium stearate or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate; or fatty acids, especially those derived from coconut oil; cationic surfactants, such as formula N + R'R''R'''R''''Y - The water-soluble quaternary ammonium salt (R radical is a hydrocarbon radical that is the same or different, optionally hydroxylated, and Y ー This includes anions of strong acids such as halide anions, sulfate anions, and sulfonic acid anions; cetyltrimethylammonium bromide (one of the cationic surfactants that can be used), formula N + This includes amine salts of R'R''R''' (where R radicals are identical or different hydrocarbon radicals, optionally hydroxylated); octadecylamine hydrochloride (one of the cationic surfactants that can be used); nonionic surfactants, such as sorbitan esters optionally polyoxyethylenelated, particularly polysorbate 80 or polyoxyethylenelated alkyl ethers; polyethylene glycol stearate, polyoxyethylenelated derivatives of castor oil, polyglycerol esters, polyoxyethylenelated fatty alcohols, polyoxyethylenelated fatty acids, or copolymers of ethylene oxide and propylene oxide; and amphoteric surfactants, such as betaine-substituted lauryl compounds.

[0510] The disclosed compounds and pharmaceutically acceptable carriers may be sterile when administered to a subject. Suitable pharmaceutical carriers may also contain additives such as starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk powder, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, and polysorbate 20. The composition may also contain, if desired, trace amounts of wetting agents or emulsifiers, or pH buffering agents.

[0511] The pharmaceutical formulations described herein are prepared by methods well known in the pharmaceutical field. If necessary, one or more adjuncts (e.g., buffers, flavorings, surfactants, etc.) are also added. The choice of carrier is determined by the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical practices.

[0512] Furthermore, the compounds and / or compositions of this disclosure are administered to human or animal subjects by known procedures, including oral, sublingual, or intraoral administration. In some embodiments, the compounds and / or compositions are administered orally.

[0513] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the composition in question is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) water-retaining agents such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds; and (7) such as acetyl alcohol and monostearate. (8) Wetting agents such as glycerol, (9) Absorbents such as kaolin and bentonite clay, (10) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof, and colorants. In the case of capsules, tablets and pills, the composition may also contain buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using additives such as lactose and high molecular weight polyethylene glycol.

[0514] For oral administration, formulations of the compounds of this disclosure may be provided in dosage forms such as capsules, tablets, powders, granules, or as suspensions or solutions. Capsule formulations may be made of gelatin, soft gel, or solid. Tablets and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, additives, fillers, or lubricants, each of which is known in the art. Examples of such include carbohydrates such as lactose or sucrose, anhydrous calcium hydrogen phosphate, corn starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearate, silicon dioxide, talc, sodium starch glycolate, acacia, flavorings, preservatives, buffering agents, disintegrants, and colorants. The orally administered composition may contain one or more of the necessary activating agents, such as sweeteners (e.g., fructose, aspartame, or saccharin), flavoring agents (e.g., peppermint, wintergreen, or cherry oil), coloring agents, and preservatives, in order to obtain a pharmaceutically acceptable preparation.

[0515] Tablets can be prepared by compression or molding with one or more adjuncts as needed. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of the target composition moistened with an inert liquid diluent using a suitable machine. Tablets, as well as other solid dosage forms such as dragées, capsules, pills, and granules, may be prepared with or without notches using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field, as needed.

[0516] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents, or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the compositions of interest, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0517] The suspension may contain, in addition to the target composition, suspending agents (e.g., ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters), microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, as well as mixtures thereof.

[0518] Formulations for rectal or vaginal administration may be provided as suppositories, which can be prepared by mixing the composition with one or more suitable non-irritating additives or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, and which are solid at room temperature but liquid at body temperature, and therefore melt in the body cavity and release the activator.

[0519] The transdermal dosage forms of the target composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active components can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0520] Ointments, pastes, creams, and gels may contain additives such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof, in addition to the target composition.

[0521] Powders and sprays may contain additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder or mixtures thereof, in addition to the target composition. Sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0522] The compositions and compounds of this disclosure may, alternatively, be administered by aerosol. This is done by preparing aqueous aerosols, liposome preparations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. Ultrasonic nebulizers may be used to minimize exposure of the drug to shear, which may cause degradation of the compounds contained in the composition of interest. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the composition of interest together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular composition of interest, but typically include nonionic surfactants (Tween®, Pluronic®, or polyethylene glycol), serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, and glycine, buffers, salts, and harmless proteins such as sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0523] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include a composition of interest in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile solutions or dispersions for injection immediately before use, which may contain antioxidants, buffers, bacteriostatic agents, solutes to make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0524] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, as well as injectable organic esters such as ethyl oleate, and cyclodextrins. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. For example, the crystalline forms provided herein may be milled to obtain a specific particle size, and in at least some embodiments, such crystalline forms may remain substantially stable upon milling.

[0525] For example, compositions suitable for subcutaneous administration, including suspensions of the disclosed crystalline form, are provided herein. Subcutaneous administration may have advantages over intravenous administration, which typically requires a physician's visit and can be more painful and invasive. Typical doses of the crystalline compound, when administered to a patient, may be about 1 mg to about 8 mg of the compound. In some embodiments, pharmaceutically acceptable compositions formed from the disclosed crystalline form are disclosed herein, for example, by mixing the crystalline form with additives and / or solvents.

[0526] In some embodiments, compositions comprising disclosed crystalline forms are provided herein that are suitable for subcutaneous administration at dosage levels sufficient to deliver approximately 0.001 mg / kg to approximately 100 mg / kg, approximately 0.01 mg / kg to approximately 50 mg / kg, approximately 0.1 mg / kg to approximately 40 mg / kg, approximately 0.5 mg / kg to approximately 30 mg / kg, approximately 0.001 mg / kg to approximately 4 mg / kg, approximately 0.1 mg / kg to approximately 10 mg / kg, and approximately 1 mg / kg to approximately 25 mg / kg of the target's body weight, administered daily, once or more times daily, every other day, every three or four days, weekly, every two weeks, every three weeks or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple doses (e.g., two, three, four, five, six, seven, eight, nine or ten doses). In certain embodiments, administration may be performed once, twice, or three times per week.

[0527] The treatment can be continued for a long or short period as needed. The composition may be administered, for example, in regimens of 1 to 4 times per day, or more. Preferred treatment periods may be, for example, at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 6 months, at least about 1 year, or indefinitely. The treatment period may be terminated when the desired result, for example, a weight loss target, is achieved. The treatment regimen may include a correction phase, during which a dose sufficient to result in weight loss is administered, followed by a maintenance phase, during which a lower dose sufficient to result in weight gain is administered, for example. Preferred maintenance doses are likely to be found in the lower portion of the dose range provided herein, but correction and maintenance doses can be readily established for individual subjects by those skilled in the art without excessive experimentation based on the disclosures herein. Maintenance doses may be used to maintain the weight of subjects previously controlled by other means, including diet and exercise, obesity procedures such as bypass or banding surgery, or treatments using other pharmacological agents.

[0528] composition In certain embodiments, pharmaceutical compositions comprising a crystalline form of compound I-1 or a solvate thereof as described herein are provided herein. In certain embodiments, the pharmaceutical compositions provided herein comprise one or more pharmaceutically acceptable additives as described herein. In some embodiments, immediate-release capsules comprising a crystalline form of compound I-1 (e.g., form A) or a solvate thereof are provided herein. In some embodiments, the immediate-release capsule comprises about 10 mg of a crystalline form of compound I-1 (e.g., form A) or a solvate thereof. In some embodiments, the immediate-release capsule comprises about 50 mg of a crystalline form of compound I-1 (e.g., form A) or a solvate thereof. In some embodiments, the immediate-release capsule comprises about 100 mg of a crystalline form of compound I-1 (e.g., form A) or a solvate thereof. In some embodiments, the immediate-release capsule comprises a powder blend intermediate, which can be produced by directly blending a crystalline form of compound I-1 (e.g., form A) or a solvate thereof with one or more pharmaceutically acceptable additives. kit

[0529] In one embodiment, a kit is provided for treating or alleviating a planned disease or disorder. For example, the disclosed kit includes, for example, a disclosed crystalline compound, for example, a crystalline form of the compound of formula (I), arranged in a first container. In some embodiments, the kit may further include, for example, a pharmaceutically acceptable additive arranged in a second container. Such a planned kit may include written instructions for use describing the preparation of a pharmaceutical composition suitable for administration to a patient from its crystalline form. For example, the written instructions may describe, for example, preparing a pharmaceutically acceptable form for administration to a patient by mixing the additive and the crystalline compound disclosed herein. The disclosed kit may further include written instructions for use describing how to administer the resulting composition to a patient. process

[0530] In some embodiments, a process for preparing a disclosed crystalline form of a compound of formula (I), for example, compound I-1, is intended herein, comprising the steps of: a) preparing a solution of compound I-1 in a solvent containing at least one of EtOH, ACN, MEK, SiO, IPAc, IPA, THF, MtBE, toluene, 1,4-dioxane, and water; b) heating the solution to completely dissolve compound I-1; c) adjusting the temperature to precipitate a solid from the solution; and d) isolating the crystalline form of compound I-1.

[0531] In some embodiments, the solvent is EtOH. In some embodiments, the solvent contains ACN. In some embodiments, the solvent contains SiO. In some embodiments, the solvent contains IPAc. In some embodiments, the solvent contains IPA. In some embodiments, the solvent contains THF. In some embodiments, the solvent contains MtBE. In some embodiments, the solvent contains toluene. In some embodiments, the solvent contains 1,4-dioxane. In some embodiments, the solvent contains EtOH and water (9v / 1v). In some embodiments, the step of heating the solution includes heating the solution to about 50°C. In some embodiments, the step of adjusting the temperature includes cooling the solution to about 5°C.

[0532] A process for preparing the compound of formula I-1, wherein the compound of formula I-2 is acidified with an HCl solution, thereby producing the compound of formula I-1: [ka] A process including the step of forming is further disclosed herein.

[0533] In other embodiments, the disclosed process involves coupling methacrylic anhydride with a compound of formula 3, thereby producing a compound of formula I-2: [ka] The process further includes the step of forming.

[0534] In other embodiments, the disclosed process involves coupling the compound of formula 1 with the compound of formula 2, thereby producing the compound of formula 3: [ka] The process further includes the step of forming. Deuterated analog

[0535] Those skilled in the art will recognize that deuterated analogs of compounds of formula (I), formula (II), formula (III), or formula (IV) can be prepared using deuterated starting materials by the synthesis processes described herein. As used herein, “deuterated analog” of a given formula means a compound having the structure of the said formula, except that the structure has at least one substitution of hydrogen with deuterium.

[0536] In one embodiment, the synthesis processes and methods described in detail herein are intended for use in producing deuterated compounds for use in generating deuterated analogs of compounds of formula (I). In some embodiments, this disclosure is intended for deuterated analogs (anologues) of formula (I). For example, the following compounds: [ka] The synthesis of deuterated analogs of formula (I) is intended, but is not limited to this.

[0537] In one embodiment, the synthesis processes and methods described in detail herein are intended for use in producing deuterated compounds for use in generating deuterated analogs of compounds of formula (II). In some embodiments, this disclosure is intended for deuterated analogs of formula (II). For example, the following compounds: [ka] [ka] The synthesis of deuterated analogs of formula (II) is intended, but is not limited to this.

[0538] In one embodiment, the synthesis processes and methods described in detail herein are intended for use in producing deuterated compounds for use in generating deuterated analogs of compounds of formula (III). In some embodiments, this disclosure is intended for deuterated analogs of formula (III). For example, the following compounds: [ka] [ka] The synthesis of deuterated analogs of formula (III) is intended, but is not limited to this.

[0539] In one embodiment, the synthesis processes and methods described in detail herein are intended for use in producing deuterated compounds for use in generating deuterated analogs of compounds of formula (IV). In some embodiments, this disclosure is intended for deuterated analogs of formula (IV). For example, the following compounds: [ka] [ka] The synthesis of deuterated analogs of formula (IV) is intended, but is not limited to this. [Examples]

[0540] The compounds described herein can be prepared by several methods based on the teachings contained herein and synthetic procedures known in the art. The following non-limiting examples illustrate the disclosure herein.

[0541] X-ray powder diffraction (XRPD): Unless otherwise specified, X-ray powder diffraction patterns were acquired using a Bruker D2 Phaser Gen 2 with Cu-Ka radiation irradiation (30kV, 10mA), a θ-θ goniometer, a divergent slit (0.2mm), and an SSD160 (1D mode) detector with a 4.799° aperture. The software used for data acquisition was Diffrac.Commander version 6.5.0.1, and the data were displayed using Diffra.Eva version 4.2.1.11. XRPD diffractograms were acquired by reflection on a flat silica zero background plate at 15 rotations per minute under ambient conditions. The acquisition range was 2θ from 3.0 to 40.0°, with a step size of 0.02025° and an acquisition time of 0.25 seconds per step.

[0542] Differential Scanning Calorimetry (DSC): DSC data were acquired using a TA Instruments Q2000 DSC. A specified amount of sample (2.0–10.0 mg) was placed in an aluminum pan and heated at 10°C / min from 40°C to 300°C, or as per the experimental instructions. A 100 ml / min dry nitrogen purge was maintained over the sample. Instrument control and data acquisition were performed using Q Advantage software release version 5.5.23. Data were processed and displayed using TA Universal Analysis 2000 software version 4.5A build 4.5.0.5.

[0543] Thermogravimetric Analysis (TGA): TGA data is obtained from TA Instruments' Q5000. Samples were collected using TGA. A specified amount of sample (2.0–10.0 mg) was placed in an aluminum pan and heated at 10°C / min from 40°C to 300°C, or as per the instructions for the experiment. A 25 ml / min dry nitrogen purge was maintained over the sample. Instrument control and data acquisition were performed using Q Advantage software release version 5.5.23. Data were processed and displayed using TA Universal Analysis 2000 software version 4.5A build 4.5.0.5.

[0544] Dynamic Vapor Desorption (DVS): Dynamic vapor sorption (DVS) was performed using TA Instruments' QS000 SA. A predetermined amount of 2.0–10.0 mg of sample was placed in a platinum pan. The sample was equilibrated at 0% relative humidity (RH) at 50°C for 60 minutes. The sample was then equilibrated at 25°C, and the humidity was ramped from 0% to 95% RH in 5% increments every hour. A similar ramp profile was used for the desorption cycle. XRPD analysis was also performed on the DVS-treated samples. [Table 1A]

[0545] Ion chromatography (IC): Data were collected using IC MagicNet software on a Metrohm 930 Compact IC Flex equipped with an 858 Professional autosampler and an 800 Dosino dosing unit monitor. Accurately weighed samples were prepared as storage solutions in suitable solvents. Quantification was performed by comparison with standard solutions of known concentrations of the ion to be analyzed. Analysis was performed in double-rows, and values ​​are shown as the mean unless otherwise specified. Cation chromatography method: [Table 1B] Methods of anion chromatography: [Table 1C] (Example 1) Synthesis of N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide hydrochloride (compound I-1) Step 1. Preparation of Compound 3 [ka]

[0546] This is purified water that has been inertened with nitrogen in a 400L glass-lined container. After draining, the reaction was started. Purified water (31.4 kg, 2.5 vol) and anhydrous tripotassium phosphate (11.1 kg, 2 equivalents) were added to a 400 L container. The mixture was stirred and cooled to 15.4°C. The K3PO4 aqueous solution was transferred to a clean plastic drum. Compound 1 (12.5 kg, 1 equivalent) and Compound 2 (9.6 kg, 1.2 equivalents) were added to a 400 L container and then flushed with nitrogen. Dimethylacetamide (DMAc, 94.8 kg, 8 vol), followed by the K3PO4 aqueous solution, was added. A moderate amount of heat was generated upon addition of the K3PO4 aqueous solution. The addition rate was adjusted to bring the reaction temperature to 60°C (t max The temperature was maintained below 31.1°C. At this point, the reaction mixture was heterogeneous. The contents of the container were degassed by nitrogen pressure cycling from 1 barg to 0 barg (3 times). Next, cataCXium A Pd G2 (chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II), 0.53 kg, 3 mol%) was added to the container as a suspension in DMAc (0.93 + 0.95 kg). The catalyst formed a concentrated suspension in DMAc. The contents of the container were heated at 80°C for 2 hours. The color of the reactants changed from light brown to dark brown as the reaction progressed. The reaction mixture was cooled to 19.9°C. While maintaining the contents below 25°C (tr 15.9~20.3°C), purified water (150.2 kg, 12 volumes) was added to the container over 2 hours. The reaction mixture was aged at 15.4°C for 16 hours.

[0547] The mixture was filtered through a large oyster filter (Φ820mm), and the cake was washed with 1:1 DMAc-water (11.6 + 12.5 kg, 1 + 1 volume), then with pure water (50.2 kg, 4 volumes) to obtain a water-soaked cake of crude material. The crude filter cake was transferred to a 400 L container. Next, MeOH (88.8 kg, 9 volumes) was added to the container, and the contents were cooled to below 20°C (tr 16.5°C). While maintaining the contents of the container below 20°C (tr 13.9~16.8°C), aqueous HCl solution (4.16 kg, 1.6 equivalents) was added over 12 minutes using a dispensing pump. Solution V = 135 L. Solka-Floc 100NF (6.0 kg, to form a bed approximately 5 cm thick) was added to the large oyster filter. Next, the contents of the 400L container were filtered through Solka-Floc, and the waste cake was washed with MeOH (10.4 kg, 1 vol). Filtration took approximately 1.5 hours. The MeOH-filtered solution of compound 4·HCl was returned to the 400L container. Quadrasil MP (7.0 kg, 60 wt% relative to theoretical compound 4) was placed in a small Oyster filter (Φ416 mm), and the contents of the 400L container were recirculated through this scavenger for 4 hours.

[0548] The solution was pumped back into a 400L container from a small Oyster filter, and the scavenger cake was washed with MeOH (10.2 kg, 1 vol) and placed in the same container. A 110L CUNO unit was assembled with a 12'' carbon cartridge (R53SP). The contents of the 400L container were recirculated for 1 hour through the carbon cartridge of the CUNO unit. The contents of the CUNO unit were pumped into the 400L container. The unit was then washed with MeOH (10.2 kg, 1 vol). To the 400L container, a solution of triethylamine (4.26 kg, 1.6 equivalents) in MeOH (9.8 kg, 1 vol) was added over 2 hours while maintaining the contents temperature below 20°C (tr 13.0~13.8°C), and compound 3 was precipitated as a free base. The resulting slurry was aged at 15.2°C for 18 hours. The slurry was filtered through an Oyster filter, and the filter cake was rinsed with MeOH (20.2 kg, 2 volumes). The product cake was dried in vacuum at 50°C for 16 hours. Compound 3 was obtained (11.59 kg, yield: 83.0%). Step 2. Preparation of Compound I-1 mixture [ka]

[0549] A 400 L glass-lined reactor was placed under complete vacuum for 3 hours before the batch was started to remove trace amounts of residual washing solvent. All processing was carried out under a nitrogen atmosphere. 2,2,2-trifluoroethanol (TFE) (52.8 kg, 4 vols) and methacrylic anhydride (7.1 kg, 94 wt%, 43.0 mol, 2.0 equivalents) were added to the reactor, and the contents were cooled to 10°C. While maintaining the temperature below 30°C, a solution of ethylenediamine (0.26 kg, 4.3 mol, 0.2 equivalents) in TFE (2.8 kg, 0.2 vols) was added, and the contents were aged at 20°C for 1 hour. A pre-mixed solution of compound 3 (9.5 kg, 21.5 mol, 1.0 equivalent) in TFE (79.2 kg, 6 vols) was added, and the contents were aged at 20°C for 16 hours. The clear solution of compound 4 was removed from the reactor and placed in a clean, plastic-lined drum.

[0550] All reaction mixtures, solvents, and liquid reagents from this point onward were added to a container through a 1.0 micron filter to remove turbidity from the batch. The reaction mixture was returned to a 400 L container, and the solution was concentrated to a volume of 19 L under partial vacuum at <45°C. The resulting solution was diluted with SiO2 (171 kg, 20 vols), and the batch was cooled to 20°C. While maintaining the contents of the container below 25°C, 6N HCl in isopropanol (3.2 kg, 21.5 mol, 1.0 equivalent) was added over 1 hour. The suspension was then aged at 20°C for 17.5 hours.

[0551] While maintaining the contents of the container below 25°C, 6N HCl (3.2 kg, 21.5 mol, 1.0 equivalent) in isopropanol was added over 1 hour. The suspension was then aged at 20°C for 17.5 hours. The mixture was filtered through a large oyster filter, and the cake was washed with ELISA (17.1 kg (2 volumes) × 2). Filtration was very fast (<10 minutes). The sample was removed from the wet cake, and the solid morphology was confirmed by XRPD. Polymorph "Morph D" was obtained.

[0552] The wet cake was returned to a 400L container and siRNA (213.8 kg, 25 vols) was added. A 0.5 M solution of K2CO3 (49.7 kg, 23.77 mol, 1.1 equivalents) was added over 30 minutes. By the end of the addition, the suspension had changed to a clear two-phase mixture. The contents were allowed to mature for 1 hour. A precipitate of free base formed within minutes of the completion of the K2CO3 aqueous solution addition. A sample was taken from the lower aqueous layer and the pH was checked using pH test paper. The pH was 9. The mixture was filtered through a large oyster filter and the cake was washed with siRNA / H2O 1:1 (2 vols). Filtration was rapid (<15 minutes). The two-phase K2CO3 / siRNA aqueous solution was returned to a 400L container and the lower aqueous layer was removed. The organic layer was washed with H2O (47.5 kg, 5 vols) and the lower aqueous layer was removed. The wet cake was placed in a 400 L container and added to SiO2. While maintaining the contents of the container below 25°C, 6N HCl (3.6 kg, 23.7 mol, 1.1 equivalents) in isopropanol was added over 1 hour. The suspension was then aged at 20°C for 17.5 hours. The mixture was filtered through a large Oyster filter, and the cake was washed with SiO2 (17.1 kg (2 volumes) × 2). Filtration was very fast (<10 minutes). The sample was removed from the wet cake, and the solid morphology was confirmed by XRPD. Polymorph "Morphology J" was obtained.

[0553] The wet cake was returned to a 400L container, and water (4.8 kg, 0.5 vol) and ethanol (EtOH) (33.8 kg, 4.5 vol) were added. The suspension was heated from 20 to 50°C over 150 minutes, maintained at 50°C for 180 minutes, and cooled from 50 to 20°C over 150 minutes. The suspension was aged at 20°C for 10 hours. The suspension was heated again from 20 to 50°C over 150 minutes, maintained at 50°C for 180 minutes, and cooled from 50 to 20°C over 150 minutes. The suspension was aged at 20°C for 10 hours. The sample was removed, and the solid morphology was confirmed by XRPD. Polymorph "Morph A" was obtained. The mixture was filtered through a medium-sized oyster filter, and the cake was washed with EtOH / H2O 9:1 (2 vol). The product was dried under nitrogen sweep in a vacuum at 60°C for 18.5 hours to obtain 9.00 kg of compound I-1 (77% yield) and compound 6. Compound I-1: MS[M+1] = 510.20. 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.78 - 7.66 (m, 2H), 7.33 (m, J = 8.6, 2.3 Hz, 3H), 7.21 - 7.16 (m, 2H), 7.12 (s, 0H), 5.80 (s, 1H), 5.54 (d, J = 1.7 Hz, 1H), 3.59 (s, 3H), 2.42 (s, 3H), 1.95 (d, J = 1.2 Hz, 3H).

[0554] HPLC method using a column: HALO ES-CN, 4.6 × 150 mm 2.7 μm; flow rate: 1.0 mL / min; column temperature: 40°C; mobile phase A: 0.1% TFA in water; mobile phase B: 0.1% TFA in acetonitrile; and the following gradient: [Table 1D] This revealed that compound I-1 had a liquid chromatography area percentage (LCAP) of 99.1, and compound 6 (RRT=0.84) had an LCAP of 0.42. (Example 2) Purification of compound I-1 [ka]

[0555] All processing was carried out under a nitrogen atmosphere. The container was rinsed with methanol (MeOH) (12.6 kg) and discarded as waste. From this point onward, all solvents and liquid reagents were added to the container through a 1.0 micron filter to remove turbidity from the batch. Crude mixtures containing compound I-1 (3.8 kg, 7.0 mol, 1.0 equivalent) and impurity compound 6 from step 2 of Example 1, as well as methanol (42.1 kg, 14 vol), were added to the reactor, and the contents were cooled to 18°C. A solution of NaOH (46-51% in H2O, 1.1 kg, 8.4 mol, 1.2 equivalents) in MeOH (3.0 kg, 1.0 vol) was added over 5 minutes. During the addition of NaOH, the solvent was absorbed by the solid to form a gel, which then turned back into a suspension after 3-4 minutes.

[0556] The contents were aged at 20°C for 3 hours. The sample was taken out and the LCAP of impurity compound 6 in the solid was confirmed by HPLC. The LCAP of compound 6 in the solid was 0.02. The suspension was filtered through a small Oyster filter and the cake was washed with MeOH (4 volumes). The wet cake was put back into the container and ethyl acetate (34.3 kg, 10 volumes) was added. While maintaining the contents of the container below 25°C, 6N HCl in isopropanol (1.0 kg, 7.0 mol, 1.0 equivalent) was added over 30 minutes. The suspension was then aged at 20°C for 4 hours. The sample was taken out and the LCAP of impurity compound 6 in the solid was confirmed by HPLC. The LCAP of compound 6 in the solid was 0.02. The suspension was filtered through a small Oyster filter and the cake was washed with ELISA (6.9 kg (2 volumes)) and then with ethanol (EtOH) (12.0 kg (4 volumes) × 2). The sample was removed from the wet cake, and the solid morphology was confirmed by XRPD. A mixture of polymorphs A and 4 was obtained.

[0557] The wet cake was returned to the container, and water (1.9 kg, 0.5 vol) and ethanol (13.5 kg, 4.5 vol) were added. The suspension was heated from 20 to 50°C over 150 minutes, maintained at 50°C for 180 minutes, and cooled from 50 to 20°C over 150 minutes. The suspension was aged at 20°C for 10 hours. The sample was taken out, and the morphology of the solid was confirmed by XRPD. Polymorph "Morph A" was obtained. The sample was taken out, and the LCAP of impurity compound 6 in the solid was confirmed by HPLC (column: HALO ES-CN, 4.6 × 150 mm 2.7 μm; flow rate: 1.0 mL / min; column temperature: 40°C; operating time: 25 minutes; mobile phase A: 0.1% TFA in water; mobile phase B: 0.1% TFA in acetonitrile; RT1: 7.8 min (compound 6); RT2: 9.1 min (compound I-1)). The LCAP of compound 6 in solid form was 0.02. The mixture was filtered through a small Oyster filter, and the cake was washed with EtOH / H2O 9:1 (2 volumes). Filtration was very fast (<10 minutes). The product was dried under nitrogen sweep, in vacuum, at 60°C for 18.5 hours to obtain 2.8 kg of compound I-1 (74% yield, LCAP=99.9).

[0558] Conclusion: The objective was to develop a process to reduce the level of impurity RRT0.84 from 0.42 LCAP to less than 0.15 LCAP, as shown in Example 1. Using this optimized process, the impurity RRT0.84 was reduced to 0.02 LCAP against the target of less than 0.15 LCAP, and the overall purity improved from 99.1 LCAP to 99.9 LCAP. (Example 3) Synthesis of (R)-N-(4-(4-amino-7-methyl-5-(4-(pyrrolidinyl-1-carbonyl)cyclohexa-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-methylphenyl)methacrylamide (compound II-1) [ka] Step 1. Preparation of N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide [ka]

[0559] 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (10 g, 42.8 mmol), methacryloyl chloride (3.87 g, 42.8 mmol), pyridine (10.1 g, 128 mmol), dichloromethane (150 mL), and a stirring bar were placed in a round-bottom flask. The solution was stirred at 0°C for 1 hour. The reaction mixture was quenched with water and extracted with DCM. The organic phase was dehydrated with Na2SO4, filtered, and allowed to stand under vacuum. The resulting crude material was purified by silica gel chromatography. Concentration under vacuum yielded N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (12 g, 98%) as a yellow oil. Step 2: Preparation of N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-methylphenyl)methacrylamide [ka]

[0560] In a round-bottom flask, N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1 g, 3.48 mmol), 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine (1.22 g, 3.48 mmol), Pd(dppf)Cl2 (254 mg, 348 μmol), K3PO4 (2.20 g, 10.4 mmol), DMF / H2O (16:1) (15 mL), and a stirring bar were placed. The solution was stirred at 50°C for 2 hours. The reaction mixture was quenched with water and extracted with DCM. The organic phase was washed three times with brine, dehydrated with Na2SO4, filtered, and evaporated under vacuum. The resulting crude material was purified by silica gel chromatography. Concentration in a vacuum yielded N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-methylphenyl)methacrylamide (440 mg, 33%) as a solid. Step 3: (R)-N-(4-(4-amino-7-methyl-5-(4-(pyrrolidin-1-carbonyl)cyclohexa-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-methylphenyl)methacrylamide [ka]

[0561] In a resealable reaction vial, N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-methylphenyl)methacrylamide (200 mg, 517 μmol), 1-[(1R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-carbonyl]pyrrolidine (156 mg, 517 μmol), Pd(pddf)Cl2 (37.8 mg, 517 μmol), Na2CO3 (164 mg, 1.55 mmol), DMF (10 mL), and a stirring bar were added. The vial was then evacuated and purged three times with nitrogen. The mixture was stirred at 90°C for 2 hours. The reaction mixture was quenched with water and extracted with DCM. The organic phase was washed three times with brine, dehydrated with Na2SO4, filtered, and evaporated under vacuum. The resulting crude material was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*250, 5um; mobile phase A: water (10MMOL / L NH4HCO3), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 40B to 62B over 8 minutes; 220 nm). Lyophilization yielded (R)-N-(4-(4-amino-7-methyl-5-(4-(pyrrolidin-1-carbonyl)cyclohexa-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)-3-methylphenyl)methacrylamide (40 mg, 16%) as a solid. MS[M+1]=499.35.1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.10 (s, 1H), 7.71 (t, J = 2.7 Hz, 1H), 7.62 (ddd, J = 8.0, 5.6, 2.2 Hz, 1H), 7.18 (dd, J = 8.3, 6.6 Hz, 1H), 6.48 (d, J = 17.0 Hz, 2H), 5.91 - 5.79 (m, 1H), 5.66 (ddt, J = 14.5, 4.1, 2.2 Hz, 1H), 5.54 (t, J = 1.5 Hz, 1H), 3.56 - 3.39 (m, 2H), 3.34 (s, 3H), 3.27 (q, J = 6.9 Hz, 2H), 2.73 (p, J = 6.3 Hz, 1H), 2.21 (q, J = 15.7, 12.1 Hz, 2H), 2.06 (s, 3H), 2.01 - 1.80 (m, 7H), 1.80 - 1.70 (m, 2H), 1.56 (q, J = 7.9, 7.0 Hz, 2H). (Example 4) Synthesis of 6-(6-ethynyl-4-methoxypyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (compound III-1) [ka] Step 1. Preparation of 5-bromo-2-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine [ka]

[0562] In a resealable reaction vial, 5-bromo-2-iodo-4-methoxypyridine (600 mg, 2.00 mmol), CuI (152 mg, 800 μmol), Et3N (606 mg, 6.00 mmol), Pd(PPh3)2Cl2 (280 mg, 400 μmol), DMF (15 mL), and a stirring bar were added. The vial was then evacuated, purged three times with nitrogen, and tert-butyl(ethynyl)dimethylsilane (280 mg, 2.00 mmol) was added. The mixture was stirred at 50°C for 2 hours. The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with brine, dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The resulting crude material was purified by silica gel chromatography (PE:EA = 8:1). Concentration in a vacuum yielded 5-bromo-2-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine (500 mg, 80%) as a solid. Step 2. Preparation of (6-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine-3-yl)boronic acid [ka]

[0563] In a resealable reaction vial, 5-bromo-2-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine (480 mg, 1.54 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (467 mg, 1.84 mmol), AcOK (452 ​​mg, 4.62 mmol), Pd(dppf)Cl2 (112 mg, 154 μmol), dioxane (10 mL), and a stirring bar were added. The vial was then evacuated, purged three times with nitrogen, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with water (15 mL), and the aqueous phase was extracted three times with EA (15 mL). The combined organic layers were washed with brine, dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The obtained crude material was purified by HPLC (acetonitrile / water 0%-60%, 30 minutes). By freeze-drying, (6-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine-3-yl)boronic acid (400 mg, 94%) was obtained as a solid. Step 3. Preparation of 6-(6-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0564] In a resealable reaction vial, 5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-6-iodo-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (520 mg, 1.13 mmol), (6-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine-3-yl)boronic acid (380 mg, 1.37 mmol), Na2CO3 (358 mg, 3.38 mmol), Pd(dppf)Cl2 (82.6 mg, 113 μmol), DMF / H2O=16 / 1 (15 mL), and a stirring bar were added. The vial was then evacuated, purged three times with nitrogen, and the mixture was stirred at 90°C for 1 hour. The reaction mixture was diluted with water (15 mL), and the aqueous phase was extracted three times with DCM (15 mL). The combined organic layers were washed with brine, dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The resulting crude material was purified by HPLC (DCM / MeOH = 15 / 1). Freeze-drying yielded 6-(6-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 34%) as a solid. Step 4. Preparation of 6-(6-ethynyl-4-methoxypyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0565] In a round-bottom flask, 6-(6-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (180 mg, 303 μmol), TBAF (638 μg, 638 μmol), and a stirring bar were placed. Tetrahydrofuran (5 mL) was added, and the solution was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted three times with dichloromethane (10 mL). The combined organic layers were washed 10 times with brine, dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The obtained crude material was purified by HPLC (column: SunFire Prep C18 OBD column, 19 × 150 mm 5 μm 10 nm; mobile phase A: water (0.05% FA), mobile phase B: ACN (0.1% DEA) --HPLC --; flow rate: 25 mL / min; gradient: 15B to 38B over 8 minutes; 220 nm). By lyophilization, 6-(6-ethynyl-4-methoxypyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (31.1 mg, 21%) was obtained as a brown amorphous solid. MS[M+1]=481.15.1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 7.42 (s, 1H), 7.36 - 7.27 (m, 2H), 7.19 (d, J = 5.0 Hz, 1H), 7.14 - 7.07 (m, 1H), 4.48 (s, 1H), 3.87 (s, 3H), 3.61 (s, 3H), 2.41 (s, 6H). (Example 5) Synthesis of 6-(6-ethynyl-2,4-dimethylpyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (compound IV-1) [ka] Step 1. Preparation of 6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0566] In a resealable reaction vial, 4-chloro-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 4.1 mmol), N6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.82 g, 4.91 mmol), PAd2nBu Pd-G2 (0.27 g, 0.41 mmol), PAd2nBu (0.29 g, 0.82 mmol), K3PO4 (2.61 g, 12.3 mmol), dioxane (30 mL), H2O (3 mL), and a stirring bar were added. The vial was then evacuated and purged three times with nitrogen. The mixture was stirred at 70°C for 15 hours. The reaction mixture was concentrated under vacuum. The obtained crude material was purified by silica gel chromatography (eluted by MeOH / DCM = 1 / 100 to 1 / 20). Concentration in vacuum yielded 6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.7 g, 42%) as a solid. Step 2. Preparation of 6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0567] In a resealable reaction vial, 6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.7 g, 1.7 mmol), Pd(PPh3)4 (0.2 g, 0.17 mmol), THF (20 mL), and a stirring bar were added. The vial was then evacuated and purged three times with nitrogen. Zn(CH3)2 (1 M, 2.04 mL, 2.04 mmol) was added. The mixture was stirred at 70°C for 2 hours. The reaction mixture was quenched with water, extracted with DCM, dehydrated with Na2SO4, and concentrated under vacuum. The resulting crude material was purified by silica gel chromatography (elution at MeOH / DCM = 1 / 100 to 1 / 30). Concentration in a vacuum yielded 6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (0.4 g, 60%) as a solid. Step 3. Preparation of 5-bromo-6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0568] 6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (0.4 g, 1 mmol), DMF (10 mL), and a stirring bar were placed in a round-bottom flask. NBS (0.18 g, 1 mmol) was added. The mixture was stirred for 1 hour. The reaction was quenched with saturated NaHSO3 aqueous solution, extracted with DCM (50 mL x 3), the organic phases were combined, washed twice with brine, dried with Na2SO4, evaporated under vacuum, the residue was dissolved with ACN (25 mL), filtered, the filter cake was washed with ACN, and dried under reduced pressure to obtain 5-bromo-6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (440 mg, 94%) as a solid. Step 4. Preparation of 6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0569] In a round-bottom flask, 5-bromo-6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (440 mg, 0.94 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (371.5 mg, 1.1 mmol), Pd(PPh3)4 (104 mg, 0.09 mmol), K3PO4 (598 mg, 2.82 mmol), DME / H2O (10:1, 10 mL), and a stirring bar were placed. The flask was then evacuated and purged three times with nitrogen. The mixture was stirred at 90°C for 2 hours. After cooling, the mixture was diluted with water, extracted with DCM, dehydrated with Na2SO4, evaporated under vacuum, and the residue was purified by silica gel chromatography (eluted at MeOH / DCM = 1 / 100 to 1 / 10) to obtain 6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 54%) as a solid. Step 5: Preparation of 6-(6-ethynyl-2,4-dimethylpyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine [ka]

[0570] 6-(6-((tert-butyldimethylsilyl)ethynyl)-2,4-dimethylpyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.51 mmol), THF (10 mL), and a stirring bar were placed in a round-bottom flask. TBAF (0.61 mL, 0.61 mmol) was added dropwise. The mixture was stirred at room temperature for 0.5 hours. The mixture was diluted with water, extracted with DCM, washed with brine, dehydrated with Na2SO4, evaporated under vacuum, and the residue was purified by preparative HPLC to obtain 6-(6-ethynyl-2,4-dimethylpyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo [2,3-d]pyrimidine (100 mg, 41%) was obtained as a solid. MS[M+1] = 479.35. 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.48 (d, J = 5.0 Hz, 1H), 7.45 (s, 1H), 7.34-7.25 (m, 2H), 7.18 (d, J = 5.0 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 4.39 (s, 1H), 3.51 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H), 2.05 (s, 3H).

[0571] 100 mg of target was sent to chiral separation (column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH), mobile phase B: EtOH:DCM=1:1--HPLC; flow rate: 20 mL / min; gradient: 20B to 20B over 15.5 minutes; 220 / 254 nm; RT1: 10.826; RT2: 12.649; injection volume: 0.8 ml; number of cycles: 5). Freeze-drying yielded isolated rotational isomers of 6-(6-ethynyl-2,4-dimethylpyridine-3-yl)-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine, represented by the first peak (43.4 mg) and the second peak (40.2 mg). (Example 6) Polymorphic screening of N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide hydrochloride (compound I-1)

[0572] Polymorphic screening of compound I-1 (also known as N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide hydrochloride was performed in 24 different solvents using a temperature cycling method. If no suspended solid was observed when the system was cooled to 25°C, the solution was evaporated. Detailed operating procedures are listed below:

[0573] The transformation of compound I-1 (morphology D) was investigated under anhydrous and aqueous conditions at 50°C. Table 1 summarizes the results of the transformation of morphology D investigated in these studies. Compound I-1 (approximately 100 mg, morphology D) and a suitable solvent (10 volumes) were placed in separate 1.5 ml clear glass vials and heated to 50°C at 0.5°C / min (over 1 hour), stirred at 50°C for 16 hours, and cooled at -0.5°C / min (over 1 hour). After this time, the product was isolated by centrifugation at 10,000 RPM for 10 minutes, dried under reduced pressure at 40°C, and analyzed by XRPD, HPLC, and 1H NMR. If a novel XRPD pattern was identified, the dried solid with the novel XRPD pattern was also characterized by PLM, DSC, and TGA. Further polymorphic screening was performed as shown in the map of identified morphologies (Figure 12).

[0574] A summary of the solvents tested can be found in Table 1. [Table 1-1] Form A

[0575] Following the polymorph screening experiment described above, all obtained solids exhibited XRPD patterns including morphology A. Morphology A was also obtained by heating morphology G to 230°C.

[0576] Next, morphology A of compound I-1 was characterized by DSC, TGA, and DVS. The DSC scan of morphology A in Figure 1B showed a single endothermic peak at the start of 277.67°C (enthalpy: 140.7 J / g). The TGA scan (Figure 1C) showed a weight loss of 0.2503% from 33°C to 80°C and a weight loss of 0.222% from 170°C to 270°C. Dynamic water vapor sorption (DVS) data for morphology A of compound I-1 are shown in Figure 1D.

[0577] The XRPD of compound I-1, form A, is shown in Figure 1A. Table 2.1 below shows the X-ray diffraction peaks observed for compound I-1, form A, where each value is 2θ degrees: [Table 2.1] Form B

[0578] Following the polymorph screening experiment described above, all obtained solids exhibited an XRPD pattern including morphology B. Morphology B was also obtained by adding an aqueous HCl solution to a solution of free base in 2-propanol. Furthermore, morphology B was obtained by heating morphology I to approximately 220°C, morphology F to approximately 220°C, and morphology J to approximately 220°C.

[0579] Next, morphology B of compound I-1 was characterized by DSC, TGA, and DVS. The DSC scan of morphology B in Figure 2B showed an endothermic peak at approximately 217°C (enthalpy: 3.86 J / g). The TGA scan (Figure 2C) showed a weight loss of 7.15% from approximately 160°C to approximately 250°C. In summary, morphology B is the pure crystalline form of compound I-1. Dynamic water vapor sorption (DVS) data for morphology B of compound I-1 are shown in Figure 2D.

[0580] The XRPD of compound I-1, form B, is shown in Figure 2A. Table 2.2 below shows the X-ray diffraction peaks observed for compound I-1, form B, where each value is 2θ degrees: [Table 2.2-1] [Table 2.2-2] Form C

[0581] Following the polymorph screening experiments described above, all obtained solids exhibited XRPD patterns including morphology C. Morphology C was also obtained by adding aqueous HCl to a solution of free base in ethyl acetate. Furthermore, morphology C was obtained from slurries of morphology D in methyl ethyl ketone / water (19 / 1 v / v), methyl acetate / water (19 / 1 v / v), or isopropyl acetate / water (19 / 1 v / v).

[0582] Next, morphology C of compound I-1 was characterized by DSC, TGA, and DVS. The DSC scan of morphology C in Figure 3B showed an endothermic peak at approximately 190°C (enthalpy: 44.6 J / g). The TGA analysis of morphology C of compound I-1 is shown in Figure 3B. Dynamic water vapor sorption (DVS) data for morphology C of compound I-1 is shown in Figure 3D.

[0583] The XRPD of compound I-1 in form C is shown in Figure 3A. Table 2.3 below shows the X-ray diffraction peaks observed for compound I-1 in form C, where each value is 2θ degrees: [Table 2.3-1] [Table 2.3-2] Form D

[0584] Following the polymorph screening experiment described above, all obtained solids exhibited XRPD patterns including morphology D. Morphology D was also obtained by adding 6N HCl in 2-propanol to a free base in ethyl acetate (20 volumes).

[0585] Next, form D of compound I-1 is DSC, TGA, DVS and 1 Characterization was performed by 1H-NMR. A DSC scan of morphology D in Figure 4B showed an endothermic peak at the start of 156°C (enthalpy: 53.3 J / g). A TGA scan (Figure 4C) showed a 12.4% weight loss from 40°C to 130°C. Dynamic water vapor sorption data for morphology D of compound I-1 are shown in Figure 4D.

[0586] The XRPD of compound I-1 in form D is shown in Figure 4A. Table 2.4 below shows the X-ray diffraction peaks observed for compound I-1 in form D, where each value is 2θ degrees: [Table 2.4-1] [Table 2.4-2] Form E

[0587] Following the polymorphic screening experiment described above, all obtained solids exhibited XRPD patterns including morphology E. Morphology E was also obtained by slurring morphology C in ethanol (25 vol) at 50°C for 16 hours. Furthermore, morphology E was obtained by heating morphology D to 220°C.

[0588] Next, morphology E of compound I-1 was characterized by DSC. The DSC scan of morphology E of compound I-1 is shown in Figure 5B. The dynamic water vapor sorption data of morphology E of compound I-1 is shown in Figure 5D.

[0589] The XRPD of compound I-1, form E, is shown in Figure 5A. Table 2.5 below shows the X-ray diffraction peaks observed for compound I-1, form E, where each value is 2θ degrees: [Table 2.5] Form F

[0590] Following the polymorph screening experiments described above, all obtained solids exhibited XRPD patterns including morph F. Morph F was also obtained by adding HCl to a free base in ethyl acetate, with morph B added as a seed crystal. Furthermore, morph F was obtained by slurring morph D in ethyl acetate / water (19 / 1 v / v) at 50°C. Morph F was also obtained by heating morph I to 120°C.

[0591] Next, morphology F of compound I-1 was characterized by DSC, TGA, and DVS. The DSC scan of morphology F in Figure 6B showed an endothermic peak at the start of 162°C (enthalpy: 15.5 J / g). The TGA scan (Figure 6B) showed weight losses of 4.7% from 43°C to 95°C, 1.2°C from 125°C to 160°C, and 4.4% from 220°C to 260°C. Dynamic water vapor sorption data for morphology F of compound I-1 are shown in Figure 6D.

[0592] The XRPD of compound I-1 in form F is shown in Figure 6A. Table 2.6 below shows the X-ray diffraction peaks observed for compound I-1 in form F, where each value is 2θ degrees:

[0593] [Table 2.6] Form G

[0594] Following the polymorphic screening experiments described above, all obtained solids exhibited XRPD patterns including morphology G. Morphology G was also obtained by slurring morphology D in water at 50°C. Furthermore, morphology G was obtained from a slurry of morphology C in 2-propanol at 50°C.

[0595] Next, morphology G of compound I-1 was characterized by DSC, TGA, and DVS. The DSC scan of morphology G in Figure 7B showed an endothermic peak at approximately 145°C (enthalpy: 66.9 J / g). The TGA scan (Figure 7C) showed a 4.2% weight loss from 40°C to 140°C. Dynamic water vapor sorption data for morphology G of compound I-1 are shown in Figure 7D.

[0596] The XRPD of compound I-1 in morphology G is shown in Figure 7A. Table 2.7 below shows the X-ray diffraction peaks observed for compound I-1 in morphology G, where each value is 2θ degrees: [Table 2.7] Form H

[0597] Following the polymorph screening experiment described above, all obtained solids exhibited an XRPD pattern containing morphology H. Morphology H was also obtained from free base in ethyl acetate (20 volumes) after adding morphology B as a seed crystal and then adding HCl.

[0598] Next, morph H of compound I-1 was characterized by DSC, TGA, and DVS. The DSC scan of morph H in Figure 8B showed an endothermic peak at approximately 186°C (enthalpy: 39.1 J / g). The TGA scan (Figure 8B) showed a weight loss of 5.4% from 40°C to 80°C and 3.7% from 190°C to 260°C. Dynamic water vapor sorption data for morph H of compound I-1 are shown in Figure 8D.

[0599] The XRPD of compound I-1 in form H is shown in Figure 8A. Table 2.8 below shows the X-ray diffraction peaks observed for compound I-1 in form H, where each value is 2θ degrees:

[0600] [Table 2.8] Form I

[0601] Following the polymorph screening experiment described above, all obtained solids exhibited an XRPD pattern containing morphology I. Morphology I was also obtained by the desalting of morphology D and subsequent salt formation with HCl in ethyl acetate.

[0602] Next, form I of compound I-1 is DSC, TGA, DVS and 1 The compound was characterized by 1H-NMR. A DSC scan of morphology I in Figure 9B showed an endothermic peak at the start of 155.7°C (enthalpy: 33.4 J / g). A TGA scan (Figure 9B) showed a 12.1% weight loss from 40°C to 140°C. In summary, morphology I is the pure crystalline form of compound I-1. Dynamic water vapor sorption data for morphology I of compound I-1 are shown in Figure 9D.

[0603] The XRPD of compound I-1, form I, is shown in Figure 9A. Table 2.9 below shows the X-ray diffraction peaks observed for compound I-1, form I, where each value is 2θ degrees:

[0604] [Table 2.9-1] [Table 2.9-2] Form J

[0605] Following the polymorph screening experiment described above, all obtained solids exhibited an XRPD pattern containing morphology J. Morphology J was also obtained by the desalting of morphology I and subsequent salt formation with HCl in ethyl acetate.

[0606] Next, morphology J of compound I-1 was characterized by DSC, TGA, and DVS. The DSC scan of morphology J in Figure 10B showed an endothermic peak at the start of 193.8°C (enthalpy: 20.6 J / g). The TGA scan (Figure 10B) showed a weight loss of 9.1% from 40°C to 100°C. In summary, morphology J is the pure crystalline form of compound I-1. Dynamic water vapor sorption data for morphology J of compound I-1 are shown in Figure 10D.

[0607] The XRPD of compound I-1 in form J is shown in Figure 10A. Table 2.10 below shows the X-ray diffraction peaks observed for compound I-1 in form J, where each value is 2θ degrees: [Table 2.10] Form K

[0608] Following the polymorph screening experiment described above, all obtained solids exhibited XRPD patterns containing morphology K. Morphology K was also obtained by slurring morphology C in THF (25 vol) at 50°C for 16 hours.

[0609] Next, morphology K of compound I-1 was characterized by DSC, TGA, and DVS. The DSC scan of morphology K in Figure 11B showed an endothermic peak at approximately 147°C (enthalpy: 10.7 J / g). The TGA scan (Figure 11B) showed a weight loss of 5.4% from 170°C to 230°C. In summary, morphology K is the pure crystalline form of compound I-1. Dynamic water vapor sorption data for morphology K of compound I-1 are shown in Figure 11D.

[0610] The XRPD of compound I-1 in form K is shown in Figure 11A. Table 2.11 below shows the X-ray diffraction peaks observed for compound I-1 in form K, where each value is 2θ degrees:

[0611] [Table 2.11] (Example 7) Competitive equilibrium study of the suspension of N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide hydrochloride (compound I-1).

[0612] Competitive equilibration of the suspension was investigated. Equal volumes of various polymorphs and suitable solvents (25 volumes) were placed in separate 1.5 ml clear glass vials and stirred at 25°C and 50°C. Morphological transformation was monitored by XRPD analysis.

[0613] Competitive suspension equilibration experiments investigating the stability of the morphology in various organic solvents demonstrated that morphology A was obtainable under most of the conditions investigated (Table 3.1). The fastest conversion rates occurred in the solvent with the highest solubility. Conversion of different morphologies of the mixture to morphology A was observed in methanol (solubility 18.7 mg / ml) after 24 hours at both 25°C and 50°C, and in ethanol (solubility 2.3 mg / ml) between 24 hours and 4 days. Conversion of the crystalline morphology of the mixture to morphology A was observed in various solvents (Table 3.1), but the fastest conversion to morphology A was observed in methanol and ethanol at both temperatures. [Table 3.1-1] [Table 3.2-2]

[0614] Further investigations were conducted to establish the stability of the polymorphisms when morphs D and I are matured in the absence of a seed crystal of morph A.

[0615] The mixture of the two forms (1 / 1 w / w) was placed in a 1.5 ml clear glass vial and stirred at 50°C for 16 hours. After this time, the product was isolated by centrifugation at 10,000 rpm for 10 minutes, dried under reduced pressure at 40°C, and analyzed by XRPD, HPLC, and 1H NMR. Competitive slurry conversion experiments containing equal parts of form D and form I in ethanol / water (19 / 1 v / v, 10 volumes) resulted in the formation of form A after 24 hours at 20°C and 50°C (Table 3.2). The conversion of the mixture of form D and form I to form A was observed in ethanol at 50°C after 7 days. Form E was produced by forming a slurry of the mixture of form D and form I in ethanol at 20°C. [Table 3.2] (Example 8) Preparation of the salt form of N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidine-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)methacrylamide

[0616] The free base of compound I-1 (compound I-2, 30 mg) was suspended in IPA (20 volumes, 600 μl at 50°C). The solution / suspension was then treated with 1 mol equivalent of the acid shown in Table 4. The suspension was then cooled to 5°C at 0.1°C / min and maintained at this temperature for 16 hours. Stirring (500 rpm) was maintained throughout. Any gum-like material formed was aged between 25 and 50°C (4 hours at each temperature for 24 hours). The suspension was isolated by suction filtration, air-dried, and then analyzed by XRPD. Any novel patterns identified by XRPD were further analyzed by NMR, TGA, DSC, and stability for 1 week at 40C / 75%RH.

[0617] Several samples were analyzed for their solubility in fasting-simulated intestinal fluid (FaSSIF) and their final pH in the solution.

[0618] The results of the salt screening ...

Claims

[Claim 1] The invention described herein.

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