Polymorphs and synthetic methods for azetidinone inhibitors of KRAS-G12D

Abstract

This article provides 2-fluoro-5-((5 S ,5a S 6 S 9 R )-1-Fluoro-12-(((2) R 7a S )-2-fluorotetrahydro-1 H -Pyrrolizine-7a(5 H )-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5 H -4-oxa-3,10a,11,13,14-pentaza-6,9-methylnaphtho[1,8- ab Polymorphs and crystalline forms of hepta-en-2-yl)-3-methyl-4-(trifluoromethyl)aniline (compound of formula (I), pharmaceutical compositions thereof, and methods of use thereof, for example, in the treatment of cancer. This document also provides methods for manufacturing compound of formula (I) Right now 2-Fluoro-5-((5 S ,5a S 6 S 9 R )-1-Fluoro-12-(((2) R 7a S )-2-fluorotetrahydro-1 H -Pyrrolizine-7a(5 H )-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5 H -4-oxa-3,10a,11,13,14-pentaza-6,9-methylnaphtho[1,8- ab A method for synthesizing heptadecan-2-yl)-3-methyl-4-(trifluoromethyl)aniline is also provided. Compounds that can be used for its synthesis are also provided. For example, The compounds of formulas (A), (B), (By), and (H) and methods for synthesizing these compounds.

Description

Cross-references to related applications

[0001] This application claims priority and benefit to U.S. Provisional Application No. 63 / 602,285, filed November 22, 2023, and U.S. Provisional Application No. 63 / 602,244, filed November 22, 2023. The disclosure of each of the foregoing applications is incorporated herein by reference in its entirety. Technical Field

[0002] The techniques described herein generally relate to polymorphs of aza-tetracyclooxazine inhibitors of KRAS-G12D. The techniques described herein also generally relate to the synthesis of small organic molecules with pharmaceutical activity, and more specifically, to the synthesis of aza-tetracyclooxazine inhibitors of KRAS-G12D. Background Technology

[0003] Ras is a small GTP-binding protein that acts as a nucleotide-dependent switch in central growth signaling pathways. In response to extracellular signals, Ras binds to GDP under the catalysis of guanine nucleotide exchange factors (GEFs), particularly SOS1 protein. GDP The state transitions to GTP binding (Ras) GTP ) State. Active Ras GTP Ras mediates a variety of growth-stimulating functions through direct interactions with effectors, including Raf, PI3K, and Ral guanine nucleotide dissociation stimulants. Ras' intrinsic GTPase activity subsequently hydrolyzes GTP to GDP, thereby terminating Ras signaling. Ras GTPase activity can be further enhanced through its interactions with GTPase-activating proteins (GAPs), including neurofibromin 1 tumor inhibitors.

[0004] Mutant Ras exhibits reduced GTPase activity, which prolongs its activated state, thereby promoting Ras-dependent signaling and the survival or growth of cancer cells. Mutations in Ras affect its ability to interact with GAP or convert GTP back to GDP, leading to prolonged activation of the protein and consequently prolonged signals instructing the cell to continue growing and dividing. Because these signals drive cell growth and division, overactive RAS signaling may ultimately lead to cancer. Mutations in any of the three major genotypes of RAS (HRas, NRas, or KRas) are common events in human tumorigenesis. Among the three Ras subtypes (K, N, and H), KRas is the most frequently mutated.

[0005] The most common KRas mutations occur at residues G12 and G13 of the P ring, as well as residue Q61. G12D is a common mutation in the KRas gene (glycine-12 to aspartic acid). Ras mutations in cancer are associated with poor prognosis. In mice, inactivation of oncogenic Ras leads to tumor shrinkage. Therefore, Ras is widely considered an extremely important tumor target.

[0006] The compound of formula (I) disclosed herein (2-fluoro-5-((5S,5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptadene-2-yl)-3-methyl-4-(trifluoromethyl)aniline) is an inhibitor of the G12D mutant KRas (KRas-G12D) and can therefore be used to treat cancer. For a KRas-G12D inhibitor to become a useful therapeutic agent, it should possess an appropriate balance of various characteristics, including affinity and selectivity for KRas-G12D, inhibitory activity, duration of activity, oral bioavailability, tissue distribution, and stability (e.g., shelf life, reconstitutionability, and crystallizability). An appropriate balance of such a combination of characteristics can lead to improved efficacy, safety, tolerability, patient compliance, manufacturing efficiency, and more for KRas-G12D inhibitors. The identification and isolation of crystalline forms can facilitate the preparation and development of KRas-G12D inhibitors with appropriate properties, including bioavailability, chemical stability, thermal stability, solubility, hygroscopicity, particle size, yield, impurity content during crystallization, drying characteristics, grinding characteristics, and stability during tableting. However, significant complexities exist surrounding the identification and selection of solid forms of pharmaceutical compounds. Currently, there is no reliable predictability regarding the quantity and properties of solid forms and their practicality as crystalline solids used as active pharmaceutical ingredients. Furthermore, it is known that different crystalline forms of small molecules may have different levels of bioavailability in some cases, such as varying solubility under specific conditions (e.g., in the human body). Nevertheless, it remains impossible to predict how many polymorphs exist for a given small molecule, under what conditions they form, or what their properties will be. Mixtures of single-component crystalline materials are caused by polymorphism, and it is impossible to predict a priori whether or not a compound even exists, let alone how to successfully prepare it. See, for example, Cruz-Cabesa et al., “Facts and fictions about polymorphism,” Chem. Soc. Rev., 44, 8619 (2015). See also Jones et al., 2006, “Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement,” MRS Bulletin 31:875-879 (it is currently generally impossible to predict by calculation the number of observable polymorphs even for the simplest molecules).

[0007] Therefore, it is still necessary to identify and isolate the stable crystalline form of compound (I) (2-fluoro-5-((5S,5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptadene-2-yl)-3-methyl-4-(trifluoromethyl)aniline).

[0008] Furthermore, certain exemplary methods for preparing compounds of formula (I) are disclosed in U.S. Provisional Application No. 63 / 343,959, filed May 19, 2022, and International Application No. PCT / US2023 / 022914, filed May 19, 2023, the disclosures of which are incorporated herein by reference in their entirety. However, it is generally desirable to design a synthetic process that provides products in an efficient manner, for example, by using environmentally sustainable steps or by using inexpensive and reasonably available reagents, to prepare products free from a significant amount of undesirable impurities within acceptable limits and with appropriate yields. Therefore, the synthetic process for compounds of formula (I) disclosed herein advantageously offers beneficial aspects such as one or more of the following: energy-efficient process conditions, convenient reagent selection, complexity of required unit operations, scalability, and others. Summary of the Invention

[0009] This article provides solutions to the above-mentioned problems and other problems in this field.

[0010] More specifically, this disclosure provides compounds of formula (I). (I) Various polymorphs (including crystalline forms) and pharmaceutical compositions thereof, and methods of using said crystalline forms and pharmaceutical compositions, for example in the treatment of cancer.

[0011] In one aspect, this disclosure provides a crystalline form of a compound of formula (I).

[0012] In some embodiments, the crystalline form is an anhydrous crystalline form (i.e., anhydrous). In some embodiments, the anhydrous crystalline form is form J, form O, form U, form AC, or form AG. In some embodiments, the anhydrous crystalline form is form J. In some embodiments, the anhydrous crystalline form is form O. In some embodiments, the anhydrous crystalline form is form U. In some embodiments, the anhydrous crystalline form is form AC. In some embodiments, the anhydrous crystalline form is form AG.

[0013] In some embodiments, the crystalline form is a hydrated crystalline form (i.e., a hydrate). In some embodiments, the hydrated crystalline form is form D, form G, form N, form Q, form AA, form AK, or form AL. In some embodiments, the hydrated crystalline form is form D. In some embodiments, the hydrated crystalline form is form G. In some embodiments, the hydrated crystalline form is form N. In some embodiments, the hydrated crystalline form is form Q. In some embodiments, the hydrated crystalline form is form AA. In some embodiments, the hydrated crystalline form is form AK. In some embodiments, the hydrated crystalline form is form AL.

[0014] In some embodiments, the crystalline form is a solvated crystalline form (i.e., a solvate). In some embodiments, the solvated crystalline form is a solvate of 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (ACN), tetrahydrofuran (THF), dimethylformamide (DMF), 1,4-dioxane, dimethylacetamide (DMAc), isopropanol (IPA), methyl tert-butyl ether (MTBE), ethyl acetate (EtOAc), acetone, isopropyl acetate (IPAc), chloroform (CHCl3), dichloromethane (DCM), cyclopentyl methyl ether (CPME), anisole, diisopropyl ether, toluene, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), 1,2-propanediol, 1,2-dimethoxyethane, or 2-tert-butoxyethanol. In some embodiments, the solvated crystallization form is one of the forms described herein: A, C / S, E, F, H, I, L, M, R, T, V, W, X, Y, Z, AD, AE, AH, AI, AJ, AP, AQ, or AR. In some embodiments, the solvated crystallization form is form A. In some embodiments, the solvated crystallization form is form C / S. In some embodiments, the solvated crystallization form is form E. In some embodiments, the solvated crystallization form is form F. In some embodiments, the solvated crystallization form is form H. In some embodiments, the solvated crystallization form is form I. In some embodiments, the solvated crystallization form is form L. In some embodiments, the solvated crystallization form is form M. In some embodiments, the solvated crystallization form is form R. In some embodiments, the solvated crystallization form is form T. In some embodiments, the solvated crystallization form is form V. In some embodiments, the solvated crystallization form is form W. In some embodiments, the solvated crystallization form is form X. In some embodiments, the solvated crystallization form is form Y. In some embodiments, the solvated crystallization form is form Z. In some embodiments, the solvated crystallization form is form AD. In some embodiments, the solvated crystal form is form AE. In some embodiments, the solvated crystal form is form AH. In some embodiments, the solvated crystal form is form AI. In some embodiments, the solvated crystal form is form AJ. In some embodiments, the solvated crystal form is form AP. In some embodiments, the solvated crystal form is form AQ. In some embodiments, the solvated crystal form is form AR.

[0015] In some embodiments, the crystalline form is a metastable crystalline form. In some embodiments, the metastable crystalline form is form B / AF, form K, form AB, form AM, form AN, form AO, or form P as described herein. In some embodiments, the metastable crystalline form is form B / AF. In some embodiments, the metastable crystalline form is form K. In some embodiments, the metastable crystalline form is form AB. In some embodiments, the metastable crystalline form is form AM. In some embodiments, the metastable crystalline form is form AN. In some embodiments, the metastable crystalline form is form AO. In some embodiments, the metastable crystalline form is form P.

[0016] In one aspect, this disclosure provides a pharmaceutical composition comprising the crystalline form of this disclosure and at least one pharmaceutically acceptable excipient.

[0017] In one aspect, this disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the crystalline form or pharmaceutical composition described herein. In some embodiments, the subject is a human being.

[0018] In one aspect, this disclosure provides a method for modulating the activity of a KRas mutant protein, the method comprising reacting the mutant protein with a crystalline form or pharmaceutical composition described herein.

[0019] In one aspect, this disclosure provides a method for inhibiting the proliferation of a cell population, the method comprising contacting the cell population with a crystalline form or pharmaceutical composition described herein.

[0020] In one aspect, this disclosure provides a method for inhibiting tumor metastasis in a subject, the method comprising administering to the subject a therapeutically effective amount of the crystalline form or pharmaceutical composition described herein. In some embodiments, the subject is a human being.

[0021] This disclosure also provides for preparative methods. (I) The synthetic process of the compound (i.e., 2-fluoro-5-((5S,5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptadene-2-yl)-3-methyl-4-(trifluoromethyl)aniline), and the compounds that can be used to synthesize it and the synthetic process for it.

[0022] In one aspect, this disclosure provides a method for preparative (I) A method involving compounds. In some embodiments, the method includes the following steps: a) React compound (A) with compound (B) to prepare compound (C): (A) (B) (C); b) Reacting compound (C) with one or more reagents to prepare compound (D): (D); c) Reacting compound (D) with an oxidizing agent to prepare compound (E): (E); d) Reacting compound (E) with compound (F) to prepare compound (G): (F) (G); e) Reacting compound (G) with compound (Ha) to prepare compound (Ja): (Ha) (Ja), where Boc is a tert-butyloxycarbonyl group; and f) React the compound of formula (Ja) with an acidic reagent to prepare the compound of formula (I).

[0023] In some implementations, the method includes the following steps: a) React compound (A) with compound (B) to prepare compound (C): (A) (B) (C); b) Reacting compound (C) with one or more reagents to prepare compound (D): (D); c) Reacting compound (D) with an oxidizing agent to prepare compound (E): (E); d) Reacting compound (E) with compound (F) to prepare compound (G): (F) (G); e) Reacting compound (G) with compound (H) to prepare compound (J): (H) (J), where PMB is p-methoxybenzyl; and f) React the compound of formula (J) with an acidic reagent to prepare the compound of formula (I).

[0024] On the other hand, this disclosure provides a method for preparative... (A) A method involving a compound. In some embodiments, the method includes the following steps: a) Reaction of compound of formula (Aw) with TMPMgCl The reaction of LiCl and BrCF2CF2Br prepares a compound of formula (Ax): (Aw) (Ax); b) Reacting compound (Ax) with NHS and EDC to prepare compound (Ay): (Ay); c) Reacting compound of formula (Ay) with S-methylisothiourea to prepare compound of formula (Az): (Az); and d) Reacting compound of formula (Az) with NMI and DMA to prepare compound of formula (A).

[0025] In one aspect, this disclosure provides a method for preparative (B) A method involving a compound. In some embodiments, the method includes the following steps: a) Reacting compound of formula (Bv) with benzyl bromide to prepare compound of formula (Bw): (Bv) (Bw); b) Reacting compound (Bw) with s-BuLi, TMEDA, and acetaldehyde to prepare compound (Bx') and a mixture thereof: (Bx') (Bx''); c) Reacting a compound of formula (Bx') and a mixture of compounds of formula (Bx'') with H2, Pd / C, and D(+)-10-camphorsulfonic acid to prepare compound of formula (By): (By); d) Reacting compound (By) with (Boc)₂O to prepare compound (Bz): (Bz); and e) React compound of formula (Bz) with a basic reagent to prepare compound of formula (B).

[0026] In another aspect, this document provides a method for preparing compounds of formula (H). In some embodiments, the method includes the following steps: a) Reacting compound of formula (Hu) with NBS to prepare compound of formula (Hv): (Hu) (Hv); b) Reacting compound of formula (Hv) with hydrogen over a platinum / vanadium / carbon catalyst to prepare compound of formula (Hw); (Hw); c) Reacting compound of formula (Hw) with PMBCl to prepare compound of formula (Hx): (Hx); d) Reacting compound of formula (Hx) with NIS to prepare compound of formula (Hy): (Hy); e) To prepare compound of formula (Hz) by reacting compound of formula (Hy) with MeO2CCF2SO2F in the presence of CuI: (Hz); and f) React the compound of formula (Hz) with n-BuLi and B(OiPr)3 to prepare the compound of formula (H).

[0027] In one aspect, this disclosure provides compounds that can be used to synthesize compounds of formula (I). In some embodiments, the compound is of formula (I). (A) Compound. In some embodiments, the compound is of the formula... (B) Compound. In some embodiments, the compound is of the formula... (H) compound. In some embodiments, the compound is of the formula... (By) compound. Attached Figure Description

[0028] Figure 1An exemplary X-ray powder diffraction (XRPD) pattern of form J is depicted.

[0029] Figure 2 An exemplary XRPD diagram of form O is depicted.

[0030] Figure 3 An exemplary XRPD diagram of form U is depicted.

[0031] Figure 4 An exemplary XRPD diagram of the form AC is depicted.

[0032] Figure 5A An exemplary XRPD diagram of the form AG is depicted.

[0033] Figure 5B Exemplary thermogravimetric analysis (TGA) (top) and differential scanning calorimetry (DSC) thermograms of form AG are depicted.

[0034] Figure 5C An exemplary DVS diagram of the form AG is depicted.

[0035] Figure 5D An exemplary SEM micrograph of the form AG is depicted.

[0036] Figure 5E Exemplary superimposed XRPD plots of form AG obtained under the following conditions: after heating at 80 °C and 51% RH for 21 days (top plot); after heating at 70 °C and 75% RH for 28 days (middle plot); and at ambient temperature and RH (bottom plot).

[0037] Figure 5F Exemplary XRPD plots of the form AG obtained under the following conditions are depicted: after 8 days of pulping in water (top plot), after 3 days of pulping in water (middle plot), and without pulping in water (bottom plot).

[0038] Figure 6 An exemplary XRPD diagram of form D is depicted.

[0039] Figure 7 An exemplary XRPD diagram of form G obtained before drying (top) and after drying (bottom) is depicted.

[0040] Figure 8 An exemplary XRPD diagram of form N is depicted.

[0041] Figure 9 An exemplary XRPD diagram of form Q is depicted.

[0042] Figure 10 An exemplary XRPD diagram of form AA is depicted.

[0043] Figure 11 An exemplary XRPD diagram of form AK is depicted.

[0044] Figure 12 An exemplary XRPD diagram of form AL is depicted.

[0045] Figure 13 An exemplary XRPD diagram of form A is depicted.

[0046] Figure 14 An exemplary XRPD diagram in the form of C / S is depicted.

[0047] Figure 15 An exemplary XRPD diagram of form E is depicted.

[0048] Figure 16 An overlay of an exemplary XRPD plot of form F (top) and a computed / predicted XRPD plot (bottom) is shown.

[0049] Figure 17 An exemplary XRPD diagram of form H is depicted.

[0050] Figure 18 An exemplary XRPD diagram of form I is depicted.

[0051] Figure 19 An exemplary XRPD diagram of form L is depicted.

[0052] Figure 20 An exemplary XRPD diagram of form M is depicted.

[0053] Figure 21 An exemplary XRPD diagram of form R is depicted.

[0054] Figure 22 An exemplary XRPD diagram of form T is depicted.

[0055] Figure 23 An exemplary XRPD diagram of form V is depicted.

[0056] Figure 24 An exemplary XRPD diagram of form W is depicted.

[0057] Figure 25 An exemplary XRPD diagram of form X is depicted.

[0058] Figure 26 An exemplary XRPD diagram of form Y is depicted.

[0059] Figure 27 An exemplary XRPD diagram of form Z is depicted.

[0060] Figure 28 An exemplary XRPD diagram of the form AD is depicted.

[0061] Figure 29 An exemplary XRPD plot of form AE is depicted. This XRPD plot is for a wet sample (from toluene solvent); the dry sample has an additional peak at 9.59 ± 0.2 °2θ and a lower degree of crystallinity.

[0062] Figure 30 An exemplary XRPD diagram of the form AH is depicted.

[0063] Figure 31 An exemplary XRPD diagram of formal AI is depicted.

[0064] Figure 32 An exemplary XRPD diagram of the form AJ is depicted.

[0065] Figure 33 An exemplary XRPD diagram of the form AP obtained before drying (top) and after drying (bottom) is depicted.

[0066] Figure 34 An exemplary XRPD diagram of the form AQ is depicted.

[0067] Figure 35 An exemplary XRPD diagram of the form AR is depicted.

[0068] Figure 36 An exemplary XRPD diagram of form B / AF is depicted.

[0069] Figure 37 An exemplary XRPD diagram of form K is depicted.

[0070] Figure 38 An exemplary XRPD diagram of form AB is depicted.

[0071] Figure 39 An exemplary XRPD diagram of the form AM is depicted.

[0072] Figure 40 An exemplary XRPD diagram of form AN is depicted.

[0073] Figure 41An exemplary XRPD diagram of the form AO is depicted.

[0074] Figure 42 An exemplary XRPD diagram of the form AP obtained before drying (top) and after drying (bottom) is depicted.

[0075] Figure 43 X-ray powder diffraction (XRPD) patterns depicting the representative crystalline form of the compound of formula (I) (referred to as form AG) are shown.

[0076] Figure 44 Thermogravimetric analysis (TGA) (top) and differential scanning calorimetry (DSC) (bottom) spectra of the representative crystalline form of compound (I) (referred to as form AG) are depicted.

[0077] Figure 45 Dynamic vapor adsorption (DVS) plots depicting the representative crystalline form of the compound of formula (I) (referred to as form AG) are shown.

[0078] Figure 46 XRPD diagrams depicting representative crystalline forms of (1S,6S,9R,9aS)-1-methylhexahydro-1H,3H-6,9-bridged iminooxazolo[3,4-a]azapyridine-3-one (1S)-(+)-CSA salt are shown. Detailed Implementation

[0079] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. See, for example: Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd edition, J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Methods, apparatus, and materials similar to or equivalent to any of the methods, apparatus, and materials described herein may be used in the practice of this invention.

[0080] The following definitions are provided to aid in understanding certain terms frequently used herein and are not intended to limit the scope of this disclosure. All references cited herein are incorporated herein in their entirety.

[0081] The term "this paper" refers to the entire application.

[0082] It should be understood that, unless expressly waived or improperly permitted, any embodiment described herein, including those described under different aspects and different parts of this disclosure (including embodiments described only in the embodiments), may be combined with one or more other embodiments of this disclosure. The combination of embodiments is not limited to those specific combinations claimed via any of the dependent claims. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where elements are presented as a list (e.g., in a Markush group format), each subgroup of elements is also disclosed, and any element may be removed from that group.

[0083] Specifically, it is contemplated that any limitations discussed with respect to one embodiment provided herein may apply to any other embodiment provided herein. Furthermore, any crystalline form or pharmaceutical composition described herein may be used in any method provided herein, and any method provided herein may be used to produce or utilize any crystalline form or pharmaceutical composition described herein.

[0084] While the disclosure herein provides for the illustrated embodiments, it should be understood that they are not intended to limit the crystalline forms, pharmaceutical compositions, and methods described herein to those embodiments. Rather, this disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of this disclosure.

[0085] All publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of any ambiguity, this specification (including its specific definitions) shall prevail. Furthermore, any particular embodiment of this disclosure that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Because such embodiments are considered to be known to those skilled in the art, they may be excluded even if not expressly stated herein. Any particular embodiment of this disclosure may be excluded from any claim for any reason, whether or not related to the existence of the prior art.

[0086] Unless otherwise indicated herein, the description of numerical ranges herein is intended only as a shorthand for referring to each individual value falling within that range and including its endpoints, and each individual value is incorporated into the specification as if it were described separately herein. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein may be performed in any suitable order. Unless otherwise stated, the use of any and all embodiments or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate the embodiments and does not constitute a limitation on the scope of the claims. No language in the specification should be construed as indicating that any unclaimed element is essential.

[0087] As used herein, in the context of describing elements (especially in the context of the following claims), the terms “a” and “the” and similar references should be interpreted as covering both singular and plural, unless otherwise indicated herein or clearly contradicted by the context.

[0088] As used herein, unless otherwise stated, the terms “about” and “approximately” when referring to a dose, amount, or weight percentage of an ingredient in a composition or dosage form mean a dose, amount, or weight percentage that is generally accepted by those skilled in the art to provide an equivalent pharmacological effect to that obtained by the specified dose, amount, or weight percentage. An equivalent dose, amount, or weight percentage may be in the range of 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percentage. In certain embodiments, the equivalent dose, amount, or weight percentage is within 10%, 5%, or 1% of the specified dose, amount, or weight percentage.

[0089] As used herein, and unless otherwise specified, the terms “about” and “approximately” when referring to a numerical value or range of values ​​(e.g., XRPD peak value) used to characterize a particular solid form described herein, indicate that the value or range of values ​​may deviate from a given value to a degree that would be reasonable to a person skilled in the art, while still describing the solid form. In one embodiment, the value of the XRPD peak position may vary up to ±0.1° 2θ (or ±0.05 degrees 2θ) while still describing a particular XRPD peak. Additionally, as used herein, and unless otherwise specified, the terms “about” and “approximately” when referring to a numerical value or range of values ​​indicate that the value or range of values ​​may deviate from a given value to a degree that would be reasonable to a person skilled in the art, while still describing the process.

[0090] As used herein, the term “or” should be understood to mean “and / or” unless the context clearly indicates otherwise.

[0091] Throughout the specification, the word “comprise” or variations such as “comprises” and “comprising” should be understood to imply inclusion of the stated integers (or components) or groups of integers (or components), but not to exclude any other integers (or components) or groups of integers (or components).

[0092] As used herein, the term “comprising” means “including, but not limited to”. “Comprising” and “including, but not limited to” are used interchangeably. Therefore, these terms will be understood to imply the inclusion of the stated integers (or components) or groups of integers (or components), but not to exclude any other integers (or components) or groups of integers (or components).

[0093] Throughout this specification, where a composition is described as having, including, or comprising (or variations thereof) a specific component, it is contemplated that the composition may also consist substantially of or be composed of said component. Similarly, where a method or process is described as having, including, or comprising specific process steps, the process may also consist substantially of or be composed of said process steps. Furthermore, it should be understood that the order of the steps or the sequence of certain actions is not important, as long as the compositions and methods described herein remain operable. Additionally, two or more steps or actions may be performed simultaneously.

[0094] Any of the method steps or sequences disclosed and / or claimed herein may be performed under an inert gas atmosphere, more specifically under nitrogen or argon. Furthermore, the methods and processes of the present invention may be performed as semi-continuous or continuous processes, more preferably as continuous processes.

[0095] Furthermore, many of the method steps and sequences described herein can be carried out in series. Typically, series reactions are conducted in a single reactor without the need to separate intermediates.

[0096] The compounds described herein, or those used in the methods described herein, may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may employ racemic, diastereomer, or enantiomer as starting materials or intermediates. Mixtures of specific diastereomers may be separated or enriched with one or more specific diastereomers by chromatography or crystallization. Similarly, mixtures of enantiomers may be separated or enriched enantiomerically using the same techniques or other techniques known in the art. Each of the asymmetric carbon or nitrogen atoms may be of an R or S configuration, and both of these configurations are contemplated herein.

[0097] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included. When the stereochemistry is specified by a solid wedge or dashed line indicating a specific configuration, that stereoisomer is designated and defined. Unless otherwise stated, the use of a solid wedge or dashed line signifies relative stereochemistry.

[0098] The term "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include diastereomers, enantiomers, transisomers, and conformational isomers.

[0099] The term "chirality" refers to the property of not overlapping with its mirror-image partner, while the term "chirality" refers to a molecule that can overlap with its mirror-image partner.

[0100] The term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical procedures (such as electrophoresis) and chromatographic methods (such as HPLC).

[0101] The term "enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0102] The term "restricted rotation isomer" refers to two conformational isomers produced by restricted rotation around a single bond, where the spatial strain barrier of the rotation can be high enough to allow separation of each conformational isomer.

[0103] The stereochemical definitions and conventions used in this article generally follow those of SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley and Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes D and L or (+) and (-) are used to specify the sign that a compound rotates plane-polarized light, where (-) or L means the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are generally referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in chemical reactions or processes where there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomers.

[0104] As used herein, the term "solid form" refers to a physical form that is not primarily in a liquid or gaseous state. A solid form can be a crystalline form or a mixture thereof. In some embodiments, the solid form can be a liquid crystal. A solid form can be a crystalline form as defined herein.

[0105] As used herein, the terms “crystalline form” and “crystalline shape” are used interchangeably to distinguish crystals with different properties (e.g., different XRPD patterns and / or different DSC scan results) and to refer to a crystalline solid form. In some embodiments, the crystalline form of the compounds described herein may be substantially free of amorphous solids and / or other crystalline forms. In some embodiments, the crystalline form of the compounds described herein may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50% by weight of one or more amorphous solids and / or other crystalline forms. In some embodiments, the crystalline form described herein is pure. In some embodiments, the crystalline form of the compounds described herein may have a purity of about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90%.

[0106] As used herein, the term "amorphous" or "amorphous solid" refers to a substantially non-crystalline solid form as determined by X-ray diffraction. Specifically, the term "amorphous solid" describes a disordered solid form, i.e., a solid form lacking long-range crystalline order. In some embodiments, the amorphous solid of the compounds described herein may be substantially free of other amorphous solids and / or crystalline forms. In some embodiments, the amorphous solid may be pure. In some embodiments, the amorphous solid of the compounds described herein may have a purity of about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90%.

[0107] The terms “anhydrous” and “waterless” are used interchangeably herein and, when applied to a compound or a crystalline form of a compound, refer to a solid state in which the compound contains no structural water or other solvent molecules within its crystal lattice. In some embodiments, the form does not contain levels of water or other solvent molecules detectable by standard methods and instruments used by those skilled in the art. In some embodiments, the anhydrous form exhibits a weight loss of <1% w / w when evaluated by thermogravimetric analysis at temperatures up to 150 °C. The anhydrous form may adsorb water when stored under humid conditions (e.g., at 80% relative humidity (RH)). In some embodiments, the anhydrous form adsorbs less than 1% w / w of moisture when stored at 25 °C / 80% RH.

[0108] As used herein, the terms "solvent" and "solventized" refer to the crystalline form provided herein, which further includes stoichiometric or non-stoichiometric solvents bonded by non-covalent intermolecular forces (e.g., hydrogen bonds). In the case where the solvent is water, the solvate is a "hydrate". In the case where the solvent is not water, the crystalline form can be described as a solvate of that solvent. For example, where the solvent is ethanol, the crystalline form can be described as an ethanol solvate.

[0109] As used herein, the term "metastable" generally refers to a crystalline form of a compound that transforms over time into one or more other thermodynamically more stable forms. In some cases, metastable crystalline forms are more soluble but less stable than the forms they transform into.

[0110] When referring to peaks in the XRPD plot of a crystalline form of compound (I), the term "characteristic peak" refers to a set of peaks with 2θ values ​​in the range of 0° to 40° that, as a whole, uniquely belong to one of the crystalline forms of compound (I). Unless otherwise defined, the XRPD plot is obtained using a Cu Kα X-ray source.

[0111] In the context of the polymorphs or crystalline forms disclosed herein, the term “stable” refers to the stability of a polymorph or crystalline form relative to heat and / or humidity and / or time and / or another polymorph or crystalline form.

[0112] As used herein, and unless otherwise specified, "pure" crystals are defined as substantially free of other crystalline or amorphous solids or other compounds, and contain less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% by weight of one or more other solid forms. Detection of other solid forms can be performed, for example, by diffraction analysis, thermal analysis, elemental combustion analysis, and / or spectroscopic analysis. Detection of other compounds can be performed, for example, by mass spectrometry, spectroscopic analysis, thermal analysis, elemental combustion analysis, and / or chromatographic analysis.

[0113] The term "pharmaceutically acceptable" refers to a diluent, excipient, or carrier in a formulation that is compatible with the other components of the formulation and is harmless to the recipient.

[0114] The terms “active ingredient,” “active agent,” “active substance,” “pharmaceutical,” “drug,” and “therapeutic agent” refer to substances, alone or in combination with one or more pharmaceutically acceptable excipients, administered to a subject for the treatment, prevention, or improvement of one or more symptoms of a condition, ailment, or disease.

[0115] As used in this article, "reagent" refers to a substance that consumes or promotes a chemical reaction process.

[0116] The “yield” of each of the reactions described in this article is expressed as a percentage of the theoretical yield.

[0117] The "administration" of a drug to a subject, or the "application" of such a drug, can be performed using one of a variety of methods known to those skilled in the art. For example, the drug can be administered intravenously, intra-arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., via a skin catheter). The compound or drug can also be suitably introduced via a rechargeable or biodegradable polymer device or other device (e.g., a patch and a pump) or formulation that provides a prolonged, slow, or controlled release of the compound or drug. Administration can also be performed, for example, once, multiple times, and / or over one or more prolonged time periods. In some embodiments, administration includes both direct administration (including self-administration) and indirect administration (including the act of prescribing a drug). For example, as used herein, a physician instructing a patient to self-administer a drug or having a drug administered by another person and / or prescribing a drug to a patient is administering the drug to the patient. When the method involves one or more drugs or modes of treatment as part of a treatment regimen, this disclosure contemplates that the drugs can be administered at the same or different times and via the same or different routes of administration. The appropriate method of administering a substance, compound, or agent to a subject will also depend on factors such as the subject's age, whether the subject is active or inactive at the time of administration, whether the subject has cognitive impairment at the time of administration, the degree of impairment, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity).

[0118] As used herein, the terms “co-administration,” “in combination with,” and their grammatical equivalents cover the administration of two or more agents to animals (including humans) such that the two agents and / or their metabolites are present simultaneously in the subject. Co-administration includes simultaneous administration in separate compositions, administration in separate compositions at different times (i.e., sequential administration), or administration in a composition in which both agents are present.

[0119] Disease, symptom, and condition are used interchangeably in this article.

[0120] As used herein, "mutant KRas-mediated disease" refers to a disease (e.g., cancer as described herein) that has the symptoms or requires treatment as set forth herein, and is wholly or partially associated with, a result of, a function of, or otherwise related to, the mutant KRas activity as described herein. In one such embodiment, the mutant KRas is KRas G12D.

[0121] The terms “cancer” and “cancerous,” “vesicle” and “tumor,” as well as related terms, are used interchangeably in this document and refer to or describe a physiological condition in mammals typically characterized by uncontrolled cell growth. A “tumor” contains one or more cancer cells. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma) and lung cancer, including small cell lung cancer, non-small cell lung cancer (“NSCLC”), lung adenocarcinoma, and lung squamous cell carcinoma. Other cancers include skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx (oral cavity), lips, tongue, mouth, salivary glands, esophagus, larynx, hepatocellular carcinoma, stomach, gastrointestinal tract, small intestine, large intestine, pancreas, cervix, ovary, liver, bladder, hepatocellular carcinoma, breast, colon, rectum, colorectal, genitourinary system, biliary tract, thyroid gland, mastoid process, hepatic, endometrium, uterus, salivary glands, kidneys or renal tract cancers, prostate, testes, vulva, peritoneum, anus, penis, bone, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system cancer, brain, head and neck cancer, Hodgkin's disease, and related metastases. Other examples of myeloproliferative disorders include myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, myelofibrosis (such as primary myelofibrosis), and chronic myeloid leukemia (CML).

[0122] As used herein, "chemotherapeutic agent" is a pharmaceutical agent that can be used to treat a given condition, such as cancer or an inflammatory condition. Examples of chemotherapeutic agents are well known in the art. Furthermore, chemotherapeutic agents include any pharmaceutically acceptable salts, acids, or derivatives of chemotherapeutic agents, as well as combinations of two or more of them.

[0123] As used herein, “subject,” “individual,” or “patient” refers to a vertebrate, and these terms are used interchangeably herein. In some embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, livestock (such as cattle), loitering animals, pets (such as guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In some embodiments, the mammal is a human. In embodiments that include administration of the substance to a patient, this is typically required. In one embodiment, the subject is a human with cancer or at risk of cancer.

[0124] As used herein, “effective amount” or “therapeutic effective amount” is at least the minimum amount required to achieve a measurable improvement or prevention of the cancer described herein. The effective amount described herein can vary depending on factors such as the patient’s disease state, age, sex, and weight, and the ability of the agent to elicit the expected response in the patient. An effective amount is also the amount in which the beneficial effects of treatment outweigh any toxic or harmful effects of treatment. Beneficial or desired clinical outcomes include, for example: elimination or reduction of risk, reduction of severity, delay of disease onset (including biochemical, histological, and / or behavioral symptoms of the disease that occur during disease development, its complications, and intermediate pathological phenotypes), reduction of one or more symptoms caused by the disease, improvement of the quality of life of patients with the disease, reduction of the dosage of other drugs required to treat the disease, enhancement of the effects of another drug (e.g., by targeting), delay of disease progression, and / or prolongation of survival. In some embodiments, an effective amount of the drug may have the following effects: reduction of the number of cancer cells; reduction of tumor size; inhibition (i.e., slowing or stopping) of cancer cell invasion into surrounding organs; inhibition (i.e., slowing or stopping) of tumor metastasis; inhibition (i.e., slowing or stopping) of tumor growth; and / or relief of one or more of the symptoms associated with the disease. The effective dose can be applied once or multiple times.

[0125] As used herein, the terms "treating" and "treatment" refer to a clinical intervention aimed at altering the natural processes of the treated patient or cells in the clinicopathological process. Ideal treatment outcomes include slowing disease progression, alleviating or reducing disease conditions, and mitigating or improving prognosis. For example, a patient is considered successfully "treated" if one or more symptoms associated with the cancer described herein are reduced or eliminated, including but not limited to reducing cancer cell proliferation (or destroying cancer cells), alleviating symptoms caused by the disease, improving the quality of life of a patient with the disease, reducing the dosage of other medications required to treat the disease, and / or prolonging the patient's survival.

[0126] As used herein, the term “delayed progression” refers to the postponement, halting, slowing, stabilizing, stabilizing, and / or slowing of the development of the cancer described herein. Such delay can vary in length depending on the patient’s cancer history and / or the patient to be treated. It will be apparent to those skilled in the art that adequate or significant delay can effectively encompass prevention, as the patient will not develop cancer or experience a recurrence.

[0127] As used herein, the terms “inhibition” and “reduction” or any variations thereof include any measurable reduction or complete inhibition that achieves the desired result. For example, a reduction of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range thereof, may be made, resulting in a reduction in activity compared to normal.

[0128] The terms “antagonist” and “inhibitor” are used interchangeably herein and refer to agents that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of the protein (such as a mutant form of KRas). Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological function of the target protein. While the preferred antagonists herein specifically interact with (e.g., bind to) the target, substances that inhibit the biological activity of the target protein by interacting with other members of a signal transduction pathway in which the target protein is a member are also specifically included within this definition. Preferred biological activities inhibited by antagonists are associated with tumor development, growth, or spread.

[0129] The term "packaging insert" is used to refer to instructions that are typically included in the commercial packaging of therapeutic products, which contain information concerning the indications, usage, dosage, administration, contraindications, and / or warnings related to the use of such therapeutic products.

[0130] This document discloses solid forms of compounds of formula (I) as described herein, pharmaceutical compositions comprising such solid forms, and methods of using such solid forms of compounds of formula (I).

[0131] Polymorphs and crystal forms This disclosure provides the solid form of the compound of formula (I): (I).

[0132] The compound of formula (I) may also be referred to as 2-fluoro-5-((5S,5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylbridgednaphtho[1,8-ab]heptadene-2-yl)-3-methyl-4-(trifluoromethyl)aniline. In some embodiments, this disclosure provides various polymorphs (i.e., crystalline forms) of the compound of formula (I).

[0133] While not intended to be bound by any particular theory, solid forms can be characterized by physical properties such as stability, solubility and dissolution rate, density, compressibility, hardness, morphology, cleavage, viscosity, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability. These physical properties influence specific processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization), making certain solid forms suitable for manufacturing solid dosage forms. Such properties can be determined using specific analytical chemistry techniques, including solid-state analysis techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis).

[0134] The solid forms described in this article can be characterized by a variety of methods, including, for example, single-crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), dynamic vapor adsorption (DVS), thermogravimetric analysis (TGA), and hot-stage microscopy), spectrometry (e.g., infrared, Raman, and solid-state nuclear magnetic resonance), high-performance liquid chromatography (HPLC), ultra-high-performance liquid chromatography (UHPLC), proton nuclear magnetic resonance, etc.

[0135] Techniques used to characterize crystal forms include, for example, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy (e.g., infrared (IR) and Raman spectroscopy), solid-state and solution nuclear magnetic resonance (NMR) spectroscopy (including... 1 ¹H NMR and F NMR), scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, dynamic vapor adsorption (DVS) analysis, solubility studies and dissolution studies.

[0136] Crystalline forms are typically characterized by X-ray powder diffraction (XRPD). An XRPD plot (peaks, typically expressed in 2-theta) is generally considered a fingerprint of a specific crystalline form. The relative intensities of XRPD peaks can vary depending on, in particular, sample preparation techniques, crystal size distribution, filters, sample setup procedures, and the specific instrument used. In some cases, an XRPD plot may contain more (i.e., new peaks) or fewer peaks (i.e., peaks may disappear), depending on the type or setup of the instrument. In some cases, any particular peak in an XRPD plot may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the type or setup of the instrument, its sensitivity, measurement conditions, and / or the purity of the crystalline form. In some cases, any particular peak in an XRPD plot may appear in a symmetrical or asymmetrical shape (e.g., with shoulders). Furthermore, instrument variations and other factors can also affect the 2-theta value. Those skilled in the art who understand these variations are able to use XRPD, as well as other known physicochemical techniques, to identify or determine the defining characteristics or properties of a particular crystalline form. A subset of the full XRPD spectrum may be distinctive enough to characterize a particular polymorph. That is, by evaluating the presence or absence of a few characteristic peaks (such as 3, 4, 5, 6, 7, 8, or more), it may be meaningful to distinguish two or more polymorphs of the same compound. The number and identity of such characteristic peaks will depend on the polymorph. XRPD spectra are typically obtained using a Cu Kα X-ray source (which may also be referred to as the Cu Kα wavelength).

[0137] The purity of the solid form presented in this article can be determined using standard analytical methods such as thin-layer chromatography (TLC), gel electrophoresis, gas chromatography, ultra-high performance liquid chromatography (UHPLC), and mass spectrometry (MS).

[0138] Anhydrous crystal form In some embodiments, the solid form of the compound of formula (I) corresponds to the following solid forms: form J, form O, form U, form AC, form AG, form D, form G, form N, form Q, form AA, form AK, form AL, form A, form C / S, form E, form F, form H, form I, form L, form M, form R, form T, form V, form W, form X, form Y, form Z, form AD, form AE, form AH, form AI, form AJ, form AP, form AQ, form AR, form B / AF, form K, form AB, form AM, form AN, form AO, form P, or mixtures thereof. In some embodiments, the solid form of the compound of formula (I) is form J. In some embodiments, the solid form of the compound of formula (I) is form O. In some embodiments, the solid form of the compound of formula (I) is form U. In some embodiments, the solid form of the compound of formula (I) is form AC. In some embodiments, the solid form of the compound of formula (I) is form AG. In some embodiments, the solid form of the compound of formula (I) is form D. In some embodiments, the solid form of the compound of formula (I) is form G. In some embodiments, the solid form of the compound of formula (I) is form N. In some embodiments, the solid form of the compound of formula (I) is form Q. In some embodiments, the solid form of the compound of formula (I) is form AA. In some embodiments, the solid form of the compound of formula (I) is form AK. In some embodiments, the solid form of the compound of formula (I) is form AL. In some embodiments, the solid form of the compound of formula (I) is form A. In some embodiments, the solid form of the compound of formula (I) is form C / S. In some embodiments, the solid form of the compound of formula (I) is form E. In some embodiments, the solid form of the compound of formula (I) is form F. In some embodiments, the solid form of the compound of formula (I) is form H. In some embodiments, the solid form of the compound of formula (I) is form I. In some embodiments, the solid form of the compound of formula (I) is form L. In some embodiments, the solid form of the compound of formula (I) is form M. In some embodiments, the solid form of the compound of formula (I) is form R. In some embodiments, the solid form of the compound of formula (I) is form T. In some embodiments, the solid form of the compound of formula (I) is form V. In some embodiments, the solid form of the compound of formula (I) is form W. In some embodiments, the solid form of the compound of formula (I) is form X. In some embodiments, the solid form of the compound of formula (I) is form Y.In some embodiments, the solid form of the compound of formula (I) is form Z. In some embodiments, the solid form of the compound of formula (I) is form AD. In some embodiments, the solid form of the compound of formula (I) is form AE. In some embodiments, the solid form of the compound of formula (I) is form AH. In some embodiments, the solid form of the compound of formula (I) is form AI. In some embodiments, the solid form of the compound of formula (I) is form AJ. In some embodiments, the solid form of the compound of formula (I) is form AP. In some embodiments, the solid form of the compound of formula (I) is form AQ. In some embodiments, the solid form of the compound of formula (I) is form AR. In some embodiments, the solid form of the compound of formula (I) is form B / AF. In some embodiments, the solid form of the compound of formula (I) is form K. In some embodiments, the solid form of the compound of formula (I) is form AB. In some embodiments, the solid form of the compound of formula (I) is form AM. In some embodiments, the solid form of the compound of formula (I) is form AN. In some embodiments, the solid form of the compound of formula (I) is form AO. In some embodiments, the solid form of the compound of formula (I) is form P. In some embodiments, the solid form of the compound of formula (I) is a mixture of any two or more of the aforementioned forms.

[0139] In some embodiments, the solid form is an anhydrous crystalline form (i.e., anhydrous). In some embodiments, the anhydrous crystalline form is form J, form O, form U, form AC, or form AG as described herein. In some embodiments, the anhydrous crystalline form is form J. In some embodiments, the anhydrous crystalline form is form O. In some embodiments, the anhydrous crystalline form is form U. In some embodiments, the anhydrous crystalline form is form AC. In some embodiments, the anhydrous crystalline form is form AG.

[0140] Form J In some embodiments, the compound of formula (I) is in solid form, form J. In some embodiments, the compound of formula (I) is in anhydrous crystalline form, form J. In some embodiments, the anhydrous crystalline form is form J, characterized by an XRPD diagram substantially as shown in FIG1. ​​In some embodiments, form J is characterized in that the XRPD diagram comprises, as shown in FIG1, an XRPD diagram of form J. Figure 1The XRPD peaks shown may be one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks. In some embodiments, form J is characterized in that the XRPD graph contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 1.

[0141] The representative XRPD peak of form J is: Table 1 In some embodiments, this document provides a solid form of the compound of formula (I), wherein the solid form is form J. In some embodiments, the solid form is characterized in that the XRPD diffraction pattern includes at least two XRPD peaks selected from the group consisting of approximately 16.4 ± 0.2, 6.8 ± 0.2, 18.9 ± 0.2, 15.6 ± 0.2, 9.4 ± 0.2, 18.2 ± 0.2, 8.42 ± 0.2, 13.7 ± 0.2, 8.8 ± 0.2, and 19.7 ± 0.2 degrees 2θ. In some embodiments, the solid form is characterized in that the XRPD diffraction pattern includes at least three XRPD peaks selected from the group consisting of about 16.4 ± 0.2, 6.8 ± 0.2, 18.9 ± 0.2, 15.6 ± 0.2, 9.4 ± 0.2, 18.2 ± 0.2, 8.4 ± 0.2, 13.7 ± 0.2, 8.8 ± 0.2, and 19.7 ± 0.2 degrees 2θ. In some embodiments, the solid form is characterized by an XRPD diffraction pattern comprising at least four XRPD peaks selected from the group consisting of approximately 16.4 ± 0.2, 6.8 ± 0.2, 18.9 ± 0.2, 15.6 ± 0.2, 9.4 ± 0.2, 18.2 ± 0.2, 8.4 ± 0.2, 13.7 ± 0.2, 8.8 ± 0.2, and 19.7 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0142] In some embodiments, the anhydrous crystalline form is form J, characterized by a TGA thermogram showing a weight loss of approximately 2.6% at temperatures up to 180 °C.

[0143] In some embodiments, the anhydrous crystalline form is form J, characterized in that the DSC thermogram includes at least one endothermic peak at about 110 °C, about 138 °C, or about 178 °C. In some embodiments, the anhydrous crystalline form is form J, characterized in that the DSC thermogram includes endothermic peaks at about 110 °C, about 138 °C, and about 178 °C.

[0144] In some embodiments, the anhydrous crystalline form is form J, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG1; b. a TGA thermogram showing a weight loss of about 2.6% at up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at about 110 °C, about 138 °C, or about 178 °C. In some embodiments, the anhydrous crystalline form is form J, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG1; b. a TGA thermogram showing a weight loss of about 2.6% at up to 180 °C; and c. a DSC thermogram containing endothermic peaks at about 110 °C, about 138 °C, and about 178 °C. In some embodiments, the anhydrous crystalline form is form J as described herein.

[0145] In some embodiments, form J is pure. In some embodiments, form J is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form J is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0146] Form O In some embodiments, the anhydrous crystalline form is form O, characterized by an XRPD pattern substantially as shown in FIG2. In some embodiments, form O is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG2. In some embodiments, form O is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 2. Representative XRPD peaks of form O are: Table 2 In some embodiments, this document provides a solid form of the compound of formula (I), wherein the solid form is form O. In some embodiments, the solid form, form O, is characterized in that its XRPD diffraction pattern contains at least two XRPD peaks selected from the group consisting of approximately 15.1 ± 0.2, 19.7 ± 0.2, 9.3 ± 0.2, 18.8 ± 0.2, 7.0 ± 0.2, 15.4 ± 0.2, 8.5 ± 0.2, 24.8 ± 0.2, 21.4 ± 0.2, and 15.9 ± 0.2 degrees 2θ. In some embodiments, form O is characterized in that the XRPD diffraction pattern includes at least one peak selected from the group consisting of about 15.1 ± 0.2, 19.7 ± 0.2, and 9.3 ± 0.2 degrees 2θ; and at least one, at least two, at least three, at least four, or at least five additional peaks selected from the group consisting of about 18.8 ± 0.2, 7.0 ± 0.2, 15.4 ± 0.2, 8.5 ± 0.2, 24.8 ± 0.2, 21.4 ± 0.2, and 15.9 ± 0.2 degrees 2θ. In some embodiments, form O is characterized by an XRPD diffraction pattern containing XRPD peaks at approximately 15.1 ± 0.2, 19.7 ± 0.2, and 9.3 ± 0.2 degrees 2θ; and at least three additional peaks selected from the group consisting of approximately 18.8 ± 0.2, 7.0 ± 0.2, 15.4 ± 0.2, 8.5 ± 0.2, 24.8 ± 0.2, 21.4 ± 0.2, and 15.9 ± 0.2 degrees 2θ. In some embodiments, form O is characterized by an XRPD diffraction pattern containing XRPD peaks at approximately 15.1 ± 0.2, 19.7 ± 0.2, 9.3 ± 0.2, 18.8 ± 0.2, 7.0 ± 0.2, 15.4 ± 0.2, 8.5 ± 0.2, 24.8 ± 0.2, 21.4 ± 0.2, and 15.9 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0147] In some embodiments, the anhydrous crystalline form is form O, characterized by a TGA thermogram showing a weight loss of approximately 3.1% at temperatures up to 180 °C.

[0148] In some embodiments, the anhydrous crystalline form is form O, characterized in that the DSC thermogram contains at least one endothermic peak at about 70 °C or about 195 °C. In some embodiments, the anhydrous crystalline form is form O, characterized in that the DSC thermogram contains endothermic peaks at about 70 °C and about 195 °C.

[0149] In some embodiments, the anhydrous crystalline form is form O, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG2; b. a TGA thermogram showing a weight loss of approximately 3.1% at up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at approximately 70 °C or approximately 195 °C. In some embodiments, the anhydrous crystalline form is form O, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG2; b. a TGA thermogram showing a weight loss of approximately 3.1% at up to 180 °C; and c. a DSC thermogram containing endothermic peaks at approximately 70 °C and approximately 195 °C. In some embodiments, the anhydrous crystalline form is form O as described herein.

[0150] In some embodiments, form O is pure. In some embodiments, form O is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form O is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0151] Form U In some embodiments, the anhydrous crystalline form is form U, characterized by an XRPD pattern substantially as shown in FIG3. In some embodiments, form U is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG3. In some embodiments, form U is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 3. Representative XRPD peaks of form U are: Table 3 In some embodiments, this document provides a solid form of the compound of formula (I), wherein the solid form is form U. In some embodiments, the solid form, i.e., form U, is characterized in that the XRPD diffraction pattern comprises at least two XRPD peaks selected from the group consisting of approximately 18.1 ± 0.2 degrees, 5.9 ± 0.2 degrees, 18.7 ± 0.2 degrees, 19.2 ± 0.2 degrees, 17.6 ± 0.2 degrees, 22.0 ± 0.2 degrees, 20.4 ± 0.2 degrees, 15.8 ± 0.2 degrees, 17.3 ± 0.2 degrees, and 15.1 ± 0.2 degrees 2θ. In some embodiments, the solid form, i.e., form U, is characterized in that the XRPD diffraction pattern comprises at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD peaks selected from the group consisting of approximately 18.1 ± 0.2 degrees, 5.9 ± 0.2 degrees, 18.7 ± 0.2 degrees, 19.2 ± 0.2 degrees, 17.6 ± 0.2 degrees, 22.0 ± 0.2 degrees, 20.4 ± 0.2 degrees, 15.8 ± 0.2 degrees, 17.3 ± 0.2 degrees, and 15.1 ± 0.2 degrees 2θ. In some embodiments, the solid form U is characterized by an XRPD diffraction pattern comprising at least one peak selected from approximately 18.1 ± 0.2 degrees, 5.9 ± 0.2 degrees, and 18.7 ± 0.2 degrees 2θ; and at least two, at least three, at least four, or at least five peaks selected from approximately 19.2 ± 0.2 degrees, 17.6 ± 0.2 degrees, 22.0 ± 0.2 degrees, 20.4 ± 0.2 degrees, 15.8 ± 0.2 degrees, 17.3 ± 0.2 degrees, and 15.1 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0152] In some embodiments, the anhydrous crystalline form is form U, characterized by a TGA thermogram showing a weight loss of approximately 1.3% at temperatures up to 190 °C.

[0153] In some embodiments, the anhydrous crystalline form is form U, characterized in that the DSC thermogram contains an endothermic peak at about 205°C.

[0154] In some embodiments, the anhydrous crystalline form is form U, characterized by two or more of the following: a. an XRPD plot substantially as shown in Figure 3; b. a TGA thermogram showing a weight loss of approximately 1.3% at temperatures up to 190 °C; and c. a DSC thermogram containing an endothermic peak at approximately 205 °C. In some embodiments, the anhydrous crystalline form is form U as described herein.

[0155] In some embodiments, form U is pure. In some embodiments, form U is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form U is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0156] Form AC In some embodiments, the anhydrous crystalline form is form AC, characterized by an XRPD pattern substantially as shown in FIG. 4. In some embodiments, form AC is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 4. In some embodiments, form AC is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 4. Representative XRPD peaks of form AC are: Table 4 In some embodiments, this document provides a solid form of the compound of formula (I), wherein the solid form is form AC. In some embodiments, the solid form, i.e., form AC, is characterized in that the XRPD diffraction pattern comprises at least two XRPD peaks selected from the group consisting of approximately 6.0 ± 0.2 degrees, 20.2 ± 0.2 degrees, 15.6 ± 0.2 degrees, 16.8 ± 0.2 degrees, 23.4 ± 0.2 degrees, 15.0 ± 0.2 degrees, 19.2 ± 0.2 degrees, 16.3 ± 0.2 degrees, 23.6 ± 0.2 degrees, and 22.9 ± 0.2 degrees 2θ. In some embodiments, the solid form AC is characterized by an XRPD diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD peaks selected from the group consisting of approximately 6.0 ± 0.2°, 20.2 ± 0.2°, 15.6 ± 0.2°, 16.8 ± 0.2°, 23.4 ± 0.2°, 15.0 ± 0.2°, 19.2 ± 0.2°, 16.3 ± 0.2°, 23.6 ± 0.2°, and 22.9 ± 0.2°. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0157] In some embodiments, the anhydrous crystalline form is form AC, characterized by a TGA thermogram showing a weight loss of approximately 2.3% at temperatures up to 160 °C.

[0158] In some embodiments, the anhydrous crystalline form is form AC, characterized in that the DSC thermogram contains an endothermic peak at approximately 163 °C.

[0159] In some embodiments, the anhydrous crystalline form is form AC, characterized by two or more of the following: a. an XRPD plot substantially as shown in Figure 4; b. a TGA thermogram showing a weight loss of approximately 2.3% up to 160 °C; and c. a DSC thermogram containing an endothermic peak at approximately 163 °C. In some embodiments, the anhydrous crystalline form is form AC as described herein.

[0160] In some embodiments, form AC is pure. In some embodiments, form AC is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AC is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0161] Form AG In some embodiments, the anhydrous crystalline form is form AG, characterized by an XRPD plot containing characteristic peaks at approximately 19.3 ± 0.2, 13.1 ± 0.2, and 15.4 ± 0.2 degrees 2θ. In some embodiments, the XRPD plot further contains at least one additional characteristic peak selected from the group consisting of approximately 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ. In some embodiments, the XRPD plot further contains characteristic peaks at approximately 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ. In some embodiments, the anhydrous crystalline form is AG, characterized in that the XRPD spectrum contains one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen characteristic XRPD peaks as shown in Table 39. In some embodiments, the anhydrous crystalline form is form AG, characterized in that the XRPD spectrum contains at least 15 characteristic peaks as shown in Table 39. In some embodiments, the anhydrous crystalline form is form AG, characterized in that the XRPD spectrum is substantially as shown in FIG5A. In some embodiments, the anhydrous crystalline form is AG, characterized in that the XRPD spectrum contains one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen characteristic XRPD peaks as shown in FIG5A. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source. In some embodiments, form AG is characterized in that the XRPD spectrum contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 6. Another representative set of XRPD peaks for the form AG is: Table 6 In some embodiments, the form is form AG, characterized in that the XRPD plot includes: a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least two peaks selected from the group consisting of: 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ. In some embodiments, the form is form AG, characterized in that the XRPD plot comprises: a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least three peaks selected from the group consisting of 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ. In some embodiments, the form is form AG, characterized in that the XRPD plot comprises: a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least four peaks selected from the group consisting of 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ. In some embodiments, the form is form AG, characterized in that the XRPD plot comprises: a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least five, at least six, at least seven, or at least eight peaks selected from the group consisting of 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ. In some embodiments, the form is form AG, characterized in that the XRPD plot includes: a peak at approximately 13.1 ± 0.2 degrees 2θ and a peak at approximately 19.3 ± 0.2 degrees 2θ, and at least one peak selected from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.In some embodiments, the form is form AG, characterized in that the XRPD plot comprises: a peak at approximately 13.1 ± 0.2 degrees 2θ and a peak at approximately 19.3 ± 0.2 degrees 2θ, and at least two peaks selected from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ. In some embodiments, the form is form AG, characterized in that the XRPD plot comprises: a peak at approximately 13.1 ± 0.2 degrees 2θ and a peak at approximately 19.3 ± 0.2 degrees 2θ, and at least three peaks selected from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ. In some embodiments, the form is form AG, characterized in that the XRPD plot comprises: a peak at approximately 13.1 ± 0.2 degrees 2θ and a peak at approximately 19.3 ± 0.2 degrees 2θ, and at least four, at least five, at least six, or at least seven peaks selected from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ. In some other embodiments, the form is form AG, characterized in that the XRPD plot includes: at least two peaks selected from the group consisting of approximately 13.1 ± 0.2, 19.3 ± 0.2, and 15.4 ± 0.2 degrees 2θ; and at least one peak selected from the group consisting of 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ. In some other embodiments, the form is form AG, characterized in that the XRPD plot includes: peaks at approximately 13.1 ± 0.2, 19.3 ± 0.2, and 15.4 ± 0.2 degrees 2θ; and at least one peak selected from the group consisting of 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.In some embodiments, the form is form AG, characterized in that the XRPD spectrum comprises: peaks at approximately 13.1 ± 0.2, 19.3 ± 0.2, and 15.4 ± 0.2 degrees 2θ; and at least two, at least three, at least four, or at least five peaks selected from the group consisting of 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0162] In some embodiments, the form is form AG, characterized in that the XRPD plot includes peaks at approximately 13.1 ± 0.2, 19.3 ± 0.2, 15.4 ± 0.2 degrees 2θ, and 18.5 ± 0.2 degrees 2θ. In some embodiments, the XRPD plot further includes one or more peaks at approximately 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, or 10.7 ± 0.2 degrees 2θ. In some embodiments, the XRPD plot further includes two, three, or four additional peaks selected from the group consisting of 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, or 10.7 ± 0.2 degrees 2θ. In some embodiments, the form AG is further characterized by a weight loss of <1% w / w at temperatures up to 150 °C as determined by thermogravimetric analysis. In some embodiments, the form AG is further characterized by a weight loss of <2% w / w at temperatures up to 180 °C as determined by thermogravimetric analysis. In some embodiments, the XRPD spectra are obtained using a Cu Kα source.

[0163] In some embodiments, the anhydrous crystalline form is form AG, characterized by a TGA thermogram showing a weight loss of approximately 1.1% at temperatures up to 180 °C. In some embodiments, the anhydrous crystalline form is form AG, characterized by a TGA thermogram substantially as shown in FIG. 5B. In some embodiments, the compound of formula (I) is in form AG, characterized by a TGA thermogram showing a weight loss of less than 2% at temperatures up to 180 °C. In still further embodiments, the compound of formula (I) is in form AG, characterized by a weight loss of <1% w / w at temperatures up to 150 °C as determined by thermogravimetric analysis.

[0164] In some embodiments, the anhydrous crystalline form is form AG, characterized in that the DSC thermogram contains an endothermic peak at approximately 219 °C. In some embodiments, the anhydrous crystalline form is form AG, characterized in that it is substantially as follows: Figure 5B The DSC thermogram shown is shown.

[0165] In some embodiments, the anhydrous crystalline form is form AG, characterized by a dynamic vapor adsorption (DVS) diagram substantially as shown in FIG5C.

[0166] In some embodiments, the anhydrous crystalline form is form AG, characterized by a scanning electron microscope (SEM) micrograph as shown in FIG5D.

[0167] In some embodiments, the anhydrous crystalline form is form AG, characterized by two or more of the following: a. an XRPD plot containing characteristic peaks at approximately 19.3 ± 0.2, 13.1 ± 0.2, and 15.4 ± 0.2 degrees 2θ; b. a TGA thermogram showing a weight loss of approximately 1.1% at 180 °C; c. a DSC thermogram containing an endothermic peak at approximately 219 °C; d. a dynamic vapor adsorption (DVS) plot substantially as shown in Figure 5C; and e. a scanning electron microscope (SEM) micrograph substantially as shown in Figure 5D. In some embodiments, the anhydrous crystalline form is form AG, characterized by two or more of the following: a. an XRPD plot substantially as shown in Figure 5A; b. a characteristic peak at approximately 19.3 ± 0.2, 13.1 ± 0.2, and 15.4 ± 0.2 degrees 2θ; c. a characteristic peak at approximately 19.3 ± 0.2, 13.1 ± 0.2, and 15.4 ± 0.2 degrees 2θ; d. a dynamic vapor adsorption (DVS) plot substantially as shown in Figure 5C; and e. a scanning electron microscope (SEM) micrograph substantially as shown in Figure 5D. Figure 5B a. A TGA thermogram shown in Figure 5B; c. A DSC thermogram essentially as shown in Figure 5C; d. A DVS diagram essentially as shown in Figure 5C; and e. A SEM micrograph essentially as shown in Figure 5D. In some embodiments, the anhydrous crystalline form is the form AG described herein.

[0168] In some embodiments, form AG is pure. In some embodiments, form AG is substantially free of other solid forms (e.g., amorphous solids) described herein. In some embodiments, form AG has a purity of not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%. In some embodiments, form AG comprises less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, or less than 0.1% by weight of another form of the compound of formula (I). In some embodiments, other forms of the compound of formula (I) are amorphous forms of the compound of formula (I). In some embodiments, form AG comprises less than 5% by weight of the amorphous form of the compound of formula (I). In some embodiments, form AG comprises less than 1% by weight of the amorphous form of the compound of formula (I).

[0169] In some embodiments, form AG is a white to off-white solid. A method for producing form AG is further provided herein, comprising combining a compound of formula (I) with a solvent comprising a C1-C6 alcohol; and crystallizing the compound of formula (I) from the composition, wherein the crystallized compound of formula (I) is form AG. In some embodiments, the compound of formula (I) is combined with a solvent to form a solution, i.e., a liquid mixture substantially free of solids. This combination may be heated, for example, to between 30 °C and 50 °C, or about 35 °C to 45 °C, or about 40 °C. In some embodiments, the solution is seeded with a seed slurry of form AG, which may be produced by the methods provided herein; in other embodiments, the solution is not seeded. In some embodiments, the solvent comprises ethanol, or methanol, or propanol. In some embodiments, crystallization comprises subsequently adding a second solvent in which the compound of formula (I) is less soluble in order to form crystals. In some embodiments, the second solvent comprises a nonpolar solvent, such as C3-C6 alcohol. 10Alkanes. In some embodiments, the second solvent is pentane, hexane, or heptane. Without wishing to be bound by any theory, such nonpolar solvents may help reduce the solubility of the compound of formula (I) in alcohols, thereby increasing the crystallization yield. In some embodiments, crystallization comprises forming a solution of the compound of formula (I) in a solvent containing C1-C6 alcohols, such as at least 80%, at least 90%, at least 95%, or at least 99% of C1-C6 alcohols, such as propanol, ethanol, or methanol; heating the solution to between 30°C and 50°C, or about 35°C to 45°C, or about 40°C; optionally adding a seed slurry of form AG; and adding a C3-C... 10 A second solvent of an alkane is added to the solution to produce form AG, wherein the second solvent is hexane or heptane. In some embodiments, the second solvent is at least 80%, at least 90%, at least 95%, or at least 99% C3-C4 hydrocarbons. 10 Alkanes, such as hexane or heptane. In some embodiments, a second solvent is added such that the final ratio of the first solvent to the second solvent is about 1:2 to 1:6, or about 1:3 to 1:5, or about 1:4. In some embodiments, the method further includes cooling the mixture, such as cooling to between 15°C and 35°C, or 20°C and 30°C, or 20°C and 25°C, or about 23°C. In some embodiments, the solids are separated, washed, and dried to produce AG in the form of at least 90%, at least 95%, or at least 98% purity.

[0170] Hydrated crystal form In some embodiments, the solid form is a hydrated crystalline form (i.e., a hydrate). In some embodiments, the hydrated crystalline form is form D, form G, form N, form Q, form AA, form AK, or form AL as described herein. In some embodiments, the hydrated crystalline form is form D. In some embodiments, the hydrated crystalline form is form G. In some embodiments, the hydrated crystalline form is form N. In some embodiments, the hydrated crystalline form is form Q. In some embodiments, the hydrated crystalline form is form AA. In some embodiments, the hydrated crystalline form is form AK. In some embodiments, the hydrated crystalline form is form AL.

[0171] Form D In some embodiments, the hydrated crystalline form is form D, characterized by an XRPD pattern substantially as shown in FIG. 6. In some embodiments, form D is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 6. In some embodiments, form D is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 7. Representative XRPD peaks of form D are: Table 7 In some embodiments, the form is form D, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 8.7 ± 0.2, 7.5 ± 0.2, 8.2 ± 0.2, 17.6 ± 0.2, 15.2 ± 0.2, 19.1 ± 0.2, 19.8 ± 0.2, 15.5 ± 0.2, 11.9 ± 0.2, and 14.3 ± 0.2 degrees 2θ. In some embodiments, the form is form D, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, at least seven, or at least eight peaks selected from groups of approximately 8.7 ± 0.2, 7.5 ± 0.2, 8.2 ± 0.2, 17.6 ± 0.2, 15.2 ± 0.2, 19.1 ± 0.2, 19.8 ± 0.2, 15.5 ± 0.2, 11.9 ± 0.2, and 14.3 ± 0.2 degrees 2θ. In some embodiments, the form is form D, characterized in that the XRPD spectrum comprises: at least one peak selected from the group consisting of approximately 8.7 ± 0.2, 7.5 ± 0.2, and 8.2 ± 0.2 degrees 2θ; and at least one, at least two, at least three, at least four, or at least five peaks selected from the group consisting of approximately 17.6 ± 0.2, 15.2 ± 0.2, 19.1 ± 0.2, 19.8 ± 0.2, 15.5 ± 0.2, 11.9 ± 0.2, and 14.3 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0172] In some embodiments, the hydrated crystalline form is form D, characterized by a TGA thermogram showing a weight loss of approximately 4.0% at temperatures up to 180 °C.

[0173] In some embodiments, the hydrated crystal form is form D, characterized in that the DSC thermogram contains at least one endothermic peak at about 80 °C or about 159 °C.

[0174] In some embodiments, the hydrated crystalline form is form D, characterized in that the DSC thermogram contains endothermic peaks at about 80 °C and about 159 °C. In some embodiments, the hydrated crystalline form is form D, characterized in that two or more of the following are present: a. substantially an XRPD plot as shown in FIG. 6; b. a TGA thermogram showing a weight loss of about 4.0% up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at about 80 °C or about 159 °C. In some embodiments, the hydrated crystalline form is form D, characterized in that two or more of the following are present: a. substantially an XRPD plot as shown in FIG. 6; b. a TGA thermogram showing a weight loss of about 4.0% up to 180 °C; and c. a DSC thermogram containing endothermic peaks at about 80 °C and about 159 °C. In some embodiments, the hydrated crystalline form is form D as described herein.

[0175] In some embodiments, form D is pure. In some embodiments, form D is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form D is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0176] Form G In some embodiments, the hydrated crystalline form is form G, characterized by an XRPD pattern substantially as shown in FIG. 7. In some embodiments, form G is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 7. In some embodiments, form G is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 8. Representative XRPD peaks of form G are: Table 8 In some embodiments, the form is form G, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 5.9 ± 0.2, 16.5 ± 0.2, 11.8 ± 0.2, 6.5 ± 0.2, 22.2 ± 0.2, 21.1 ± 0.2, 17.7 ± 0.2, 27.5 ± 0.2, 15.8 ± 0.2, and 13.0 ± 0.2 degrees 2θ. In some embodiments, the form is form G, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, at least seven, or at least eight peaks selected from groups of approximately 5.9 ± 0.2, 16.5 ± 0.2, 11.8 ± 0.2, 6.5 ± 0.2, 22.2 ± 0.2, 21.1 ± 0.2, 17.7 ± 0.2, 27.5 ± 0.2, 15.8 ± 0.2, and 13.0 ± 0.2 degrees 2θ. In some embodiments, the form is form G, characterized in that the XRPD spectrum comprises: at least one peak selected from the group consisting of approximately 5.9 ± 0.2, 16.5 ± 0.2, and 11.8 ± 0.2 degrees 2θ; and at least one peak selected from the group consisting of approximately 6.5 ± 0.2, 22.2 ± 0.2, 21.1 ± 0.2, 17.7 ± 0.2, 27.5 ± 0.2, 15.8 ± 0.2, and 13.0 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a CuKα source.

[0177] In some embodiments, the hydrated crystalline form is form G, characterized by a TGA thermogram showing a weight loss of approximately 5.4% at temperatures up to 180 °C.

[0178] In some embodiments, the hydrated crystalline form is form G, characterized in that the DSC thermogram includes at least one endothermic peak at about 83 °C, about 167 °C, or about 192 °C. In some embodiments, the hydrated crystalline form is form G, characterized in that the DSC thermogram includes endothermic peaks at about 83 °C, about 167 °C, and about 192 °C.

[0179] In some embodiments, the hydrated crystalline form is form G, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 7; b. a TGA thermogram showing a weight loss of approximately 5.4% up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at approximately 83 °C, approximately 167 °C, or approximately 192 °C. In some embodiments, the hydrated crystalline form is form G, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 7; b. a TGA thermogram showing a weight loss of approximately 5.4% up to 180 °C; and c. a DSC thermogram containing endothermic peaks at approximately 83 °C, approximately 167 °C, and approximately 192 °C. In some embodiments, the hydrated crystalline form is form G as described herein.

[0180] In some embodiments, form G is pure. In some embodiments, form G is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form G is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0181] Form N In some embodiments, the hydrated crystalline form is form N, characterized by an XRPD pattern substantially as shown in FIG8. In some embodiments, form N is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG8. In some embodiments, form N is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 9. Representative XRPD peaks of form N are: Table 9 In some embodiments, the form is form N, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 15.7 ± 0.2, 16.1 ± 0.2, 15.5 ± 0.2, 19.6 ± 0.2, 20.6 ± 0.2, 24.0 ± 0.2, 21.2 ± 0.2, 5.7 ± 0.2, 22.3 ± 0.2, and 6.6 ± 0.2 degrees 2θ. In some embodiments, the form is form N, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 15.7 ± 0.2, 16.1 ± 0.2, 15.5 ± 0.2, 19.6 ± 0.2, 20.6 ± 0.2, 24.0 ± 0.2, 21.2 ± 0.2, 5.7 ± 0.2, 22.3 ± 0.2, and 6.6 ± 0.2 degrees 2θ. In some embodiments, the form is form N, characterized in that the XRPD spectrum comprises at least one peak selected from the group consisting of approximately 15.7 ± 0.2, 16.1 ± 0.2, and 15.5 ± 0.2 degrees 2θ; and at least one, at least two, at least three, or at least four peaks selected from the group consisting of approximately 19.6 ± 0.2, 20.6 ± 0.2, 24.0 ± 0.2, 21.2 ± 0.2, 5.7 ± 0.2, 22.3 ± 0.2, and 6.6 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0182] In some embodiments, the hydrated crystalline form is form N, characterized by a TGA thermogram showing a weight loss of approximately 3.9% at temperatures up to 180 °C.

[0183] In some embodiments, the hydrated crystalline form is form N, characterized in that the DSC thermogram includes at least one endothermic peak at about 60 °C, about 131 °C, or about 172 °C. In some embodiments, the hydrated crystalline form is form N, characterized in that the DSC thermogram includes endothermic peaks at about 60 °C, about 131 °C, and about 172 °C.

[0184] In some embodiments, the hydrated crystalline form is form N, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG8; b. a TGA thermogram showing a weight loss of approximately 3.9% up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at approximately 60 °C, approximately 131 °C, or approximately 172 °C. In some embodiments, the hydrated crystalline form is form N, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG8; b. a TGA thermogram showing a weight loss of approximately 3.9% up to 180 °C; and c. a DSC thermogram containing endothermic peaks at approximately 60 °C, approximately 131 °C, and approximately 172 °C. In some embodiments, the hydrated crystalline form is form N as described herein.

[0185] In some embodiments, form N is pure. In some embodiments, form N is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form N is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0186] Form Q In some embodiments, the hydrated crystalline form is form Q, characterized by an XRPD pattern substantially as shown in FIG9. In some embodiments, form Q is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG9. In some embodiments, form Q is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 10. Representative XRPD peaks of form Q are: Table 10 In some embodiments, the form is form Q, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 8.5 ± 0.2, 6.2 ± 0.2, 17.0 ± 0.2, 17.9 ± 0.2, 19.2 ± 0.2, 17.6 ± 0.2, 18.6 ± 0.2, 20.6 ± 0.2, 16.5 ± 0.2, and 20.9 ± 0.2 degrees 2θ. In some embodiments, the form is form Q, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 8.5 ± 0.2, 6.2 ± 0.2, 17.0 ± 0.2, 17.9 ± 0.2, 19.2 ± 0.2, 17.6 ± 0.2, 18.6 ± 0.2, 20.6 ± 0.2, 16.5 ± 0.2, and 20.9 ± 0.2 degrees 2θ. In some embodiments, the form is form Q, characterized in that the XRPD spectrum comprises: at least one peak selected from the group consisting of approximately 8.5 ± 0.2, 6.2 ± 0.2, and 17.0 ± 0.2 degrees 2θ; and at least one, at least two, at least three, at least four, or at least five peaks selected from the group consisting of approximately 17.9 ± 0.2, 19.2 ± 0.2, 17.6 ± 0.2, 18.6 ± 0.2, 20.6 ± 0.2, 16.5 ± 0.2, and 20.9 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0187] In some embodiments, the hydrated crystalline form is form Q, characterized by a TGA thermogram showing a weight loss of approximately 4.9% at temperatures up to 180 °C.

[0188] In some embodiments, the hydrated crystalline form is form Q, characterized in that the DSC thermogram includes at least one endothermic peak at about 96 °C or about 155 °C. In some embodiments, the hydrated crystalline form is form Q, characterized in that the DSC thermogram includes endothermic peaks at about 96 °C and about 155 °C.

[0189] In some embodiments, the hydrated crystalline form is form Q, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG9; b. a TGA thermogram showing a weight loss of approximately 4.9% up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at approximately 96 °C or approximately 155 °C. In some embodiments, the hydrated crystalline form is form Q, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG9; b. a TGA thermogram showing a weight loss of approximately 4.9% up to 180 °C; and c. a DSC thermogram containing endothermic peaks at approximately 96 °C and approximately 155 °C. In some embodiments, the hydrated crystalline form is form Q as described herein.

[0190] In some embodiments, form Q is pure. In some embodiments, form Q is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form Q is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0191] Form AA In some embodiments, the hydrated crystalline form is form AA, characterized by an XRPD pattern substantially as shown in FIG. 10. In some embodiments, the hydrated crystalline form is form AA as described herein. In some embodiments, form AA is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 10. In some embodiments, form AA is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 11. Representative XRPD peaks of form AA are: Table 11 In some embodiments, the form is form AA, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 6.8 ± 0.2, 16.9 ± 0.2, 9.1 ± 0.2, 16.0 ± 0.2, 7.7 ± 0.2, 8.4 ± 0.2, 15.7 ± 0.2, 18.7 ± 0.2, 19.7 ± 0.2, and 13.2 ± 0.2 degrees 2θ. In some embodiments, the form is form AA, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 6.8 ± 0.2, 16.9 ± 0.2, 9.1 ± 0.2, 16.0 ± 0.2, 7.7 ± 0.2, 8.4 ± 0.2, 15.7 ± 0.2, 18.7 ± 0.2, 19.7 ± 0.2, and 13.2 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0192] In some embodiments, form AA is pure. In some embodiments, form AA is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AA is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0193] Form AK In some embodiments, the hydrated crystalline form is form AK, characterized by an XRPD pattern substantially as shown in FIG11. In some embodiments, form AK is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG11. In some embodiments, form AK is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 12. Representative XRPD peaks of form AK are: Table 12 In some embodiments, the form is form AK, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 14.6 ± 0.2, 16.8 ± 0.2, 20.3 ± 0.2, 16.4 ± 0.2, 14.3 ± 0.2, 7.7 ± 0.2, 19.1 ± 0.2, 17.1 ± 0.2, 10.5 ± 0.2, and 15.4 ± 0.2 degrees 2θ. In some embodiments, the form is form AK, characterized in that the XRPD spectrum comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 14.6 ± 0.2, 16.8 ± 0.2, 20.3 ± 0.2, 16.4 ± 0.2, 14.3 ± 0.2, 7.7 ± 0.2, 19.1 ± 0.2, 17.1 ± 0.2, 10.5 ± 0.2, and 15.4 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0194] In some embodiments, the hydrated crystalline form is form AK, characterized by a TGA thermogram showing a weight loss of approximately 7.2% at temperatures up to 180 °C.

[0195] In some embodiments, the hydrated crystalline form is form AK, characterized in that the DSC thermogram contains at least one endothermic peak at about 49 °C, about 117 °C, or about 157 °C.

[0196] In some embodiments, the hydrated crystalline form is form AK, characterized by a DSC thermogram containing endothermic peaks at about 49 °C, about 117 °C, and about 157 °C. In some embodiments, the hydrated crystalline form is form AK, characterized by two or more of the following: a. substantially an XRPD plot as shown in FIG11; b. a TGA thermogram showing a weight loss of about 7.2% up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at about 49 °C, about 117 °C, or about 157 °C. In some embodiments, the hydrated crystalline form is form AK, characterized by two or more of the following: a. substantially an XRPD plot as shown in FIG11; b. a TGA thermogram showing a weight loss of about 7.2% up to 180 °C; and c. a DSC thermogram containing endothermic peaks at about 49 °C, about 117 °C, and about 157 °C. In some embodiments, the hydrated crystalline form is form AK as described herein.

[0197] In some embodiments, form AK is pure. In some embodiments, form AK is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AK is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0198] Form AL In some embodiments, the hydrated crystalline form is form AL, characterized by an XRPD pattern substantially as shown in FIG. 12. In some embodiments, form AL is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 12. In some embodiments, form AL is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 13. Representative XRPD peaks of form AL are: Table 13 In some embodiments, the form is form AL, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 6.2 ± 0.2, 18.5 ± 0.2, 6.6 ± 0.2, 16.7 ± 0.2, 13.8 ± 0.2, 16.0 ± 0.2, 21.0 ± 0.2, 22.3 ± 0.2, 17.5 ± 0.2, and 12.3 ± 0.2 degrees 2θ. In some embodiments, the form is form AL, characterized in that the XRPD pattern comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 6.2 ± 0.2, 18.5 ± 0.2, 6.6 ± 0.2, 16.7 ± 0.2, 13.8 ± 0.2, 16.0 ± 0.2, 21.0 ± 0.2, 22.3 ± 0.2, 17.5 ± 0.2, and 12.3 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0199] In some embodiments, the hydrated crystalline form is form AL, characterized by a TGA thermogram showing a weight loss of approximately 7.6% at temperatures up to 180 °C.

[0200] In some embodiments, the hydrated crystalline form is form AL, characterized in that the DSC thermogram includes at least one endothermic peak at about 99 °C, about 146 °C, or about 159 °C. In some embodiments, the hydrated crystalline form is form AL, characterized in that the DSC thermogram includes endothermic peaks at about 99 °C, about 146 °C, and about 159 °C.

[0201] In some embodiments, the hydrated crystalline form is form AL, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 12; b. a TGA thermogram showing a weight loss of approximately 7.6% up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at approximately 99 °C, approximately 146 °C, or approximately 159 °C. In some embodiments, the hydrated crystalline form is form AL, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 12; b. a TGA thermogram showing a weight loss of approximately 7.6% up to 180 °C; and c. a DSC thermogram containing endothermic peaks at approximately 99 °C, approximately 146 °C, and approximately 159 °C. In some embodiments, the hydrated crystalline form is form AL as described herein.

[0202] In some embodiments, form AL is pure. In some embodiments, form AL is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AL is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0203] Solvated crystallization In some embodiments, the solid form is a solvated crystalline form (i.e., a solvate). In some embodiments, the solvated crystalline form is a solvate of 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (ACN), tetrahydrofuran (THF), dimethylformamide (DMF), 1,4-dioxane, dimethylacetamide (DMAc), isopropanol (IPA), methyl tert-butyl ether (MTBE), ethyl acetate (EtOAc), acetone, isopropyl acetate (IPAc), chloroform (CHCl3), dichloromethane (DCM), cyclopentyl methyl ether (CPME), anisole, diisopropyl ether, toluene, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), 1,2-propanediol, 1,2-dimethoxyethane, or 2-tert-butoxyethanol. In some embodiments, the solvated crystallization form is one of the forms described herein: A, C / S, E, F, H, I, L, M, R, T, V, W, X, Y, Z, AD, AE, AH, AI, AJ, AP, AQ, or AR. In some embodiments, the solvated crystallization form is form A. In some embodiments, the solvated crystallization form is form C / S. In some embodiments, the solvated crystallization form is form E. In some embodiments, the solvated crystallization form is form F. In some embodiments, the solvated crystallization form is form H. In some embodiments, the solvated crystallization form is form I. In some embodiments, the solvated crystallization form is form L. In some embodiments, the solvated crystallization form is form M. In some embodiments, the solvated crystallization form is form R. In some embodiments, the solvated crystallization form is form T. In some embodiments, the solvated crystallization form is form V. In some embodiments, the solvated crystallization form is form W. In some embodiments, the solvated crystallization form is form X. In some embodiments, the solvated crystallization form is form Y. In some embodiments, the solvated crystallization form is form Z. In some embodiments, the solvated crystallization form is form AD. In some embodiments, the solvated crystal form is form AE. In some embodiments, the solvated crystal form is form AH. In some embodiments, the solvated crystal form is form AI. In some embodiments, the solvated crystal form is form AJ. In some embodiments, the solvated crystal form is form AP. In some embodiments, the solvated crystal form is form AQ. In some embodiments, the solvated crystal form is form AR.

[0204] Form A In some embodiments, the solvated crystalline form is a 2-MeTHF solvate. In some embodiments, the 2-MeTHF solvate is form A. In some embodiments, the solvated crystalline form is form A, characterized by an XRPD pattern substantially as shown in FIG. 13. In some embodiments, form A is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 13. In some embodiments, form A is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 14. Representative XRPD peaks of form A are: Table 14 In some embodiments, the form is form A, characterized in that the XRPD plot contains at least two peaks selected from the group consisting of approximately 6.0 ± 0.2, 18.3 ± 0.2, 9.3 ± 0.2, 20.6 ± 0.2, 15.6 ± 0.2, 17.1 ± 0.2, 8.9 ± 0.2, 14.9 ± 0.2, and 17.4 ± 0.2 degrees 2θ. In some embodiments, the form is form A, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from the group consisting of approximately 6.0 ± 0.2, 18.3 ± 0.2, 9.3 ± 0.2, 20.6 ± 0.2, 15.6 ± 0.2, 17.1 ± 0.2, 8.9 ± 0.2, 14.9 ± 0.2, and 17.4 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0205] In some embodiments, the solvated crystallization form is form A, characterized by a TGA thermogram showing a weight loss of approximately 11.5% at temperatures up to 180 °C.

[0206] In some embodiments, the solvated crystallization form is form A, characterized in that the DSC thermogram contains an endothermic peak at about 149 °C.

[0207] In some embodiments, the solvated crystalline form is form A, characterized by two or more of the following: a. substantially the XRPD plot shown in Figure 13; b. a TGA thermogram showing a weight loss of approximately 11.5% at up to 180 °C; and c. a DSC thermogram containing an endothermic peak at approximately 149 °C. In some embodiments, the solvated crystalline form is form A as described herein.

[0208] In some embodiments, form A is pure. In some embodiments, form A is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form A is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0209] C / S format In some embodiments, the solvated crystalline form is an MTBE solvate. In some embodiments, the MTBE solvate is in form C / S (the free base form C and form S are the same crystalline form). In some embodiments, the solvated crystalline form is in form C / S, characterized by an XRPD pattern substantially as shown in FIG14. In some embodiments, form C / S is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG14. In some embodiments, form C / S is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 15. Representative XRPD peaks of form C / S are: Table 15 In some embodiments, the form is a C / S form, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 5.9 ± 0.2, 17.2 ± 0.2, 18.2 ± 0.2, 20.6 ± 0.2, 15.4 ± 0.2, 9.0 ± 0.2, 14.8 ± 0.2, 15.1 ± 0.2, 19.8 ± 0.2, and 16.1 ± 0.2 degrees 2θ. In some embodiments, the form is a C / S form, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 5.9 ± 0.2, 17.2 ± 0.2, 18.2 ± 0.2, 20.6 ± 0.2, 15.4 ± 0.2, 9.0 ± 0.2, 14.8 ± 0.2, 15.1 ± 0.2, 19.8 ± 0.2, and 16.1 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0210] In some embodiments, the solvated crystallization form is the C / S form, characterized by a TGA thermogram showing a weight loss of about 4.9% at up to 110 °C and about 5.0% between 110 °C and 180 °C.

[0211] In some embodiments, the solvated crystallization form is the C / S form, characterized in that the DSC thermogram contains an endothermic peak at approximately 147 °C.

[0212] In some embodiments, the solvated crystalline form is the form C / S, characterized by two or more of the following: a. an XRPD plot substantially as shown in Figure 14; b. a TGA thermogram showing a weight loss of approximately 4.9% up to 110 °C and approximately 5.0% between 110 and 180 °C; and c. a DSC thermogram containing an endothermic peak at approximately 147 °C. In some embodiments, the solvated crystalline form is the form C / S described herein.

[0213] In some embodiments, form C / S is pure. In some embodiments, form C / S is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form C / S is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0214] Form E In some embodiments, the solvated crystalline form is an ACN solvate. In some embodiments, the ACN solvate is form E. In some embodiments, the solvated crystalline form is form E, characterized by an XRPD pattern substantially as shown in FIG. 15. In some embodiments, form E is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 15. In some embodiments, form E is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 16. Representative XRPD peaks of form E are: Table 16 In some embodiments, the form is form E, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 15.6 ± 0.2, 20.1 ± 0.2, 19.6 ± 0.2, 6.5 ± 0.2, 10.3 ± 0.2, 14.7 ± 0.2, 16.1 ± 0.2, 23.4 ± 0.2, 17.2 ± 0.2, and 22.9 ± 0.2 degrees 2θ. In some embodiments, the form is form E, characterized in that the XRPD pattern comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 15.6 ± 0.2, 20.1 ± 0.2, 19.6 ± 0.2, 6.5 ± 0.2, 10.3 ± 0.2, 14.7 ± 0.2, 16.1 ± 0.2, 23.4 ± 0.2, 17.2 ± 0.2, and 22.9 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0215] In some embodiments, the solvated crystallization form is form E, characterized by a TGA thermogram showing a weight loss of approximately 7.3% at temperatures up to 180 °C.

[0216] In some embodiments, the solvated crystalline form is form E, characterized in that the DSC thermogram includes at least one endothermic peak at about 68 °C, about 164 °C, or about 195 °C. In some embodiments, the solvated crystalline form is form E, characterized in that the DSC thermogram includes endothermic peaks at about 68 °C, about 164 °C, and about 195 °C.

[0217] In some embodiments, the solvated crystalline form is form E, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 15; b. a TGA thermogram showing a weight loss of approximately 7.3% up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at approximately 68 °C, approximately 164 °C, or approximately 195 °C. In some embodiments, the solvated crystalline form is form E, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 15; b. a TGA thermogram showing a weight loss of approximately 7.3% up to 180 °C; and c. a DSC thermogram containing endothermic peaks at approximately 68 °C, approximately 164 °C, and approximately 195 °C. In some embodiments, the solvated crystalline form is form E as described herein.

[0218] In some embodiments, form E is pure. In some embodiments, form E is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form E is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0219] Form F In some embodiments, the solvated crystalline form is an acetone solvate. In some embodiments, the acetone solvate is form F. In some embodiments, the solvated crystalline form is form F, characterized by an XRPD pattern substantially as shown in FIG. 16. In some embodiments, the solvated crystalline form is form F as described herein. In some embodiments, form F is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 16. In some embodiments, form F is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 17. Representative XRPD peaks of form F are: Table 17 In some embodiments, the form is form F, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 6.4 ± 0.2, 19.8 ± 0.2, 9.9 ± 0.2, 14.2 ± 0.2, 16.4 ± 0.2, 15.9 ± 0.2, 12.9 ± 0.2, 24.0 ± 0.2, 9.4 ± 0.2, and 25.7 ± 0.2 degrees 2θ. In some embodiments, the form is form F, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 6.4 ± 0.2, 19.8 ± 0.2, 9.9 ± 0.2, 14.2 ± 0.2, 16.4 ± 0.2, 15.9 ± 0.2, 12.9 ± 0.2, 24.0 ± 0.2, 9.4 ± 0.2, and 25.7 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0220] In some embodiments, the solvated crystallization form is form F, characterized by a TGA thermogram showing a weight loss of approximately 1.9% at temperatures up to 180 °C.

[0221] In some embodiments, the solvated crystalline form is form F, characterized in that the DSC thermogram includes at least one endothermic peak at about 51 °C, about 95 °C, or about 194 °C. In some embodiments, the solvated crystalline form is form F, characterized in that the DSC thermogram includes an endothermic peak at about 51 °C, about 95 °C, or about 194 °C.

[0222] In some embodiments, the solvated crystalline form is form F, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 16; b. a TGA thermogram showing a weight loss of about 1.9% up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at about 51 °C, about 95 °C, or about 194 °C. In some embodiments, the solvated crystalline form is form F, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 16; b. a TGA thermogram showing a weight loss of about 1.9% up to 180 °C; and c. a DSC thermogram containing endothermic peaks at about 51 °C, about 95 °C, and about 194 °C. In some embodiments, the solvated crystalline form is form F as described herein.

[0223] In some embodiments, form F is pure. In some embodiments, form F is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form F is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0224] Form H In some embodiments, the solvated crystalline form is a THF solvate. In some embodiments, the THF solvate is form H. In some embodiments, the solvated crystalline form is form H, characterized by an XRPD pattern substantially as shown in FIG. 17. In some embodiments, form H is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 17. In some embodiments, form H is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 18. Representative XRPD peaks of form H are: Table 18 In some embodiments, the form is form H, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 19.0 ± 0.2, 14.9 ± 0.2, 15.7 ± 0.2, 6.3 ± 0.2, 19.8 ± 0.2, 8.9 ± 0.2, 10.1 ± 0.2, 23.1 ± 0.2, 8.4 ± 0.2, and 22.2 ± 0.2 degrees 2θ. In some embodiments, the form is form H, characterized in that the XRPD spectrum comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 19.0 ± 0.2, 14.9 ± 0.2, 15.7 ± 0.2, 6.3 ± 0.2, 19.8 ± 0.2, 8.9 ± 0.2, 10.1 ± 0.2, 23.1 ± 0.2, 8.4 ± 0.2, and 22.2 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0225] In some embodiments, the solvated crystallization form is form H, characterized by a TGA thermogram showing a weight loss of approximately 11.2% at temperatures up to 180 °C.

[0226] In some embodiments, the solvated crystalline form is form H, characterized in that the DSC thermogram includes at least one endothermic peak at about 132 °C or about 192 °C. In some embodiments, the solvated crystalline form is form H, characterized in that the DSC thermogram includes endothermic peaks at about 132 °C and about 192 °C.

[0227] In some embodiments, the solvated crystalline form is form H, characterized by two or more of the following: a. substantially as shown in FIG. 17; b. a TGA thermogram showing a weight loss of approximately 11.2% at up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at approximately 132 °C or approximately 192 °C. In some embodiments, the solvated crystalline form is form H, characterized by two or more of the following: a. substantially as shown in FIG. 17; b. a TGA thermogram showing a weight loss of approximately 11.2% at up to 180 °C; and c. a DSC thermogram containing at least one endothermic peak at approximately 132 °C or approximately 192 °C. Figure 17 a. The XRPD plot shown; b. The TGA thermogram showing a weight loss of approximately 11.2% up to 180 °C; and c. The DSC thermogram containing endothermic peaks at approximately 132 °C and approximately 192 °C. In some embodiments, the solvated crystalline form is form H as described herein.

[0228] In some embodiments, form H is pure. In some embodiments, form H is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form H is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0229] Form I In some embodiments, the solvated crystalline form is a DMF solvate. In some embodiments, the DMF solvate is form I. In some embodiments, the solvated crystalline form is form I, characterized by an XRPD pattern substantially as shown in FIG18. In some embodiments, form I is characterized in that the XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG18. In some embodiments, form I is characterized in that the XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 19. Representative XRPD peaks of form I are: Table 19 In some embodiments, the form is form I, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 19.2 ± 0.2, 15.7 ± 0.2, 6.2 ± 0.2, 23.3 ± 0.2, 15.2 ± 0.2, 28.1 ± 0.2, 22.8 ± 0.2, 8.4 ± 0.2, 22.5 ± 0.2, and 9.9 ± 0.2 degrees 2θ. In some embodiments, the form is Form I, characterized in that the XRPD pattern comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 19.2 ± 0.2, 15.7 ± 0.2, 6.2 ± 0.2, 23.3 ± 0.2, 15.2 ± 0.2, 28.1 ± 0.2, 22.8 ± 0.2, 8.4 ± 0.2, 22.5 ± 0.2, and 9.9 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0230] In some embodiments, the solvated crystallization form is Form I, characterized by a TGA thermogram showing a weight loss of approximately 10.1% at temperatures up to 180 °C.

[0231] In some embodiments, the solvated crystallization form is form I, characterized in that the DSC thermogram contains an endothermic peak at about 152 °C.

[0232] In some embodiments, the solvated crystalline form is form I, characterized by two or more of the following: a. substantially the XRPD plot shown in Figure 18; b. a TGA thermogram showing a weight loss of approximately 10.1% at temperatures up to 180 °C; and c. a DSC thermogram containing an endothermic peak at approximately 152 °C. In some embodiments, the solvated crystalline form is form I as described herein.

[0233] In some embodiments, Form I is pure. In some embodiments, Form I is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of Form I is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0234] Form L In some embodiments, the solvated crystalline form is a 1,4-dioxane solvate. In some embodiments, the 1,4-dioxane solvate is form L. In some embodiments, the solvated crystalline form is form L, characterized by an XRPD diagram substantially as shown in FIG. 19. In some embodiments, form L is characterized in that the XRPD diagram comprises, as shown in FIG. 19. Figure 19 The XRPD peaks shown may be one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks. In some embodiments, form L is characterized in that the XRPD plot contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 20. Representative XRPD peaks of form L are: Table 20 In some embodiments, the form is form L, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 18.5 ± 0.2, 15.8 ± 0.2, 19.6 ± 0.2, 6.1 ± 0.2, 15.1 ± 0.2, 23.4 ± 0.2, 8.5 ± 0.2, 16.2 ± 0.2, 9.1 ± 0.2, and 28.4 ± 0.2 degrees 2θ. In some embodiments, the form is form L, characterized in that the XRPD pattern comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 18.5 ± 0.2, 15.8 ± 0.2, 19.6 ± 0.2, 6.1 ± 0.2, 15.1 ± 0.2, 23.4 ± 0.2, 8.5 ± 0.2, 16.2 ± 0.2, 9.1 ± 0.2, and 28.4 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0235] In some embodiments, the solvated crystallization form is form L, characterized by a TGA thermogram showing a weight loss of approximately 8.4% at temperatures up to 180 °C.

[0236] In some embodiments, the solvated crystallization form is form L, characterized in that the DSC thermogram contains an endothermic peak at approximately 144 °C.

[0237] In some embodiments, the solvated crystalline form is form L, characterized by two or more of the following: a. an XRPD plot substantially as shown in Figure 19; b. a TGA thermogram showing a weight loss of approximately 8.4% at up to 180 °C; and c. a DSC thermogram containing an endothermic peak at approximately 144 °C. In some embodiments, the solvated crystalline form is form L as described herein.

[0238] In some embodiments, form L is pure. In some embodiments, form L is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form L is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0239] Form M In some embodiments, the solvated crystalline form is a DMAc solvate. In some embodiments, the DMAc solvate is form M. In some embodiments, the solvated crystalline form is form M, characterized by an XRPD pattern substantially as shown in FIG20. In some embodiments, form M is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG20. In some embodiments, form M is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 21. Representative XRPD peaks of form M are: Table 21 In some embodiments, the form is form M, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 6.0 ± 0.2, 18.9 ± 0.2, 25.0 ± 0.2, 22.8 ± 0.2, 9.7 ± 0.2, 14.9 ± 0.2, 17.0 ± 0.2, 27.7 ± 0.2, 21.6 ± 0.2, and 16.6 ± 0.2 degrees 2θ. In some embodiments, the form is form M, characterized in that the XRPD pattern comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 6.0 ± 0.2, 18.9 ± 0.2, 25.0 ± 0.2, 22.8 ± 0.2, 9.7 ± 0.2, 14.9 ± 0.2, 17.0 ± 0.2, 27.7 ± 0.2, 21.6 ± 0.2, and 16.6 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0240] In some embodiments, the solvated crystallization form is form M, characterized in that the TGA thermogram shows a weight loss of approximately 12.5% ​​at temperatures up to 180°C.

[0241] In some embodiments, the solvated crystallization form is form M, characterized in that the DSC thermogram contains an endothermic peak at approximately 159°C.

[0242] In some embodiments, the solvated crystalline form is form M, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG20; b. a TGA thermogram showing a weight loss of approximately 12.5% ​​at up to 180°C; and c. a DSC thermogram containing an endothermic peak at approximately 159°C. In some embodiments, the solvated crystalline form is form M as described herein.

[0243] In some embodiments, form M is pure. In some embodiments, form M is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form M is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0244] Form R In some embodiments, the solvated crystalline form is an IPA solvate. In some embodiments, the IPA solvate is form R. In some embodiments, the solvated crystalline form is form R, characterized by an XRPD pattern substantially as shown in FIG. 21. In some embodiments, form R is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 21. In some embodiments, form R is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 22. Representative XRPD peaks of form R are: Table 22 In some embodiments, the form is form R, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 5.3 ± 0.2, 19.7 ± 0.2, 15.7 ± 0.2, 21.3 ± 0.2, 14.5 ± 0.2, 17.1 ± 0.2, 6.7 ± 0.2, 21.0 ± 0.2, 16.3 ± 0.2, and 25.9 ± 0.2 degrees 2θ. In some embodiments, the form is form R, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 5.3 ± 0.2, 19.7 ± 0.2, 15.7 ± 0.2, 21.3 ± 0.2, 14.5 ± 0.2, 17.1 ± 0.2, 6.7 ± 0.2, 21.0 ± 0.2, 16.3 ± 0.2, and 25.9 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0245] In some embodiments, the solvated crystallization form is form R, characterized by a TGA thermogram showing a weight loss of approximately 6.3% at temperatures up to 180°C.

[0246] In some embodiments, the solvated crystallization form is form R, characterized in that the DSC thermogram contains an endothermic peak at approximately 165°C.

[0247] In some embodiments, the solvated crystalline form is form R, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG21; b. a TGA thermogram showing a weight loss of approximately 6.3% up to 180°C; and c. a DSC thermogram containing an endothermic peak at approximately 165°C. In some embodiments, the solvated crystalline form is form R as described herein.

[0248] In some embodiments, form R is pure. In some embodiments, form R is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form R is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0249] Form T In some embodiments, the solvated crystalline form is an EtOAc solvate. In some embodiments, the EtOAc solvate is form T. In some embodiments, the solvated crystalline form is form T, characterized by substantially as follows: Figure 22 The XRPD plot shown in Figure 22. In some embodiments, form T is characterized in that the XRPD plot contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Figure 22. In some embodiments, form T is characterized in that the XRPD plot contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 23. Representative XRPD peaks of form T are: Table 23 In some embodiments, the form is form T, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 6.0 ± 0.2, 15.7 ± 0.2, 18.5 ± 0.2, 8.8 ± 0.2, 9.2 ± 0.2, 9.4 ± 0.2, 20.4 ± 0.2, 17.3 ± 0.2, 17.7 ± 0.2, and 14.4 ± 0.2 degrees 2θ. In some embodiments, the form is form T, characterized in that the XRPD pattern comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 6.0 ± 0.2, 15.7 ± 0.2, 18.5 ± 0.2, 8.8 ± 0.2, 9.2 ± 0.2, 9.4 ± 0.2, 20.4 ± 0.2, 17.3 ± 0.2, 17.7 ± 0.2, and 14.4 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0250] In some embodiments, the solvated crystallization form is form T, characterized in that the TGA thermogram shows a weight loss of approximately 11.7% at temperatures up to 180°C.

[0251] In some embodiments, the solvated crystallization form is form T, characterized in that the DSC thermogram contains an endothermic peak at approximately 134 °C.

[0252] In some embodiments, the solvated crystalline form is form T, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG22; b. a TGA thermogram showing a weight loss of approximately 11.7% up to 180°C; and c. a DSC thermogram containing an endothermic peak at approximately 134°C. In some embodiments, the solvated crystalline form is form T as described herein.

[0253] In some embodiments, form T is pure. In some embodiments, form T substantially does not contain other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form T is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0254] Form V In some embodiments, the solvated crystalline form is an IPAc solvate. In some embodiments, the IPAc solvate is form V. In some embodiments, the solvated crystalline form is form V, characterized by an XRPD pattern substantially as shown in FIG. 23. In some embodiments, form V is characterized in that the XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 23. In some embodiments, form V is characterized in that the XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 24. Representative XRPD peaks of form V are: Table 24 In some embodiments, the form is form V, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 15.9 ± 0.2, 5.8 ± 0.2, 19.5 ± 0.2, 15.0 ± 0.2, 17.6 ± 0.2, 23.5 ± 0.2, 8.5 ± 0.2, 21.6 ± 0.2, 9.4 ± 0.2, and 17.3 ± 0.2 degrees 2θ. In some embodiments, the form is form V, characterized in that the XRPD pattern comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 15.9 ± 0.2, 5.8 ± 0.2, 19.5 ± 0.2, 15.0 ± 0.2, 17.6 ± 0.2, 23.5 ± 0.2, 8.5 ± 0.2, 21.6 ± 0.2, 9.4 ± 0.2, and 17.3 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0255] In some embodiments, the solvated crystallization form is form V, characterized in that the TGA thermogram shows a weight loss of approximately 13.5% at temperatures up to 180°C.

[0256] In some embodiments, the solvated crystalline form is form V, characterized in that the DSC thermogram includes at least one endothermic peak at about 55°C, about 110°C, or about 175°C. In some embodiments, the solvated crystalline form is form V, characterized in that the DSC thermogram includes endothermic peaks at about 55°C, about 110°C, and about 175°C.

[0257] In some embodiments, the solvated crystalline form is form V, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 23; b. a TGA thermogram showing a weight loss of approximately 13.5% up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 55°C, approximately 110°C, or approximately 175°C. In some embodiments, the solvated crystalline form is form V, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 23; b. a TGA thermogram showing a weight loss of approximately 13.5% up to 180°C; and c. a DSC thermogram containing endothermic peaks at approximately 55°C, approximately 110°C, and approximately 175°C. In some embodiments, the solvated crystalline form is form V as described herein.

[0258] In some embodiments, form V is pure. In some embodiments, form V is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form V is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0259] Form W In some embodiments, the solvated crystalline form is a CHCl3 solvate. In some embodiments, the CHCl3 solvate is form W. In some embodiments, the solvated crystalline form is form W, characterized by an XRPD pattern substantially as shown in FIG. 24. In some embodiments, form W is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 24. In some embodiments, form W is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 25. Representative XRPD peaks of form W are: Table 25 In some embodiments, the form is form W, characterized in that the XRPD plot includes at least two peaks selected from a group consisting of approximately 5.7 ± 0.2, 19.7 ± 0.2, 16.3 ± 0.2, 13.3 ± 0.2, 21.4 ± 0.2, 6.3 ± 0.2, 6.1 ± 0.2, 21.6 ± 0.2, 18.8 ± 0.2, and 14.7 ± 0.2 degrees 2θ. In some embodiments, the form is form W, characterized in that the XRPD pattern comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 5.7 ± 0.2, 19.7 ± 0.2, 16.3 ± 0.2, 13.3 ± 0.2, 21.4 ± 0.2, 6.3 ± 0.2, 6.1 ± 0.2, 21.6 ± 0.2, 18.8 ± 0.2, and 14.7 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0260] In some embodiments, the solvated crystallization form is form W, characterized in that the TGA thermogram shows a weight loss of approximately 8.9% at temperatures up to 180°C.

[0261] In some embodiments, the solvated crystalline form is form W, characterized in that the DSC thermogram includes at least one endothermic peak at about 93°C or about 143°C. In some embodiments, the solvated crystalline form is form W, characterized in that the DSC thermogram includes endothermic peaks at about 93°C and about 143°C.

[0262] In some embodiments, the solvated crystalline form is form W, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 24; b. a TGA thermogram showing a weight loss of approximately 8.9% up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 93°C or approximately 143°C. In some embodiments, the solvated crystalline form is form W, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 24; b. a TGA thermogram showing a weight loss of approximately 8.9% up to 180°C; and c. a DSC thermogram containing endothermic peaks at approximately 93°C and approximately 143°C. In some embodiments, the solvated crystalline form is form W as described herein.

[0263] In some embodiments, form W is pure. In some embodiments, form W is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form W is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0264] Form X In some embodiments, the solvated crystalline form is a DCM solvate. In some embodiments, the DCM solvate is form X. In some embodiments, the solvated crystalline form is form X, characterized by an XRPD pattern substantially as shown in FIG. 25. In some embodiments, form X is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 25. In some embodiments, form X is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 26. Representative XRPD peaks of form X are: Table 26 In some embodiments, the form is form X, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 19.9 ± 0.2, 5.8 ± 0.2, 22.5 ± 0.2, 23.5 ± 0.2, 13.2 ± 0.2, 17.4 ± 0.2, 15.1 ± 0.2, 14.1 ± 0.2, 17.7 ± 0.2, and 21.5 ± 0.2 degrees 2θ. In some embodiments, the form is form X, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 19.9 ± 0.2, 5.8 ± 0.2, 22.5 ± 0.2, 23.5 ± 0.2, 13.2 ± 0.2, 17.4 ± 0.2, 15.1 ± 0.2, 14.1 ± 0.2, 17.7 ± 0.2, and 21.5 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0265] In some embodiments, the solvated crystallization form is form X, characterized in that the TGA thermogram shows a weight loss of approximately 8.4% at temperatures up to 180°C.

[0266] In some embodiments, the solvated crystalline form is form X, characterized in that the DSC thermogram includes at least one endothermic peak at about 126°C, about 137°C, or about 161°C. In some embodiments, the solvated crystalline form is form X, characterized in that the DSC thermogram includes endothermic peaks at about 126°C, about 137°C, and about 161°C.

[0267] In some embodiments, the solvated crystalline form is form X, characterized by two or more of the following: a. substantially an XRPD plot as shown in FIG. 25; b. a TGA thermogram showing a weight loss of about 8.4% up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at about 126°C, about 137°C, or about 161°C. In some embodiments, the solvated crystalline form is form X, characterized by two or more of the following: a. substantially an XRPD plot as shown in FIG. 25; b. a TGA thermogram showing a weight loss of about 8.4% up to 180°C; and c. a DSC thermogram containing endothermic peaks at about 126°C, about 137°C, and about 161°C. In some embodiments, the solvated crystalline form is form X as described herein.

[0268] In some embodiments, form X is pure. In some embodiments, form X is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form X is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0269] Form Y In some embodiments, the solvated crystalline form is a CMPE solvate. In some embodiments, the CMPE solvate is form Y. In some embodiments, the solvated crystalline form is form Y, characterized by an XRPD pattern substantially as shown in FIG. 26. In some embodiments, form Y is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 26. In some embodiments, form Y is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 27. Representative XRPD peaks of form Y are: Table 27 In some embodiments, the form is form Y, characterized in that the XRPD plot includes at least two peaks selected from a group consisting of approximately 5.9 ± 0.2, 18.2 ± 0.2, 17.3 ± 0.2, 15.0 ± 0.2, 20.6 ± 0.2, 15.4 ± 0.2, 8.9 ± 0.2, 19.8 ± 0.2, 23.4 ± 0.2, and 9.3 ± 0.2 degrees 2θ. In some embodiments, the form is form Y, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 5.9 ± 0.2, 18.2 ± 0.2, 17.3 ± 0.2, 15.0 ± 0.2, 20.6 ± 0.2, 15.4 ± 0.2, 8.9 ± 0.2, 19.8 ± 0.2, 23.4 ± 0.2, and 9.3 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0270] In some embodiments, the solvated crystallization form is form Y, characterized in that the TGA thermogram shows a weight loss of approximately 12.4% at temperatures up to 180°C.

[0271] In some embodiments, the solvated crystalline form is form Y, characterized in that the DSC thermogram includes at least one endothermic peak at about 125°C or about 141°C. In some embodiments, the solvated crystalline form is form Y, characterized in that the DSC thermogram includes endothermic peaks at about 125°C and about 141°C.

[0272] In some embodiments, the solvated crystalline form is form Y, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 26; b. a TGA thermogram showing a weight loss of approximately 12.4% up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 125°C or approximately 141°C. In some embodiments, the solvated crystalline form is form Y, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 26; b. a TGA thermogram showing a weight loss of approximately 12.4% up to 180°C; and c. a DSC thermogram containing endothermic peaks at approximately 125°C and approximately 141°C. In some embodiments, the solvated crystalline form is form Y as described herein.

[0273] In some embodiments, form Y is pure. In some embodiments, form Y is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form Y is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0274] Form Z In some embodiments, the solvated crystalline form is anisole solvate. In some embodiments, the anisole solvate is form Z. In some embodiments, the solvated crystalline form is form Z, characterized by substantially as follows: Figure 27 The XRPD plot shown in Figure 27. In some embodiments, form Z is characterized in that the XRPD plot contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Figure 27. In some embodiments, form Z is characterized in that the XRPD plot contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 28. Representative XRPD peaks of form Z are: Table 28 In some embodiments, the form is form Z, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 5.9 ± 0.2, 18.2 ± 0.2, 17.3 ± 0.2, 15.0 ± 0.2, 20.6 ± 0.2, 15.4 ± 0.2, 8.9 ± 0.2, 19.8 ± 0.2, 23.4 ± 0.2, and 9.3 ± 0.2 degrees 2θ. In some embodiments, the form is form Z, characterized in that the XRPD pattern comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 5.9 ± 0.2, 18.2 ± 0.2, 17.3 ± 0.2, 15.0 ± 0.2, 20.6 ± 0.2, 15.4 ± 0.2, 8.9 ± 0.2, 19.8 ± 0.2, 23.4 ± 0.2, and 9.3 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0275] In some embodiments, the solvated crystallization form is form Z, characterized in that the TGA thermogram shows a weight loss of approximately 13.1% at temperatures up to 180°C.

[0276] In some embodiments, the solvated crystallization form is form Z, characterized in that the DSC thermogram contains an endothermic peak at about 105°C.

[0277] In some embodiments, the solvated crystalline form is form Z, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 27; b. a TGA thermogram showing a weight loss of approximately 13.1% at up to 180°C; and c. a DSC thermogram containing an endothermic peak at approximately 105°C. In some embodiments, the solvated crystalline form is form Z as described herein.

[0278] In some embodiments, form Z is pure. In some embodiments, form Z is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form Z is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0279] Form AD In some embodiments, the solvated crystalline form is a diisopropyl ether solvate. In some embodiments, the diisopropyl ether solvate is form AD. In some embodiments, the solvated crystalline form is form AD, characterized by an XRPD pattern substantially as shown in FIG. 28. In some embodiments, form AD is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 28. In some embodiments, form AD is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 29. Representative XRPD peaks of form AD are: Table 29 In some embodiments, the form is form AD, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 15.7 ± 0.2, 5.9 ± 0.2, 17.5 ± 0.2, 9.4 ± 0.2, 15.0 ± 0.2, 19.1 ± 0.2, 8.4 ± 0.2, 23.1 ± 0.2, 22.6 ± 0.2, and 22.1 ± 0.2 degrees 2θ. In some embodiments, the form is form AD, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 15.7 ± 0.2, 5.9 ± 0.2, 17.5 ± 0.2, 9.4 ± 0.2, 15.0 ± 0.2, 19.1 ± 0.2, 8.4 ± 0.2, 23.1 ± 0.2, 22.6 ± 0.2, and 22.1 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0280] In some embodiments, the solvated crystallization form is form AD, characterized in that the TGA thermogram shows a weight loss of approximately 11.0% at temperatures up to 180°C.

[0281] In some embodiments, the solvated crystalline form is form AD, characterized in that the DSC thermogram includes at least one endothermic peak at about 64°C, about 116°C, or about 179°C. In some embodiments, the solvated crystalline form is form AD, characterized in that the DSC thermogram includes endothermic peaks at about 64°C, about 116°C, and about 179°C.

[0282] In some embodiments, the solvated crystalline form is form AD, characterized by two or more of the following: a. substantially an XRPD plot as shown in FIG. 28; b. a TGA thermogram showing a weight loss of about 11.0% at up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at about 64°C, about 116°C, or about 179°C. In some embodiments, the solvated crystalline form is form AD, characterized by two or more of the following: a. substantially an XRPD plot as shown in FIG. 28; b. a TGA thermogram showing a weight loss of about 11.0% at up to 180°C; and c. a DSC thermogram containing endothermic peaks at about 64°C, about 116°C, and about 179°C. In some embodiments, the solvated crystalline form is form AD as described herein.

[0283] In some embodiments, form AD is pure. In some embodiments, form AD is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AD is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0284] AE format In some embodiments, the solvated crystalline form is a toluene solvate. In some embodiments, the toluene solvate is form AE. In some embodiments, the solvated crystalline form is form AE, characterized by an XRPD pattern substantially as shown in FIG29. In some embodiments, form AE is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG29. In some embodiments, form AE is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 30. Representative XRPD peaks of form AE are: Table 30 In some embodiments, the form is form AE, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 5.5 ± 0.2, 14.6 ± 0.2, 15.1 ± 0.2, 9.9 ± 0.2, 21.5 ± 0.2, 20.6 ± 0.2, 22.4 ± 0.2, 16.3 ± 0.2, 19.9 ± 0.2, and 7.0 ± 0.2 degrees 2θ. In some embodiments, the form is form AE, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 5.5 ± 0.2, 14.6 ± 0.2, 15.1 ± 0.2, 9.9 ± 0.2, 21.5 ± 0.2, 20.6 ± 0.2, 22.4 ± 0.2, 16.3 ± 0.2, 19.9 ± 0.2, and 7.0 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0285] In some embodiments, the solvated crystallization is in form AE, characterized by a TGA thermogram showing a weight loss of approximately 12.4% at temperatures up to 180°C.

[0286] In some embodiments, the solvated crystallization form is form AE, characterized in that the DSC thermogram includes at least one endothermic peak at about 56°C or about 115°C. In some embodiments, the solvated crystallization form is form AE, characterized in that the DSC thermogram includes endothermic peaks at about 56°C and about 115°C.

[0287] In some embodiments, the solvated crystalline form is form AE, characterized by two or more of the following: a. substantially as shown in FIG. 29; b. a TGA thermogram showing a weight loss of approximately 12.4% at up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 56°C or approximately 115°C. In some embodiments, the solvated crystalline form is form AE, characterized by two or more of the following: a. substantially as shown in FIG. 29; b. a TGA thermogram showing a weight loss of approximately 12.4% at up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 56°C or approximately 115°C. Figure 29 a. The XRPD plot shown; b. The TGA thermogram showing a weight loss of approximately 12.4% up to 180°C; and c. The DSC thermogram containing endothermic peaks at approximately 56°C and approximately 115°C. In some embodiments, the solvated crystallization form is the form AE described herein.

[0288] In some embodiments, form AE is pure. In some embodiments, form AE is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AE is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0289] Form AH In some embodiments, the solvated crystalline form is an NMP solvate. In some embodiments, the NMP solvate is form AH. In some embodiments, the solvated crystalline form is form AH, characterized by an XRPD pattern substantially as shown in FIG30. In some embodiments, form AH is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG30. In some embodiments, form AH is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 31. Representative XRPD peaks of form AH are: Table 31 In some embodiments, the form is form AH, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 5.9 ± 0.2, 19.0 ± 0.2, 9.6 ± 0.2, 16.7 ± 0.2, 17.0 ± 0.2, 14.6 ± 0.2, 24.7 ± 0.2, 22.8 ± 0.2, 17.4 ± 0.2, and 18.5 ± 0.2 degrees 2θ. In some embodiments, the form is form AH, characterized in that the XRPD spectrum comprises at least three, at least four, at least five, at least six, or at least seven peaks selected from a group consisting of approximately 5.9 ± 0.2, 19.0 ± 0.2, 9.6 ± 0.2, 16.7 ± 0.2, 17.0 ± 0.2, 14.6 ± 0.2, 24.7 ± 0.2, 22.8 ± 0.2, 17.4 ± 0.2, and 18.5 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0290] In some embodiments, the solvated crystallization form is form AH, characterized in that the TGA thermogram shows a weight loss of approximately 14.6% at temperatures up to 190°C.

[0291] In some embodiments, the solvated crystalline form is form AH, characterized in that the DSC thermogram includes at least one endothermic peak at about 156°C or about 173°C. In some embodiments, the solvated crystalline form is form AH, characterized in that the DSC thermogram includes endothermic peaks at about 156°C and about 173°C.

[0292] In some embodiments, the solvated crystalline form is form AH, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 30; b. a TGA thermogram showing a weight loss of approximately 14.6% up to 190°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 156°C or approximately 173°C. In some embodiments, the solvated crystalline form is form AH, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 30; b. a TGA thermogram showing a weight loss of approximately 14.6% up to 190°C; and c. a DSC thermogram containing endothermic peaks at approximately 156°C and approximately 173°C. In some embodiments, the solvated crystalline form is form AH as described herein.

[0293] In some embodiments, form AH is pure. In some embodiments, form AH is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AH is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0294] Formal AI In some embodiments, the solvated crystallization form is a DMSO solvate. In some embodiments, the DMSO solvate is in form AI. In some embodiments, the solvated crystallization form is in form AI, characterized by substantially as follows: Figure 31 The XRPD graph shown in Figure 31. In some embodiments, the formal AI is characterized in that the XRPD graph contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Figure 31. In some embodiments, the formal AI is characterized in that the XRPD graph contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 32. Representative XRPD peaks of the formal AI are: Table 32 In some embodiments, the form is form AI, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 18.8 ± 0.2, 15.7 ± 0.2, 6.2 ± 0.2, 15.0 ± 0.2, 23.5 ± 0.2, 19.4 ± 0.2, 19.7 ± 0.2, 9.0 ± 0.2, 8.5 ± 0.2, and 9.9 ± 0.2 degrees 2θ. In some embodiments, the form is form AI, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 18.8 ± 0.2, 15.7 ± 0.2, 6.2 ± 0.2, 15.0 ± 0.2, 23.5 ± 0.2, 19.4 ± 0.2, 19.7 ± 0.2, 9.0 ± 0.2, 8.5 ± 0.2, and 9.9 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0295] In some embodiments, the solvated crystallization form is form AI, characterized in that the TGA thermogram shows a weight loss of approximately 12.0% at temperatures up to 190°C.

[0296] In some embodiments, the solvated crystallization form is form AI, characterized in that the DSC thermogram contains at least one endothermic peak at about 155°C or about 166°C.

[0297] In some embodiments, the solvated crystallization form is form AI, characterized in that the DSC thermogram contains endothermic peaks at about 155°C and about 166°C.

[0298] In some embodiments, the solvated crystalline form is form AI, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 31; b. a TGA thermogram showing a weight loss of approximately 12.0% up to 190°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 155°C or approximately 160°C. In some embodiments, the solvated crystalline form is form AI, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 31; b. a TGA thermogram showing a weight loss of approximately 12.0% up to 190°C; and c. a DSC thermogram containing endothermic peaks at approximately 155°C and approximately 166°C. In some embodiments, the solvated crystalline form is form AI as described herein.

[0299] In some embodiments, the form AI is pure. In some embodiments, the form AI is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of the form AI is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0300] AJ (Form) In some embodiments, the solvated crystalline form is a CHCl3 solvate. In some embodiments, the CHCl3 solvate is form AJ. In some embodiments, the solvated crystalline form is form AJ, characterized by an XRPD pattern substantially as shown in FIG. 32. In some embodiments, form AJ is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 32. In some embodiments, form AJ is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 33. Representative XRPD peaks of form AJ are: Table 33 In some embodiments, the form is form AJ, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 14.5 ± 0.2, 20.7 ± 0.2, 19.1 ± 0.2, 19.4 ± 0.2, 20.3 ± 0.2, 16.7 ± 0.2, 8.1 ± 0.2, 17.0 ± 0.2, 17.8 ± 0.2, and 10.8 ± 0.2 degrees 2θ. In some embodiments, the form is form AJ, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 14.5 ± 0.2, 20.7 ± 0.2, 19.1 ± 0.2, 19.4 ± 0.2, 20.3 ± 0.2, 16.7 ± 0.2, 8.1 ± 0.2, 17.0 ± 0.2, 17.8 ± 0.2, and 10.8 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0301] In some embodiments, the solvated crystallization form is form AJ, characterized in that the TGA thermogram shows a weight loss of approximately 17.3% at temperatures up to 180°C.

[0302] In some embodiments, the solvated crystalline form is form AJ, characterized in that the DSC thermogram includes at least one endothermic peak at about 112°C or about 138°C. In some embodiments, the solvated crystalline form is form AJ, characterized in that the DSC thermogram includes endothermic peaks at about 112°C and about 138°C.

[0303] In some embodiments, the solvated crystalline form is form AJ, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 32; b. a TGA thermogram showing a weight loss of approximately 17.3% up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 112°C or approximately 138°C. In some embodiments, the solvated crystalline form is form AJ, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 32; b. a TGA thermogram showing a weight loss of approximately 17.3% up to 180°C; and c. a DSC thermogram containing endothermic peaks at approximately 112°C and approximately 138°C. In some embodiments, the solvated crystalline form is form AJ as described herein.

[0304] In some embodiments, form AJ is pure. In some embodiments, form AJ is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AJ is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0305] AP Form In some embodiments, the solvated crystalline form is a 1,2-propanediol solvate. In some embodiments, the 1,2-propanediol solvate is form AP. In some embodiments, the solvated crystalline form is form AP, characterized by an XRPD pattern substantially as shown in FIG. 33. In some embodiments, form AP is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 33. In some embodiments, form AP is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 34. Representative XRPD peaks of form AP are: Table 34 In some embodiments, the form is form AP, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 7.6 ± 0.2, 19.0 ± 0.2, 22.8 ± 0.2, 17.6 ± 0.2, 11.4 ± 0.2, 17.3 ± 0.2, 17.1 ± 0.2, 3.8 ± 0.2, 6.2 ± 0.2, and 16.4 ± 0.2 degrees 2θ. In some embodiments, the form is form AP, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 7.6 ± 0.2, 19.0 ± 0.2, 22.8 ± 0.2, 17.6 ± 0.2, 11.4 ± 0.2, 17.3 ± 0.2, 17.1 ± 0.2, 3.8 ± 0.2, 6.2 ± 0.2, and 16.4 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0306] In some embodiments, the solvated crystallization form is form AP, characterized in that the TGA thermogram shows a weight loss of approximately 18.7% at temperatures up to 180°C.

[0307] In some embodiments, the solvated crystalline form is form AP, characterized in that the DSC thermogram includes at least one endothermic peak at about 77°C or about 130°C. In some embodiments, the solvated crystalline form is form AP, characterized in that the DSC thermogram includes endothermic peaks at about 77°C and about 130°C.

[0308] In some embodiments, the solvated crystalline form is form AP, characterized by two or more of the following: a. substantially as shown in FIG. 33; b. a TGA thermogram showing a weight loss of approximately 18.7% at up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 77°C or approximately 130°C. In some embodiments, the solvated crystalline form is form AP, characterized by two or more of the following: a. substantially as shown in FIG. 33; b. a TGA thermogram showing a weight loss of approximately 18.7% at up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 77°C or approximately 130°C. Figure 33 a. The XRPD plot shown; b. The TGA thermogram showing a weight loss of approximately 18.7% up to 180°C; and c. The DSC thermogram containing endothermic peaks at approximately 77°C and approximately 130°C. In some embodiments, the solvated crystallization form is the form AP described herein.

[0309] In some embodiments, form AP is pure. In some embodiments, form AP is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AP is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0310] Form AQ In some embodiments, the solvated crystalline form is a 1,2-dimethoxyethane solvate. In some embodiments, the 1,2-dimethoxyethane solvate is form AQ. In some embodiments, the solvated crystalline form is form AQ, characterized by an XRPD pattern substantially as shown in FIG. 34. In some embodiments, form AQ is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 34. In some embodiments, form AQ is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 35. Representative XRPD peaks of form AQ are: Table 35 In some embodiments, the form is form AQ, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 17.6 ± 0.2, 18.1 ± 0.2, 9.0 ± 0.2, 6.1 ± 0.2, 20.8 ± 0.2, 15.4 ± 0.2, 23.7 ± 0.2, 15.1 ± 0.2, 19.8 ± 0.2, and 9.3 ± 0.2 degrees 2θ. In some embodiments, the form is form AQ, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 17.6 ± 0.2, 19.0 ± 0.2, 22.8 ± 0.2, 17.6 ± 0.2, 11.4 ± 0.2, 17.3 ± 0.2, 17.1 ± 0.2, 3.8 ± 0.2, 6.2 ± 0.2, and 16.4 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0311] In some embodiments, the solvated crystallization form is form AQ, characterized in that the TGA thermogram shows a weight loss of approximately 10.0% at temperatures up to 180°C.

[0312] In some embodiments, the solvated crystallization form is form AQ, characterized in that the DSC thermogram contains an endothermic peak at approximately 145°C.

[0313] In some embodiments, the solvated crystalline form is form AQ, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 34; b. a TGA thermogram showing a weight loss of approximately 10.0% at up to 180°C; and c. a DSC thermogram containing an endothermic peak at approximately 145°C. In some embodiments, the solvated crystalline form is form AQ as described herein.

[0314] In some embodiments, form AQ is pure. In some embodiments, form AQ is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AQ is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0315] AR Form In some embodiments, the solvated crystalline form is a 2-tert-butoxyethanol solvate. In some embodiments, the 2-tert-butoxyethanol solvate is form AR. In some embodiments, the solvated crystalline form is form AR, characterized by an XRPD pattern substantially as shown in FIG. 35. In some embodiments, form AR is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG. 35. In some embodiments, form AR is characterized in that its XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in Table 36. Representative XRPD peaks of form AR are: Table 36 In some embodiments, the form is form AR, characterized in that the XRPD plot contains at least two peaks selected from a group consisting of approximately 17.1 ± 0.2, 5.7 ± 0.2, 16.2 ± 0.2, 19.3 ± 0.2, 19.0 ± 0.2, 11.4 ± 0.2, 12.4 ± 0.2, 14.7 ± 0.2, 20.2 ± 0.2, and 22.9 ± 0.2 degrees 2θ. In some embodiments, the form is form AR, characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from groups consisting of approximately 17.1 ± 0.2, 5.7 ± 0.2, 16.2 ± 0.2, 19.3 ± 0.2, 19.0 ± 0.2, 11.4 ± 0.2, 12.4 ± 0.2, 14.7 ± 0.2, 20.2 ± 0.2, and 22.9 ± 0.2 degrees 2θ. In some embodiments, the XRPD spectrum is obtained using a Cu Kα source.

[0316] In some embodiments, the solvated crystallization form is form AR, characterized in that the TGA thermogram shows a weight loss of approximately 26.0% at temperatures up to 180°C.

[0317] In some embodiments, the solvated crystalline form is form AR, characterized in that the DSC thermogram includes at least one endothermic peak at about 50°C, about 72°C, or about 135°C. In some embodiments, the solvated crystalline form is form AR, characterized in that the DSC thermogram includes endothermic peaks at about 50°C, about 72°C, and about 135°C.

[0318] In some embodiments, the solvated crystalline form is form AR, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 35; b. a TGA thermogram showing a weight loss of approximately 26.0% up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 50°C, approximately 72°C, or approximately 135°C. In some embodiments, the solvated crystalline form is form AR, characterized by two or more of the following: a. an XRPD plot substantially as shown in FIG. 35; b. a TGA thermogram showing a weight loss of approximately 26.0% up to 180°C; and c. a DSC thermogram containing endothermic peaks at approximately 50°C, approximately 72°C, and approximately 135°C. In some embodiments, the solvated crystalline form is form AR as described herein.

[0319] In some embodiments, form AR is pure. In some embodiments, form AR is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AR is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0320] Metastable crystalline form In some embodiments, the crystalline form is a metastable crystalline form. In some embodiments, the metastable crystalline form is form B / AF, form K, form AB, form AM, form AN, form AO, or form P as described herein. In some embodiments, the metastable crystalline form is form B / AF (the free base form B and form AF are the same crystalline form). In some embodiments, the metastable crystalline form is form K. In some embodiments, the metastable crystalline form is form AB. In some embodiments, the metastable crystalline form is form AM. In some embodiments, the metastable crystalline form is form AN. In some embodiments, the metastable crystalline form is form AO. In some embodiments, the metastable crystalline form is form P. The various metastable crystalline forms described herein are summarized below: Form B / AF In some embodiments, the metastable crystalline form is form B / AF, characterized by an XRPD plot substantially as shown in FIG36. In some embodiments, the metastable crystalline form is form B / AF as described herein. In some embodiments, form B / AF is characterized in that the XRPD plot contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG36.

[0321] In some embodiments, form B / AF is pure. In some embodiments, form B / AF is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form B / AF is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0322] Form K In some embodiments, the metastable crystalline form is form K, characterized by an XRPD plot substantially as shown in FIG37. In some embodiments, the metastable crystalline form is form K as described herein. In some embodiments, form K is characterized in that the XRPD plot contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG37.

[0323] In some embodiments, form K is pure. In some embodiments, form K is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form K is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0324] Form AB In some embodiments, the metastable crystalline form is form AB, characterized by an XRPD plot substantially as shown in FIG38. In some embodiments, the metastable crystalline form is form AB as described herein. In some embodiments, form AB is characterized in that the XRPD plot contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG38.

[0325] In some embodiments, form AB is pure. In some embodiments, form AB is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AB is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0326] Form AM In some embodiments, the metastable crystalline form is form AM, characterized by an XRPD pattern substantially as shown in FIG39. In some embodiments, the metastable crystalline form is form AM as described herein. In some embodiments, form AM is characterized in that the XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG39.

[0327] In some embodiments, form AM is pure. In some embodiments, form AM is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AM is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0328] Form AN In some embodiments, the metastable crystalline form is form AN, characterized by an XRPD plot substantially as shown in FIG40. In some embodiments, the metastable crystalline form is form AN as described herein. In some embodiments, form AN is characterized in that the XRPD plot contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG40.

[0329] In some embodiments, form AN is pure. In some embodiments, form AN is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AN is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0330] Form AO In some embodiments, the metastable crystalline form is form AO, characterized by an XRPD plot substantially as shown in FIG41. In some embodiments, the metastable crystalline form is form AO as described herein. In some embodiments, form AO is characterized in that the XRPD plot contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG41.

[0331] In some embodiments, form AO is pure. In some embodiments, form AO is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form AO is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0332] Form P In some embodiments, the metastable crystalline form is form P, characterized by an XRPD pattern substantially as shown in FIG42. In some embodiments, form P is characterized in that the XRPD pattern contains one, two, three, four, five, six, seven, eight, nine, ten, or all of the characteristic XRPD peaks shown in FIG42.

[0333] In some embodiments, the metastable crystalline form is form P, characterized by a TGA thermogram showing a weight loss of approximately 5.6% at temperatures up to 180°C. In some embodiments, the metastable crystalline form is form P, characterized by a DSC thermogram containing at least one endothermic peak at approximately 78°C or approximately 157°C. In some embodiments, the metastable crystalline form is form P, characterized by a DSC thermogram containing endothermic peaks at approximately 78°C and approximately 157°C. In some embodiments, the metastable crystalline form is form P, characterized by two or more of the following: a. substantially the XRPD plot shown in FIG. 42; b. a TGA thermogram showing a weight loss of approximately 5.6% at temperatures up to 180°C; and c. a DSC thermogram containing at least one endothermic peak at approximately 78°C or approximately 157°C. In some embodiments, the metastable crystalline form is form P, characterized by two or more of the following: a. an XRPD plot substantially as shown in Figure 42; b. a TGA thermogram showing a weight loss of approximately 5.6% up to 180°C; and c. a DSC thermogram containing endothermic peaks at approximately 78°C and approximately 157°C. In some embodiments, the crystalline form is form P as described herein.

[0334] In some embodiments, form P is pure. In some embodiments, form P is substantially free of other solid forms described herein (e.g., amorphous solids). In some embodiments, the purity of form P is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.9%.

[0335] Pharmaceutical Compositions / Formulations The solid form of the compound of formula (I) disclosed herein can be formulated according to standard pharmaceutical practices for use in therapeutic combinations for the treatment (including prophylactic treatment) of hyperproliferative diseases in mammals, including humans. This disclosure provides a pharmaceutical composition comprising the solid form of a compound of formula (I) disclosed herein, and one or more pharmaceutically acceptable carriers, gliding agents, diluents, or excipients.

[0336] Suitable carriers, diluents, flow aids and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

[0337] The formulations can be prepared using conventional dissolving and mixing procedures. The compounds of this invention are typically formulated into pharmaceutical dosage forms to provide easily controlled drug dosages and ensure patient compliance with prescribed regimens.

[0338] Depending on the method of administration, pharmaceutical compositions (or formulations) for administration can be packaged in various ways. Typically, articles for dispensing include containers in which the pharmaceutical formulation is deposited in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. Containers may also include intervention protection components to prevent accidental contact with the packaged contents. Additionally, the container is labeled with a description of its contents. Appropriate warnings may also be included on the label.

[0339] Pharmaceutical formulations of the compounds of formula (I) disclosed herein, in solid form, can be prepared using pharmaceutically acceptable diluents, carriers, excipients, gliding agents, or stabilizers for various routes and types of administration (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publ. Co., Easton, Pa.), in the form of lyophilized formulations, ground powders, or aqueous solutions. Formulation can be performed by mixing with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the receptor at the dose and concentration used) at ambient temperature with appropriate pH and desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but can range from about 3 to about 8.

[0340] Pharmaceutical preparations are preferably sterile. In particular, preparations intended for internal administration must be sterile. Such sterilization can be easily achieved through filtration using sterile filter membranes.

[0341] Pharmaceutical preparations are typically stored as solid compositions, tablets, pills, capsules, lyophilized preparations, or aqueous solutions.

[0342] The pharmaceutical formulations disclosed herein are administered and given in accordance with good medical practice (i.e., dosage, concentration, schedule, duration of treatment, solvent, and route of administration). Factors to be considered in this context include the specific disease being treated, the individual patient's clinical condition, the cause of the disease, the site of drug delivery, the method of administration, the timing of administration, and other factors known to the practicing physician.

[0343] Acceptable diluents, carriers, excipients, and stabilizers are non-toxic to the receptor at the doses and concentrations used and include: buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl ammonium chloride; benzalkonium chloride, benzyl chloride; phenol, butanol, ethanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10). (1 residue) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as lactose, sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc-protein complexes); and / or nonionic surfactants, such as TWEEN™ (including Tween 80), PLURONICS™, or polyethylene glycol (PEG) (including PEG400). Active pharmaceutical ingredients can also be encapsulated in microcapsules (e.g., hydroxymethyl cellulose microcapsules, gelatin microcapsules, and poly(methyl methacrylate) microcapsules, respectively) prepared by cohesive techniques or interfacial polymerization, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in crude emulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 18th edition (1995), Mack Publ. Co., Easton, Pa. Other examples of pharmaceutical formulations can be found in: Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, Vol. 3, 2nd edition, New York, NY.

[0344] Tablets may contain one or more pharmaceutically acceptable carriers, glidants, diluents, or excipients selected from microcrystalline cellulose, lactose, sodium starch glycolate, and magnesium stearate.

[0345] Pharmaceutically acceptable gliding agents may be selected from silica, powdered cellulose, microcrystalline cellulose, metal stearates, sodium aluminosilicate, sodium benzoate, calcium carbonate, calcium silicate, corn starch, magnesium carbonate, asbestos-free talc, Stearoet C, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof.

[0346] This pharmaceutical formulation includes formulations suitable for the routes of administration detailed herein. The formulation can be conveniently presented in unit dose form and can be prepared using any method well known in the field of pharmaceutical technology. Techniques and formulations are commonly found in Remington's Pharmaceutical Sciences, 18th edition (1995), Mack Publishing Co., Easton, Pa. Such methods involve the step of associating the active ingredient with a carrier constituting one or more auxiliary components. Generally, the formulation is prepared by uniformly and tightly binding the active ingredient with a liquid carrier or a subdivided solid carrier, or both, and then, if necessary, shaping the product.

[0347] The pharmaceutical composition can be in the form of a sterile injectable formulation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated using suitable dispersants or wetting agents and suspending agents already mentioned above, according to known techniques. The sterile injectable formulation can be a solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution in 1,3-butanediol, or prepared from a lyophilized powder. Acceptable media and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectables.

[0348] Treatment methods and uses The solid forms and pharmaceutical compositions comprising them described herein can be used as Ras inhibitors. In one aspect, the solid forms and pharmaceutical compositions described herein can be used as KRas inhibitors. In another aspect, the solid forms and pharmaceutical compositions described herein can be used as NRas inhibitors. In yet another aspect, the solid forms and pharmaceutical compositions described herein can be used as HRas inhibitors. In one embodiment, the solid forms and pharmaceutical compositions described herein can be used as both G12D Ras inhibitors and G12D KRas inhibitors.

[0349] This document provides a method for contacting cells (such as ex vivo cells) with the solid form and pharmaceutical composition described herein to inhibit Ras activity (e.g., KRas activity) in the cells. In another embodiment, the activity is mutant G12D KRas activity.

[0350] This article further provides a method for treating cancers containing KRas mutations, the method comprising administering an effective amount of the solid form or pharmaceutical composition described herein to a patient suffering from such cancer. In one embodiment, the KRas mutation is KRas G12D mutation.

[0351] In one embodiment, the method further includes testing a sample from a patient (e.g., as illustrated herein) for the presence of KRas prior to administration of the solid form or pharmaceutical composition described herein. G12D Mutation. In one such embodiment, in determining the patient sample's response to KRas... G12D After a mutation is confirmed to be positive (e.g., present), the solid form or pharmaceutical composition described herein is administered to the patient.

[0352] The methods for treating cancer described in this article involve the treatment of cancers such as acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumors, embryonal tumors, germ cell tumors, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, and CNS. Cancer, endometrial cancer, ependymoma, esophageal cancer, sensory neuroblastoma, Ewing sarcoma, extracranial germ cell tumors, gonadal germ cell tumors, ocular cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, occult primary and metastatic squamous cell carcinoma of the neck. Midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and sinus carcinoma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, parathyroid carcinoma, penile cancer, pharyngeal cancer, pleural pulmonary blastoma, primary central nervous system (CNS) cancer. Lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.

[0353] In some embodiments, the cancer is a hematologic malignancy, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendiceal cancer, or pancreatic cancer. In one embodiment, the cancer is pancreatic cancer, lung cancer, or colon cancer. Lung cancer may be adenocarcinoma, non-small cell lung cancer (NSCLC), or small cell lung cancer (SCLC). In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is lung adenocarcinoma.

[0354] The methods described herein can also be used to test samples from patients for the presence of KRas prior to administration of the solid form or pharmaceutical composition described herein. G12D Mutation. In one embodiment, KRas was found to be present in a patient sample. G12D Following the mutation, the patient is administered either a solid form or a pharmaceutical composition. In one embodiment, this is unless the patient sample contains KRas. G12D Mutation, otherwise do not administer the solid form or pharmaceutical composition described herein to the patient.

[0355] In one embodiment, the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In another embodiment, the cancer is histologically undetermined (including KRas). G12D (Mutation). In one such embodiment, pancreatic cancer, lung cancer, or colorectal cancer contains KRas. G12D mutation.

[0356] This article further provides treatment options including KRas in patients with this type of lung cancer. G12D A method for treating mutated lung cancer. In one such embodiment, a treatment comprising KRas is provided in a patient suffering from such lung cancer. G12D A method (M1) for treating mutated lung cancer, comprising administering to a patient an effective amount of the solid form or pharmaceutical composition described herein. In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In one embodiment, the lung cancer is adenocarcinoma, NSCLC, squamous cell lung cancer (SCLC), or large cell lung cancer. In another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is adenoma, carcinoid tumor, or undifferentiated carcinoma. The lung cancer may be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer. The method provided herein includes administering the compound as a first-line (1L) therapy.

[0357] This article further provides information on the treatment of patients with this type of pancreatic cancer, including those with KRas. G12D A method for treating mutated pancreatic cancer. In one such embodiment, a treatment comprising KRas is provided in a patient with pancreatic cancer.G12D A method (M2) for mutated pancreatic cancer, comprising administering to a patient an effective amount of the solid form or pharmaceutical composition described herein. In one embodiment, the patient has previously received radiation therapy and one or more chemotherapy agents. In one embodiment, the pancreatic cancer is stage 0, I, or II. In another embodiment, the pancreatic cancer is stage III or IV.

[0358] This article further provides information on treatments involving KRas in patients with this type of colon cancer. G12D A method for treating mutated colon cancer. In one such embodiment, a treatment containing KRas is provided in a patient suffering from this disease. G12D A method (M3) for treating mutated colon cancer, comprising administering to a patient an effective amount of the solid form or pharmaceutical composition described herein. In one embodiment, the colon cancer is stage I or II. In another embodiment, the colon cancer is stage III or IV.

[0359] In one embodiment of the methods M1, M2, and M3 described herein, the method further includes: (a) Determining the presence or absence of the KRasG12D mutation in samples taken from patients with a suspected diagnosis of cancer; and (b) Administer to the patient an effective amount of the solid form or pharmaceutical composition described herein.

[0360] This article further provides a method for treating tissue-unknown cancers containing KRasG12D mutations. In one embodiment of such a method, the method includes: (a) Determining the presence or absence of the KRasG12D mutation in samples taken from patients with a suspected diagnosis of cancer; and (b) Administer to the patient an effective amount of the solid form or pharmaceutical composition described herein.

[0361] In one embodiment of such a method, the patient is diagnosed with the cancer described herein. In another embodiment of such a method, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is collected before any treatment is administered. In another such embodiment, the sample is collected before administration of the solid form or pharmaceutical composition described herein and after administration of another chemotherapeutic agent. In yet another embodiment of such a method, the solid form or pharmaceutical composition described herein is administered as provided herein (e.g., orally or intravenously).

[0362] This document also provides the solid form or pharmaceutical composition described herein for use as a therapeutically active substance. In one such embodiment, the solid form or pharmaceutical composition may be used to contain Kras.G12D Therapeutic treatments for mutated cancers.

[0363] This document further provides the solid form or pharmaceutical composition described herein for containing KRas. G12D Therapeutic and / or preventative treatments for mutated cancers. In one embodiment, a solid form or pharmaceutical composition is used to prepare a drug containing KRas. G12D Therapeutic treatments for mutated cancers. This article further provides the use of the solid forms or pharmaceutical compositions described herein in the manufacture of medicaments for inhibiting tumor metastasis.

[0364] This document further provides a method for inhibiting tumor metastasis, the method comprising administering a therapeutically effective amount of the solid form or pharmaceutical composition described herein to a patient suffering from a tumor. In one embodiment, inhibition is targeted at KRas... G12D Mutated tumors. In another embodiment, the inhibition of tumor metastasis in a patient, as described herein, results in a reduction in tumor size. In another embodiment, the inhibition of tumor metastasis in the patient described herein results in a stable tumor size (e.g., no further growth). In yet another embodiment, the inhibition of tumor metastasis in a patient, as described herein, results in a reduction of cancer and / or its symptoms.

[0365] This document further provides a method for inhibiting cell population proliferation, the method comprising contacting the cell population with a solid form or pharmaceutical composition described herein. In one embodiment, the cell population is in a human patient. In another embodiment, the cell population comprises KRas G12D mutation.

[0366] This document further provides a method for inhibiting KRas in a patient requiring treatment, comprising administering to the patient a therapeutically effective amount of the solid form or pharmaceutical composition described herein. In one embodiment, the inhibited KRas is KRas G12D In another embodiment, inhibition of KRas leads to a reduction in tumor size. In yet another embodiment, inhibition of KRas leads to relief of cancer and / or its symptoms.

[0367] This document further provides a method for modulating the activity of a KRas mutant protein, the method comprising reacting the mutant protein with a solid form or pharmaceutical composition described herein. In one embodiment, the mutant protein comprises KRas. G12DMutation. In one embodiment, the activity of KRas is reduced upon contact with the solid form or pharmaceutical composition described herein. In another embodiment, downregulation of the activity of the KRas mutant protein treats the cancer described herein in a patient. In another embodiment, downregulation of the activity of the KRas mutant protein results in a reduction in tumor size. In yet another embodiment, downregulation of the activity of the KRas mutant protein results in relief of the cancer and / or its symptoms described herein.

[0368] In some embodiments, the method provided herein includes making cells react with KRas sufficient to inhibit KRas in the cells. G12D The active amount of the solid form or pharmaceutical composition described herein contacts, thereby inhibiting KRas in cells. G12D Activity. In some embodiments, the method provided herein includes reacting tissue with an agent sufficient to inhibit KRas activity in the tissue. G12D The active amount of the solid form or pharmaceutical composition described herein comes into contact with the tissue to inhibit KRas. G12D Activity. In some embodiments, the method provided herein includes subjecting the patient described herein to KRas activity sufficient to inhibit KRas in the patient. G12D The active amount of the solid form or pharmaceutical composition described herein is contacted to inhibit KRas in the patient. G12D active.

[0369] This article further provides KRas for the preparation of labeled markers. G12D A method for mutating proteins, which includes making KRas G12D The mutant protein reacts with the labeled solid form or pharmaceutical composition described herein to produce labeled KRas. G12D Mutant protein. In one embodiment, the marker is an imaging agent. In another embodiment, the labeled KRas G12D It can be used to detect whether G12D mutated KRas are present or absent in patient samples, thereby detecting whether cancer mediated by mutated KRas is present or absent.

[0370] This document further provides methods for inhibiting Ras-mediated cell signaling. In one embodiment, the method comprises contacting cells with an effective amount of the solid form or pharmaceutical composition disclosed herein. Inhibition of Ras-mediated signal transduction can be evaluated and demonstrated in a variety of ways known in the art. Non-limiting examples include showing (a) decreased GTPase activity of Ras; (b) decreased GTP-binding affinity or increased GDP-binding affinity; (c) increased K-off of GTP or decreased K-off of GDP; (d) decreased levels of downstream signaling molecules in the Ras pathway, such as decreased pMEK levels; and / or (e) decreased binding of the Ras complex to downstream signaling molecules (including, but not limited to, Raf). Kits and commercially available assays can be used to determine one or more of the above.

[0371] KRas mutations, including the G12D mutant, have also been identified in hematologic malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, some embodiments involve administering the solid form or pharmaceutical composition described herein to a patient requiring treatment for a hematologic malignancy. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the currently disclosed compounds can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, the compounds described herein or pharmaceutically acceptable salts thereof can be used to treat lymphomas, such as Hodgkin lymphoma or all subtypes of non-Hodgkin lymphoma.

[0372] Whether a tumor or cancer contains KRas can be determined by evaluating the nucleotide sequence encoding the KRas protein, evaluating the amino acid sequence of the KRas protein, or evaluating the characteristics of hypothetical KRas mutant proteins. G12D Mutation. The sequence of wild-type human KRas (e.g., accession number NP203524) is known in the art.

[0373] Methods for detecting mutations in the KRas nucleotide sequence are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting assay, and microarray analysis. In some embodiments, the G12d KRas mutation in a sample is assessed by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRas G12D mutation is used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRas G12D mutation is identified using direct sequencing of specific regions in the KRas gene (e.g., exon 2 and / or exon 3). This technique will identify all possible mutations in the sequenced region.

[0374] Used to determine whether a tumor or cancer contains KRas. G12D Mutation methods can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed into cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0375] This document further provides the use of the solid form or pharmaceutical composition described herein in the manufacture of a medicament for treating cancer. In some embodiments, the medicament is formulated for oral administration. In some embodiments, the medicament is formulated for injection (e.g., IV administration). In some embodiments, the cancer comprises KRas G12D Mutation. In some embodiments, the cancer is a hematologic cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the use of the compounds described herein, or stereoisomers, transisomers, tautomers, or pharmaceutical salts thereof, is provided in the manufacture of a medicament for inhibiting tumor metastasis.

[0376] Combination therapy The solid forms and pharmaceutical compositions described herein can be used alone or in combination with other therapeutic agents to treat the diseases or conditions described herein. The second agent in a pharmaceutical combination formulation or dosing regimen preferably has an activity complementary to that of the solid forms or pharmaceutical compositions described herein, such that they do not adversely affect each other. Combination therapy can provide a “synergistic effect” and is proven to be “synergistic,” meaning that the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by using them alone.

[0377] Combination therapy can be administered simultaneously or sequentially. When administered sequentially, the composition may be administered two or more times. Combination administration includes the combined administration of individual formulations or single-drug formulations, as well as sequential administration in any order, wherein preferably, both (or all) of the active agents exert their biological activity simultaneously over a period of time.

[0378] The combination therapy described herein comprises the administration of the solid form or pharmaceutical composition described herein, and the use of at least one other treatment method. The amounts of the solid form or pharmaceutical composition described herein and the relative timing of administration of the other pharmaceutically active agents will be selected to achieve the desired combination therapeutic effect.

[0379] In various embodiments of this method, additional therapeutic agents are epidermal growth factor receptor (EGFR) inhibitors, phosphatidylinositol kinase (PI3K) inhibitors, insulin-like growth factor receptor (IGF1R) inhibitors, Janus kinase (JAK) inhibitors, Met kinase inhibitors, SRC family kinase inhibitors, mitogen-activated protein kinase (MEK) inhibitors, extracellular signal-regulated kinase (ERK) inhibitors, topoisomerase inhibitors (such as irinotecan, or such as etoposide, or such as doxorubicin), taxanes (such as antimicrotubule agents, including paclitaxel and docetaxel), antimetabolites (such as 5-FU or gemcitabine), or alkylating agents (such as cisplatin or cyclophosphamide), or taxanes.

[0380] In some embodiments, additional therapeutic agents are epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib or afatinib. In some embodiments, additional therapeutic agents are gefitinib, osimertinib, or dacomitinib. In some embodiments, additional therapeutic agents are monoclonal antibodies, such as cetuximab (Erbitux) or panitumumab (Vectibix). In some embodiments, the GFR inhibitor is a dual or all-HER inhibitor. In other embodiments, additional therapeutic agents are phosphatidylinositol-3-kinase (PI3K) inhibitors, such as GDC-0077, GDC-0941, MLN1117, BYL719 (alpelisib), or BKM120 (buparlisib). GDC-0941 refers to 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine or its salts (e.g., dimethylsulfonate).

[0381] In other embodiments, the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor. For example, in some embodiments, the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541. In other embodiments, the additional therapeutic agent is IGOSI-906 (Linsitinib), BMS-754807, or in other embodiments, the additional therapeutic agent is a neutralizing monoclonal antibody specific to IGF1R, such as AMG-479 (ganitumab), CP-751,871 (figitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), or R-1507 (robatumumab).

[0382] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor. In some embodiments, the additional therapeutic agent is CYT387, GLPG0634, baricitinib, lettaurtinib, momelotinib, paccitinib, ruxolitinib, or TG101348.

[0383] In some other embodiments, an additional therapeutic agent is an anti-glypican 3 antibody. In some embodiments, the anti-glypican 3 antibody is codrituzumab.

[0384] In some other embodiments, the additional therapeutic agent is an antibody-drug conjugate (ADC). In some embodiments, the ADC is polotuzumab vedoti, RG7986, RG7882, RG6109, or RO7172369.

[0385] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist. In some embodiments, the MDM2 antagonist is idasanutlin.

[0386] In some other embodiments, an additional therapeutic agent is an anti-CD40 agonist antibody. In some embodiments, the anti-CD40 agonist antibody is selicrelumab (RG7876).

[0387] In some other embodiments, the additional therapeutic agent is a bispecific antibody. In some embodiments, the bispecific antibody is RG7828 (BTCT4465A), RG7802, RG7386 (FAP-DR5), RG6160, RG6026, ERY974, or anti-HER2 / CD3.

[0388] In some other embodiments, the additional therapeutic agent is a targeted immune cytokine. In some embodiments, the targeted immune cytokine is RG7813 or RG7461.

[0389] In some other embodiments, the additional therapeutic agent is an antibody that targets the colony-stimulating factor-1 receptor (CSF-1R). In some embodiments, the (CSF-1R) antibody is emactuzumab.

[0390] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine. In some embodiments, the personalized cancer vaccine is RG6180.

[0391] In some other embodiments, the additional therapeutic agent is an inhibitor of BET (bromodomain and terminal exofamily) proteins (BRD2 / 3 / 4 / T). In some embodiments, the BET inhibitor is RG6146.

[0392] In some other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT. In some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0393] In some other embodiments, the additional therapeutic agent is a selective estrogen receptor degrader (SERD). In some other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545, giredestrant).

[0394] In some other embodiments, additional therapeutic agents are MET kinase inhibitors, such as crizotinib, tivantinib, AMG337, cabozantinib, or foretinib. In other embodiments, additional therapeutic agents are MET-neutralizing monoclonal antibodies, such as onartuzumab.

[0395] In more embodiments, the additional therapeutic agent is an SRC family non-receptor tyrosine kinase inhibitor. For example, in some embodiments, the additional therapeutic agent is an inhibitor of a subfamily of SRC family non-receptor tyrosine kinases. Exemplary inhibitors in this regard include dasatinib. Other examples in this regard include ponatinib, saracatinib, and bosutinib.

[0396] In some other embodiments, the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor. In some of these embodiments, the MEK inhibitor is trametinib, selumetinib, COTELLIC®, PD0325901, or RO5126766. In other embodiments, the MEK inhibitor is GSK-1120212, also known as trametinib.

[0397] In some other embodiments, the additional therapeutic agent is an extracellular signal-regulated kinase (ERK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is SCH722984 or GDC-0994.

[0398] In other embodiments, the protein kinase inhibitor is taselisib, ipatasertib, GDC-0575, GDC-5573 (HM95573), RG6114 (GDC-0077), CKI27, afatinib, axitinib, atezolizumab, bevacizumab, bosutinib, cetuximab, crizotinib, dasatinib, nilotinib, fantatinib, gefitinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pilgatanib sodium, ranibumab, ruxotinib, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, or vemurafenib. In many other embodiments, an additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is irinotecan. In some other embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include paclitaxel and docetaxel.

[0399] In addition to the other therapeutic agents described above, other chemotherapeutic agents are currently known in the art and can be used in combination with the solid forms and pharmaceutical compositions described herein. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0400] Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Cascade® (bicalutamide), Iressa® (gefitinib), and doxorubicin, as well as a range of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; azacyclopropane derivatives such as benzodopa, carboquone, meturedopa, and uredopa; ethylene imine and methylamelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, and triethylenethiophosphaoramide. Trimethylolmelamine; nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, estradiol, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novobichin, phenesterine, prednimustine, trofosfamide, uracil mustard; and nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine.Antibiotics, such as aclacinomysins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin C, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycins, dactinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, and mycophenolic acid. The following are listed as potential drug derivatives: nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, and trimetrexate; and purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine.Pyrimidine analogues, such as ancitabine, azacitidine, 6-azaguanidine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and fluxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenergics, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as frolinicacid; aceglatone; and aldophosphamide. glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; londamine; mitoguazone; mitoxantrone; mopidamol; nitraerine; pentostatin; phenamet; pirarubicin; podophyllinic acid acid); 2-ethylhydrazine; procarbazine; polysaccharide K; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethan; vindesine;Dacarbazine; mannomustine; mitobronitol; mitolactalol; piperobroman; gacytosine; cytarabine (“Ara-C”); cyclophosphamide; thiotepa; taxanes, for example, paclitaxel (TAXOL); TM (Bristol-Myers Squibb Oncology, Princeton, NJ) and TAXOTERE TMRhone-Poulenc Rorer, Antony, France); retinoids; esperamicins; capecitabine; and any of the above-mentioned medicinal salts, acids, or derivatives. Also included as suitable chemotherapeutic cell modulators are antihormonal agents that regulate or inhibit hormonal effects on tumors, such as antiestrogens, including, for example, tamoxifen (Nolvadex™), raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene; and antiandrogens, such as flutamide, nilutamide, bicalutamide, and leuprolide. And goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda®; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS2000; and difluoromethylornithine (DFMO). Where necessary, compounds described herein, or their pharmaceutical salts or pharmaceutical compositions, may be used in combination with commonly prescribed anticancer drugs, such as Herceptin®, Avastin®, Gazyva®, Tecentriq®, Alecensa®, Perjeta®, Venclexta™, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-aminopyridine-2-carboxymethylthiosqualide, Amonafide, Anthracenedione, and anti-CD22.Immunotoxins, antitumor drugs, antitumor herbal remedies, apaziquone, atiprimod, azathioprine, beloteccan, bendamustine, BIBW 2992, Biricodar, brostallicin, bryostatin, sulfonyl butyrate, CBV (chemotherapy), Calyculin, cell cycle nonspecific antitumor drugs, dichloroacetic acid, Discodermolide, elsamitrucin, enocitabine, epochhilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE Chemotherapy regimens, IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, proteasome inhibitors, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinomycin A, Sapacitabine, Stanford V, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel, Triplatinum Tetranitrate, Tri(2-chloroethyl)amine, Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126, or Tariquidar(Zosuquidar).

[0401] The exact method of administering the solid form or pharmaceutical composition along with other therapeutic agents will be apparent to those skilled in the art. In some exemplary embodiments, the solid form or pharmaceutical composition thereof and other therapeutic agents are administered together. In other embodiments, the solid form or pharmaceutical composition and other therapeutic agents are administered alone.

[0402] In some embodiments, a solid form or pharmaceutical composition and an additional therapeutic agent are administered simultaneously or separately with a second agent. Such combined administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the solid form or pharmaceutical composition and any of the other therapeutic agents described herein may be formulated together in the same dosage form and administered simultaneously. Alternatively, the solid form or pharmaceutical composition and any of the other therapeutic agents described herein may be administered simultaneously, wherein both agents are present in separate formulations. In another alternative, the solid form or pharmaceutical composition may be administered immediately after the administration of any of the other therapeutic agents described herein, or vice versa. In some embodiments of the separate administration regimen, the solid form or pharmaceutical composition and any of the other therapeutic agents described herein may be administered minutes, hours, or days apart.

[0403] Products This document also provides articles or “kits” containing materials that can be used to treat the cancers described herein. In one embodiment, the kit comprises a container containing the solid form or pharmaceutical composition described herein. The kit may also include a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. Containers can be formed from a variety of materials, such as glass or plastic. The container can contain the solid form or pharmaceutical composition described herein (which is effective for treating the condition) and may have a sterile access point (e.g., the container may be an intravenous solution bag or vial with a stopper that can be punctured through a subcutaneous needle). At least one active agent in the container is the solid form or pharmaceutical composition described herein. Optionally or additionally, the article may also include a second container containing a pharmaceutical diluent, such as sterile water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextran solution. It may further include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0404] In another embodiment, the kit is suitable for delivering the solid form or solid oral form of the pharmaceutical composition described herein, such as tablets or capsules. Such kits may include a number of unit doses. One example of such kits is blister packaging. Blister packaging is well known in the packaging industry and is widely used for packaging unit dosage forms of pharmaceuticals.

[0405] Enumerated Examples Example 1. An anhydrous crystalline form comprising a compound of formula (I): (I).

[0406] Example 2. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form J, characterized by essentially the XRPD diagram shown in FIG1.

[0407] Example 3. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form J, characterized by a thermogravimetric analysis (TGA) chromatogram showing a weight loss of approximately 2.6% at temperatures up to 180°C.

[0408] Example 4. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form J, characterized by a differential scanning calorimetry (DSC) thermogram containing at least one endothermic peak at about 110°C, about 138°C, or about 178°C.

[0409] Example 5. The anhydrous crystalline form according to Example 4, wherein the anhydrous crystalline form is form J, characterized in that the DSC thermogram contains endothermic peaks at approximately 110°C, approximately 138°C and approximately 178°C.

[0410] Example 6. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form J, characterized by two or more of the following: a. Basically, the XRPD diagram is shown in Figure 1; b. TGA thermograms show a weight loss of approximately 2.6% when the temperature is increased up to 180°C; and c. The DSC thermogram contains at least one endothermic peak at about 110 °C, about 138 °C, or about 178 °C.

[0411] Example 7. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form J, characterized by two or more of the following: a. Basically, the XRPD diagram is shown in Figure 1; b. TGA thermograms show a weight loss of approximately 2.6% when the temperature is increased up to 180°C; and c. The DSC thermogram contains endothermic peaks at approximately 110°C, approximately 138°C, and approximately 178°C.

[0412] Example 8. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form O, characterized by essentially the XRPD diagram shown in FIG2.

[0413] Example 9. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form O, characterized in that the TGA thermogram shows a weight loss of approximately 3.1% at temperatures up to 180°C.

[0414] Example 10. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form O, characterized in that the DSC thermogram contains at least one endothermic peak at about 70°C or about 195°C.

[0415] Example 11. The anhydrous crystalline form according to Example 10, wherein the anhydrous crystalline form is form O, characterized in that the DSC thermogram contains endothermic peaks at about 70°C and about 195°C.

[0416] Example 12. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form O, characterized by two or more of the following: a. Basically, the XRPD diagram is shown in Figure 2; b. TGA thermograms show a weight loss of approximately 3.1% when the temperature is increased up to 180°C; and c. The DSC thermogram contains at least one endothermic peak at about 70 °C or about 195 °C.

[0417] Example 13. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form O, characterized by two or more of the following: a. Basically, the XRPD diagram is shown in Figure 2; b. TGA thermograms show a weight loss of approximately 3.1% when the temperature is increased up to 180°C; and c. The DSC thermogram contains endothermic peaks at approximately 70 °C and approximately 195 °C.

[0418] Example 14. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form U, characterized by essentially the XRPD diagram shown in FIG3.

[0419] Example 15. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form U, characterized in that the TGA thermogram shows a weight loss of approximately 1.3% at temperatures up to 190°C.

[0420] Example 16. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form U, characterized in that the DSC thermogram contains an endothermic peak at approximately 205°C.

[0421] Example 17. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form U, characterized by two or more of the following: a. Basically, the XRPD diagram is shown in Figure 3; b. TGA thermograms show a weight loss of approximately 1.3% when the temperature is increased up to 190°C; and c. The DSC thermogram contains an endothermic peak at approximately 205 °C.

[0422] Example 18. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AC, characterized by essentially the XRPD diagram shown in FIG4.

[0423] Example 19. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AC, characterized in that the TGA thermogram shows a weight loss of approximately 2.3% at temperatures up to 160°C.

[0424] Example 20. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AC, characterized in that the DSC thermogram contains an endothermic peak at approximately 163°C.

[0425] Example 21. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AC, characterized by two or more of the following: a. Basically, the XRPD diagram is shown in Figure 4; b. TGA thermograms show a weight loss of approximately 2.3% when the temperature is increased up to 160°C; and c. The DSC thermogram contains an endothermic peak at approximately 163 °C.

[0426] Example 22. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AG, characterized in that the XRPD plot contains characteristic peaks at approximately 19.3 ± 0.2, 13.1 ± 0.2, and 15.4 ± 0.2 degrees 2θ.

[0427] Example 23. The anhydrous crystalline form according to Example 22, wherein the XRPD plot further includes at least one additional characteristic peak selected from the group consisting of approximately 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

[0428] Example 24. The anhydrous crystalline form according to Example 22, wherein the XRPD plot further includes characteristic peaks at approximately 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

[0429] Example 25. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AG, characterized in that the XRPD plot contains at least 15 peaks as shown in Table 39.

[0430] Example 26. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AG, characterized by essentially the XRPD pattern shown in FIG5A.

[0431] Example 27. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AG, characterized in that the TGA thermogram shows a weight loss of approximately 1.1% at temperatures up to 180°C.

[0432] Example 28. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AG, characterized by a TGA thermogram as shown in FIG5B.

[0433] Example 29. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AG, characterized in that the DSC thermogram contains an endothermic peak at approximately 219°C.

[0434] Example 30. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AG, characterized by a DSC thermogram substantially as shown in FIG5B.

[0435] Example 31. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AG, characterized by a dynamic vapor adsorption (DVS) diagram substantially as shown in FIG5C.

[0436] Example 32. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AG, characterized by a scanning electron microscope (SEM) micrograph as shown in FIG5D.

[0437] Example 33. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AG, characterized by two or more of the following: a. The XRPD plot contains characteristic peaks at approximately 19.3 ± 0.2, 13.1 ± 0.2, and 15.4 ± 0.2 degrees 2θ; b. TGA thermograms show a weight loss of approximately 1.1% at 180°C; c. The DSC thermogram contains an endothermic peak at approximately 219 °C; d. Essentially, the dynamic vapor adsorption (DVS) diagram is shown in Figure 5C; and e. Essentially a scanning electron microscope (SEM) photomicrograph as shown in Figure 5D.

[0438] Example 34. The anhydrous crystalline form according to Example 1, wherein the anhydrous crystalline form is form AG, characterized by two or more of the following: a. Basically, the XRPD diagram shown in Figure 5A; b. Essentially, the TGA thermogram is shown in Figure 5B; c. Essentially, the DSC thermogram is shown in Figure 5B; d. Essentially, the DVS diagram is shown in Figure 5C; and e. Essentially, the SEM micrograph shown in Figure 5D.

[0439] Example 35. A pharmaceutical composition comprising an anhydrous crystalline form according to any one of Examples 1 to 34 and at least one pharmaceutically acceptable excipient.

[0440] Example 36. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the anhydrous crystalline form of any one of Examples 1 to 34 or the pharmaceutical composition of Example 35.

[0441] Example 37. The method according to Example 36, wherein the cancer is characterized by a KRas mutation.

[0442] Example 38. The method according to Example 37, wherein the KRas mutation corresponds to KRas G12D mutation.

[0443] Example 39. The method according to any one of Examples 36 to 38, further comprising testing the sample from the subject for the presence of KRas prior to administration. G12D mutation.

[0444] Example 40. The method according to Example 39, wherein KRas is shown in the patient sample. G12D After the mutation, the crystalline form is administered to the patient.

[0445] Example 41. The method according to any one of Examples 36 to 40, wherein the cancer is tissue-agnostic.

[0446] Example 42. The method according to any one of Examples 36 to 40, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0447] Example 43. The method according to Example 42, wherein the cancer is lung cancer.

[0448] Example 44. The method according to Example 43, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.

[0449] Example 45. The method according to Example 42, wherein the cancer is pancreatic cancer.

[0450] Example 46. The method according to Example 42, wherein the cancer is colorectal cancer.

[0451] Example 47. The method according to any one of Examples 36 to 46, further comprising administering at least one additional therapeutic agent.

[0452] Example 48. The method according to Example 47, wherein at least one additional therapeutic agent is selected from epidermal growth factor receptor (EGFR) inhibitors, phosphatidylinositol kinase (PI3K) inhibitors, insulin-like growth factor receptor (IGF1R) inhibitors, Janus kinase (JAK) inhibitors, Met kinase inhibitors, SRC family kinase inhibitors, mitogen-activated protein kinase (MEK) inhibitors, extracellular signal-regulated kinase (ERK) inhibitors, topoisomerase inhibitors, taxanes, antimetabolites, or alkylating agents.

[0453] Example 49. A method for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with an anhydrous crystalline form according to any one of Examples 1 to 34 or a pharmaceutical composition according to Example 35.

[0454] Example 50. A method for inhibiting cell population proliferation, comprising contacting the cell population with an anhydrous crystalline form according to any one of Examples 1 to 34 or a pharmaceutical composition according to Example 35.

[0455] Example 51. The method of Example 50, wherein proliferation inhibition is measured by a decrease in cell viability of a cell population.

[0456] Example 52. A method for inhibiting tumor metastasis in a subject, comprising administering to the subject a therapeutically effective amount of the anhydrous crystalline form of any one of Examples 1 to 34 or the pharmaceutical composition of Example 35.

[0457] Example 53. The anhydrous crystalline form of the compound of formula (I) according to any one of Examples 1 to 34 or the pharmaceutical composition according to Example 35, for the treatment of cancer.

[0458] Example 54. Use of the anhydrous crystalline form of the compound of formula (I) according to any one of Examples 1 to 34 or the pharmaceutical composition according to Example 35 for the treatment of cancer.

[0459] Example 55. Use of the anhydrous crystalline form of the compound of formula (I) according to any one of Examples 1 to 34 or the pharmaceutical composition according to Example 35 in the manufacture of a medicament for treating cancer.

[0460] Example II-1. A solid form of a compound of formula (I): (I), The solid form is: Crystallization polymorph J; Crystallization polymorphism N; Crystallization polymorphic form O; or AG is a polycrystalline form.

[0461] Example II-2. The solid form according to Example II-1, wherein the solid form is a crystalline polymorphic form AG.

[0462] Example II-3. The solid form according to Example II-2, wherein the solid form is form AG, characterized in that the XRPD plot contains a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least two peaks selected from the group consisting of 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

[0463] Example II-4. A solid form according to Example II-2 or II-3, wherein the solid form is form AG, characterized in that the XRPD plot contains a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least three peaks selected from the group consisting of 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

[0464] Example II-5. A solid form according to any one of Examples II-2 to II-4, wherein the solid form is form AG, characterized in that the XRPD plot contains a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least four peaks selected from the group consisting of 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

[0465] Example II-6. A solid form according to any one of Examples II-2 to II-5, wherein the solid form is form AG, characterized in that the XRPD plot contains a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least five, at least six, at least seven, or at least eight peaks selected from the group consisting of 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.

[0466] Example II-7. The solid form according to Example II-2 or II-3, wherein the solid form is form AG, characterized in that the XRPD diagram includes: The peaks at approximately 13.1 ± 0.2 degrees 2θ and at approximately 19.3 ± 0.2 degrees 2θ; and Select at least one peak from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

[0467] Example II-8. A solid form according to any one of Examples II-2 to II-4 or II-7, wherein the solid form is form AG, characterized in that the XRPD diagram comprises: The peaks at approximately 13.1 ± 0.2 degrees 2θ and at approximately 19.3 ± 0.2 degrees 2θ; and Select at least two peaks from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

[0468] Example II-9. A solid form according to any one of Examples II-2 to II-5, II-7 or II-8, wherein the solid form is form AG, characterized in that the XRPD diagram comprises: The peaks at approximately 13.1 ± 0.2 degrees 2θ and at approximately 19.3 ± 0.2 degrees 2θ; and Select at least three peaks from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

[0469] Example II-10. A solid form according to any one of Examples II-2 to II-9, wherein the solid form is form AG, characterized in that the XRPD diagram comprises: The peaks at approximately 13.1 ± 0.2 degrees 2θ and at approximately 19.3 ± 0.2 degrees 2θ; and Select at least four, at least five, at least six, or at least seven peaks from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.

[0470] Example II-11. The solid form according to Example II-2 or II-3, wherein the solid form is form AG, characterized in that the XRPD diagram includes: Select at least two peaks from the group consisting of 13.1 ± 0.2, 19.3 ± 0.2, and 15.4 ± 0.2 degrees 2θ; and Select at least one peak from the group consisting of 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

[0471] Example II-12. The solid form according to Example II-2, wherein the solid form is form AG, characterized in that the XRPD plot contains characteristic peaks at approximately 19.3 ± 0.2, 13.1 ± 0.2, and 15.4 ± 0.2 degrees 2θ.

[0472] Example II-13. The solid form according to Example II-12, wherein the XRPD plot further includes at least one additional characteristic peak selected from the group consisting of approximately 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

[0473] Example II-14. The solid form according to Example II-12, wherein the XRPD plot further includes characteristic peaks at approximately 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

[0474] Example II-15. A solid form according to any one of Examples II-2 to II-8, wherein the solid form is form AG, characterized in that the XRPD diagram comprises: Peaks at approximately 13.1 ± 0.2, 19.3 ± 0.2, and 15.4 ± 0.2 degrees 2θ; and Select at least two, at least three, at least four, or at least five peaks from the group consisting of 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.

[0475] Example II-16. A solid form according to any one of Examples II-2 to II-9, wherein the solid form is form AG, characterized in that the XRPD diagram comprises: Peaks at approximately 13.1 ± 0.2, 19.3 ± 0.2, 15.4 ± 0.2 degrees 2θ, and 18.5 ± 0.2 degrees 2θ; and One or more peaks at approximately 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, or 10.7 ± 0.2 degrees 2θ.

[0476] Example II-17. The solid form according to any one of Examples II-2 to II-16, wherein the solid form is form AG, characterized in that the TGA thermogram shows a weight loss of about 1.1% at temperatures up to 180°C.

[0477] Example II-18. The solid form according to any one of Examples II-2 to II-17, wherein the solid form is form AG, characterized in that the DSC thermogram contains an endothermic peak at about 219°C.

[0478] Example II-19. The solid form according to any one of Examples II-2 to II-18, wherein the solid form is form AG, characterized by two or more of the following: a. The XRPD plot contains characteristic peaks at approximately 19.3 ± 0.2, 13.1 ± 0.2, and 15.4 ± 0.2 degrees 2θ; b. TGA thermograms show a weight loss of approximately 1.1% at 180°C; and c. The DSC thermogram contains an endothermic peak at approximately 219 °C; Example II-20. Solid form according to any one of Examples II-2 to II-19, wherein an XRPD spectrum is obtained using a Cu Kα source.

[0479] Example II-21. The solid form according to Example II-1, wherein the solid form is a crystalline polymorphic form J.

[0480] Example II-22. The solid form according to Example II-21, wherein the solid form is form J, characterized in that the XRPD diffraction pattern includes at least two XRPD peaks selected from the group consisting of approximately 16.4 ± 0.2, 6.8 ± 0.2, 18.9 ± 0.2, 15.6 ± 0.2, 9.4 ± 0.2, 18.2 ± 0.2, 8.42 ± 0.2, 13.7 ± 0.2, 8.8 ± 0.2 and 19.7 ± 0.2 degrees 2θ.

[0481] Example II-23. The solid form according to Example II-21, wherein the solid form is form J, characterized in that the XRPD diffraction pattern contains at least three XRPD peaks selected from the group consisting of about 16.4 ± 0.2, 6.8 ± 0.2, 18.9 ± 0.2, 15.6 ± 0.2, 9.4 ± 0.2, 18.2 ± 0.2, 8.4 ± 0.2, 13.7 ± 0.2, 8.8 ± 0.2 and 19.7 ± 0.2 degrees 2θ.

[0482] Example II-24. A solid form according to any one of Examples II-21 to II-23, wherein the solid form is form J, characterized in that the XRPD diffraction pattern comprises at least four XRPD peaks selected from the group consisting of about 16.4 ± 0.2, 6.8 ± 0.2, 18.9 ± 0.2, 15.6 ± 0.2, 9.4 ± 0.2, 18.2 ± 0.2, 8.4 ± 0.2, 13.7 ± 0.2, 8.8 ± 0.2 and 19.7 ± 0.2 degrees 2θ.

[0483] Example II-25. The solid form according to any one of Examples II-21 to II-24, wherein the solid form is form J, characterized in that the XRPD diffraction pattern comprises: XRPD peaks at 6.8±0.2 degrees 2θ and 8.8±0.2 degrees 2θ; and Select at least two XRPD peaks from the group consisting of approximately 16.4 ±0.2, 18.9 ±0.2, 15.6 ±0.2, 9.4 ±0.2, 18.2 ±0.2, 8.4 ±0.2, 13.7 ±0.2, and 19.7 ±0.2 degrees 2θ.

[0484] Example II-26. The solid form according to any one of Examples II-21 to II-25, wherein the solid form is form J, characterized in that the XRPD diffraction pattern comprises: XRPD peaks at 6.8±0.2 degrees 2θ and 8.8±0.2 degrees 2θ; and Select at least three XRPD peaks from the group consisting of approximately 16.4 ±0.2, 18.9 ±0.2, 15.6 ±0.2, 9.4 ±0.2, 18.2 ±0.2, 8.4 ±0.2, 13.7 ±0.2, and 19.7 ±0.2 degrees 2θ.

[0485] Example II-27. The solid form according to any one of Examples II-21 to II-26, wherein the solid form is form J, characterized in that the XRPD diffraction pattern comprises: XRPD peaks at 6.8±0.2 degrees 2θ and 8.8±0.2 degrees 2θ; and Select at least four XRPD peaks from the group consisting of approximately 16.4 ±0.2, 18.9 ±0.2, 15.6 ±0.2, 9.4 ±0.2, 18.2 ±0.2, 8.4 ±0.2, 13.7 ±0.2, and 19.7 ±0.2 degrees 2θ.

[0486] Example II-28. A solid form according to any one of Examples II-21 to II-27, wherein the solid form is form J, characterized in that the XRPD diffraction pattern contains the following XRPD peaks: 16.4 ±0.2, 6.8 ±0.2, 18.9 ±0.2, 15.6 ±0.2, 9.4 ±0.2, 18.2 ±0.2, 8.4 ±0.2, 13.7 ±0.2, 8.8 ±0.2, and 19.7 ±0.2 at 2θ.

[0487] Example II-29. A solid form according to any one of Examples II-21 to II-28, wherein the solid form is form J, characterized by a thermogravimetric analysis (TGA) thermogram showing a weight loss of approximately 2.6% at temperatures up to 180°C.

[0488] Example II-30. The solid form according to any one of Examples II-21 to II-29, wherein the solid form is form J, characterized by a differential scanning calorimetry (DSC) thermogram containing at least one endothermic peak at about 110°C, about 138°C, or about 178°C.

[0489] Example II-31. A solid form according to any one of Examples II-21 to II-30, wherein the solid form is form J, characterized by a differential DSC thermogram containing endothermic peaks at about 110°C, about 138°C and about 178°C.

[0490] Example II-32. The solid form according to any one of Examples II-21 to II-31, wherein the solid form is form J, characterized by two or more of the following: a. Basically, the XRPD diagram is shown in Figure 1; b. TGA thermograms show a weight loss of approximately 2.6% when the temperature is increased up to 180°C; and c. The DSC thermogram contains endothermic peaks at approximately 110°C, approximately 138°C, and approximately 178°C.

[0491] Example II-33. Solid form according to any one of Examples II-21 to II-32, wherein an XRPD spectrum is obtained using a Cu Kα source.

[0492] Example II-34. The solid form according to Example II-1, wherein the solid form is a crystalline polymorphic form O.

[0493] Example II-35. The solid form according to Example II-34, wherein the solid form is characterized in that the XRPD diffraction pattern includes at least two XRPD peaks selected from the group consisting of approximately 15.1 ± 0.2, 19.7 ± 0.2, 9.3 ± 0.2, 18.8 ± 0.2, 7.0 ± 0.2, 15.4 ± 0.2, 8.5 ± 0.2, 24.8 ± 0.2, 21.4 ± 0.2 and 15.9 ± 0.2 degrees 2θ.

[0494] Example II-36. The solid form according to Example II-34 or II-35, wherein the solid form is characterized in that the XRPD diffraction pattern comprises: XRPD peaks at approximately 15.1 ± 0.2, 19.7 ± 0.2, and 9.3 ± 0.2 degrees 2θ; and Select at least three additional peaks from the group consisting of approximately 18.8 ±0.2, 7.0 ±0.2, 15.4 ±0.2, 8.5 ±0.2, 24.8 ±0.2, 21.4 ±0.2 and 15.9 ±0.2 degrees 2θ.

[0495] Example II-37. The solid form according to any one of Examples II-34 to II-36, wherein the solid form is characterized by an XRPD diffraction pattern containing XRPD peaks at approximately 15.1 ±0.2, 19.7 ±0.2, 9.3 ±0.2, 18.8 ±0.2, 7.0 ±0.2, 15.4 ±0.2, 8.5 ±0.2, 24.8 ±0.2, 21.4 ±0.2, and 15.9 ±0.2 degrees 2θ.

[0496] Example II-38. The solid form according to any one of Examples II-34 to II-37, wherein the solid form is characterized by a TGA thermogram showing a weight loss of about 3.1% at temperatures up to 180°C.

[0497] Example II-39. The solid form according to any one of Examples II-34 to II-38, wherein the solid form is form O, characterized in that the DSC thermogram contains at least one endothermic peak at about 70°C or about 195°C.

[0498] Example II-40. The solid form according to any one of Examples II-34 to II-39, wherein the solid form is form O, characterized in that the DSC thermogram contains endothermic peaks at about 70°C and about 195°C.

[0499] Example II-41. The solid form according to Examples II-34 to II-40, wherein the solid form is form O, characterized by two or more of the following: a. XRPD peaks at approximately 15.1 ±0.2, 19.7 ±0.2, 9.3 ±0.2, 18.8 ±0.2, 7.0 ±0.2, 15.4 ±0.2, 8.5 ±0.2, 24.8 ±0.2, 21.4 ±0.2, and 15.9 ±0.2 degrees 2θ; b. TGA thermograms show a weight loss of approximately 3.1% when the temperature is increased up to 180°C; and c. The DSC thermogram contains endothermic peaks at approximately 70 °C and approximately 195 °C.

[0500] Example II-42. Solid form according to any one of Examples II-34 to II-41, wherein an XRPD spectrum is obtained using a Cu Kα source.

[0501] Example II-43. The solid form according to Example II-1, wherein the solid form is a crystalline polymorphic form N.

[0502] Example II-44. The solid form according to Example II-43, wherein the solid form is characterized in that the XRPD diffraction pattern contains at least two peaks selected from the group consisting of approximately 15.7 ±0.2, 16.1 ±0.2, 15.5 ±0.2, 19.6 ±0.2, 20.6 ±0.2, 24.0 ±0.2, 21.2 ±0.2, 5.7 ±0.2, 22.3 ±0.2 and 6.6 ± 0.2 degrees 2θ.

[0503] Example II-45. The solid form according to Example II-43 or II-44, wherein the solid form is characterized in that the XRPD plot contains at least three, at least four, at least five, at least six or at least seven peaks selected from the group consisting of approximately 15.7 ± 0.2, 16.1 ± 0.2, 15.5 ± 0.2, 19.6 ± 0.2, 20.6 ± 0.2, 24.0 ± 0.2, 21.2 ± 0.2, 5.7 ± 0.2, 22.3 ± 0.2 and 6.6 ± 0.2 degrees 2θ.

[0504] Example II-46. The solid form according to any one of Examples II-43 to II-45, wherein the solid form is characterized in that the XRPD diagram includes: Select at least one peak from the group consisting of approximately 15.7 ± 0.2, 16.1 ± 0.2, and 15.5 ± 0.2 degrees 2θ; and Select at least one, at least two, at least three, or at least four peaks from the group consisting of approximately 19.6 ± 0.2, 20.6 ± 0.2, 24.0 ± 0.2, 21.2 ± 0.2, 5.7 ± 0.2, 22.3 ± 0.2, and 6.6 ± 0.2 degrees 2θ.

[0505] Example II-47. The solid form according to any one of Examples II-43 to II-46, wherein the solid form is characterized by XRPD peaks at approximately 15.7 ± 0.2, 16.1 ± 0.2, 15.5 ± 0.2, 19.6 ± 0.2, 20.6 ± 0.2, 24.0 ± 0.2, 21.2 ± 0.2, 5.7 ± 0.2, 22.3 ± 0.2 and 6.6 ± 0.2 degrees 2θ.

[0506] Example II-48. The solid form according to any one of Examples II-43 to II-47, wherein the solid form is characterized by a TGA thermogram showing a weight loss of approximately 3.9% at temperatures up to 180°C.

[0507] Example II-49. The solid form according to any one of Examples II-43 to II-48, wherein the solid form is characterized in that the DSC thermogram contains at least one endothermic peak at about 60°C, about 131°C or about 172°C.

[0508] Example II-50. Solid form according to any one of Examples II-43 to II-49, wherein an XRPD spectrum is obtained using a Cu Kα source.

[0509] Example II-51. A pharmaceutical composition comprising a solid form according to any one of Examples II-1 to II-50 and at least one pharmaceutically acceptable excipient.

[0510] Example II-52. The pharmaceutical composition according to Example II-51, wherein the solid form is the solid form according to any one of Examples II-2 to II-20.

[0511] Example II-53. The pharmaceutical composition according to Example II-51, wherein the solid form is the solid form according to any one of Examples II-21 to II-33.

[0512] Example II-54. The pharmaceutical composition according to Example II-51, wherein the solid form is the solid form according to any one of Examples II-34 to II-42.

[0513] Example II-55. The pharmaceutical composition according to Example II-51, wherein the solid form is the solid form according to any one of Examples II-43 to II-50.

[0514] Example II-56. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition in solid form according to any one of Examples II-1 to II-50 or according to any one of Examples II-51 to II-55.

[0515] Example II-57. The method according to Example II-56, wherein the cancer is characterized by a KRas mutation.

[0516] Example II-58. The method according to Example II-57, wherein the KRas mutation corresponds to KRas G12D mutation.

[0517] Example II-59. The method according to any one of Examples II-56 to II-59, wherein the cancer is tissue-agnostic.

[0518] Example II-60. The method according to any one of Examples II-56 to II-59, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0519] Example II-61. A method for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with a solid form according to any one of Examples II-1 to II-50 or a pharmaceutical composition according to any one of Examples II-51 to II-56.

[0520] Example II-62. A method for inhibiting cell population proliferation, comprising contacting the cell population with a pharmaceutical composition in solid form according to any one of Examples II-1 to II-50 or according to any one of Examples II-51 to II-55.

[0521] Example II-63. The method according to Example II-62, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0522] Example II-64. A method for inhibiting tumor metastasis in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition in solid form according to any one of Examples II-1 to II-50 or according to any one of Examples II-51 to II-55.

[0523] Example II-65. A solid form of the compound of formula (I) according to any one of Examples II-1 to II-50, or a pharmaceutical composition according to any one of Examples II-51 to II-55, for the treatment of cancer.

[0524] Example II-66. Use of the solid form of the compound of formula (I) according to any one of Examples II-1 to II-50 or the pharmaceutical composition according to any one of Examples II-51 to II-55 for the treatment of cancer.

[0525] Example II-67. Use of the solid form of the compound of formula (I) according to any one of Examples II-1 to II-50 or the pharmaceutical composition according to any one of Examples II-51 to II-55 in the manufacture of a medicament for treating cancer.

[0526] Synthesis method This article provides an improved method for preparative formulations. (I) Methods for synthesizing compounds and intermediates that can be used in their synthesis (e.g., formula...). (A) (B) (H) and (Ha) compounds). Generally, the method provides an efficient synthetic route for preparing these compounds.

[0527] The methods disclosed herein offer several advantages. For example, in some embodiments, the methods of this disclosure utilize solvents that are relatively non-toxic, relatively inexpensive, and relatively benign from the perspectives of industrial hygiene, process safety, and environmental impact.

[0528] In some embodiments, sustainable alcohol solvents, such as methanol and ethanol, are used. Therefore, these aspects provide improved safety and significant cost savings.

[0529] In some embodiments, the methods disclosed herein significantly reduce the use of expensive reagents or materials (e.g., precious metal catalysts) in certain process steps, thereby significantly saving costs and reducing waste.

[0530] In some embodiments, the methods disclosed herein use relatively non-toxic reagents to reduce safety risks and costs.

[0531] Furthermore, in some embodiments, the methods of this disclosure allow for the use of significantly higher reactant concentrations in certain steps, thereby significantly improving process equipment efficiency and process throughput, as well as associated cost savings.

[0532] In some embodiments, the method of this disclosure eliminates the need for multiple chromatographic purification steps compared to known methods. Chromatographic purification steps require specialized and expensive process equipment, increase the number of required chemical operators, reduce throughput, and increase costs.

[0533] The method disclosed herein also eliminates the need for certain extraction steps using organic solvents and eliminates the need for multiple solvent stripping steps. Such improvements significantly reduce costs by reducing energy consumption, eliminating solvent handling and distillation steps, thereby eliminating the associated required process equipment and its operation, material handling needs, and industrial hygiene and environmental risks.

[0534] Compared with existing methods, the method disclosed herein also provides higher yield and purity.

[0535] Therefore, the discovery of the publicly disclosed method, as detailed in this paper, is a major advance in the field.

[0536] Formula (I) In one aspect, this disclosure provides a method for preparing a compound of formula (I).

[0537] In some embodiments, the method includes the following steps: a) React compound (A) with compound (B) to prepare compound (C): (A) (B) (C); b) Reacting compound (C) with one or more reagents to prepare compound (D): (D); c) Reacting compound (D) with an oxidizing agent to prepare compound (E): (E); d) Reacting compound (E) with compound (F) to prepare compound (G): (F) (G); e) Reacting compound (G) with compound (Ha) to prepare compound (Ja): (Ha) (Ja), where Boc is a tert-butyloxycarbonyl group; and f) React the compound of formula (Ja) with an acidic reagent to prepare the compound of formula (I).

[0538] In some embodiments, the conditions for steps (a) to (f) are illustrated herein by example.

[0539] In some embodiments, the method includes the following steps: a) Reacting compound (A) with compound (B) to prepare compound (C): (A) (B) (C); b) Reacting compound (C) with one or more reagents to prepare compound (D): (D); c) Reacting compound (D) with an oxidizing agent to prepare compound (E): (E); d) Reacting compound (E) with compound (F) to prepare compound (G): (F) (G); e) Reacting compound (G) with compound (H) to prepare compound (J): (H) (J); and f) React the compound of formula (J) with an acidic reagent to prepare the compound of formula (I).

[0540] In some embodiments, the conditions for steps (a) to (f) are illustrated herein by example.

[0541] Equation (I) – Step a) In some embodiments, step a) includes using an alkaline reagent. In some embodiments, the alkaline reagent comprises NaOt-Bu, NaH, or NaOt-Am. In some embodiments, the alkaline reagent comprises NaOt-Bu. In some embodiments, the alkaline reagent comprises NaH. In some embodiments, the alkaline reagent comprises NaOt-Am. In some embodiments, the alkaline reagent is NaOt-Bu, NaH, or NaOt-Am. In some embodiments, the alkaline reagent is NaOt-Bu. In some embodiments, the alkaline reagent is NaH. In some embodiments, the alkaline reagent is NaOt-Am.

[0542] In some embodiments, step a) includes using a solvent. In some embodiments, the solvent comprises NMP, THF, toluene, 2-MeTHF, MeCN, DCM, or a mixture thereof. In some embodiments, the solvent comprises a mixture of NMP and THF. In some embodiments, the solvent comprises NMP. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent comprises 2-MeTHF. In some embodiments, the solvent comprises MeCN. In some embodiments, the solvent comprises DCM. In some embodiments, the solvent is NMP, THF, toluene, 2-MeTHF, MeCN, DCM, or a mixture thereof. In some embodiments, the solvent is a mixture of NMP and THF. In some embodiments, the solvent is NMP. In some embodiments, the solvent is THF. In some embodiments, the solvent is toluene. In some embodiments, the solvent is 2-MeTHF. In some embodiments, the solvent is MeCN. In some embodiments, the solvent is DCM.

[0543] In some embodiments, step a) comprises crystallizing the compound of formula (C). In some embodiments, the compound of formula (C) is crystallized in an acidic solution. In some embodiments, the acidic solution is an aqueous solution of AcOH. In some embodiments, the acidic solution is an aqueous solution of 2% by weight of AcOH.

[0544] In some embodiments, step a) comprises using an alkaline reagent and solvent; and crystallizing the compound of formula (C). In some embodiments, step a) comprises using a mixture of NaOt-Bu and NMP and THF; and crystallizing the compound of formula (C) in an acidic solution. In some embodiments, step a) comprises using a mixture of NaOt-Bu and NMP and THF; and crystallizing the compound of formula (C) in an aqueous solution of 2 wt% AcOH.

[0545] In some embodiments, step a) includes the following: .

[0546] Equation (I) – Step b) In some embodiments, in step b), one or more reagents comprise a mixture of DIPEA and POCl3 or BOPCl. In some embodiments, in step b), one or more reagents comprise a mixture of POCl3 and DIPEA. In some embodiments, in step b), one or more reagents are a mixture of BOPCl and DIPEA. Those skilled in the art will understand that the role of POCl3 or BOPCl in step b) is as a dehydrating agent, which makes the 4-hydroxy group of formula (C) a better leaving group for the amine nucleophile; and the role of DIPEA is as a general base for removing the byproduct HCl.

[0547] In some embodiments, step b) includes using a solvent. In some embodiments, the solvent comprises MeCN, DCM, or a mixture thereof. In some embodiments, the solvent comprises MeCN. In some embodiments, the solvent comprises DCM. In some embodiments, the solvent is MeCN, DCM, or a mixture thereof. In some embodiments, the solvent is MeCN. In some embodiments, the solvent is DCM.

[0548] In some embodiments, step b) comprises crystallizing the compound of formula (D). In some embodiments, the compound of formula (D) is crystallized in a mixture of MeCN and water.

[0549] In some embodiments, in step b), one or more reagents are POCl3 and DIPEA; and step b) includes using a solvent and crystallizing the compound of formula (D). In some embodiments, in step b), one or more reagents are POCl3 and DIPEA; step b) includes using MeCN; and the compound of formula (D) is crystallized in a mixture of MeCN and water.

[0550] In some embodiments, step b) includes the following: .

[0551] Equation (I) – Step c) In some embodiments, in step c), the oxidant comprises H2O2 / Na2WO4. H2O, m-CPBA, or potassium persulfate complex salt (oxone) / RuCl3. In some embodiments, in step c), the oxidant comprises H2O2 / Na2WO4. H2O. In some embodiments, in step c), the oxidant comprises m-CPBA. In some embodiments, in step c), the oxidant comprises potassium persulfate complex salt / RuCl3. In some embodiments, in step c), the oxidant is H2O2 / Na2WO4. H2O, m-CPBA, or potassium persulfate complex salt (oxone) / RuCl3. In some embodiments, in step c), the oxidant is H2O2 / Na2WO4. H2O. In some embodiments, in step c), the oxidant is m-CPBA. In some embodiments, in step c), the oxidant is potassium persulfate / RuCl3.

[0552] In some embodiments, step c) includes using an additive. In some embodiments, the additive comprises PhP(O)(OH)2, KOAc, AcOH, KH2PO4, H3PO4, or DIPEA. In some embodiments, the additive comprises PhP(O)(OH)2. In some embodiments, the additive comprises KOAc. In some embodiments, the additive comprises AcOH. In some embodiments, the additive comprises KH2PO4. In some embodiments, the additive comprises H3PO4. In some embodiments, the additive comprises DIPEA. In some embodiments, the additive is PhP(O)(OH)2, KOAc, AcOH, KH2PO4, H3PO4, or DIPEA. In some embodiments, the additive is PhP(O)(OH)2. In some embodiments, the additive is KOAc. In some embodiments, the additive is AcOH. In some embodiments, the additive comprises KH2PO4. In some embodiments, the additive is H3PO4. In some embodiments, the additive is DIPEA.

[0553] In some embodiments, step c) includes using a solvent comprising a mixture of an organic solvent and water. In some embodiments, the solvent comprises water and one or more of toluene, n-PrOH, THF, MeCN, DCM, and EtOAc. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent comprises a mixture of toluene and water. In some embodiments, the solvent comprises n-PrOH. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises MeCN. In some embodiments, the solvent comprises DCM. In some embodiments, the solvent comprises EtOAc. In some embodiments, the solvent is toluene, n-PrOH, THF, MeCN, DCM, EtOAc, or a mixture thereof. In some embodiments, the solvent is toluene. In some embodiments, the solvent is a mixture of toluene and water. In some embodiments, the solvent is n-PrOH. In some embodiments, the solvent is THF. In some embodiments, the solvent is MeCN. In some embodiments, the solvent is DCM. In some embodiments, the solvent is EtOAc.

[0554] In some embodiments, step c) is performed at a temperature of about 15°C to about 60°C. In some embodiments, step c) is performed at a temperature of about 15°C to about 50°C. In some embodiments, step c) is performed at a temperature of about 15°C to about 45°C. In some embodiments, step c) is performed at about 45°C. In some embodiments, step c) is performed at about 50°C. In some embodiments, step c) is performed at about 60°C.

[0555] In some embodiments, step c) comprises using the compound of formula (E) directly in step d). In some embodiments, step c) comprises using the compound of formula (E) directly as a solution in toluene in step d).

[0556] In some embodiments, in step c), the oxidant is H2O2 / Na2WO4. H2O; step c) includes using a solvent and an additive; step c) is carried out at about 15°C to about 45°C; and step c) includes directly using the compound of formula (E) in step d). In some embodiments, in step c), the oxidant is H2O2 / Na2WO4. H2O; step c) involves using PhP(O)(OH)2 and a mixture of toluene and water; step c) is carried out at about 15°C to about 45°C; and step c) involves using the compound of formula (E) as a solution of toluene directly in step d).

[0557] In some embodiments, step c) includes the following: .

[0558] Equation (I) – Step d) In some embodiments, step d) includes using an alkaline reagent. In some embodiments, the alkaline reagent comprises NaOt-Am, NaOt-Bu, or NaH. In some embodiments, the alkaline reagent comprises NaOt-Am. In some embodiments, the alkaline reagent comprises NaOt-Bu. In some embodiments, the alkaline reagent comprises NaH. In some embodiments, the alkaline reagent is NaOt-Am, NaOt-Bu, or NaH. In some embodiments, the alkaline reagent is NaOt-Am. In some embodiments, the alkaline reagent is NaOt-Bu. In some embodiments, the alkaline reagent is NaH. It should be understood that salts of other alkali metals (such as potassium) will have equivalent effects.

[0559] In some embodiments, step d) includes using a solvent. In some embodiments, the solvent comprises toluene, THF, 2-MeTHF, or a mixture thereof. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises a mixture of toluene and THF. In some embodiments, the solvent comprises 2-MeTHF. In some embodiments, the solvent comprises a mixture of toluene and 2-MeTHF. In some embodiments, the solvent is toluene, THF, 2-MeTHF, or a combination thereof. In some embodiments, the solvent is toluene. In some embodiments, the solvent is THF. In some embodiments, the solvent is a mixture of toluene and THF. In some embodiments, the solvent is 2-MeTHF. In some embodiments, the solvent is a mixture of toluene and 2-MeTHF.

[0560] In some embodiments, step d) is performed at a temperature from about -10°C to about 25°C. In some embodiments, step d) is performed at a temperature from about 0°C to about 25°C. In some embodiments, step d) is performed at a temperature from about -10°C to about 5°C.

[0561] In some embodiments, step d) comprises crystallizing the compound of formula (G). In some embodiments, the compound of formula (G) is crystallized in a mixture of water and iPrOH.

[0562] In some embodiments, step d) comprises using an alkaline reagent and a solvent; step d) is carried out at a temperature of about -10°C to about 25°C; and step d) comprises crystallizing the compound of formula (G). In some embodiments, step d) comprises using a mixture of NaOt-Am and toluene and 2-MeTHF; step d) is carried out at a temperature of about -10°C to about 5°C; and the compound of formula (G) is crystallized in a mixture of water and iPrOH.

[0563] In some embodiments, step d) includes the following: .

[0564] In some embodiments, steps c) and d) occur in the same reaction vessel.

[0565] Equation (I) – Step e) In some embodiments, step e) includes using a catalyst. In some embodiments, the catalyst comprises Pd(Ad2P(n-Bu))(crotonyl)Cl, Pd(Ad2P(n-Bu))G3, Amphos Pd G3, PCy3Pd G3, Pt-Bu3Pd G3, SPhos Pd G3, RuPhos Pd G3, XPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, PdCl(crotonyl)Amphos, PdCl(crotonyl)PCy3, or PEPPSI. TM -iPr. In some embodiments, the catalyst comprises Pd(Ad2P(n-Bu))(crotonyl)Cl. In some embodiments, the catalyst comprises Pd(Ad2P(n-Bu))G3 (catalyst Pd(Ad2P(n-Bu))G3 is sometimes referred to as cataCXium A Pd G3). In some embodiments, the catalyst comprises Amphos Pd G3. In some embodiments, the catalyst comprises PCy3Pd G3. In some embodiments, the catalyst comprises Pt-Bu3Pd G3. In some embodiments, the catalyst comprises SPhos Pd G3. In some embodiments, the catalyst comprises RuPhos Pd G3. In some embodiments, the catalyst comprises XPhos Pd G3. In some embodiments, the catalyst comprises CPhos Pd G3. In some embodiments, the catalyst comprises DavePhos Pd G3. In some embodiments, the catalyst comprises PdCl(crotonyl)Amphos. In some embodiments, the catalyst comprises PdCl(crotonyl)PCy3. In some embodiments, the catalyst comprises PEPPSI. TM-iPr. In some embodiments, the catalyst is Pd(Ad2P(n-Bu))(crotonyl)Cl, Pd(Ad2P(n-Bu))G3, Amphos Pd G3, PCy3Pd G3, Pt-Bu3Pd G3, SPhos Pd G3, RuPhos Pd G3, XPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, PdCl(crotonyl)Amphos, PdCl(crotonyl)PCy3, or PEPPSI. TM -iPr. In some embodiments, the catalyst is Pd(Ad2P(n-Bu))(crotonyl)Cl. In some embodiments, the catalyst is Pd(Ad2P(n-Bu))G3. In some embodiments, the catalyst is Amphos Pd G3. In some embodiments, the catalyst is PCy3Pd G3. In some embodiments, the catalyst is Pt-Bu3Pd G3. In some embodiments, the catalyst is SPhos PdG3. In some embodiments, the catalyst is RuPhos Pd G3. In some embodiments, the catalyst is XPhos Pd G3. In some embodiments, the catalyst is CPhos Pd G3. In some embodiments, the catalyst is DavePhos Pd G3. In some embodiments, the catalyst is PdCl(crotonyl)Amphos. In some embodiments, the catalyst is PdCl(crotonyl)PCy3. In some embodiments, the catalyst is PEPPSI. TM -iPr. In some embodiments, the amount of catalyst used is 0.01-0.23 equivalents. In some embodiments, the amount of catalyst used is 0.01 equivalents. In some embodiments, the amount of catalyst Pd(Ad2P(n-Bu))(crotonyl)Cl used is 0.01 equivalents.

[0566] In some embodiments, step e) includes using an alkaline reagent. In some embodiments, the alkaline reagent comprises K3PO4. H2O, Cs2CO3, CsF, or KHCO3. In some embodiments, the alkaline reagent comprises K3PO4. H2O. In some embodiments, the basic reagent comprises Cs2CO3. In some embodiments, the basic reagent comprises CsF. In some embodiments, the basic reagent comprises KHCO3. In some embodiments, the basic reagent is K3PO4. H2O, Cs2CO3, CsF, or KHCO3. In some embodiments, the alkaline reagent is K3PO4. H2O. In some embodiments, the alkaline reagent is Cs2CO3. In some embodiments, the alkaline reagent is CsF. In some embodiments, the alkaline reagent is KHCO3.

[0567] In some embodiments, step e) includes using a solvent. In some embodiments, the solvent comprises THF, t-AmOH, water, or a mixture thereof. In some embodiments, the solvent comprises a mixture of THF and water. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises t-AmOH. In some embodiments, the solvent comprises water. In some embodiments, the solvent is THF, t-AmOH, water, or a mixture thereof. In some embodiments, the solvent is a mixture of THF and water. In some embodiments, the solvent is THF. In some embodiments, the solvent is t-AmOH. In some embodiments, the solvent is water.

[0568] In some embodiments, a palladium scavenger, preferably SiliaMetS, is used in a solvent such as acetone. TM Thiols.

[0569] In some embodiments, step e) comprises crystallizing the compound of formula (J). In some embodiments, the compound of formula (J) is crystallized in a mixture of water and acetone.

[0570] In some embodiments, step e) includes using a catalyst, a basic reagent, a solvent, and crystallizing the compound of formula (J). In some embodiments, step e) includes using Pd(Ad2P(n-Bu))(crotonyl)Cl, K3PO4 A mixture of H2O, THF, and water, and a compound of formula (J) crystallized in a mixture of water and acetone. In some embodiments, step e) comprises using Pd(Ad2P(n-Bu))(crotonyl)Cl, 0.01 equivalents of K3PO4. A mixture of H2O, THF and water, and compound of formula (J) crystallizes in a mixture of water and acetone.

[0571] In some embodiments, step e) includes the following: .

[0572] In some embodiments, step e) includes using a catalyst. In some embodiments, the catalyst comprises Pd(SPhos)(crotonyl)Cl, Pd(Ad2P(n-Bu))(crotonyl)Cl, Pd(Ad2P(n-Bu))G3, Amphos Pd G3, PCy3Pd G3, Pt-Bu3Pd G3, SPhos Pd G3, RuPhos Pd G3, XPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, PdCl(crotonyl)Amphos, PdCl(crotonyl)PCy3, or PEPPSI. TM -iPr. In some embodiments, the catalyst comprises Pd(SPhos)(crotonyl)Cl. In some embodiments, the catalyst comprises Pd(Ad2P(n-Bu))(crotonyl)Cl. In some embodiments, the catalyst comprises Pd(Ad2P(n-Bu))G3 (catalyst Pd(Ad2P(n-Bu))G3 is sometimes referred to as cataCXium A Pd G3). In some embodiments, the catalyst comprises Amphos Pd G3. In some embodiments, the catalyst comprises PCy3Pd G3. In some embodiments, the catalyst comprises Pt-Bu3Pd G3. In some embodiments, the catalyst comprises SPhos Pd G3. In some embodiments, the catalyst comprises RuPhos Pd G3. In some embodiments, the catalyst comprises XPhos Pd G3. In some embodiments, the catalyst comprises CPhos Pd G3. In some embodiments, the catalyst comprises DavePhos Pd G3. In some embodiments, the catalyst comprises PdCl(crotonyl)Amphos. In some embodiments, the catalyst comprises PdCl(crotonyl)PCy3. In some embodiments, the catalyst comprises PEPPSI TM -iPr. In some embodiments, the catalyst is Pd(SPhos)(crotonyl)Cl, Pd(Ad2P(n-Bu))(crotonyl)Cl, Pd(Ad2P(n-Bu))G3, Amphos Pd G3, PCy3Pd G3, Pt-Bu3Pd G3, SPhos Pd G3, RuPhos Pd G3, XPhos PdG3, CPhos Pd G3, DavePhos Pd G3, PdCl(crotonyl)Amphos, PdCl(crotonyl)PCy3, or PEPPSI. TM-iPr. In some embodiments, the catalyst is Pd(SPhos)Cl. In some embodiments, the catalyst is Pd(Ad2P(n-Bu))Cl. In some embodiments, the catalyst is Pd(Ad2P(n-Bu))G3. In some embodiments, the catalyst is Amphos Pd G3. In some embodiments, the catalyst is PCy3Pd G3. In some embodiments, the catalyst is Pt-Bu3Pd G3. In some embodiments, the catalyst is SPhos Pd G3. In some embodiments, the catalyst is RuPhos Pd G3. In some embodiments, the catalyst is XPhos Pd G3. In some embodiments, the catalyst is CPhos Pd G3. In some embodiments, the catalyst is DavePhos Pd G3. In some embodiments, the catalyst is PdCl(crotonyl)Amphos. In some embodiments, the catalyst is PdCl(crotonyl)PCy3. In some embodiments, the catalyst is PEPPSI. TM -iPr. In some embodiments, the amount of catalyst used is 0.001-0.200 equivalents. In some embodiments, the amount of catalyst used is 0.006 equivalents. In some embodiments, the amount of catalyst used is 0.006 equivalents of Pd(SPhos)Cl. In some embodiments, the amount of catalyst used is about 0.001-0.200 equivalents. In some embodiments, the amount of catalyst used is about 0.006 equivalents. In some embodiments, the amount of catalyst used is about 0.006 equivalents of Pd(SPhos)Cl.

[0573] In some embodiments, step e) includes using SPhos. In some embodiments, the amount of SPhos used is 0.001 equivalent to 0.010 equivalent. In some embodiments, the amount of SPhos used is 0.002 equivalent to 0.005 equivalent. In some embodiments, the amount of SPhos used is 0.003 equivalent. In some embodiments, the amount of SPhos used is about 0.001 equivalent to about 0.010 equivalent. In some embodiments, the amount of SPhos used is about 0.002 equivalent to 0.005 equivalent. In some embodiments, the amount of SPhos used is about 0.003 equivalent.

[0574] In some embodiments, step e) includes using an alkaline reagent. In some embodiments, the alkaline reagent comprises K3PO4. H2O, Cs2CO3, CsF, or KHCO3. In some embodiments, the alkaline reagent comprises K3PO4. H2O. In some embodiments, the basic reagent comprises Cs2CO3. In some embodiments, the basic reagent comprises CsF. In some embodiments, the basic reagent comprises KHCO3. In some embodiments, the basic reagent is K3PO4. H2O, Cs2CO3, CsF, or KHCO3. In some embodiments, the alkaline reagent is K3PO4. H2O. In some embodiments, the alkaline reagent is Cs2CO3. In some embodiments, the alkaline reagent is CsF. In some embodiments, the alkaline reagent is KHCO3.

[0575] In some embodiments, step e) includes using a solvent. In some embodiments, the solvent comprises THF, t-AmOH, water, or a mixture thereof. In some embodiments, the solvent comprises a mixture of THF and water. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises t-AmOH. In some embodiments, the solvent comprises water. In some embodiments, the solvent is THF, t-AmOH, water, or a mixture thereof. In some embodiments, the solvent is a mixture of THF and water. In some embodiments, the solvent is THF. In some embodiments, the solvent is t-AmOH. In some embodiments, the solvent is water.

[0576] In some embodiments, step e) comprises crystallizing the compound of formula (Ja). In some embodiments, the compound of formula (Ja) is crystallized in n-heptane.

[0577] In some embodiments, step e) includes using a catalyst, a basic reagent, a solvent, and crystallizing the compound of formula (Ja). In some embodiments, step e) includes using Pd(SPhos) (crotonyl)Cl, SPhos, and K3PO4. A mixture of H2O, THF, and water, and a compound of formula (Ja) crystallized in a mixture of water and acetone. In some embodiments, step e) comprises using 0.006 equivalents of Pd(SPhos) (crotonyl)Cl, 0.003 equivalents of SPhos, and K3PO4. A mixture of H2O, THF, and water, and a compound of formula (Ja) are crystallized in n-heptane. In some embodiments, step e) comprises using about 0.006 equivalents of Pd(SPhos) (crotonyl)Cl, about 0.003 equivalents of SPhos, and K3PO4. A mixture of H2O, THF, and water, and a compound of formula (Ja) crystallized in n-heptane.

[0578] In some embodiments, step e) includes the following: Equation (I) – Step f) In some embodiments, in step f), the acidic reagent is MsOH or TFA. In some embodiments, in step f), the acidic reagent comprises MsOH. In some embodiments, in step f), the acidic reagent comprises TFA. In some embodiments, in step f), the acidic reagent is MsOH. In some embodiments, in step f), the acidic reagent is TFA.

[0579] In some embodiments, step f) includes using a solvent. In some embodiments, the solvent comprises toluene, EtOAc, AcOH, or a mixture thereof. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent comprises EtOAc. In some embodiments, the solvent comprises AcOH. In some embodiments, the solvent is toluene, EtOAc, AcOH, or a mixture thereof. In some embodiments, the solvent is toluene. In some embodiments, the solvent is EtOAc. In some embodiments, the solvent is AcOH.

[0580] In some embodiments, step f) is performed at about 25°C or about 50°C. In some embodiments, step f) is performed at about 25°C.

[0581] In some embodiments, step f) comprises crystallizing the compound of formula (I). In some embodiments, the compound of formula (I) is crystallized in a mixture of EtOH and heptane. In some embodiments, crystallization is induced using a seed crystal of the form AG of the compound of formula (I), which is formed under the same heptane / EtOH crystallization conditions.

[0582] In some embodiments, in step f), the acidic reagent is MsOH; step f) includes using a solvent; step f) is carried out at about 25°C or about 50°C; and step f) includes crystallizing the compound of formula (I). In some embodiments, in step f), the acidic reagent is MsOH; step f) includes using toluene; step f) is carried out at about 25°C; and the compound of formula (I) is crystallized in a mixture of EtOH and heptane. In some embodiments, in step f), the acidic reagent is MsOH; step f) includes using toluene; step f) is carried out at about 25°C; and the compound of formula (I) is crystallized in a mixture of EtOH and heptane using seed crystals of form AG.

[0583] In some embodiments, step f) includes the following: .

[0584] In some embodiments, in step f), the acidic reagent is MsOH or TFA. In some embodiments, in step f), the acidic reagent comprises MsOH. In some embodiments, in step f), the acidic reagent comprises TFA. In some embodiments, in step f), the acidic reagent is MsOH. In some embodiments, in step f), the acidic reagent is TFA.

[0585] In some embodiments, step f) includes using a solvent. In some embodiments, the solvent comprises toluene, EtOAc, AcOH, or a mixture thereof. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent comprises EtOAc. In some embodiments, the solvent comprises AcOH. In some embodiments, the solvent is toluene, EtOAc, AcOH, or a mixture thereof. In some embodiments, the solvent is toluene. In some embodiments, the solvent is EtOAc. In some embodiments, the solvent is AcOH.

[0586] In some embodiments, step f) is performed at about 10°C, about 15°C, about 25°C, or about 50°C. In some embodiments, step f) is performed at about 10°C. In some embodiments, step f) is performed at about 15°C. In some embodiments, step f) is performed at about 25°C. In some embodiments, step f) is performed below 25°C (i.e., <25°C, but ≥5°C). In some embodiments, step f) is performed below 50°C.

[0587] In some embodiments, step f) comprises crystallizing the compound of formula (I). In some embodiments, the compound of formula (I) is crystallized in a mixture of EtOH and heptane. In some embodiments, crystallization is induced using a seed crystal of the form AG of the compound of formula (I), which is formed under the same heptane / EtOH crystallization conditions.

[0588] In some embodiments, in step f), the acidic reagent is MsOH; step f) includes using a solvent; step f) is carried out at about 25°C or about 50°C; and step f) includes crystallizing the compound of formula (I). In some embodiments, in step f), the acidic reagent is MsOH; step f) includes using toluene; step f) is carried out at about 25°C; and the compound of formula (I) is crystallized in a mixture of EtOH and heptane. In some embodiments, in step f), the acidic reagent is MsOH; step f) includes using toluene; step f) is carried out at about 25°C; and the compound of formula (I) is crystallized in a mixture of EtOH and heptane using seed crystals of form AG. In some embodiments, in step f), the acidic reagent is MsOH; step f) includes using toluene; step f) is carried out at a temperature below 25°C; and the compound of formula (I) is crystallized in a mixture of EtOH and heptane. In some embodiments, in step f), the acidic reagent is MsOH; step f) includes the use of toluene; step f) is carried out at a temperature below 25°C; and the compound of formula (I) is crystallized in a mixture of EtOH and heptane using seed crystals of form AG.

[0589] In some embodiments, step f) includes the following: In some embodiments, compound (A) is prepared by the methods described herein. In some embodiments, compound (B) is prepared by the methods described herein. In some embodiments, compound (F) is prepared according to the procedure for intermediate 1A in WO2022 / 216762. In some embodiments, compound (F) is prepared according to the procedure for intermediate 5 in PCT / US2023 / 022914. In some embodiments, compound (H) is prepared by the methods described herein. In some embodiments, compound (Ha) is prepared by the methods described herein. In some embodiments, in the method for preparing compound (I), compound (A) is prepared by the methods described herein; compound (B) is prepared by the methods described herein; compound (F) is prepared by the methods described herein; and compound (H) is prepared by the methods described herein. In some embodiments, in the method of preparing compound (I), compound (A) is prepared by the method described herein; compound (B) is prepared by the method described herein; compound (F) is prepared by the method described herein; and compound (Ha) is prepared by the method described herein.

[0590] In some embodiments, the method for preparing the compound of formula (I) includes the following: .

[0591] In some embodiments, the method for preparing the compound of formula (I) includes the following: .

[0592] In some embodiments, the method for preparing the compound of formula (I) includes the following: Formula (A) In one aspect, this disclosure provides a method for preparing a compound of formula (A). In some embodiments, the method includes the following steps: a) Prepare compound (Ax) by reacting the compound of formula (Aw) with a basic reagent and a brominating reagent: (Aw) (Ax); b) To prepare compound (Ay) by reacting the compound of formula (Ax) with an activating agent and a coupling agent: (Ay); c) Reacting compound of formula (Ay) with S-methylisothiourea to prepare compound of formula (Az): (Az); and d) React the compound of formula (Az) with a basic reagent to prepare the compound of formula (A).

[0593] In some embodiments, the method includes the following steps: a) Reaction of compound of formula (Aw) with TMPMgCl The reaction of LiCl and BrCF2CF2Br prepares a compound of formula (Ax): (Aw) (Ax); b) Reacting compound (Ax) with NHS and EDC to prepare compound (Ay): (Ay); c) Reacting compound of formula (Ay) with S-methylisothiourea to prepare compound of formula (Az): (Az); and d) Reacting compound of formula (Az) with NMI and DMA to prepare compound of formula (A).

[0594] In some embodiments, steps b) and c) occur in the same reaction vessel.

[0595] In some embodiments, the conditions for steps (a) – (d) are illustrated herein by example.

[0596] Formula (A) – Step a) In some embodiments, in step a), the alkaline reagent comprises TMPMgCl LiCl, LDA, LiHMDS, LiTMP or (i-Pr)2NMgCl LiCl. In some embodiments, in step a), the alkaline reagent comprises TMPMgCl. LiCl. In some embodiments, in step a), the alkaline reagent comprises LDA. In some embodiments, in step a), the alkaline reagent comprises LiHMDS. In some embodiments, in step a), the alkaline reagent comprises LiTMP. In some embodiments, in step a), the alkaline reagent comprises (i-Pr)₂NMgCl₂ LiCl. In some embodiments, in step a), the alkaline reagent is TMPMgCl. LiCl, LDA, LiHMDS, LiTMP or (i-Pr)2NMgCl LiCl. In some embodiments, in step a), the alkaline reagent is TMPMgCl. LiCl. In some embodiments, in step a), the basic reagent is LDA. In some embodiments, in step a), the basic reagent is LiHMDS. In some embodiments, in step a), the basic reagent is LiTMP. In some embodiments, in step a), the basic reagent is (i-Pr)₂NMgCl. LiCl.

[0597] In some embodiments, in step a), the brominating agent comprises BrCF₂CF₂Br, BrCCl₂CCl₂Br, NBS, or Br₂. In some embodiments, in step a), the brominating agent comprises BrCF₂CF₂Br. In some embodiments, in step a), the brominating agent comprises BrCCl₂CCl₂Br. In some embodiments, in step a), the brominating agent comprises NBS. In some embodiments, in step a), the brominating agent comprises Br₂. In some embodiments, in step a), the brominating agent is BrCF₂CF₂Br. In some embodiments, in step a), the brominating agent is BrCCl₂CCl₂Br. In some embodiments, in step a), the brominating agent is NBS. In some embodiments, in step a), the brominating agent is Br₂.

[0598] In some embodiments, step a) includes using a solvent. In some embodiments, the solvent comprises THF, MTBE, or a mixture thereof. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises MTBE. In some embodiments, the solvent is THF, MTBE, or a mixture thereof. In some embodiments, the solvent is THF. In some embodiments, the solvent is MTBE.

[0599] In some embodiments, step a) includes the following, and may include crystallizing the compound according to methods known to those skilled in the art: .

[0600] Formula (A) – Step b) In some embodiments, in step b), the activating agent comprises NHS or HOBt. In some embodiments, in step b), the activating agent comprises NHS. In some embodiments, in step b), the activating agent comprises HOBt. In some embodiments, in step b), the activating agent is NHS or HOBt. In some embodiments, in step b), the activating agent is NHS. In some embodi...

Claims

1. A solid form of a compound of formula (I): (I)， The solid form mentioned above is: Crystallization polymorph J; Crystallization polymorphism N; Crystallization polymorphic form O; or AG is a polycrystalline form.

2. The solid form according to claim 1, wherein the solid form is a crystalline polymorphic form AG.

3. The solid form of claim 2, wherein the solid form is Form AG, characterized by The XRPD plot contains: a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least two peaks selected from the group consisting of 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.

4. The solid form of claim 2 or 3, wherein the solid form is Form AG, characterized by The XRPD plot contains: a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least three peaks selected from the group consisting of 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.

5. The solid form of any one of claims 2-4, wherein the solid form is Form AG, characterized by The XRPD plot contains: a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least four peaks selected from the group consisting of 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.

6. The solid form of any one of claims 2-5, wherein the solid form is Form AG, characterized by The XRPD plot contains: a peak at approximately 13.1 ± 0.2 degrees 2θ, and at least five, at least six, at least seven, or at least eight peaks selected from groups consisting of 19.3 ± 0.2, 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.

7. The solid form of claim 2 or 3, wherein the solid form is Form AG, characterized by The XRPD graph contains: The peaks at approximately 13.1 ± 0.2 degrees 2θ and at approximately 19.3 ± 0.2 degrees 2θ; and Select at least one peak from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

8. The solid form of any one of claims 2-4 or 7, wherein the solid form is Form AG, characterized by The XRPD graph contains: The peaks at approximately 13.1 ± 0.2 degrees 2θ and at approximately 19.3 ± 0.2 degrees 2θ; and Select at least two peaks from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

9. The solid form of any one of claims 2-5, 7, or 8, wherein the solid form is Form AG, characterized by The XRPD graph contains: The peaks at approximately 13.1 ± 0.2 degrees 2θ and at approximately 19.3 ± 0.2 degrees 2θ; and Select at least three peaks from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

10. The solid form of any one of claims 2-9, wherein the solid form is Form AG, characterized by The XRPD graph contains: The peaks at approximately 13.1 ± 0.2 degrees 2θ and at approximately 19.3 ± 0.2 degrees 2θ; and Select at least four, at least five, at least six, or at least seven peaks from the group consisting of 15.4 ± 0, 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.

11. The solid form of claim 2 or 3, wherein the solid form is Form AG, characterized by The XRPD graph contains: Select at least two peaks from the group consisting of 13.1 ± 0.2, 19.3 ± 0.2, and 15.4 ± 0.2 degrees 2θ; and Select at least one peak from the group consisting of 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2 and 10.7 ± 0.2 degrees 2θ.

12. The solid form of claim 2, wherein the solid form is Form AG, characterized by The XRPD plot contains characteristic peaks at approximately 19.3 ± 0.2, 13.1 ± 0.2, and 15.4 ± 0.2 degrees 2θ.

13. The solid form of claim 12, wherein the XRPD plot further comprises at least one additional characteristic peak selected from the group consisting of: approximately 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.

14. The solid form according to claim 12, wherein the XRPD plot further includes characteristic peaks at approximately 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.

15. The solid form of any one of claims 2-8, wherein the solid form is Form AG, characterized by The XRPD graph contains: Peaks at approximately 13.1 ± 0.2, 19.3 ± 0.2, and 15.4 ± 0.2 degrees 2θ; and Select at least two, at least three, at least four, or at least five peaks from the group consisting of 18.5 ± 0.2, 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, and 10.7 ± 0.2 degrees 2θ.

16. The solid form of any one of claims 2-9, wherein the solid form is Form AG, characterized by The XRPD graph contains: Peaks at approximately 13.1 ± 0.2, 19.3 ± 0.2, 15.4 ± 0.2 degrees 2θ, and 18.5 ± 0.2 degrees 2θ; and One or more peaks at approximately 21.5 ± 0.2, 9.6 ± 0.2, 20.8 ± 0.2, 17.0 ± 0.2, 20.2 ± 0.2, or 10.7 ± 0.2 degrees 2θ.

17. The solid form of any one of claims 2-16, wherein the solid form is Form AG, characterized by The TGA thermogram shows that the weight loss is approximately 1.1% when the temperature is increased up to 180°C.

18. The solid form of any one of claims 2-17, wherein the solid form is Form AG, characterized by The DSC thermogram contains an endothermic peak at approximately 219 °C.

19. The solid form of any one of claims 2-18, wherein the solid form is Form AG, characterized by Two or more of the following: a. The XRPD plot contains characteristic peaks at approximately 19.3 ± 0.2, 13.1 ± 0.2, and 15.4 ± 0.2 degrees 2θ; b. TGA thermograms show a weight loss of approximately 1.1% at 180°C; and c. The DSC thermogram contains an endothermic peak at approximately 219 °C.

20. The solid form according to any one of claims 3 to 19, wherein the XRPD spectrum is obtained using a Cu Kα source.

21. The solid form according to claim 1, wherein the solid form is a crystalline polymorphic form J.

22. The solid form of claim 21, wherein the solid form is Form J, characterized by The XRPD diffraction pattern contains at least two XRPD peaks selected from the group consisting of approximately 16.4 ± 0.2, 6.8 ± 0.2, 18.9 ± 0.2, 15.6 ± 0.2, 9.4 ± 0.2, 18.2 ± 0.2, 8.42 ± 0.2, 13.7 ± 0.2, 8.8 ± 0.2, and 19.7 ± 0.2 degrees 2θ.

23. The solid form of claim 21 or 22, wherein the solid form is Form J, characterized by The XRPD diffraction pattern contains at least three XRPD peaks selected from the group consisting of approximately 16.4 ±0.2, 6.8 ±0.2, 18.9 ±0.2, 15.6 ±0.2, 9.4 ±0.2, 18.2 ±0.2, 8.4 ±0.2, 13.7 ±0.2, 8.8 ±0.2, and 19.7 ±0.2 degrees 2θ.

24. The solid form according to any one of claims 21 to 23, wherein the solid form is form J, characterized in that... The XRPD diffraction pattern contains at least four XRPD peaks selected from the group consisting of approximately 16.4 ±0.2, 6.8 ±0.2, 18.9 ±0.2, 15.6 ±0.2, 9.4 ±0.2, 18.2 ±0.2, 8.4 ±0.2, 13.7 ±0.2, 8.8 ±0.2, and 19.7 ±0.2 degrees 2θ.

25. The solid form according to any one of claims 21 to 24, wherein the solid form is form J, characterized in that... The XRPD diffraction pattern includes: XRPD peaks at 6.8±0.2 degrees 2θ and 8.8±0.2 degrees 2θ; and Select at least two XRPD peaks from the group consisting of approximately 16.4 ±0.2, 18.9 ±0.2, 15.6 ±0.2, 9.4 ±0.2, 18.2 ±0.2, 8.4 ±0.2, 13.7 ±0.2, and 19.7 ±0.2 degrees 2θ.

26. The solid form according to any one of claims 21 to 25, wherein the solid form is form J, characterized in that... The XRPD diffraction pattern includes: XRPD peaks at 6.8±0.2 degrees 2θ and 8.8±0.2 degrees 2θ; and Select at least three XRPD peaks from the group consisting of approximately 16.4 ±0.2, 18.9 ±0.2, 15.6 ±0.2, 9.4 ±0.2, 18.2 ±0.2, 8.4 ±0.2, 13.7 ±0.2, and 19.7 ±0.2 degrees 2θ.

27. The solid form according to any one of claims 21 to 26, wherein the solid form is form J, characterized in that... The XRPD diffraction pattern includes: XRPD peaks at 6.8±0.2 degrees 2θ and 8.8±0.2 degrees 2θ; and Select at least four XRPD peaks from the group consisting of approximately 16.4 ±0.2, 18.9 ±0.2, 15.6 ±0.2, 9.4 ±0.2, 18.2 ±0.2, 8.4 ±0.2, 13.7 ±0.2, and 19.7 ±0.2 degrees 2θ.

28. The solid form according to any one of claims 21 to 27, wherein the solid form is form J, characterized in that... The XRPD diffraction pattern includes XRPD peaks at 16.4 ±0.2, 6.8 ±0.2, 18.9 ±0.2, 15.6 ±0.2, 9.4 ±0.2, 18.2 ±0.2, 8.4 ±0.2, 13.7 ±0.2, 8.8 ±0.2, and 19.7 ±0.2 degrees 2θ.

29. The solid form according to any one of claims 21 to 28, wherein the solid form is form J, characterized in that... Thermogravimetric analysis (TGA) thermograms show that the weight loss is approximately 2.6% when the temperature is increased up to 180°C.

30. The solid form according to any one of claims 21 to 29, wherein the solid form is form J, characterized in that... Differential scanning calorimetry (DSC) thermograms contain at least one endothermic peak at approximately 110 °C, approximately 138 °C, or approximately 178 °C.

31. The solid form according to any one of claims 21 to 30, wherein the solid form is form J, characterized in that... The differential DSC thermogram contains endothermic peaks at approximately 110°C, 138°C, and 178°C.

32. The solid form according to any one of claims 21 to 31, wherein the solid form is form J, characterized by the following: Two or more items in: a. Basically, the XRPD diagram is shown in Figure 1; b. TGA thermograms show a weight loss of approximately 2.6% when the temperature is increased up to 180°C; and c. The DSC thermogram contains endothermic peaks at approximately 110°C, approximately 138°C, and approximately 178°C.

33. The solid form according to any one of claims 21 to 32, wherein the XRPD spectrum is obtained using a Cu Kα source.

34. The solid form according to claim 1, wherein the solid form is a crystalline polymorphic form O.

35. The solid form according to claim 34, wherein the solid form is characterized in that the XRPD diffraction pattern comprises at least two XRPD peaks selected from the group consisting of approximately 15.1 ±0.2, 19.7 ±0.2, 9.3 ±0.2, 18.8 ±0.2, 7.0 ±0.2, 15.4 ±0.2, 8.5 ±0.2, 24.8 ±0.2, 21.4 ±0.2, and 15.9 ±0.2 degrees 2θ.

36. The solid form according to claim 34 or 35, wherein the solid form is characterized in that the XRPD diffraction pattern comprises: XRPD peaks at approximately 15.1 ± 0.2, 19.7 ± 0.2, and 9.3 ± 0.2 degrees 2θ; and Select at least three additional peaks from the group consisting of approximately 18.8 ±0.2, 7.0 ±0.2, 15.4 ±0.2, 8.5 ±0.2, 24.8 ±0.2, 21.4 ±0.2 and 15.9 ±0.2 degrees 2θ.

37. The solid form according to any one of claims 34 to 36, wherein the solid form is characterized in that the XRPD diffraction pattern includes XRPD peaks at approximately 15.1 ± 0.2, 19.7 ± 0.2, 9.3 ± 0.2, 18.8 ± 0.2, 7.0 ± 0.2, 15.4 ± 0.2, 8.5 ± 0.2, 24.8 ± 0.2, 21.4 ± 0.2, and 15.9 ± 0.2 degrees 2θ.

38. The solid form according to any one of claims 34 to 37, wherein the solid form is characterized by a TGA thermogram showing a weight loss of about 3.1% when heated up to 180°C.

39. The solid form according to any one of claims 34 to 38, wherein the solid form is form O, characterized in that... The DSC thermogram contains at least one endothermic peak at approximately 70 °C or approximately 195 °C.

40. The solid form according to any one of claims 34 to 39, wherein the solid form is form O, characterized in that... The DSC thermogram contains endothermic peaks at approximately 70°C and approximately 195°C.

41. The solid form according to claims 34 to 40, wherein the solid form is form O, characterized by the following: Two or more items in: a. XRPD peaks at approximately 15.1 ±0.2, 19.7 ±0.2, 9.3 ±0.2, 18.8 ±0.2, 7.0 ±0.2, 15.4 ±0.2, 8.5 ±0.2, 24.8 ±0.2, 21.4 ±0.2, and 15.9 ±0.2 degrees 2θ; b. TGA thermograms show a weight loss of approximately 3.1% when the temperature is increased up to 180°C; and c. The DSC thermogram contains endothermic peaks at approximately 70 °C and approximately 195 °C.

42. The solid form according to any one of claims 35 to 41, wherein the XRPD spectrum is obtained using a Cu Kα source.

43. The solid form according to claim 1, wherein the solid form is a crystalline polymorphic form N.

44. The solid form according to claim 43, wherein the solid form is characterized in that the XRPD diffraction pattern comprises at least two peaks selected from the group consisting of approximately 15.7 ± 0.2, 16.1 ± 0.2, 15.5 ± 0.2, 19.6 ± 0.2, 20.6 ± 0.2, 24.0 ± 0.2, 21.2 ± 0.2, 5.7 ± 0.2, 22.3 ± 0.2 and 6.6 ± 0.2 degrees 2θ.

45. The solid form according to claim 43 or 44, wherein the solid form is characterized in that the XRPD plot contains at least three, at least four, at least five, at least six, or at least seven peaks selected from the group consisting of approximately 15.7 ± 0.2, 16.1 ± 0.2, 15.5 ± 0.2, 19.6 ± 0.2, 20.6 ± 0.2, 24.0 ± 0.2, 21.2 ± 0.2, 5.7 ± 0.2, 22.3 ± 0.2, and 6.6 ± 0.2 degrees 2θ.

46. ​​The solid form according to any one of claims 43 to 45, wherein the solid form is characterized in that the XRPD diagram comprises: Select at least one peak from the group consisting of approximately 15.7 ± 0.2, 16.1 ± 0.2, and 15.5 ± 0.2 degrees 2θ; and Select at least one, at least two, at least three, or at least four peaks from the group consisting of approximately 19.6 ± 0.2, 20.6 ± 0.2, 24.0 ± 0.2, 21.2 ± 0.2, 5.7 ± 0.2, 22.3 ± 0.2, and 6.6 ± 0.2 degrees 2θ.

47. The solid form according to any one of claims 43 to 46, wherein the solid form is characterized by XRPD peaks at approximately 15.7 ± 0.2, 16.1 ± 0.2, 15.5 ± 0.2, 19.6 ± 0.2, 20.6 ± 0.2, 24.0 ± 0.2, 21.2 ± 0.2, 5.7 ± 0.2, 22.3 ± 0.2, and 6.6 ± 0.2 degrees 2θ.

48. The solid form according to any one of claims 43 to 47, wherein the solid form is characterized in that the TGA thermogram shows a weight loss of about 3.9% when heated up to 180°C.

49. The solid form according to any one of claims 43 to 48, wherein the solid form is characterized in that the DSC thermogram contains at least one endothermic peak at about 60°C, about 131°C, or about 172°C.

50. The solid form according to any one of claims 43 to 49, wherein the XRPD spectrum is obtained using a Cu Kα source.

51. A pharmaceutical composition comprising: a solid form according to any one of claims 1 to 50; and at least one pharmaceutically acceptable excipient.

52. The pharmaceutical composition according to claim 51, wherein the solid form is the solid form according to any one of claims 2 to 20.

53. The pharmaceutical composition according to claim 51, wherein the solid form is the solid form according to any one of claims 21 to 33.

54. The pharmaceutical composition according to claim 51, wherein the solid form is the solid form according to any one of claims 34 to 42.

55. The pharmaceutical composition according to claim 51, wherein the solid form is the solid form according to any one of claims 43 to 50.

56. A method of treating a subject with cancer, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition in solid form according to any one of claims 1 to 50 or according to any one of claims 51 to 55.

57. The method of claim 56, wherein the cancer is characterized by a KRas mutation.

58. The method of claim 57, wherein the KRas mutation corresponds to a KRas G12D mutation.

59. The method according to any one of claims 56 to 58, wherein the cancer is of uncertain tissue origin.

60. The method according to any one of claims 56 to 59, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

61. A method for modulating the activity of a KRas mutant protein, the method comprising reacting the mutant protein with a solid form according to any one of claims 1 to 50 or a pharmaceutical composition according to any one of claims 51 to 55.

62. A method for inhibiting the proliferation of a cell population, the method comprising contacting the cell population with a solid form according to any one of claims 1 to 50 or a pharmaceutical composition according to any one of claims 51 to 55.

63. The method of claim 62, wherein the inhibition of proliferation is measured by a decrease in the cell viability of the cell population.

64. A method for inhibiting tumor metastasis in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition in solid form according to any one of claims 1 to 50 or according to any one of claims 51 to 55.

65. The solid form of the compound of formula (I) according to any one of claims 1 to 50 or the pharmaceutical composition according to any one of claims 51 to 55, for the treatment of cancer.

66. Use of the solid form of the compound of formula (I) according to any one of claims 1 to 50 or the pharmaceutical composition according to any one of claims 51 to 55 for the treatment of cancer.

67. Use of the solid form of the compound of formula (I) according to any one of claims 1 to 50 or the pharmaceutical composition according to any one of claims 51 to 55 in the manufacture of a medicament for treating cancer.

68. A method for preparing compounds of formula (I), (I)， The method includes the following steps: a) React compound (A) with compound (B) to prepare compound (C): (A) (B) (C); b) Reacting the compound of formula (C) with one or more reagents to prepare the compound of formula (D): (D)； c) Reacting the compound of formula (D) with an oxidizing agent to prepare the compound of formula (E): (E)； d) Reacting the compound of formula (E) with the compound of formula (F) to prepare the compound of formula (G): (F) (G); e) Reacting the compound of formula (G) with the compound of formula (Ha) to prepare the compound of formula (Ja): (Ha) (Ja), where Boc is a tert-butoxycarbonyl group; and f) React the compound of formula (Ja) with an acidic reagent to prepare the compound of formula (I).

69. A method for preparing compounds of formula (I), (I)， The method includes the following steps: a) React compound (A) with compound (B) to prepare compound (C): (A) (B) (C); b) Reacting the compound of formula (C) with one or more reagents to prepare the compound of formula (D): (D)； c) Reacting the compound of formula (D) with an oxidizing agent to prepare the compound of formula (E): (E)； d) Reacting the compound of formula (E) with the compound of formula (F) to prepare the compound of formula (G): (F) (G); e) Reacting the compound of formula (G) with the compound of formula (H) to prepare the compound of formula (J): (H) (J), where PMB is p-methoxybenzyl; and f) Reacting the compound of formula (J) with an acidic reagent to prepare the compound of formula (I); and Steps c) and d) occur in the same reaction vessel.

70. The method according to claim 68 or 69, wherein the compound of formula (I) prepared in step f) is separated in crystalline form AG.

71. The method of claim 68, wherein steps c) and d) occur in the same reaction vessel.

72. The method of claim 68, wherein the compound of formula (Ha) is prepared by a method comprising the following steps: a) Reacting compound of formula (Hu) with NBS to prepare compound of formula (Hv): (Huh) (Hv); b) React the compound of formula (Hv) with hydrogen over a platinum / vanadium / carbon catalyst to prepare the compound of formula (Hw); (Hw); c) Reacting the compound of formula (Hw) with NIS to prepare the compound of formula (Hr): (Hr)； d) Reacting the compound of formula (Hr) with di-tert-butyl dicarbonate to prepare the compound of formula (Hs): (Hs); e) React the compound of formula (Hs) with MeO2CCF2SO2F in the presence of CuI to prepare the compound of formula (Ht): (Ht); and f) Mix the compound of formula (Ht) with... i -PrMgCl·LiCl and B(O) i -Pr)3 reaction to prepare the compound of formula (Ha).

73. The method according to claim 69, wherein the compound of formula (H) is prepared by a method comprising the following steps: a) Reacting compound of formula (Hu) with NBS to prepare compound of formula (Hv): (Huh) (Hv); b) React the compound of formula (Hv) with hydrogen over a platinum / vanadium / carbon catalyst to prepare the compound of formula (Hw); (Hw); c) Reacting the compound of formula (Hw) with p-methoxybenzyl chloride (PMBCl) to prepare the compound of formula (Hx): (Hx); d) Reacting the compound of formula (Hx) with NIS to prepare the compound of formula (Hy): (He); e) React the compound of formula (Hy) with MeO2CCF2SO2F in the presence of CuI to prepare the compound of formula (Hz): (Hz); and f) Mix the compound of formula (Hz) with n -BuLi and B(OiPr)3 react to prepare the compound of formula (H).

74. The method according to claim 72 or 73, wherein steps a) through f) occur in the same reaction vessel.

75. The method according to claim 68 or 69, wherein the compound of formula (B) is prepared by a method comprising the following steps: a) Reacting compound of formula (Bv) with benzyl bromide to prepare compound of formula (Bw): (Bv) (Bw); b) Mix the compound of formula (Bw) with... s -BuLi, TMEDA, and acetaldehyde react to prepare compounds of formula (Bx') and mixtures of compounds of formula (Bx''): (Bx') (Bx''); c) Reacting the compound of formula (Bx') and a mixture of the compounds of formula (Bx'') with H2, Pd / C, and D(+)-10-camphorsulfonic acid to prepare the compound of formula (By): (By); d) Reacting the compound of formula (By) with (Boc)₂O to prepare the compound of formula (Bz): (Bz); and e) React the compound of formula (Bz) with a basic reagent to prepare the compound of formula (B).

76. The method of claim 75, wherein steps a) through e) occur in the same reaction vessel.

77. The method according to claim 68 or 69, wherein the compound of formula (A) is prepared by a method comprising the following steps: a) Reaction of compound of formula (Aw) with TMPMgCl The reaction of LiCl and BrCF2CF2Br prepares a compound of formula (Ax): (Oh) (Axe); b) Reacting the compound of formula (Ax) with NHS and EDC to prepare the compound of formula (Ay): (Yes); c) Mix the compound of formula (Ay) with... S -Methylisothiourea reaction to prepare compounds of formula (Az): (Az); and d) React the compound of formula (Az) with NMI and DMA to prepare the compound of formula (A).

78. The method of claim 77, wherein steps b) and c) occur in the same reaction vessel.

79. The method of claim 77, wherein step c) comprises using: vii. S-methylisothiourea hemisulfate, NaHCO3, and water; viii. Ecosorb® C941; and ix. MeCN in water.

80. The method of claim 68, wherein: The compound of formula (A) is prepared by the method according to claim 77; the compound of formula (B) is prepared by... The compound is prepared according to the method of claim 75; and the compound of formula (Ha) is prepared according to the method of claim 72.

81. The method according to claim 69, wherein: The compound of formula (A) is prepared by the method according to claim 77; the compound of formula (B) is prepared by... The compound is prepared according to the method of claim 75; and the compound of formula (H) is prepared according to the method of claim 73.

82. The method of claim 68 or 69, wherein the compound of formula (A) is processed by any of the exemplary methods disclosed herein, such as Example 5 The method is used to prepare it.

83. The method of claim 68 or 69, wherein the compound of formula (B) is processed by any of the exemplary methods disclosed herein, such as Example 6 The method is used to prepare it.

84. The method of claim 68, wherein the compound of formula (Ha) is processed by any of the exemplary methods disclosed herein, such as Example 11 The method is used to prepare it.

85. The method of claim 69, wherein the compound of formula (H) is processed by any of the exemplary methods disclosed herein, such as Example 8 The method is used to prepare it.

86. A method for preparing a compound of formula (A), (A)， The method includes the following steps: a) Reaction of compound of formula (Aw) with TMPMgCl The reaction of LiCl and BrCF2CF2Br prepares a compound of formula (Ax): (Oh) (Axe); b) Reacting the compound of formula (Ax) with NHS and EDC to prepare the compound of formula (Ay): (Yes); c) Mix the compound of formula (Ay) with... S -Methylisothiourea reaction to prepare compounds of formula (Az): (The); as well as d) React the compound of formula (Az) with NMI and DMA to prepare the compound of formula (A).

87. The method of claim 86, wherein steps b) and c) occur in the same reaction vessel.

88. A method for preparing a compound of formula (B), (B)， The method includes the following steps: a) Reacting compound of formula (Bv) with benzyl bromide to prepare compound of formula (Bw): (Bv) (Bw); b) Mix the compound of formula (Bw) with... s -BuLi, TMEDA, and acetaldehyde react to prepare compounds of formula (Bx') and mixtures of compounds of formula (Bx''): (Bx') (Bx''); c) Reacting the compound of formula (Bx') and a mixture of the compounds of formula (Bx'') with H2, Pd / C, and D(+)-10-camphorsulfonic acid to prepare the compound of formula (By): (By); d) Reacting the compound of formula (By) with (Boc)₂O to prepare the compound of formula (Bz): (Bz); as well as e) React the compound of formula (Bz) with a basic reagent to prepare the compound of formula (B).

89. The method of claim 88, wherein steps a) through e) occur in the same reaction vessel.

90. A method for preparing compounds of formula (Ha), (Ha), The method includes the following steps: a) Reacting compound of formula (Hu) with NBS to prepare compound of formula (Hv): (Huh) (Hv); b) React the compound of formula (Hv) with hydrogen over a platinum / vanadium / carbon catalyst to prepare the compound of formula (Hw); (Hw); c) Reacting the compound of formula (Hw) with NIS to prepare the compound of formula (Hr): (Hr)； d) Reacting the compound of formula (Hr) with di-tert-butyl dicarbonate to prepare the compound of formula (Hs): (Hs); e) React the compound of formula (Hs) with MeO2CCF2SO2F in the presence of CuI to prepare the compound of formula (Ht): (Ht); and f) Mix the compound of formula (Ht) with... i -PrMgCl∙LiCl and B(O i -Pr)3 reaction to prepare compound of formula (Ha).

91. A method for preparing compounds of formula (H), (H)， The method includes the following steps: a) Reacting compound of formula (Hu) with NBS to prepare compound of formula (Hv): (Huh) (Hv); b) React the compound of formula (Hv) with hydrogen over a platinum / vanadium / carbon catalyst to prepare the compound of formula (Hw); (Hw); c) Reacting the compound of formula (Hw) with PMBCl to prepare the compound of formula (Hx): (Hx); d) Reacting the compound of formula (Hx) with NIS to prepare the compound of formula (Hy): (He); e) React the compound of formula (Hy) with MeO2CCF2SO2F in the presence of CuI to prepare the compound of formula (Hz): (Hz); and f) Mix the compound of formula (Hz) with n -BuLi and B(OiPr)3 react to prepare the compound of formula (H).

92. The method according to claim 90 or 91, wherein steps a) through f) occur in the same reaction vessel.

93. The method of claim 90 or 91, wherein step b) comprises using a solvent, wherein the solvent is EtOAc or i PrOAc.

94. A compound of formula (Ha): (Ha).

95. A compound of formula (By): (By)。

Images