Solid forms of 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Abstract

Provided herein are solid forms of 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one and methods of their use in the treatment of cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 307,526, filed February 7, 2022, which is incorporated by reference herein in its entirety for all purposes.

[0002] Provided herein are solid forms of 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one and methods of their use in the treatment of cancer. [Background technology]

[0003] The compounds described herein, and their pharma- ceutically acceptable salts, are useful in the treatment of various types of cancer, including, for example, lung cancer and colorectal cancer.

[0004] It is not possible to predict whether a given molecule will crystallize in one or several crystalline forms, form solvates with different stoichiometries, or combine with other molecules to form stable cocrystals (Struct Bond (2009) 132:25-50, 27). The relative stability of the various crystalline forms, and the possibility of interconversion between forms or between amorphous and crystalline phases, for example, can significantly and unpredictably affect both physical and chemical properties, thus altering the processing, stability, bioavailability, formulation and / or storage of pharmaceutical compounds. There is no reliable predictability of the solid form and its usefulness as a crystalline or amorphous solid.

[0005] Thus, there is a need to identify and isolate stable forms of 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one. Summary of the Invention

[0006] Solutions to the above problems, as well as other problems in the art, are provided herein.

[0007] In one aspect, provided herein is a compound of formula 1 as described herein.

[0008] In another aspect, provided herein is a solid form of a compound of Formula 1. In one embodiment, the solid form is Compound A. In one embodiment, the solid form is Compound B. In one embodiment, the solid form is Compound C. In one embodiment, the solid form is Compound D. In one embodiment, the solid form is Compound E. In one embodiment, the solid form is Compound F.

[0009] In another aspect, provided herein is a solid form of Compound A corresponding to Compound A Form A described herein. In one embodiment, x is a solid form of Compound A corresponding to Compound A Form B described herein. In one embodiment, x is a solid form of Compound A corresponding to Compound A Form C described herein. In one embodiment, x is a solid form of Compound A corresponding to Compound A Form D described herein.

[0010] In another aspect, provided herein is a solid form of Compound B which corresponds to Compound B Form A. Further provided herein is a solid form of Compound C which corresponds to Compound C Form A. Further provided herein is a solid form of Compound D which corresponds to Compound D Form A. Further provided herein is a solid form of Compound E which corresponds to Compound E Form A. Further provided herein is a solid form of Compound F which corresponds to Compound F Form A.

[0011] In another aspect, provided herein is a method of treating a cancer that comprises a KRasG12C mutation in a patient having said cancer, comprising administering an effective amount of Compound 1 as described herein or a crystalline form corresponding to a form as described herein of Compound A, Compound B, Compound C, Compound D, Compound E or Compound F as described herein.

[0012] In yet another aspect, provided herein is a method of treating a cancer containing a KRasG12C mutation in a patient having said cancer, comprising determining whether the patient has the mutation, and if it is determined that the patient has the mutation, then administering an effective amount of Compound 1 as described herein, or a crystalline form corresponding to a form as described herein of Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F as described herein.

[0013] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to illustrate non-limiting embodiments. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows the XRPD spectrum of Compound A Form A. [Diagram 2] FIG. 2 shows the overlay of the TGA and DSC thermograms of Compound A Form A. [Diagram 3] FIG. 3 shows the DSC thermogram of Compound A Form A. [Figure 4] FIG. 4 shows the single crystal XRD of Compound A Form A. [Diagram 5] FIG. 5 shows the XRPD spectrum of Compound A Form B. [Figure 6] FIG. 6 shows the overlay of the TGA and DSC thermograms of Compound A Form B. [Figure 7] FIG. 7 shows the single crystal XRD of Compound A Form C. [Figure 8] FIG. 8 shows the XRPD spectrum of compound A form D. [Figure 9] FIG. 9 shows the DSC thermogram of Compound A Form D. [Figure 10] FIG. 10 shows the overlay of the TGA and DSC thermograms of Compound A Form D. [Figure 11] FIG. 11 shows an overlay of the XRPD spectra of Compound B Form A. [Figure 12] FIG. 12 shows the DSC thermogram of Compound B Form A. [Figure 13] FIG. 13 shows an overlay of the XRPD spectra of Compound C Form A. [Figure 14] FIG. 14 shows the overlay of the TGA and DSC thermograms for Compound C Form A. [Figure 15] FIG. 15 shows an overlay of the XRPD spectra of Compound D Form A. [Figure 16] FIG. 16 shows the overlay of the TGA and DSC thermograms for Compound D Form A. [Figure 17] FIG. 17 shows an overlay of the XRPD spectrum of Compound E Form A. [Figure 18] FIG. 18 shows an XRPD overlay of the slurry competition between Compound A Forms A and B. [Figure 19] FIG. 19 shows the XRPD of Compound A at various relative humidities (RH). [Figure 20] FIG. 20 shows the single crystal XRD of Compound A Form D. [Figure 21] FIG. 21 shows a diagram of the crystal packing of Compound A Form D looking down the crystallographic b-axis. [Figure 22] FIG. 22 shows a diagram of the crystal packing of Compound A Form D looking down the crystallographic c-axis. [Diagram 23] Figure 23 shows a view of the crystal packing of form C looking down the crystallographic b-axis. Only the major components of disorder are shown. [Figure 24] Figure 24 shows a view of the crystal packing of Form C looking down the crystallographic c-axis. Only the major components of disorder are shown. [Diagram 25] FIG. 25 shows a comparison of the crystal packing between hydrated form D and anhydrous form C, viewed along the crystallographic b-axis. [Figure 26] FIG. 26 shows an overlay of the XRPD spectrum of compound F form A. [Figure 27] FIG. 27 shows the overlay of the TGA and DSC thermograms of Compound F Form A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J.Wiley&Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989).In carrying out the present invention, any method, device and material similar or equivalent to those described herein can be used.

[0016] The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references mentioned herein are incorporated by reference in their entirety.

[0017] As used herein, unless otherwise specified, the terms "about" and "approximately," when referring to a dose, amount, or weight percent of a component of a composition or dosage form, means a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. The equivalent dose, amount, or weight percent can be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percent.

[0018] As used herein, unless otherwise indicated, the terms "about" and "approximately" when referring to a numerical value or range of values ​​used to characterize a particular solid form (e.g., XRPD peak value) described herein, indicate that the value or range of values ​​may deviate from the given value to an extent that would be considered reasonable by one of ordinary skill in the art while still describing the solid form. In one embodiment, the value of the XRPD peak position may vary by up to ±0.1° 2θ (or ±0.05° 2θ) while still describing the particular XRPD peak.

[0019] As used herein, unless otherwise specified, "pure" means substantially free of other crystalline or amorphous solids or other chemical compounds, and contains 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 achieved, for example, by diffraction analysis, thermal analysis, elemental combustion analysis, and / or spectroscopic analysis. Detection of other chemical compounds can be achieved, for example, by mass spectrometry, spectroscopic analysis, thermal analysis, elemental combustion analysis, and / or chromatographic analysis.

[0020] Unless otherwise specified, the terms "solvate" and "solvated" as used herein refer to a solid form of a substance that contains a solvent. The terms "hydrate" and "hydrated" refer to a solvate in which the solvent is water. As used herein, the terms "solvate" and "solvated" can also refer to a solvate of a salt, co-crystal, or molecular complex. As used herein, the terms "hydrate" and "hydrated" can also refer to a hydrate of a salt, co-crystal, or molecular complex.

[0021] The term "pharmaceutical acceptable" refers to a diluent, excipient, or carrier in a formulation that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0022] "Compound 1" has the structure: It has TIFF2025505655000001.tif49170 and has the name 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one.

[0023] "Compound A" has the structure: Refers to the compound having TIFF2025505655000002.tif48170.

[0024] In some embodiments, Compound A is also described as the adipate salt of Compound 1.

[0025] "Compound B" has the structure: Refers to the compound having TIFF2025505655000003.tif49170.

[0026] In some embodiments, Compound B is also described as Compound 1 fumarate salt.

[0027] "Compound C" has the structure: Refers to the compound having TIFF2025505655000004.tif49170.

[0028] In some embodiments, compound C is also described as the ethylene sulfonate of compound 1.

[0029] "Compound D" has the structure: Refers to the compound having TIFF2025505655000005.tif49170.

[0030] In some embodiments, compound D is also described as the besylate salt of compound 1.

[0031] "Compound E" has the structure: Refers to the compound having TIFF2025505655000006.tif49170.

[0032] In some embodiments, Compound E is also described as Compound 1 mesylate.

[0033] "Compound F" has the structure: Refers to the compound having TIFF2025505655000007.tif49170.

[0034] In some embodiments, compound F is also described as the acetate salt of compound 1.

[0035] The term "solid form" refers to a physical form that is not primarily in a liquid or gaseous state. The solid form may be a crystalline form or a mixture thereof. In certain embodiments, the solid form may be a liquid crystal. In certain embodiments, the solid form of Compound A is a solid form corresponding to Compound A Form A, Compound A Form B, Compound A Form C, Compound A Form D, Compound B Form A, Compound C Form A, Compound D Form A, or Compound E Form A, or Compound F Form A, or a mixture thereof.

[0036] In one embodiment, the solid form of Compound A is the adipate salt corresponding to Form A. In one embodiment, the solid form of Compound A is the adipate salt corresponding to Form B. In another embodiment, the solid form of Compound A is the adipate salt corresponding to Form C. In yet another embodiment, the solid form of Compound A is the adipate salt corresponding to Form D. In one embodiment, the solid form of Compound B is the fumarate salt corresponding to Form A. In another embodiment, the solid form of Compound C is the ethylenesulfonate salt corresponding to Form A. In another embodiment, the solid form of Compound D is the besylate salt corresponding to Form A. In another embodiment, the solid form of Compound E is the mesylate salt corresponding to Form A. In another embodiment, the solid form of Compound F is the acetate salt corresponding to Form A.

[0037] The term "crystalline form" or "crystalline form" refers to a solid form that is crystalline. In certain embodiments, the crystalline form of the compounds described herein may be substantially free of amorphous solids and / or other crystalline forms. In certain embodiments, the crystalline form of the compounds described herein may contain less than about 1% by weight, less than about 2% by weight, less than about 3% by weight, less than about 4% by weight, less than about 5% by weight, less than about 6% by weight, less than about 7% by weight, less than about 8% by weight, less than about 9% by weight, less than about 10% by weight, less than about 15% by weight, less than about 20% by weight, less than about 25% by weight, less than about 30% by weight, less than about 35% by weight, less than about 40% by weight, less than about 45% by weight, or less than about 50% by weight of one or more amorphous solids and / or other crystalline forms. In certain embodiments, the crystalline form described herein is pure. In certain embodiments, the crystalline forms of the compounds described herein may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% pure. In some embodiments, the crystalline forms are solid forms described herein.

[0038] The term "amorphous" or "amorphous solid" refers to a solid form that is not substantially crystalline as determined by X-ray diffraction. In particular, the term "amorphous solid" refers to a disordered solid form, i.e., a solid form that lacks long-range crystalline order. In certain embodiments, the amorphous solid of the compounds described herein may be substantially free of other amorphous solids and / or crystalline forms. In certain embodiments, the amorphous solid may be pure. In certain embodiments, the amorphous solid of the compounds described herein may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% pure.

[0039] A "patient" or "subject" is defined herein to include animals such as mammals, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens, turkeys, quails, or guinea pigs, and in one embodiment is a mammal, and in another embodiment is a human. In one embodiment, the subject is a human having or at risk for cancer.

[0040] As used herein, "essentially" refers to at least 90%, at least 95%, at least 98% or at least 99%.

[0041] In the description herein, if there is a discrepancy between a depicted structure and the name given to that structure, the depicted structure shall prevail.Furthermore, if the stereochemistry of a structure or a portion of a structure is not shown, for example, with a bold wedge or a dotted line, that structure or portion of the structure is intended to encompass all of its stereoisomers.However, in some cases where multiple chiral centers exist, structures and names may be represented as single enantiomers to aid in describing the relative stereochemistry.

[0042] Unless otherwise indicated, "a compound of the formula" or "a compound of formula" or "compounds of the formula" or "compounds of formula" refers to any compound selected from the genus of compounds defined by that formula (including any pharma- ceutically acceptable salts of any such compound, unless otherwise indicated).

[0043] The terms "treat", "treating" and "treatment" refer to a clinical intervention designed to change the natural course of the patient or cells being treated during the course of clinical pathology. Desirable effects of treatment include reducing the rate of disease progression, ameliorating or alleviating the disease state and improving remission or prognosis. For example, a patient is successfully "treated" if one or more symptoms associated with cancer as described herein are reduced or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancerous cells, reducing symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other medications required to treat the disease, and / or prolonging the patient's survival.

[0044] The term "delay in progression" of disease refers to postpone, prevent, delay, retard, stabilize and / or postpone the onset of cancer as described herein. This delay can be of various lengths of time depending on the history of cancer and / or the patient being treated. As will be appreciated by those skilled in the art, a sufficient or significant delay can essentially encompass prevention in that the patient does not develop cancer.

[0045] An "effective amount" is at least the minimum amount required to achieve a measurable improvement in cancer as described herein. The effective amount herein may vary depending on factors such as the disease state, age, sex and weight of the patient, and the ability of the agent to induce a desired response in the patient. An effective amount is also an amount in which the therapeutically beneficial effects outweigh any toxic or adverse effects of the treatment. Beneficial or desired results include results such as eliminating or reducing risk, reducing severity, delaying the onset of the disease (including the biochemical, histological and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the development of the disease), reducing one or more symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other drugs required to treat the disease, enhancing the effect of another drug by targeting, etc., delaying the progression of the disease, and / or prolonging survival. In some embodiments, an effective amount of a drug may have an effect in reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing or stopping) cancer cell invasion into peripheral organs; inhibiting (i.e., slowing or stopping) tumor metastasis; inhibiting (i.e., slowing or stopping) tumor growth; and / or alleviating one or more symptoms associated with a disorder. An effective amount may be administered in one or more administrations. An effective amount of a drug, compound, pharmaceutical composition or combination therapy described herein may be an amount sufficient to directly or indirectly achieve a therapeutic treatment. As clinically understood, an effective amount of a drug, compound or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition or combination therapy. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount when a desired result is obtained or achieved in combination with one or more other agents.

[0046] Exemplary Solvent Abbreviations Used herein [Table 1]

[0047] polymorphism Provided herein are solid forms, formulations containing such solid forms, and methods of using such solid forms of Compound 1 (e.g., Compounds A, B, C, D, or E). In one embodiment, provided herein is a solid form of Compound 1. Compound 1 can be a free base as described herein that exists in an amorphous solid form.

[0048] In one embodiment, Compound 1 is a crystalline adipate salt having the formula of Compound A described herein. In one embodiment, Compound A exists in one or more forms described herein. In one such embodiment, Compound A comprises Compound A Form A described herein. In one such embodiment, Compound A comprises Compound A Form B described herein. In one such embodiment, Compound A comprises Compound A Form C described herein. In one such embodiment, Compound A comprises Compound A Form D described herein. In another such embodiment, Compound A consists of a single form (e.g., A, B, C, D) described herein. In one embodiment, a compound or pharmaceutical composition described herein comprises two or more forms of Compound A. In one such embodiment, a compound described herein or a pharma- ceutically acceptable salt thereof comprises a mixture of Compound A Form A and Compound A Form D described herein. In one embodiment, a compound described herein or a pharma- ceutically acceptable salt thereof comprises a mixture of Compound A Form A and Compound A Form C described herein.

[0049] In another embodiment, Compound 1 is a crystalline fumarate salt having the formula of Compound B described herein. In one such embodiment, Compound B comprises Compound B Form A described herein.

[0050] In another embodiment, Compound 1 is a crystalline ethylene sulfonate salt having the formula of Compound C described herein. In one such embodiment, Compound C comprises Compound C Form A described herein.

[0051] In another embodiment, Compound 1 is a crystalline besylate salt having the formula of Compound D described herein. In one such embodiment, Compound D comprises Compound D Form A described herein.

[0052] In another embodiment, Compound 1 is a crystalline mesylate salt having the formula of Compound E described herein. In one such embodiment, Compound E comprises Compound E Form A described herein.

[0053] In another embodiment, Compound 1 is a crystalline acetate salt having the formula of Compound F described herein. In one such embodiment, Compound F comprises Compound F Form A described herein.

[0054] Solid forms can be characterized by physical properties, such as stability, solubility and dissolution rate, density, compressibility, hardness, morphology, cleavage, adhesion, solubility, water absorption, electrical properties, thermal behavior, solid state reactivity, physical stability, and chemical stability, that affect certain processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization) that make a particular solid form suitable for manufacturing solid dosage forms. Such properties can be determined using certain analytical chemistry techniques, including the solid state analytical techniques described herein (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis), and are unpredictable. No polymorph screening protocol can guarantee the identification of all crystalline forms of a given molecule.

[0055] Techniques for characterizing crystalline forms and amorphous solids include, for example, thermal analysis (e.g., differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), thermogravimetric analysis (TGA), and hot stage microscopy), spectroscopy (e.g., infrared, Raman, and solid-state nuclear magnetic resonance), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy such as infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy ( 1These include NMR (including H NMR and F NMR), scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility and dissolution studies, ultra-high performance liquid chromatography (UHPLC), and proton nuclear magnetic resonance spectroscopy.

[0056] The purity of the solid forms provided herein can be determined by standard analytical methods such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, ultra-performance liquid chromatography (UHPLC), and mass spectrometry (MS).

[0057] Compound A: Form A: In some embodiments, provided herein is a solid form corresponding to Compound A, designated as Form A. Form A is an adipic acid salt crystalline solid form of Compound 1. In one embodiment, Form A of Compound A is anhydrous. In one embodiment, Form A of Compound A is obtained from acetone, THF, or EtOAc. In one embodiment, Form A of Compound A is obtained from acetone. In another embodiment, Form A of Compound A is obtained from THF. In another embodiment, Form A of Compound A is obtained from EtOAc. In one embodiment, the stoichiometric ratio of adipic acid:free base of A form of Compound A is 0.9, 1.0, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, or 1.10. In one such embodiment, the stoichiometric ratio of adipic acid:free base of Form A of Compound A is 1.06.

[0058] In one embodiment, the solid form provided herein, e.g., Form A of Compound A, is an adipate salt and is substantially crystalline as shown by powder X-ray diffraction pattern (XRPD) measurement. In one embodiment, the XRPD of the solid form provided herein, e.g., Form A of Compound A, is substantially as shown in Figure 1. In another embodiment, the solid form provided herein, e.g., Form A of Compound A, is approximately 4.8059, 7.506, 8.5157, 9.2973, 9.6474, 11.0365, 11.1828, 11.677, 12.7936, 14.5086, 15.0086, 16.0086, 17.0086, 18.0086, 19.0086, 20.0086, 21.0086, 22.0086, 23.0086, 24.0086, 25.0086, 26.0086, 27.0086, 28.0086, 29.0086, 30.0086, 31.0086, 32.0086, 33.0086, 34.0086, 35.0086, 36.0086, 37.0086, 38.0086, 39.0086, 40.0086, 41.0086, 42.0086, 43.0086, 44.0086, 45.0086, 46.0086, 47.0086, 48.0086, 49.0086, 50.008 having one or more characteristic XRPD peaks at 15.4059, 16.1353, 16.4193, 16.6719, 16.9847, 18.7038, 18.9135, 19.3881, 19.7517, 19.9746, 20.5178, 21.1487, 21.4666, 21.9673, or 22.1828 ± 0.1 degrees 2θ. In another embodiment, a solid form provided herein, e.g., Form A of Compound A, has a molecular weight of about 4.8059, 7.506, 8.5157, 9.2973, 9.6474, 11.0365, 11.1828, 11.677, 12.7936, 14.5086, 15.4059, 16.028, 17.097, 18.097, 19.077, 20.067, 21.057, 22.047, 23.027, 24.067, 25.047, 26.027, 27.027, 28.027, 29.027, 30.027, 31.027, 32.027, 33.027, 34.027, 35.027, 36.027, 37.027, 38.027, 39.027, 40.027, 41.027, 42.027, 43.027, 44.027, 45.027, 46.027, 47.027, 48.027, 49.027, 50.027, 51.027, 52.027, 53.027, 54.027, 55.027, 56.027, 57.027, 58.027, 59.027, 60.027, 61.027, 62.027, 63.027, 64.027, having at least 3, 5, 10, 15, or 20 characteristic XPRD peaks at 16.1353, 16.4193, 16.6719, 16.9847, 18.7038, 18.9135, 19.3881, 19.7517, 19.9746, 20.5178, 21.1487, 21.4666, 21.9673, or 22.1828 ± 0.1 degrees 2θ.In yet another embodiment, a solid form provided herein, e.g., Form A of Compound A, has a molecular weight of about 4.8059, 7.506, 8.5157, 9.2973, 9.6474, 11.0365, 11.1828, 11.677, 12.7936, 14.5086, 15.4059, 16.1353, 16.4193, 17.0973, 18.0973, 19.0973, 20.0973, 21.0973, 22.0973, 23.0973, 24.0973, 25.0973, 26.0973, 27.0973, 28.0973, 29.0973, 30.0973, 31.0973, 32.0973, 33.0973, 34.0973, 35.0973, 36.0973, 37.0973, 38.0973, 39.0973, 40.0973, 41.0973, 42.0973, 43.0973, 44.0973, 45.0973, 46.0973, 47.0973, 48.0973, 49.0973, 50.0973, 51.0973, 52.0973, 53.0973, 54.0973, 55.0973, 56.0973, 57.0973, 58. having at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or all characteristic XPRD peaks at 16.6719, 16.9847, 18.7038, 18.9135, 19.3881, 19.7517, 19.9746, 20.5178, 21.1487, 21.4666, 21.9673, or 22.1828±0.1 degrees 2θ.

[0059] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound A, has a molecular weight of about 4.8059, 7.506, 8.5157, 9.2973, 9.6474, 11.0365, 11.1828, 11.677, 12.7936, 14.5086, 15.0086, 16.0086, 17.0086, 18.0086, 19.0086, 20.0086, 21.0086, 22.0086, 23.0086, 24.0086, 25.0086, 26.0086, 27.0086, 28.0086, 29.0086, 30.0086, 31.0086, 32.0086, 33.0086, 34.0086, 35.0086, 36.0086, 37.0086, 38.0086, 39.0086, 40.0086, 41.0086, 42.0086, 43.0086, 44.0086, 45.0086, 46.0086, 47.0086, 48.0086, 49.0086, 50.0086, 51.0086, 52.0086, 53.0086, 54.0086, 55.0086, 56.0086, 57.0086, 58.0086, 59. have at least ten characteristic XPRD peaks at 5.4059, 16.1353, 16.4193, 16.6719, 16.9847, 18.7038, 18.9135, 19.3881, 19.7517, 19.9746, 20.5178, 21.1487, 21.4666, 21.9673, or 22.1828 ± 0.1 degrees 2θ. In another embodiment, a solid form provided herein, e.g., Form A of Compound A, has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XPRD peaks at approximately 9.6474, 11.0365, 14.5086, 15.4059, 16.1353, 16.4193, 16.6719, 18.7038, 18.9135, or 21.9673 ± 0.1 degrees 2θ, e.g., as shown in FIG. 1 and found in Table 1 herein.

[0060] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound A, has a molecular weight of about 4.8059, 7.506, 8.5157, 9.2973, 9.6474, 11.0365, 11.1828, 11.677, 12.7936, 14.5086, 15.0087, 16.0089, 17.0089, 18.0089, 19.0089, 20.0089, 21.0089, 22.0089, 23.0089, 24.0089, 25.0089, 26.0089, 27.0089, 28.0089, 29.0089, 30.0089, 31.0089, 32.0089, 33.0089, 34.0089, 35.0089, 36.0089, 37.0089, 38.0089, 39.0089, 40.0089, 41.0089, 42.0089, 43.0089, 44.0089, 45.0089, 46.0089, 47.0089, 48.0089, 49.0089, 50.0089, 51.0089, 52.0089, 53.0089, 54.0089, 55.0089, 56.0089, 57.0089, 58.0089, 59. 15.4059, 16.1353, 16.4193, 16.6719, 16.9847, 18.7038, 18.9135, 19.3881, 19.7517, 19.9746, 20.5178, 21.1487, 21.4666, 21.9673, or 22.1828 ± 0.1 °2θ. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound A, has at least 1, 2, 3, 4, or 5 characteristic XPRD peaks at approximately 9.6474, 11.0365, 15.4059, 16.4193, 18.7038 ± 0.1 °2θ, e.g., as shown in Figure 1 and found in Table 1 herein. In one embodiment, a solid form provided herein, e.g., Form A of Compound A, has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at 9.6474, 11.0365, 15.4059, 16.4193, 18.7038 (±0.1° 2θ).

[0061] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound A, has a molecular weight of about 4.8059, 7.506, 8.5157, 9.2973, 9.6474, 11.0365, 11.1828, 11.677, 12.7936, 14.5086, 15.0086, 16.0086, 17.0086, 18.0086, 19.0086, 20.0086, 21.0086, 22.0086, 23.0086, 24.0086, 25.0086, 26.0086, 27.0086, 28.0086, 29.0086, 30.0086, 31.0086, 32.0086, 33.0086, 34.0086, 35.0086, 36.0086, 37.0086, 38.0086, 39.0086, 40.0086, 41.0086, 42.0086, 43.0086, 44.0086, 45.0086, 46.0086, 47.0086, 48.0086, 49.0086, 50.0086, 51.0086, 52.0086, 53.0086, 54.0086, 55.0086, 56.0086, 57.0086, 58.0086, 59. having at least 15 characteristic XPRD peaks at 5.4059, 16.1353, 16.4193, 16.6719, 16.9847, 18.7038, 18.9135, 19.3881, 19.7517, 19.9746, 20.5178, 21.1487, 21.4666, 21.9673, or 22.1828 ± 0.1 degrees 2θ. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound A, has a molecular weight of about 4.8059, 7.506, 8.5157, 9.2973, 9.6474, 11.0365, 11.1828, 11.677, 12.7936, 14.5086, 15.0086, 16.0086, 17.0086, 18.0086, 19.0086, 20.0086, 21.0086, 22.0086, 23.0086, 24.0086, 25.0086, 26.0086, 27.0086, 28.0086, 29.0086, 30.0086, 31.0086, 32.0086, 33.0086, 34.0086, 35.0086, 36.0086, 37.0086, 38.0086, 39.0086, 40.0086, 41.0086, 42.0086, 43.0086, 44.0086, 45.0086, 46.0086, 47.0086, 48.0086, 49.0086, 50.0086, 51.0086, 52.0086, 53.0086, 54.0086, 55.0086, 56.0086, 57.0086, 58.0086, 59. having at least 20 characteristic XPRD peaks at 5.4059, 16.1353, 16.4193, 16.6719, 16.9847, 18.7038, 18.9135, 19.3881, 19.7517, 19.9746, 20.5178, 21.1487, 21.4666, 21.9673, or 22.1828 ± 0.1 degrees 2θ. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound A, has a molecular weight of about 4.8059, 7.506, 8.5157, 9.2973, 9.6474, 11.0365, 11.1828, 11.677, 12.7936, 14.508, 15.018, 16.067, 17.055, 18.047, 19.087, 20.067, 21.037, 22.027, 23.067, 24.047, 25.027, 26.067, 27.027, 28.047, 29.027, 30.027, 31.027, 32.027, 33.027, 34.027, 35.027, 36.027, 37.027, 38.027, 39.027, 40.027, 41.027, 42.027, 43.027, 44.027, 45.027, 46.027, 47.027, 48.027, 49.027, 50.027, 51.027, 52.027, 53.027, 54.027, 55.027, 56.027, 57.027, 58.027, 59.027, 60.027, 61.027, 62.027, 63.027, 64.027, 6, 15.4059, 16.1353, 16.4193, 16.6719, 16.9847, 18.7038, 18.9135, 19.3881, 19.7517, 19.9746, 20.5178, 21.1487, 21.4666, 21.9673, and 22.1828 ± 0.1 degrees 2θ. [Table 2]

[0062] In one embodiment described herein, Form A of Compound A has a TGA thermogram substantially as shown in FIG. 2 and contains about 2% weight loss up to 100° C.

[0063] In one such embodiment, Form A of Compound A has a DSC thermogram corresponding to Figure 2, which contains two endotherms at 68.8°C and 169.1°C.

[0064] In one embodiment, Form A of Compound A has a DSC thermogram corresponding to FIG. 3, which contains one endotherm (peak) at 173.3° C.

[0065] The single crystal XRD of Compound A Form A is shown in Figure 4. The absolute stereochemistry was unambiguously determined from the diffraction data and is shown in Figure 4.

[0066] Compound A: Form B In some embodiments, provided herein is a solid form corresponding to Compound A designated as Form B. Form B is a crystalline solid form of Compound A. In one embodiment, Form B of Compound A is obtained from anti-solvent addition in DCM / toluene and then transferred to 5° C. In one embodiment, Form B of Compound A is anhydrous. In one embodiment, no morphological change is observed after air drying overnight at RT. In one embodiment, the stoichiometric ratio of adipic acid:free base of Form B of Compound A is 1.5, 1.55, 1.6, 1.65, 1.7, 1.8, 1.9, 2, 2.05 or 2.10. In one embodiment, the stoichiometric ratio of adipic acid:free base of Form B of Compound A is 1.65 or 2.10.

[0067] In one embodiment, the solid form provided herein, e.g., Form B of Compound A, is an adipate salt and is substantially crystalline as shown by powder X-ray diffraction pattern (XRPD) measurements. In one embodiment, the XRPD of the solid form provided herein, e.g., Form B of Compound A, is substantially as shown in Figure 5. In another embodiment, the solid form provided herein, e.g., Form B of Compound A, has one or more characteristic XRPD peaks at approximately 5.2063, 8.8524, 11.1301, 12.3721, 14.63, 15.6885, 17.7161, 18.2857, 19.8008, 21.9253, or 25.1335 ± 0.1 ° 2θ, e.g., as shown in Figure 5 and as found in Table 2 herein. In another embodiment, a solid form provided herein, e.g., Form B of Compound A, has at least 3, 5, 7, 9, or 10 characteristic XPRD peaks at approximately 5.2063, 8.8524, 11.1301, 12.3721, 14.63, 15.6885, 17.7161, 18.2857, 19.8008, 21.9253, or 25.1335±0.1 degrees 2θ, e.g., as shown in FIG. 5 and found in Table 2 herein. In yet another embodiment, a solid form provided herein, e.g., Form B of Compound A, has characteristic XPRD peaks at at least 5, 6, 7, 8, 9, 10, or all at approximately 5.2063, 8.8524, 11.1301, 12.3721, 14.63, 15.6885, 17.7161, 18.2857, 19.8008, 21.9253, or 25.1335±0.1 degrees 2θ, e.g., as shown in FIG. 5 and found in Table 2 herein.

[0068] In yet another embodiment, a solid form provided herein, e.g., Form B of Compound A, has at least ten characteristic XPRD peaks at approximately 5.2063, 8.8524, 11.1301, 12.3721, 14.63, 15.6885, 17.7161, 18.2857, 19.8008, 21.9253, or 25.1335±0.1 degrees 2θ, e.g., as shown in FIG. 5 and found in Table 2 herein. In another embodiment, a solid form provided herein, e.g., Form B of Compound A, has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XPRD peaks at approximately 5.2063, 8.8524, 12.3721, 14.63, 15.6885, 17.7161, 18.2857, 19.8008, 21.9253, or 25.1335 ± 0.1 degrees 2θ, e.g., as shown in Figure 5 and found in Table 2 herein.

[0069] In yet another embodiment, a solid form provided herein, e.g., Form B of Compound A, has at least five characteristic XPRD peaks at about 5.2063, 8.8524, 11.1301, 12.3721, 14.63, 15.6885, 17.7161, 18.2857, 19.8008, 21.9253, or 25.1335±0.1 degrees 2θ, e.g., as shown in Figure 5 and found in Table 2 herein. In yet another embodiment, a solid form provided herein, e.g., Form B of Compound A, has at least one, two, three, four, or five characteristic XPRD peaks at about 5.2063, 14.63, 17.7161, 21.9253, 25.1335±0.1 degrees 2θ, e.g., as shown in Figure 5 and found in Table 2 herein. In one embodiment, a solid form provided herein, e.g., Form B of Compound A, has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at 5.2063, 14.63, 17.7161, 21.9253, 25.1335 (±0.1 degrees 2θ). [Table 3]

[0070] In one embodiment described herein, Compound A Form B has a TGA thermogram substantially as shown in Figure 6, including a weight loss of about 2.2% up to 100°C. After heating Compound A Form to about 90°C under nitrogen, no change in form may be observed.

[0071] In one such embodiment, Form B of Compound A has a DSC thermogram corresponding to Figure 6, containing two broad endotherms at 55.7°C and 109.6°C and a small endotherm at 158.8°C.

[0072] Compound A: Form C: In some embodiments, provided herein is a solid form corresponding to Compound A, designated as Form C. Form C is a crystalline solid form of Compound A. In one embodiment, Form C of Compound A is an anhydrate. In one such embodiment, Form C of Compound A is a variant with a low occupancy of Form D. In one embodiment, Form C is a disordered lattice when compared to Form A or Form D of Compound A. In another such embodiment, the asymmetric unit comprises one molecule of Compound A with a positionally disordered methylpyrrolidine ring and one adipate anion (approximately 50 / 50) with one COO-group disordered across two sites. (See Examples below). In one embodiment, Form C of Compound A is formed by dehydrating Form D of Compound A. In one such embodiment, the percentage of Form D of Compound A after drying is less than 20%, 15%, 12%, 10%, 8%, 6%, 5%, 2% or 1%.

[0073] In one embodiment, the solid form provided herein, e.g., Form C of Compound A, is an adipate salt and is substantially crystalline as shown by powder X-ray diffraction pattern (XRPD) measurement. In one embodiment, the XRPD of the solid form provided herein, e.g., Form C of Compound A, is equivalent to Form A of Compound A.

[0074] The single crystal XRD of Compound A Form C is shown in FIG.

[0075] Compound A: Form D: In some embodiments, provided herein is a solid form corresponding to Compound A designated as Form D. Form D is a crystalline solid form of Compound B. In one embodiment, Form D of Compound A is a hemihydrate. In one embodiment, Form D of Compound A is formed by exposing Form A or Form C of Compound A described herein to increasing percentages of relative humidity (rh). In one embodiment, Form D can be dried, thereby reforming Form A and / or Form C of Compound A. In one such embodiment, the percentage of Form D of Compound A after drying is less than 20%, 15%, 12%, 10%, 8%, 6%, 5%, 2% or 1%.

[0076] In one embodiment, the solid form provided herein, e.g., Form D of Compound A, is an adipate salt and is substantially crystalline as shown by powder X-ray diffraction pattern (XRPD) measurement. In one embodiment, the XRPD of the solid form provided herein, e.g., Form D of Compound A, is substantially as shown in Figure 8. In another embodiment, a solid form provided herein, e.g., Form D of Compound A, has one or more characteristic XRPD peaks at approximately 7.4529, 9.309, 9.7745, 11.0487, 11.2178, 11.6936, 12.8642, 14.65, 14.9254, 15.2452, 15.5252, 16.0821, 16.3536, 16.6345, 17.1089, 17.3151, 18.6477, 18.7908, 19.5758, 19.8874, 20.2, 20.6308, 21.0403, 21.6587, or 22.0397 ± 0.1 degrees 2θ, e.g., as shown in FIG. 8 and found in Table 3 herein. In another embodiment, a solid form provided herein, e.g., Form D of Compound A, has a molecular weight of about 7.4529, 9.309, 9.7745, 11.0487, 11.2178, 11.6936, 12.8642, 14.65, 14.9254, 15.2452, 15.525, 16.0625, 17.0515, 18.0425, 19.0225, 20.0625, 21.0225, 22.0625, 23.0625, 24.0625, 25.0625, 26.0625, 27.0625, 28.0625, 29.0625, 30.0625, 31.0625, 32.0625, 33.0625, 34.0625, 35.0625, 36.0625, 37.0625, 38.0625, 39.0625, 40.0625, 41.0625, 42.0625, 43.0625, 44.0625, 45.0625, 46.0625, 47.0625, 48.0625, 49.0625, 50.0625, 51.0625, 52.0625, 53.0625, 54.0625, 55.0625, 56.0625, 57.0625, 58.0625, 59.0 2, 16.0821, 16.3536, 16.6345, 17.1089, 17.3151, 18.6477, 18.7908, 19.5758, 19.8874, 20.2, 20.6308, 21.0403, 21.6587, or 22.0397 ± 0.1 degrees 2θ.In yet another embodiment, a solid form provided herein, e.g., Form D of Compound A, has a molecular weight of about 7.4529, 9.309, 9.7745, 11.0487, 11.2178, 11.6936, 12.8642, 14.65, 14.9254, 15.2452, 15.5252, 16.0821, 16.3536, 17.4936, 18.5136, 19.66136, 20.06136, 21.05136, 22.04136, 23.02136, 24.06136, 25.09136, 26.06136, 27.06136, 28.06136, 29.06136, 30.06136, 31.06136, 32.06136, 33.06136, 34.06136, 35.06136, 36.06136, 37.06136, 38.06136, 39.06136, 40.06136, 41.06136, 42.06136, 43.06136, 44.06136, 45.06136, 46.06136, 47.06136, 48.06136, 49.06136, 50.06136, 51.06136, 52.06136, 53.06136, 54. 16.6345, 17.1089, 17.3151, 18.6477, 18.7908, 19.5758, 19.8874, 20.2, 20.6308, 21.0403, 21.6587, or 22.0397 ± 0.1 degrees 2θ.

[0077] In yet another embodiment, a solid form provided herein, e.g., Form D of Compound A, has a molecular weight of about 7.4529, 9.309, 9.7745, 11.0487, 11.2178, 11.6936, 12.8642, 14.65, 14.9254, 15.2452, e.g., as shown in FIG. 8 and found in Table 3 herein. , 15.5252, 16.0821, 16.3536, 16.6345, 17.1089, 17.3151, 18.6477, 18.7908, 19.5758, 19.8874, 20.2, 20.6308, 21.0403, 21.6587, or 22.0397 ± 0.1 degrees 2θ. In yet another embodiment, a solid form provided herein, e.g., Form D of Compound A, has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XPRD peaks at approximately 15.2452, 11.0487, 18.6477, 18.7908, 9.7745, 11.2178, 16.6345, 16.0821, 16.3536, or 20.6308 ± 0.1 degrees 2θ, e.g., as shown in FIG. 8 and found in Table 3 herein.

[0078] In yet another embodiment, a solid form provided herein, e.g., Form D of Compound A, has a molecular weight of about 7.4529, 9.309, 9.7745, 11.0487, 11.2178, 11.6936, 12.8642, 14.65, 14.9254, 15.245, e.g., as shown in FIG. 8 and found in Table 3 herein. 8, 17.3151, 18.6477, 18.7908, 19.5758, 19.8874, 20.2, 20.6308, 21.0403, 21.6587, or 22.0397 ± 0.1 °2θ. In yet another embodiment, a solid form provided herein, e.g., Form D of Compound A, has at least 1, 2, 3, 4, or 5 characteristic XPRD peaks at approximately 9.7745, 11.0487, 15.2452, 18.6477, 18.7908 ± 0.1 °2θ, e.g., as shown in Figure 8 and found in Table 3 herein. In one embodiment, a solid form provided herein, e.g., Form D of Compound A, has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at 9.7745, 11.0487, 15.2452, 18.6477, 18.7908 (±0.1 degrees 2θ).

[0079] In yet another embodiment, a solid form provided herein, e.g., Form D of Compound A, has a molecular weight of about 7.4529, 9.309, 9.7745, 11.0487, 11.2178, 11.6936, 12.8642, 14.65, 14.9254, 15.2452, e.g., as shown in FIG. 8 and found in Table 3 herein. , 15.5252, 16.0821, 16.3536, 16.6345, 17.1089, 17.3151, 18.6477, 18.7908, 19.5758, 19.8874, 20.2, 20.6308, 21.0403, 21.6587, or 22.0397 ± 0.1 degrees 2θ.

[0080] In yet another embodiment, a solid form provided herein, e.g., Form D of Compound A, has a molecular weight of about 7.4529, 9.309, 9.7745, 11.0487, 11.2178, 11.6936, 12.8642, 14.65, 14.9254, 15.2452, e.g., as shown in FIG. 8 and found in Table 3 herein. , 15.5252, 16.0821, 16.3536, 16.6345, 17.1089, 17.3151, 18.6477, 18.7908, 19.5758, 19.8874, 20.2, 20.6308, 21.0403, 21.6587, or 22.0397 ± 0.1 degrees 2θ.

[0081] In yet another embodiment, a solid form provided herein, e.g., Form D of Compound A, has characteristic XPRD peaks at approximately all of 7.4529, 9.309, 9.7745, 11.0487, 11.2178, 11.6936, 12.8642, 14.65, 14.9254, 15.2452, 15.5252, 16.0821, 16.3536, 16.6345, 17.1089, 17.3151, 18.6477, 18.7908, 19.5758, 19.8874, 20.2, 20.6308, 21.0403, 21.6587, or 22.0397 ± 0.1 degrees 2θ, e.g., as shown in FIG. 8 and found in Table 3 herein.

[0082] In one embodiment, the single crystal XRD of Compound A Form D is provided in Figure 21. Crystal packing and other scXRD information of Compound A Form D is as described herein (e.g., in the Examples). [Table 4]

[0083] In one embodiment described herein, Compound A Form D has a DSC thermogram substantially as shown in Figure 9. In one embodiment, the DSC of Compound A Form D has one endotherm (peak) at about 173.4°C.

[0084] In one embodiment described herein, Form B of Compound A has a TGA thermogram substantially as shown in FIG. 10 and contains about 1.4% weight loss up to 100° C.

[0085] Compound B: Form A In some embodiments, provided herein is a solid form corresponding to Compound B designated as Form A. Compound B Form A is a crystalline solid form of the fumarate salt of Compound B. In one embodiment, Compound B Form A is obtained from acetone and air-dried at RT. In one embodiment, Compound B Form A is anhydrous.

[0086] In one embodiment, Compound B Form A was heated to 100° C. under N 2 protection, and no morphological changes were observed before and after cooling and exposure to ambient conditions.

[0087] In one embodiment, the solid form provided herein, e.g., Form A of Compound B, is a fumarate salt and is substantially crystalline as shown by powder X-ray diffraction pattern (XRPD) measurement. In one embodiment, the XRPD of the solid form provided herein, e.g., Form A of Compound B, is substantially as shown in Figure 11. In another embodiment, a solid form provided herein, e.g., Form A of Compound B, has one or more characteristic XRPD peaks at approximately 6.6796, 7.8754, 8.4472, 8.724, 9.6832, 12.1433, 13.3393, 14.1386, 14.9097, 15.2963, 17.4837, 18.5763, 19.4416, 20.3394, 21.4642, 22.4341, 23.0009, 23.3901, 23.7124, 24.7816, 26.1995, 26.7708, 27.7302, or 30.9939 ± 0.1 degrees 2θ, e.g., as shown in FIG. 11 and as found in Table 4 herein. In another embodiment, a solid form provided herein, e.g., Form A of Compound B, has a molecular weight of about 6.6796, 7.8754, 8.4472, 8.724, 9.6832, 12.1433, 13.3393, 14.1386, 14.9097, 15.2963, 17.096, 18.095, 19.095, 20.095, 21.095, 22.095, 23.095, 24.095, 25.095, 26.095, 27.095, 28.095, 29.095, 30.095, 31.095, 32.095, 33.095, 34.095, 35.095, 36.095, 37.095, 38.095, 39.095, 40.095, 41.095, 42.095, 43.095, 44.095, 45.095, 46.095, 47.095, 48.095, 49.095, 50.095, 51.095, 52.095, 53.095, 54.095, 55.095, 56.095, 57.095, 58.095, 59.095, 60.095, 61.095, 62.095, 63.095, 64.095, 65.095, 66.095, having at least 3, 5, 10, 15, or 20 characteristic XPRD peaks at 4837, 18.5763, 19.4416, 20.3394, 21.4642, 22.4341, 23.0009, 23.3901, 23.7124, 24.7816, 26.1995, 26.7708, 27.7302, or 30.9939 ± 0.1 degrees 2θ.In yet another embodiment, a solid form provided herein, e.g., Form A of Compound B, has a molecular weight of about 6.6796, 7.8754, 8.4472, 8.724, 9.6832, 12.1433, 13.3393, 14.1386, 14.9097, 15.2963, 17.4837, 18.5763, 19.4 416, 20.3394, 21.4642, 22.4341, 23.0009, 23.3901, 23.7124, 24.7816, 26.1995, 26.7708, 27.7302, or 30.9939 ± 0.1 degrees 2θ.

[0088] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound B, has at least ten characteristic XPRD peaks at approximately 6.6796, 7.8754, 8.4472, 8.724, 9.6832, 12.1433, 13.3393, 14.1386, 14.9097, 15.2963, 17.4837, 18.5763, 19.4416, 20.3394, 21.4642, 22.4341, 23.0009, 23.3901, 23.7124, 24.7816, 26.1995, 26.7708, 27.7302, or 30.9939 ± 0.1 degrees 2θ, e.g., as shown in FIG. 11 and found in Table 4 herein. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound B, has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XPRD peaks at approximately 6.6796, 13.3393, 14.9097, 15.2963, 17.4837, 19.4416, 20.3394, 23.0009, 23.7124, or 26.7708 ± 0.1 degrees 2θ, e.g., as shown in FIG. 11 and found in Table 4 herein.

[0089] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound B, has at least five characteristic XPRD peaks at approximately 6.6796, 7.8754, 8.4472, 8.724, 9.6832, 12.1433, 13.3393, 14.1386, 14.9097, 15.2963, 17.4837, 18.5763, 19.4416, 20.3394, 21.4642, 22.4341, 23.0009, 23.3901, 23.7124, 24.7816, 26.1995, 26.7708, 27.7302, or 30.9939 ± 0.1 degrees 2θ, e.g., as shown in FIG. 11 and found in Table 4 herein. In yet another embodiment, a solid form provided herein, e.g., Compound B Form A, has at least one, two, three, four, or five characteristic XPRD peaks at approximately 6.6796, 14.9097, 15.2963, 19.4416, 23.7124 ± 0.1 degrees 2θ, e.g., as shown in Figure 11 and as found in Table 4 herein. In one embodiment, a solid form provided herein, e.g., Compound B Form A, has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at 6.6796, 14.9097, 15.2963, 19.4416, 23.7124 (± 0.1 degrees 2θ).

[0090] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound B, has at least 15 characteristic XPRD peaks at approximately 6.6796, 7.8754, 8.4472, 8.724, 9.6832, 12.1433, 13.3393, 14.1386, 14.9097, 15.2963, 17.4837, 18.5763, 19.4416, 20.3394, 21.4642, 22.4341, 23.0009, 23.3901, 23.7124, 24.7816, 26.1995, 26.7708, 27.7302, or 30.9939 ± 0.1 degrees 2θ, e.g., as shown in FIG. 11 and found in Table 4 herein.

[0091] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound B, has at least 20 characteristic XPRD peaks at approximately 6.6796, 7.8754, 8.4472, 8.724, 9.6832, 12.1433, 13.3393, 14.1386, 14.9097, 15.2963, 17.4837, 18.5763, 19.4416, 20.3394, 21.4642, 22.4341, 23.0009, 23.3901, 23.7124, 24.7816, 26.1995, 26.7708, 27.7302, or 30.9939 ± 0.1 degrees 2θ, e.g., as shown in FIG. 11 and found in Table 4 herein.

[0092] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound B, has characteristic XPRD peaks at approximately all of 6.6796, 7.8754, 8.4472, 8.724, 9.6832, 12.1433, 13.3393, 14.1386, 14.9097, 15.2963, 17.4837, 18.5763, 19.4416, 20.3394, 21.4642, 22.4341, 23.0009, 23.3901, 23.7124, 24.7816, 26.1995, 26.7708, 27.7302, and 30.9939 ± 0.1 degrees 2θ, e.g., as shown in FIG. 11 and as found in Table 4 herein. [Table 5]

[0093] In one embodiment described herein, Form A of Compound B has a DSC thermogram substantially as shown in FIG.

[0094] In one such embodiment, the DSC thermogram includes an endotherm at about 58.7°C and an overlapping peak with a peak temperature of 157.1°C.

[0095] In another embodiment, Form A of Compound B is pure. In one such embodiment, Form A of Compound B is substantially free of other solid forms (e.g., amorphous solids) described herein. In another embodiment, the purity of Form A of Compound B is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.9% or more.

[0096] Compound C: Form A: In some embodiments, provided herein is a solid form corresponding to Compound C, designated as Form A. Form A of Compound C is the ethylsulfonate crystalline solid form of Compound C. In one embodiment, Form A of Compound C is obtained from ethyl acetate and air-dried at RT.

[0097] In one embodiment, Form A of Compound C was heated to 100° C. under N 2 protection, and no morphological changes were observed before and after cooling and exposure to ambient conditions.

[0098] In one embodiment, the solid form provided herein, e.g., Form A of Compound C, is an ethylenesulfonate salt and is substantially crystalline as shown by powder X-ray diffraction pattern (XRPD) measurements. In one embodiment, the XRPD of the solid form provided herein, e.g., Form A of Compound C, is substantially as shown in Figure 13. In another embodiment, the solid form provided herein, e.g., Form A of Compound C, has one or more characteristic XRPD peaks at approximately 5.5814, 8.7554, 11.1932, 12.5401, 13.5091, 14.2557, 15.8682, 16.3963, 16.834, 17.5707, 18.9739, 20.2549, 21.3525, 26.5569 ± 0.1 ° 2θ, e.g., as shown in Figure 13 and as found in Table 5 herein. In another embodiment, a solid form provided herein, e.g., Form A of Compound C, has at least 3, 5, 7, 10, or 12 characteristic XPRD peaks at approximately 5.5814, 8.7554, 11.1932, 12.5401, 13.5091, 14.2557, 15.8682, 16.3963, 16.834, 17.5707, 18.9739, 20.2549, 21.3525, 26.5569 ± 0.1 degrees 2θ, e.g., as shown in FIG. 13 and as found in Table 5 herein. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound C, has at least 5, 6, 7, 8, 9, 10, 11, 12, 13, or all characteristic XPRD peaks at approximately 5.5814, 8.7554, 11.1932, 12.5401, 13.5091, 14.2557, 15.8682, 16.3963, 16.834, 17.5707, 18.9739, 20.2549, 21.3525, 26.5569 ± 0.1 degrees 2θ, e.g., as shown in FIG. 13 and as found in Table 5 herein.

[0099] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound C, has at least ten characteristic XPRD peaks at approximately 5.5814, 8.7554, 11.1932, 12.5401, 13.5091, 14.2557, 15.8682, 16.3963, 16.834, 17.5707, 18.9739, 20.2549, 21.3525, 26.5569 ± 0.1 degrees 2θ, e.g., as shown in FIG. 13 and as found in Table 5 herein. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound C, has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XPRD peaks at approximately 12.5401, 17.5707, 16.834, 21.3525, 26.5569, 8.7554, 14.2557, 16.3963, 20.2549, 11.1932 ± 0.1 degrees 2θ, e.g., as shown in FIG. 13 and as found in Table 5 herein.

[0100] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound C, has at least five characteristic XPRD peaks at approximately 5.5814, 8.7554, 11.1932, 12.5401, 13.5091, 14.2557, 15.8682, 16.3963, 16.834, 17.5707, 18.9739, 20.2549, 21.3525, 26.5569 ± 0.1 °2θ, e.g., as shown in Figure 13 and as found in Table 5 herein. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound C, has at least five characteristic XPRD peaks at approximately 12.5401, 17.5707, 16.834, 21.3525, 26.5569 ± 0.1 degrees 2θ, e.g., as shown in Figure 13 and as found in Table 5 herein. In one embodiment, a solid form provided herein, e.g., Form A of Compound C, has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at 12.5401, 17.5707, 16.834, 21.3525, 26.5569 (± 0.1 degrees 2θ). [Table 6]

[0101] In one embodiment described herein, Compound C Form A has a TGA thermogram substantially as shown in Figure 14. In one embodiment, a weight loss of 8.6% up to 100°C is observed.

[0102] In one embodiment, Compound C Form A has a DSC thermogram substantially as shown in Figure 14, which includes two endotherms at 81.0°C and 149.2°C (peak temperatures).

[0103] In another embodiment, Form A of Compound C is pure. In one such embodiment, Form A of Compound C is substantially free of other solid forms (e.g., amorphous solids) described herein. In another embodiment, the purity of Form A of Compound C is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.9% or more.

[0104] Compound D: Form A: In some embodiments, provided herein is a solid form corresponding to Compound D, designated as Form A. Form A of Compound D is a crystalline solid form of Compound D. In one embodiment, Form A of Compound D is obtained from evaporation of acetone / n-heptane (1:1 v / v).

[0105] In one embodiment, the solid form provided herein, e.g., Form A of Compound D, is a besylate salt and is substantially crystalline as shown by powder X-ray diffraction pattern (XRPD) measurements. In one embodiment, the XRPD of the solid form provided herein, e.g., Form A of Compound D, is substantially as shown in Figure 15. In another embodiment, the solid form provided herein, e.g., Form A of Compound D, has one or more characteristic XRPD peaks at approximately 7.3809, 9.2213, 10.7407, 12.7588, 13.6799, 14.654, 15.8145, 17.1195, 18.5979, 19.5937, 20.8941, 21.9068, 24.4114, 25.2558 ± 0.1 ° 2θ, e.g., as shown in Figure 15 and as found in Table 6 herein. In another embodiment, a solid form provided herein, e.g., Form A of Compound D, has at least 3, 5, 7, 10, or 12 characteristic XPRD peaks at approximately 7.3809, 9.2213, 10.7407, 12.7588, 13.6799, 14.654, 15.8145, 17.1195, 18.5979, 19.5937, 20.8941, 21.9068, 24.4114, 25.2558 ± 0.1 degrees 2θ, e.g., as shown in FIG. 15 and found in Table 6 herein. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound D, has at least 5, 6, 7, 8, 9, 10, 11, 12, 13, or all characteristic XPRD peaks at approximately 7.3809, 9.2213, 10.7407, 12.7588, 13.6799, 14.654, 15.8145, 17.1195, 18.5979, 19.5937, 20.8941, 21.9068, 24.4114, 25.2558 ± 0.1 degrees 2θ, e.g., as shown in FIG. 15 and found in Table 6 herein.

[0106] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound D, has at least ten characteristic XPRD peaks at approximately 7.3809, 9.2213, 10.7407, 12.7588, 13.6799, 14.654, 15.8145, 17.1195, 18.5979, 19.5937, 20.8941, 21.9068, 24.4114, 25.2558 ± 0.1 degrees 2θ, e.g., as shown in FIG. 15 and found in Table 6 herein. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound D, has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XPRD peaks at approximately 7.3809, 10.7407, 12.7588, 14.654, 15.8145, 17.1195, 18.5979, 21.9068, 24.4114, 25.2558 ± 0.1 degrees 2θ, e.g., as shown in FIG. 15 and found in Table 6 herein.

[0107] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound D, has at least five characteristic XPRD peaks at approximately 7.3809, 9.2213, 10.7407, 12.7588, 13.6799, 14.654, 15.8145, 17.1195, 18.5979, 19.5937, 20.8941, 21.9068, 24.4114, 25.2558 ± 0.1 degrees 2θ, e.g., as shown in FIG. 15 and found in Table 6 herein. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound D, has at least five characteristic XPRD peaks at approximately 7.3809, 10.7407, 14.654, 18.5979, 25.2558 ± 0.1 degrees 2θ, e.g., as shown in Figure 15 and as found in Table 6 herein. In one embodiment, a solid form provided herein, e.g., Form A of Compound D, has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at 7.3809, 10.7407, 14.654, 18.5979, 25.2558 (± 0.1 degrees 2θ). [Table 7]

[0108] In one embodiment described herein, Compound D Form A has a TGA thermogram substantially as shown in Figure 16. In one embodiment, a weight loss of 7.7% up to 170°C was observed.

[0109] In one embodiment, Compound D Form A has a DSC thermogram substantially as shown in Figure 16, including one endotherm at 75.8° C. In one embodiment, the stoichiometric ratio of benzenesulfonic acid:free base is 1, 1.01, 1.02 or 1.03.

[0110] In another embodiment, Form A of Compound D is pure. In one such embodiment, Form A of Compound D is substantially free of other solid forms (e.g., amorphous solids) described herein. In another embodiment, the purity of Form A of Compound D is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.9% or more.

[0111] Compound E: Form A: In some embodiments, provided herein is a solid form corresponding to Compound E, designated as Form A. Compound E Form A is a crystalline solid form of Compound E. In one embodiment, Compound E Form A is obtained from acetone.

[0112] In one embodiment, the solid form provided herein, e.g., Form A of Compound E, is a mesylate salt and is substantially crystalline as shown by powder X-ray diffraction pattern (XRPD) measurement. In one embodiment, the XRPD of the solid form provided herein, e.g., Form A of Compound E, is substantially as shown in Figure 17. In another embodiment, the solid form provided herein, e.g., Form A of Compound E, has one or more characteristic XRPD peaks at approximately 5.9702, 6.2798, 7.766, 11.9769, 12.4314, 14.8918, 15.5087, 16.002, 17.9217, 18.9264, 20.6365, 22.334, 23.8046, 25.8171, 26.1887 ± 0.1 ° 2θ, e.g., as shown in Figure 17 and as found in Table 7 herein. In another embodiment, a solid form provided herein, e.g., Form A of Compound E, has at least 3, 5, 8, 10, or 12 characteristic XPRD peaks at approximately 5.9702, 6.2798, 7.766, 11.9769, 12.4314, 14.8918, 15.5087, 16.002, 17.9217, 18.9264, 20.6365, 22.334, 23.8046, 25.8171, 26.1887 ± 0.1 °2θ, e.g., as shown in Figure 17 and found in Table 7 herein. In yet another embodiment, a solid form provided herein, e.g., Compound E, has at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all characteristic XPRD peaks at approximately 5.9702, 6.2798, 7.766, 11.9769, 12.4314, 14.8918, 15.5087, 16.002, 17.9217, 18.9264, 20.6365, 22.334, 23.8046, 25.8171, 26.1887 ± 0.1 degrees 2θ, e.g., as shown in FIG. 17 and as found in Table 7 herein.

[0113] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound E, has at least ten characteristic XPRD peaks at approximately 5.9702, 6.2798, 7.766, 11.9769, 12.4314, 14.8918, 15.5087, 16.002, 17.9217, 18.9264, 20.6365, 22.334, 23.8046, 25.8171, 26.1887 ± 0.1 degrees 2θ, e.g., as shown in Figure 17 and found in Table 7 herein. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound E, has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic XPRD peaks at approximately 20.6365, 12.4314, 5.9702, 6.2798, 18.9264, 22.334, 14.8918, 25.8171, 16.002, 23.8046 ± 0.1 degrees 2θ, e.g., as shown in FIG. 17 and as found in Table 7 herein.

[0114] In yet another embodiment, a solid form provided herein, e.g., Form A of Compound E, has at least five characteristic XPRD peaks at approximately 5.9702, 6.2798, 7.766, 11.9769, 12.4314, 14.8918, 15.5087, 16.002, 17.9217, 18.9264, 20.6365, 22.334, 23.8046, 25.8171, 26.1887 ± 0.1 °2θ, e.g., as shown in Figure 17 and found in Table 7 herein. In yet another embodiment, a solid form provided herein, e.g., Form A of Compound E, has at least five characteristic XPRD peaks at approximately 5.9702, 6.2798, 12.4314, 18.9264, 20.6365 ± 0.1 degrees 2θ, e.g., as shown in Figure 17 and as found in Table 7 herein. In one embodiment, a solid form provided herein, e.g., Form A of Compound E, has an X-ray powder diffraction pattern including characteristic X-ray powder diffraction peaks using CuKα radiation at 5.9702, 6.2798, 12.4314, 18.9264, 20.6365 (± 0.1 degrees 2θ). [Table 8]

[0115] In another embodiment, Form A of Compound E is pure. In one such embodiment, Form A of Compound E is substantially free of other solid forms (e.g., amorphous solids) described herein. In another embodiment, the purity of Form A of Compound E is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.9% or more.

[0116] Methods of Treating Cancer The compounds and solid forms described herein inhibit KRas G12C It can be administered to a patient in an effective amount (e.g., an amount described herein) to treat the mutation-mediated cancer. In one such embodiment, the cancer is a solid tumor (e.g., lung cancer, CRC, or pancreatic cancer). It is understood that the methods described herein also include treatment with a pharmaceutical composition described herein that includes a compound described herein (e.g., compound 1 or a solid form of compound A, B, C, D, E, or F described herein). In one embodiment, KRas G12C There is a method of treating mutation-mediated lung cancer in a patient having such cancer, comprising administering to a patient having cancer an effective amount of a solid form corresponding to compound A, B, C, D, E or F, or a mixture thereof, as described herein.

[0117] In one embodiment, KRas G12C In one embodiment, a method of treating lung cancer mediated by a mutation in KRas in a patient having such lung cancer comprises administering to the patient an effective amount of Compound A as described herein. G12CA method of treating mutation-mediated pancreatic cancer in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of a solid form of Compound F (e.g., Forms A, B, C or D, or a mixture thereof) as described herein.

[0118] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having a lung cancer that includes a mutation an effective amount of Compound A Form A described herein. In one embodiment, the method includes administering to a patient having a lung cancer that includes a mutation in KRas G12C The method includes administering to a patient having a lung cancer comprising a mutation an effective amount of pure Compound A Form A (e.g., substantially free of another solid form, such as Compound A Form B, Compound A Form C, or Compound A Form D). In one such embodiment, Compound A Form A has a crystalline purity of 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the method includes administering to a patient having a lung cancer comprising a mutation an effective amount of pure Compound A Form A (e.g., substantially free of another solid form, such as Compound A Form B, Compound A Form C, or Compound A Form D). In one such embodiment, Compound A Form A has a crystalline purity of 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. G12CThe method includes administering to a patient having a lung cancer comprising the mutation an effective amount of Compound A Form A, which comprises one or more solid forms of Compound A other than Form A. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form A, which further comprises a percentage of Compound A Form D. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form A, which comprises about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50% of Compound A Form D. In another such embodiment, the mixture of Compound A Form A and Form D may comprise less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90% of Compound A Form D. In another such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A further comprising a percentage of Compound A Form C. In one such embodiment, the method comprises administering Compound A Form A, comprising Compound A Form C, in a percentage of about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form C may comprise Compound A Form C in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%.

[0119] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having a lung cancer that includes a mutation an effective amount of Compound A Form D described herein. In one embodiment, the method includes administering to a patient having a lung cancer that includes a mutation in KRas G12C The method includes administering to a patient having a lung cancer comprising a mutation an effective amount of pure Compound A Form D (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form C). In one such embodiment, Compound A Form D has a crystalline purity of 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the method includes administering to a patient having a lung cancer comprising a mutation an effective amount of pure Compound A Form D (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form C). In one such embodiment, Compound A Form D has a crystalline purity of 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. G12CThe method includes administering to a patient having a lung cancer comprising the mutation an effective amount of Compound A Form A, which comprises one or more solid forms of Compound A other than Form A. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form A, which further comprises a percentage of Compound A Form D. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form A, which comprises Compound A Form D, in a percentage of about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form D may comprise Compound A Form D in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%. In another such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, further comprising a percentage of Compound A Form C. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, comprising Compound A Form C, in a percentage between about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form C may comprise Compound A Form C in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%.

[0120] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having a lung cancer comprising a mutation an effective amount of Compound A Form C described herein. In one embodiment, the method includes administering to a patient having a lung cancer comprising a mutation in KRas G12C The method includes administering to a patient having a lung cancer comprising a mutation an effective amount of pure Compound A Form C (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form D). In one such embodiment, the crystalline purity of Compound A Form C is 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the method includes administering to a patient having a lung cancer comprising a mutation an effective amount of pure Compound A Form C (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form D). In one such embodiment, the crystalline purity of Compound A Form C is 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. G12CThe method includes administering to a patient having a lung cancer comprising the mutation an effective amount of Compound A Form c, which comprises one or more solid forms other than Compound c Form A. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form C, which further comprises a percentage of Compound A Form A and / or Form D. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form C, which comprises about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50% of Compound A Form A and / or Form D. In another such embodiment, the mixture of Compound A Form C comprises less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90% of Compound A Form A and / or Form D.

[0121] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having lung cancer that includes a mutation an effective amount of Compound A Form B described herein. In one embodiment, the method includes administering to a patient having lung cancer that includes a mutation in KRas G12C The method includes administering to a patient having a lung cancer comprising a mutation an effective amount of pure Compound A Form B (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form C, or Compound A Form D). In one such embodiment, the crystalline purity of Compound A Form B is 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the method includes administering to a patient having a lung cancer comprising a mutation an effective amount of pure Compound A Form B (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form C, or Compound A Form D). In one such embodiment, the crystalline purity of Compound A Form B is 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. G12CThe method includes administering to a patient having a lung cancer comprising the mutation an effective amount of compound A form B, which comprises one or more solid forms of compound B other than form A. In one such embodiment, the method includes administering to the patient an effective amount of compound A form B, which further comprises a percentage of compound A form A, form C and / or form D. In one such embodiment, the method includes administering to the patient an effective amount of compound A form b, which comprises about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, 10%-50%, or 25%-75% of compound A form A, form C and / or form D. In another such embodiment, the mixture of Compound A Form B contains Compound A Form A, Form C and / or Form D in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80% or 90%.

[0122] In one embodiment, KRas G12C In one embodiment, a method of treating a lung cancer mediated by a mutation in KRas in a patient having such a lung cancer comprises administering to the patient an effective amount of Compound B as described herein. G12C A method of treating lung cancer mediated by a mutation in a patient having such lung cancer, comprising administering to the patient an effective amount of a solid form of Compound B (e.g., Form A) as described herein. In one such embodiment, a KRas mutation is mediated by a mutation in the KRas G12C A method of treating mutation-mediated lung cancer in a patient having such lung cancer, comprising administering to the patient an effective amount of Compound B Form A as described herein.

[0123] In one embodiment, KRas G12C In one embodiment, a method of treating lung cancer mediated by a mutation in KRas in a patient having such lung cancer comprises administering to the patient an effective amount of Compound C as described herein. G12CA method of treating lung cancer mediated by a mutation in a patient having such lung cancer, comprising administering to the patient an effective amount of a solid form of Compound C (e.g., Form A) as described herein. In one such embodiment, the method comprises administering to the patient an effective amount of a solid form of Compound C (e.g., Form A) as described herein. G12C A method of treating mutation-mediated lung cancer in a patient having such lung cancer, comprising administering to the patient an effective amount of Compound C Form A as described herein.

[0124] In one embodiment, KRas G12C In one embodiment, a method of treating lung cancer mediated by a mutation in KRas in a patient having such lung cancer comprises administering to the patient an effective amount of compound D as described herein. G12C A method of treating lung cancer mediated by a mutation in a patient having such lung cancer, comprising administering to the patient an effective amount of a solid form of Compound D (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating mutation-mediated lung cancer in a patient having such lung cancer, comprising administering to the patient an effective amount of Compound D Form A as described herein.

[0125] In one embodiment, KRas G12C In one embodiment, a method of treating lung cancer mediated by a mutation in KRas in a patient having such lung cancer comprises administering to the patient an effective amount of compound E as described herein. G12C A method of treating lung cancer mediated by a mutation in a patient having such lung cancer, comprising administering to the patient an effective amount of a solid form of Compound E (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating mutation-mediated lung cancer in a patient having such lung cancer, comprising administering to the patient an effective amount of Compound E Form A as described herein.

[0126] In one embodiment, KRas G12C In one such embodiment, a method of treating lung cancer mediated by a mutation in a patient having such lung cancer comprises administering to the patient an effective amount of compound F as described herein. G12C A method of treating lung cancer mediated by a mutation in a patient having such lung cancer, comprising administering to the patient an effective amount of a solid form of Compound F (e.g., Form A) as described herein. In one such embodiment, the method comprises administering to the patient an effective amount of a solid form of Compound F (e.g., Form A) as described herein. G12C A method of treating mutation-mediated lung cancer in a patient having such lung cancer, comprising administering to the patient an effective amount of Compound F Form A as described herein.

[0127] In such embodiments, the lung cancer is G12C In another embodiment of the method provided herein, the lung cancer is an adenocarcinoma, a squamous cell lung cancer or a large cell lung cancer. In one such embodiment, the cancer is a lung adenocarcinoma. In another such embodiment, the lung cancer is a small cell lung cancer. In another embodiment, the lung cancer is a small cell lung cancer. In yet another embodiment, the lung cancer is an adenocarcinoma, a carcinoid tumor, or an anaplastic carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer.

[0128] Further provided herein is the use of Compound 1, Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, or a solid form thereof as described herein for treating a lung cancer as described herein (UL1). Further provided herein is the use of Compound A Form A as described herein for treating a lung cancer as described herein (UL2). Further provided herein is the use of Compound C Form A as described herein for treating a lung cancer as described herein (UL3). Further provided herein is the use of Compound D Form A as described herein for treating a lung cancer as described herein (UL4).

[0129] In one embodiment, KRas G12C There is a method of treating mutation-mediated colorectal cancer in a patient having such cancer, comprising administering to a patient having cancer an effective amount of a solid form corresponding to compound A, B, C, D, E or F, or a mixture thereof, as described herein.

[0130] In one embodiment, KRas G12C In one such embodiment, a method of treating colorectal cancer mediated by a mutation in a patient having such colorectal cancer comprises administering to the patient an effective amount of Compound A as described herein. G12C A method of treating mutation-mediated colorectal cancer in a patient having such colorectal cancer, comprising administering to the patient an effective amount of a solid form of Compound A (e.g., e.g., Form A, B, C or D, or a mixture thereof) as described herein.

[0131] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having colorectal cancer that includes a mutation an effective amount of Compound A Form A described herein. In one embodiment, the method includes administering to a patient having colorectal cancer that includes a mutation in KRas G12CThe method includes administering to a patient having colorectal cancer comprising a mutation an effective amount of pure Compound A Form A (e.g., substantially free of another solid form, such as Compound A Form B, Compound A Form C, or Compound A Form D). In one such embodiment, Compound A Form A has a crystalline purity of 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the ... a colorectal cancer comprising a mutation in a KRas G12C The method comprises administering to a patient having a mutation-containing colorectal cancer an effective amount of Compound A Form A, which comprises one or more solid forms of Compound A other than Form A. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, which further comprises a percentage of Compound A Form D. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, which comprises about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50% of Compound A Form D. In another such embodiment, the mixture of Compound A Form A and Form D may comprise less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90% of Compound A Form D. In another such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A further comprising a percentage of Compound A Form C. In one such embodiment, the method comprises administering Compound A Form A, comprising Compound A Form C, in a percentage of about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form C may comprise Compound A Form C in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%.

[0132] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having colorectal cancer that includes a mutation an effective amount of Compound A Form D described herein. In one embodiment, the method includes administering to a patient having colorectal cancer that includes a mutation in KRas G12CThe method includes administering to a patient having colorectal cancer comprising a mutation an effective amount of pure Compound A Form D (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form C). In one such embodiment, Compound A Form D has a crystalline purity of 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the method includes administering to a patient having colorectal cancer comprising a mutation an effective amount of pure Compound A Form D (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form C). In one such embodiment, Compound A Form D has a crystalline purity of 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. G12C The method comprises administering to a patient having a colorectal cancer comprising the mutation an effective amount of Compound A Form A, which comprises one or more solid forms of Compound A other than Form A. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, which further comprises a percentage of Compound A Form D. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, which comprises Compound A Form D, in a percentage of about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form D may comprise Compound A Form D in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%. In another such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, further comprising a percentage of Compound A Form C. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, comprising Compound A Form C, in a percentage between about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form C may comprise Compound A Form C in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%.

[0133] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having colorectal cancer that includes a mutation an effective amount of Compound A Form C described herein. In one embodiment, the method includes administering to a patient having colorectal cancer that includes a mutation in KRas G12CThe method includes administering to a patient having colorectal cancer comprising a mutation an effective amount of pure Compound A Form C (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form D). In one such embodiment, Compound A Form C has a crystalline purity of 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the method includes administering to a patient having colorectal cancer comprising a mutation an effective amount of pure Compound A Form C (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form D). In one such embodiment, Compound A Form C has a crystalline purity of 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. G12C The method comprises administering to a patient having a mutation-containing colorectal cancer an effective amount of Compound A Form c, which comprises one or more solid forms of Compound c other than Form A. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form C, which further comprises a percentage of Compound A Form A and / or Form D. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form C, which comprises about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50% of Compound A Form A and / or Form D. In another such embodiment, the mixture of Compound A Form C comprises less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90% of Compound A Form A and / or Form D.

[0134] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having colorectal cancer that includes a mutation an effective amount of Compound A Form B described herein. In one embodiment, the method includes administering to a patient having colorectal cancer that includes a mutation in KRas G12C The method includes administering to a patient having colorectal cancer comprising a mutation an effective amount of pure Compound A Form B (e.g., substantially free of another solid form of Compound A Form A, Compound A Form C, or Compound A Form D). In one such embodiment, the crystalline purity of Compound A Form B is 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the ... a colorectal cancer comprising a mutation an effective amount of pure Compound A Form B (e.g., substantially free of another solid form of Compound A Form B, such as Compound A Form C, Compound A Form D, Compound A Form D). G12CThe method comprises administering to a patient having colorectal cancer comprising the mutation an effective amount of compound A form B, which comprises one or more solid forms of compound B other than form A. In one such embodiment, the method comprises administering to the patient an effective amount of compound A form B, which further comprises a percentage of compound A form A, form C and / or form D. In one such embodiment, the method comprises administering to the patient an effective amount of compound A form b, which comprises about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, 10%-50% or 25%-75% of compound A form A, form C and / or form D. In another such embodiment, the mixture of Compound A Form B contains Compound A Form A, Form C and / or Form D in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80% or 90%.

[0135] In one embodiment, KRas G12C A method of treating colorectal cancer mediated by a mutation in a patient having such colorectal cancer, comprising administering to the patient an effective amount of compound B as described herein. In one such embodiment, G12C A method of treating colorectal cancer mediated by a mutation in a patient having such colorectal cancer, comprising administering to the patient an effective amount of a solid form of Compound B (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating mutation-mediated colorectal cancer in a patient having such colorectal cancer, comprising administering to the patient an effective amount of Compound B Form A as described herein.

[0136] In one embodiment, KRas G12C In one such embodiment, a method of treating colorectal cancer mediated by a mutation in a patient having such colorectal cancer comprises administering to the patient an effective amount of Compound C as described herein. G12CA method of treating colorectal cancer mediated by a mutation in a patient having such colorectal cancer, comprising administering to the patient an effective amount of a solid form of Compound C (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating mutation-mediated colorectal cancer in a patient having such colorectal cancer, comprising administering to the patient an effective amount of Compound C Form A as described herein.

[0137] In one embodiment, KRas G12C A method of treating colorectal cancer mediated by a mutation in a patient having such colorectal cancer, comprising administering to the patient an effective amount of compound D as described herein. In one such embodiment, G12C A method of treating colorectal cancer mediated by a mutation in a patient having such colorectal cancer, comprising administering to the patient an effective amount of a solid form of Compound D (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating mutation-mediated colorectal cancer in a patient having such colorectal cancer, comprising administering to the patient an effective amount of Compound D Form A as described herein.

[0138] In one embodiment, KRas G12C A method of treating colorectal cancer mediated by a mutation in a patient having such colorectal cancer, comprising administering to the patient an effective amount of compound E as described herein. G12C A method of treating colorectal cancer mediated by a mutation in a patient having such colorectal cancer, comprising administering to the patient an effective amount of a solid form of Compound E (e.g., Form A) as described herein. In one such embodiment, a KRas G12CA method of treating mutation-mediated colorectal cancer in a patient having such colorectal cancer, comprising administering to the patient an effective amount of Compound E Form A as described herein.

[0139] In one embodiment, KRas G12C In one such embodiment, a method of treating colorectal cancer mediated by a mutation in a patient having such colorectal cancer comprises administering to the patient an effective amount of compound F as described herein. G12C A method of treating colorectal cancer mediated by a mutation in a patient having such colorectal cancer, comprising administering to the patient an effective amount of a solid form of Compound F (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating mutation-mediated colorectal cancer in a patient having such colorectal cancer, comprising administering to the patient an effective amount of Compound F Form A as described herein.

[0140] Further provided herein is the use of Compound 1, Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, or a solid form thereof as described herein (UC1) for treating colorectal cancer as described herein. Further provided herein is the use of Compound A Form A as described herein (UC2) for treating colorectal cancer as described herein. Further provided herein is the use of Compound A Form C as described herein (UC3) for treating colorectal cancer as described herein. Further provided herein is the use of Compound A Form D as described herein (UC4) for treating colorectal cancer as described herein.

[0141] In one embodiment, KRas G12CThere is a method of treating mutation-mediated pancreatic cancer in a patient having such cancer, comprising administering to a patient having cancer an effective amount of a solid form corresponding to compound A, B, C, D, E or F, or a mixture thereof, as described herein.

[0142] In one embodiment, KRas G12C In one such embodiment, a method of treating a pancreatic cancer mediated by a mutation in a patient having such pancreatic cancer comprises administering to the patient an effective amount of Compound A as described herein. G12C A method of treating mutation-mediated pancreatic cancer in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of a solid form of Compound A (e.g., Forms A, B, C or D, or a mixture thereof) as described herein.

[0143] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having pancreatic cancer that includes a mutation an effective amount of Compound A Form A described herein. In one embodiment, the method includes administering to a patient having pancreatic cancer that includes a mutation in KRas G12C The method includes administering to a patient having pancreatic cancer comprising a mutation an effective amount of pure Compound A Form A (e.g., substantially free of another solid form, such as Compound A Form B, Compound A Form C, or Compound A Form D). In one such embodiment, Compound A Form A has a crystalline purity of 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the ... G12CThe method includes administering to a patient having a pancreatic cancer comprising a mutation an effective amount of Compound A Form A, which comprises one or more solid forms of Compound A other than Form A. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form A, which further comprises a percentage of Compound A Form D. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form A, which comprises Compound A Form D, in a percentage of about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form D may comprise Compound A Form D in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%. In another such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A further comprising a percentage of Compound A Form C. In one such embodiment, the method comprises administering Compound A Form A, comprising Compound A Form C, in a percentage of about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form C may comprise Compound A Form C in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%.

[0144] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having pancreatic cancer that includes a mutation an effective amount of Compound A Form D described herein. In one embodiment, the method includes administering to a patient having pancreatic cancer that includes a mutation in KRas G12C The method includes administering to a patient having pancreatic cancer comprising a mutation an effective amount of pure Compound A Form D (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form C). In one such embodiment, Compound A Form D has a crystalline purity of 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the ... in Compound A Form D. G12CThe method includes administering to a patient having a pancreatic cancer comprising a mutation an effective amount of Compound A Form A, which comprises one or more solid forms of Compound A other than Form A. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form A, which further comprises a percentage of Compound A Form D. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form A, which comprises Compound A Form D, in a percentage of about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form D may comprise Compound A Form D in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%. In another such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, further comprising a percentage of Compound A Form C. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, comprising Compound A Form C, in a percentage between about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form C may comprise Compound A Form C in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%.

[0145] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having pancreatic cancer that includes a mutation an effective amount of Compound A Form C described herein. In one embodiment, the method includes administering to a patient having pancreatic cancer that includes a mutation in KRas G12C The method includes administering to a patient having pancreatic cancer comprising a mutation an effective amount of pure Compound A Form C (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form D). In one such embodiment, Compound A Form C has a crystalline purity of 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the ... G12CThe method includes administering to a patient having a pancreatic cancer comprising the mutation an effective amount of Compound A Form c, which comprises one or more solid forms of Compound A other than Form c. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form C, which further comprises a percentage of Compound A Form A and / or Form D. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form C, which comprises about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50% of Compound A Form A and / or Form D. In another such embodiment, the mixture of Compound A Form C comprises less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90% of Compound A Form A and / or Form D.

[0146] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having pancreatic cancer that includes a mutation an effective amount of Compound A Form B described herein. In one embodiment, the method includes administering to a patient having pancreatic cancer that includes a mutation in KRas G12C The method includes administering to a patient having pancreatic cancer comprising a mutation an effective amount of pure Compound A Form B (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form C, or Compound A Form D). In one such embodiment, the crystalline purity of Compound A Form B is 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the ... in KRas G12CThe method includes administering to a patient having a pancreatic cancer comprising the mutation an effective amount of Compound A Form B, which comprises one or more solid forms of Compound A other than Form B. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form B, which further comprises a percentage of Compound A Form A, Form C and / or Form D. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form b, which comprises about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, 10%-50%, or 25%-75% of Compound A Form A, Form C and / or Form D. In another such embodiment, the mixture of Compound A Form B contains Compound A Form A, Form C and / or Form D in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80% or 90%.

[0147] In one embodiment, KRas G12C In one such embodiment, a method of treating a pancreatic cancer mediated by a mutation in a patient having such pancreatic cancer comprises administering to the patient an effective amount of Compound B as described herein. G12C A method of treating a pancreatic cancer mediated by a mutation in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of a solid form of Compound B (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating mutation-mediated pancreatic cancer in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of Compound B Form A as described herein.

[0148] In one embodiment, KRas G12C In one such embodiment, a method of treating a pancreatic cancer mediated by a mutation in a patient having such pancreatic cancer comprises administering to the patient an effective amount of Compound C as described herein. G12CA method of treating a pancreatic cancer mediated by a mutation in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of a solid form of Compound C (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating mutation-mediated pancreatic cancer in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of Compound C Form A as described herein.

[0149] In one embodiment, KRas G12C A method of treating a pancreatic cancer mediated by a mutation in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of Compound D as described herein. In one such embodiment, a KRas G12C A method of treating a pancreatic cancer mediated by a mutation in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of a solid form of Compound D (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating mutation-mediated pancreatic cancer in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of Compound D Form A as described herein.

[0150] In one embodiment, KRas G12C In one such embodiment, a method of treating a pancreatic cancer mediated by a mutation in a patient having such pancreatic cancer comprises administering to the patient an effective amount of compound E as described herein. G12C A method of treating a pancreatic cancer mediated by a mutation in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of a solid form of Compound E (e.g., Form A) as described herein. In one such embodiment, a KRas G12CA method of treating mutation-mediated pancreatic cancer in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of Compound E Form A as described herein.

[0151] In one embodiment, KRas G12C In one such embodiment, a method of treating a pancreatic cancer mediated by a mutation in a patient having such pancreatic cancer comprises administering to the patient an effective amount of compound F as described herein. G12C A method of treating a pancreatic cancer mediated by a mutation in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of a solid form of Compound F (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating mutation-mediated pancreatic cancer in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of Compound F Form A as described herein.

[0152] KRas G12C Further provided herein is a method of treating a cross-organ cancer comprising a mutation in a patient having such cancer. In one such embodiment, the method comprises treating a patient having a cross-organ cancer comprising a mutation in KRas G12C Mutations and cross-organ cancers (a) KRas expression in samples from patients diagnosed with suspected cancer G12C Determining the presence or absence of mutations, and (b) treating in a patient with such cancer by administering to the patient an effective amount of a solid form of Compound A described herein (e.g., Forms A, B, C, or D, or a mixture thereof). Includes.

[0153] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having a cross-organ cancer comprising a mutation an effective amount of Compound A Form A described herein. In one embodiment, the method includes administering to a patient having a cross-organ cancer comprising a mutation in KRas G12CThe method includes administering to a patient having a cross-organ cancer comprising a mutation an effective amount of pure Compound A Form A (e.g., substantially free of another solid form, such as Compound A Form B, Compound A Form C, or Compound A Form D). In one such embodiment, Compound A Form A has a crystalline purity of 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the method includes administering to a patient having a cross-organ cancer comprising a mutation an effective amount of pure Compound A Form A (e.g., substantially free of another solid form, such as Compound A Form B, Compound A Form C, or Compound A Form D). In one such embodiment, Compound A Form A has a crystalline purity of 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. G12C The method includes administering to a patient having a cross-organ cancer comprising a mutation an effective amount of Compound A Form A, which comprises one or more solid forms of Compound A other than Form A. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form A, which further comprises a percentage of Compound A Form D. In one such embodiment, the method includes administering to the patient an effective amount of Compound A Form A, which comprises about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50% of Compound A Form D. In another such embodiment, the mixture of Compound A Form A and Form D may comprise less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90% of Compound A Form D. In another such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A further comprising a percentage of Compound A Form C. In one such embodiment, the method comprises administering Compound A Form A, comprising Compound A Form C, in a percentage of about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form C may comprise Compound A Form C in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%.

[0154] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having a cross-organ cancer comprising a mutation an effective amount of Compound A Form D described herein. In one embodiment, the method includes administering to a patient having a cross-organ cancer comprising a mutation in KRas G12CThe method includes administering to a patient having a cross-organ cancer comprising a mutation an effective amount of pure Compound A Form D (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form C). In one such embodiment, the crystalline purity of Compound A Form D is 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the method includes administering to a patient having a cross-organ cancer comprising a mutation an effective amount of pure Compound A Form D (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form C). In one such embodiment, the crystalline purity of Compound A Form D is 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. G12C The method comprises administering to a patient having a cross-organ cancer comprising a mutation an effective amount of Compound A Form A, which comprises one or more solid forms of Compound A other than Form A. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, which further comprises a percentage of Compound A Form D. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, which comprises Compound A Form D, in a percentage of about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form D may comprise Compound A Form D in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%. In another such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, further comprising a percentage of Compound A Form C. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form A, comprising Compound A Form C, in a percentage between about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50%. In another such embodiment, the mixture of Compound A Form A and Form C may comprise Compound A Form C in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90%.

[0155] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having a cross-organ cancer comprising a mutation an effective amount of Compound A Form C described herein. In one embodiment, the method includes administering to a patient having a cross-organ cancer comprising a mutation in KRas G12CThe method includes administering to a patient having a cross-organ cancer comprising a mutation an effective amount of pure Compound A Form C (e.g., substantially free of another solid form, such as Compound A Form A, Compound A Form B, or Compound A Form D). In one such embodiment, the crystalline purity of Compound A Form C is 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the ..., G12C The method comprises administering to a patient having a cross-organ cancer comprising the mutation an effective amount of Compound A Form c, which comprises one or more solid forms of Compound A other than Form c. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form C, which further comprises a percentage of Compound A Form A and / or Form D. In one such embodiment, the method comprises administering to the patient an effective amount of Compound A Form C, which comprises about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, or 10%-50% of Compound A Form A and / or Form D. In another such embodiment, the mixture of Compound A Form C comprises less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90% of Compound A Form A and / or Form D.

[0156] In one embodiment, the method comprises administering to a subject a subject a KRas G12C The method includes administering to a patient having a cross-organ cancer comprising a mutation an effective amount of Compound A Form B as described herein. In one embodiment, the method includes administering to a patient having a cross-organ cancer comprising a mutation in KRas G12C The method includes administering to a patient having a cross-organ cancer comprising a mutation an effective amount of pure Compound A Form B (e.g., substantially free of another solid form of Compound A Form A, Compound A Form C, or Compound A Form D). In one such embodiment, the crystalline purity of Compound A Form B is 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%. In another embodiment, the ... in Compound A Form B (e.g., substantially free of another solid form of Compound A Form B, such as Compound A Form C, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A Form D, Compound A G12CThe method comprises administering to a patient having a cross-organ cancer comprising the mutation an effective amount of compound A form B, which comprises one or more solid forms other than compound B form A. In one such embodiment, the method comprises administering to the patient an effective amount of compound A form B, which further comprises a percentage of compound A form A, form C and / or form D. In one such embodiment, the method comprises administering to the patient an effective amount of compound A form b, which comprises about 0.1%-10%, 0.5%-20%, 1%-30%, 1%-40%, 1%-50%, 10%-50% or 25%-75% of compound A form A, form C and / or form D. In another such embodiment, the mixture of Compound A Form B contains Compound A Form A, Form C and / or Form D in an amount less than about 0.5%, 1%, 2%, 5%, 7%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80% or 90%.

[0157] In one embodiment, KRas G12C A method of treating a mutation-mediated trans-organ cancer in a patient having such a trans-organ cancer comprises administering to the patient an effective amount of compound B as described herein. In one such embodiment, G12C A method of treating a trans-organ cancer mediated by a mutation in a patient having such a trans-organ cancer, comprising administering to the patient an effective amount of a solid form of Compound B (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating a mutation-mediated trans-organ cancer in a patient having such a trans-organ cancer, comprising administering to the patient an effective amount of Compound B Form A as described herein.

[0158] In one embodiment, KRas G12C A method of treating a trans-organ cancer mediated by a mutation in a patient having such a trans-organ cancer comprises administering to the patient an effective amount of Compound C as described herein. In one such embodiment, G12CA method of treating a trans-organ cancer mediated by a mutation in a patient having such a trans-organ cancer, comprising administering to the patient an effective amount of a solid form of Compound C (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating a mutation-mediated trans-organ cancer in a patient having such trans-organ cancer, comprising administering to the patient an effective amount of Compound C Form A as described herein.

[0159] In one embodiment, KRas G12C A method of treating a trans-organ cancer mediated by a mutation in a patient having such a trans-organ cancer comprises administering to the patient an effective amount of compound D as described herein. In one such embodiment, G12C A method for treating a trans-organ cancer mediated by a mutation in a patient having such a trans-organ cancer, comprising administering to the patient an effective amount of a solid form of Compound D (e.g., Form A) as described herein. In one such embodiment, a KRas G12C A method of treating a mutation-mediated trans-organ cancer in a patient having such trans-organ cancer, comprising administering to the patient an effective amount of Compound D Form A as described herein.

[0160] In one embodiment, KRas G12C A method of treating a trans-organ cancer mediated by a mutation in a patient having such a trans-organ cancer comprises administering to the patient an effective amount of compound E as described herein. G12C A method of treating a trans-organ cancer mediated by a mutation in a patient having such a trans-organ cancer, comprising administering to the patient an effective amount of a solid form of Compound E (e.g., Form A) as described herein. In one such embodiment, a KRas G12CA method of treating a mutation-mediated trans-organ cancer in a patient having such trans-organ cancer, comprising administering to the patient an effective amount of Compound E Form A as described herein.

[0161] In one embodiment, KRas G12C A method of treating a trans-organ cancer mediated by a mutation in a patient having such a trans-organ cancer comprises administering to the patient an effective amount of compound F as described herein. In one such embodiment, G12C A method of treating a trans-organ cancer mediated by a mutation in a patient having such a trans-organ cancer, comprising administering to the patient an effective amount of a solid form of Compound F (e.g., Form A) as described herein. In one such embodiment, a KRas mutation is mediated by a trans-organ cancer. G12C A method of treating a mutation-mediated trans-organ cancer in a patient having such a trans-organ cancer, comprising administering to the patient an effective amount of compound F form A as described herein.

[0162] Further provided herein is the use of Compound 1, Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, or solid forms thereof as described herein (UP1) for treating a trans-organ cancer as described herein. Further provided herein is the use of Compound A Form A as described herein (UP2) for treating a trans-organ cancer as described herein. Further provided herein is the use of Compound A Form C as described herein (UP3) for treating a trans-organ cancer as described herein. Further provided herein is the use of Compound A Form D as described herein (UP4) for treating a trans-organ cancer as described herein.

[0163] In one embodiment of the methods and uses described herein, Compound 1 or a solid form described herein (e.g., Compound A Forms A / B / C / D, Compound B, Compound C, Compound D, Compound E, or Compound F) is administered as a fixed dose QD administration. In one embodiment, administration is oral (PO) and Compound 1 or a solid form described herein (e.g., Compound A Forms A / B / C / D, Compound B, Compound C, Compound D, Compound E, or Compound F) is formulated as a tablet or capsule. In one embodiment, Compound 1 or a solid form described herein (e.g., Compound A Forms A / B / C / D, Compound B, Compound C, Compound D, Compound E, or Compound F) is administered in a dose range of 5 mg to 600 mg, 5 mg to 500 mg, 5 mg to 400 mg, 5 mg to 300 mg, 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 25 mg to 30 mg, ...50 mg, 5 mg to 50 mg, 5 mg to 50 mg, 5 mg to 50 mg, 5 mg to 50 mg, 5 mg to 50 mg, 5 mg to 50 mg, 5 mg to 50 mg, 5 mg to 50 mg, 5 mg to 50 mg, 5 mg to 50 mg, 5 mg to 50 mg, 5 mg to 5 Administered in amounts of 600mg, 25mg-500mg, 25mg-400mg, 25mg-300mg, 25mg-250mg, 25mg-200mg, 25mg-150mg, 25mg-100mg, 25mg-50mg, 50mg-600mg, 50mg-500mg, 50mg-400mg, 50mg-300mg, 50mg-250mg, 50mg-200mg, 50mg-150mg, or 50mg-100mg QD. In another embodiment, Compound 1 or a solid form described herein (e.g., Compound A Forms A / B / C / D, Compound B, Compound C, Compound D, Compound E, or Compound F) is administered in an amount of about 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg. In another embodiment, Compound A Form A or Compound A Form D described herein is administered in an amount of about 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg.

[0164] kit: Compound 1 and the solid forms described herein (e.g., Compound A, Compound B, Compound C, Compound D, Compound E and / or Compound F) can be provided as an article of manufacture (i.e., a kit) comprising one or more of the compounds described herein for administration. In one embodiment, the kit comprises Compound A or a solid form thereof (e.g., Compound A Form A, B, C or D) described herein for administration as described herein. In one such embodiment, the kit comprises Compound A Form A or Compound A Form D described herein. In another embodiment, the kit comprises Compound B Form A. In another embodiment, the kit comprises Compound C Form A. In yet another embodiment, the kit comprises Compound D Form A. In yet another embodiment, the kit comprises Compound E Form A. In yet another embodiment, the kit comprises Compound F Form A.

[0165] In some examples, the article of manufacture further comprises a package insert comprising instructions for treating or delaying the progression of a solid tumor (e.g., lung cancer, CRC, or pancreatic cancer as described herein). In one such embodiment, the cancer is NSCLC. In one embodiment, the article of manufacture further comprises a package insert comprising instructions for using Compound 1 or a solid form (e.g., Compound A, Compound B, Compound C, Compound D, Compound E, and / or Compound F) as described herein to treat or delay the progression of NSCLC in a patient. In one embodiment, the article of manufacture further comprises a package insert comprising instructions for using Compound 1 or a solid form (e.g., Compound A, Compound B, Compound C, Compound D, Compound E, and / or Compound F) as described herein to treat or delay the progression of pancreatic cancer in a patient. In one embodiment, the article of manufacture further comprises a package insert comprising instructions for using Compound 1 or a solid form (e.g., Compound A, Compound B, Compound C, Compound D, Compound E, and / or Compound F) as described herein to treat or delay the progression of CRC in a patient.

[0166] In such kits, Compound 1 or a solid form described herein (e.g., Compound A, Compound B, Compound C, Compound D, Compound E and / or Compound F) is provided in a container. Suitable containers include, for example, bottles, vials, bags, and syringes. The containers can be formed from a variety of materials, such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloys (such as stainless steel or Hastelloy). In some examples, the container holds the formulation, and a label on or associated with the container can indicate instructions for use. The article of manufacture or kit can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some examples, the article of manufacture further includes one or more additional agents (e.g., additional chemotherapeutic or anti-neoplastic agents). Suitable containers for one or more agents include, for example, bottles, vials, bags, and syringes.

[0167] Any article of manufacture or kit described herein may include instructions for administering Compound 1 or a solid form described herein (e.g., Compound A, Compound B, Compound C, Compound D, Compound E and / or Compound F) to a patient according to any of the methods described herein.

[0168] Embodiments: Several exemplary embodiments of the present invention are provided below.

[0169] Embodiment 1 Structure: Compound with TIFF2025505655000016.tif49170.

[0170] Embodiment 2. Compound A TIFF2025505655000017.tif49170, having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 9.6474, 11.0365, 15.4059, 16.4193, 18.7038 (±0.1° 2θ).

[0171] Embodiment 3. The crystalline form of embodiment 2, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern comprising at least five characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 1.

[0172] Embodiment 4. The crystalline form of embodiment 2, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern comprising at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 1.

[0173] Embodiment 5. The crystalline form of embodiment 2, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern substantially as shown in FIG.

[0174] Embodiment 6. The crystalline form of embodiment 2, wherein said crystalline form of Compound A has a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 2.

[0175] Embodiment 7. The crystalline form of embodiment 2, wherein said crystalline form of Compound A has a corresponding DSC thermogram substantially as shown in Figure 2.

[0176] Embodiment 8. Compound A: TIFF2025505655000018.tif49170, having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 5.2063, 14.63, 17.7161, 21.9253, 25.1335 (±0.1° 2θ).

[0177] Embodiment 9. The crystalline form of embodiment 8, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern comprising at least five characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 2.

[0178] Embodiment 10. The crystalline form of embodiment 8, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern comprising at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 2.

[0179] Embodiment 11. The crystalline form of embodiment 8, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern substantially as shown in FIG.

[0180] Embodiment 12. A crystalline form comprising compound A: TIFF2025505655000019.tif49170

[0181] Embodiment 13. Compound A: TIFF2025505655000020.tif49170, having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 9.7745, 11.0487, 15.2452, 18.6477, 18.7908 (±0.1° 2θ).

[0182] Embodiment 14. The crystalline form of embodiment 13, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern comprising at least five characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 3.

[0183] Embodiment 15. The crystalline form of embodiment 13, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern comprising at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 3.

[0184] Embodiment 16. The crystalline form of embodiment 13, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern substantially as shown in FIG.

[0185] Embodiment 17. The crystalline form of embodiment 13, wherein said crystalline form of Compound A has a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 10.

[0186] Embodiment 18. The crystalline form of embodiment 13, wherein said crystalline form of Compound A has a corresponding DSC thermogram substantially as shown in Figure 9.

[0187] Embodiment 19. Compound B: TIFF2025505655000021.tif49170, having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 6.6796, 14.9097, 15.2963, 19.4416, 23.7124 (±0.1° 2θ).

[0188] Embodiment 20. The crystalline form of embodiment 19, wherein said crystalline form of Compound B has an X-ray powder diffraction pattern comprising at least five characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 4.

[0189] Embodiment 21. The crystalline form of embodiment 19, wherein said crystalline form of Compound B has an X-ray powder diffraction pattern comprising at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 4.

[0190] Embodiment 22. The crystalline form of embodiment 19, wherein said crystalline form of Compound B has an X-ray powder diffraction pattern substantially as shown in FIG.

[0191] Embodiment 23 The crystalline form of embodiment 19, wherein said crystalline form of Compound B has a corresponding DSC thermogram substantially as shown in FIG.

[0192] Embodiment 24. Compound C: TIFF2025505655000022.tif49170, having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 12.5401, 17.5707, 16.834, 21.3525, 26.5569 (±0.1° 2θ).

[0193] Embodiment 25. The crystalline form of embodiment 24, wherein said crystalline form of Compound C has an X-ray powder diffraction pattern comprising at least five characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 5.

[0194] Embodiment 26. The crystalline form of embodiment 24, wherein said crystalline form of Compound C has an X-ray powder diffraction pattern comprising at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 5.

[0195] Embodiment 27. The crystalline form of embodiment 24, wherein said crystalline form of Compound C has an X-ray powder diffraction pattern substantially as shown in FIG. 13.

[0196] Embodiment 28. The crystalline form of embodiment 24, wherein said crystalline form of Compound C has a TGA thermogram substantially corresponding to the representative TGA thermogram shown in FIG. 14.

[0197] Embodiment 29. The crystalline form of embodiment 24, wherein said crystalline form of Compound C has a corresponding DSC thermogram substantially as shown in FIG.

[0198] Embodiment 30. Compound D: TIFF2025505655000023.tif49170, having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 7.3809, 10.7407, 14.654, 18.5979, 25.2558 (±0.1° 2θ).

[0199] Embodiment 31. The crystalline form of embodiment 30, wherein said crystalline form of Compound D has an X-ray powder diffraction pattern comprising at least five characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 6.

[0200] Embodiment 32. The crystalline form of embodiment 30, wherein said crystalline form of Compound D has an X-ray powder diffraction pattern comprising at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 6.

[0201] Embodiment 33 The crystalline form of embodiment 30, wherein said crystalline form of Compound D has an X-ray powder diffraction pattern substantially as shown in FIG.

[0202] Embodiment 34. The crystalline form of embodiment 30, wherein said crystalline form of Compound D has a TGA thermogram substantially corresponding to the representative TGA thermogram shown in FIG. 16.

[0203] Embodiment 35 The crystalline form of embodiment 30, wherein said crystalline form of Compound D has a corresponding DSC thermogram substantially as shown in FIG.

[0204] Embodiment 36. Compound E: TIFF2025505655000024.tif49170, having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 5.9702, 6.2798, 12.4314, 18.9264, 20.6365 (±0.1° 2θ).

[0205] Embodiment 37. The crystalline form of embodiment 36, wherein said crystalline form of Compound E has an X-ray powder diffraction pattern comprising at least five characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 7.

[0206] Embodiment 38. The crystalline form of embodiment 36, wherein said crystalline form of Compound E has an X-ray powder diffraction pattern comprising at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as set forth in Table 7.

[0207] Embodiment 39. The crystalline form of embodiment 36, wherein said crystalline form of Compound E has an X-ray powder diffraction pattern substantially as shown in FIG. 17.

[0208] Embodiment 40. A pharmaceutical composition comprising a solid form according to any one of claims 2 to 39 and at least one pharma- ceutically acceptable excipient.

[0209] Embodiment 41. The pharmaceutical composition of embodiment 40, wherein the composition is formulated for oral administration.

[0210] Embodiment 42. A method of treating a cancer comprising a KRasG12C mutation in a patient having cancer, comprising administering an effective amount of a compound according to embodiment 1 or a crystalline form according to any one of embodiments 2 to 39.

[0211] Embodiment 43. A method for treating a cancer comprising a KRasG12C mutation in a patient having cancer, comprising: determining whether the patient has the mutation; administering to said patient an effective amount of a compound of claim 1 or a crystalline form of any one of embodiments 2-39 if said patient is determined to have said mutation; A method comprising:

[0212] Embodiment 44. The method of embodiment 42 or 43, wherein the cancer comprises lung cancer, colorectal cancer, or pancreatic cancer.

[0213] Embodiment 45 The method of embodiment 42 or 43, wherein the cancer is lung cancer.

[0214] Embodiment 46. The method of embodiment 45, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0215] Embodiment 47 The method of embodiment 42 or 43, wherein the cancer is colorectal cancer.

[0216] Embodiment 48 The method of embodiment 42 or 43, wherein the cancer is pancreatic cancer.

[0217] Embodiment 49. A method for inhibiting proliferation of a cell population, said cell population comprising a KRasG12C mutation, said method comprising contacting said cell population with a compound of claim 1 or a crystalline form of any one of embodiments 2 to 39.

[0218] Embodiment 50. A method for inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to embodiment 1 or a crystalline form according to any one of embodiments 2 to 39.

[0219] Embodiment 51. Use of a compound according to embodiment 1 or a crystalline form according to any one of embodiments 2 to 39 in the manufacture of a medicament for treating cancer.

[0220] Embodiment 52. The use of embodiment 51, wherein the cancer comprises lung cancer, colorectal cancer, or pancreatic cancer.

[0221] Embodiment 53. A compound according to embodiment 1 or a crystalline form according to any one of embodiments 2 to 39 for use in a method for treating cancer.

[0222] Embodiment 54. The compound of embodiment 53, wherein the cancer comprises lung cancer, colorectal cancer, or pancreatic cancer.

[0223] Working Example The following examples are offered by way of illustration and not by way of limitation.

[0224] Example 1: Compound 1 was initially screened for pharma- ceutically acceptable salts and polymorphs in 21 acids and 4 solvent systems. (Table 8) For each solvent, acetone, EtOAc, THF and MeOH / H2O (19:1, v / v), the free base and the corresponding acid were mixed at a molar charge ratio of 1:1 and stirred at RT overnight. Due to the observation that all samples were clear solutions, all samples were transferred to stir at 5 °C overnight. The solids obtained at 5 °C were examined by XRPD. For clear solutions, anti-solvent (n-heptane for acetone, THF and EtOAc; H2O for MeOH / H2O) was added. The mixtures were then stirred at 5 °C for 3 days. The solids obtained were characterized by XRPD and other samples were transferred to heat-cool between 5 and 50 °C. The solids obtained were characterized by XRPD and the clear solutions were transferred to slow evaporation at RT. [Table 9]

[0225] A total of six crystalline hits were obtained, as summarized in Table 9. The salt hits were characterized by XRPD, TGA, DSC, HPLC and NMR. [Table 10]

[0226] A range of conditions was also investigated by starting with amorphous material from a range of solvents / solvent mixtures and carrying out ageing at two different temperatures.

[0227] Amorphous material (25 mg) in an HPLC vial was treated with 5 volumes (125 μl) of solvent and the sample was placed on a 50° C. shaker or 5° C. stirrer for 7 days, as observed upon solvent addition. Any solids were filtered using a fritted filter and analyzed first by XRPD. Any solutions were treated with anti-solvent with increasing solvent:anti-solvent ratios until a maximum ratio of 1:5 was reached at 25° C. Samples were then cooled to 5° C. at 0.1° C. / min and held over the weekend. The solution from cooling was allowed to evaporate at RT, the cap removed, and the cloudy sample was filtered using a fritted filter and analyzed first by XRPD.

[0228] Starting with amorphous material, aging at both low and high temperatures for 7 days left the majority of the sample as a solution. The solution from the 50° C. age was treated with an anti-solvent, which remained as a mostly clear solution after addition of a 1:5 solvent:anti-solvent ratio and cooling to 5° C. The sample was then evaporated, which yielded Compound A Forms A / D, which were mostly amorphous, or a gum. The solution resulting from the 5° C. age was kept at 5° C. for the duration of the project and remained as a solution. [Table 11] TIFF2025505655000028.tif83170 [Table 12] TIFF2025505655000030.tif64170

[0229] Example 2: A total of 62 polymorph screening experiments were performed on the free base through different crystallization methods. Better crystallinity was observed for the sample obtained by slow evaporation in ACN with adipic acid, designated Compound A Form A, compared to the starting material.

[0230] Single crystal data of Compound A Form A was obtained, as shown in Figure 4. The single crystal analysis results indicate that Compound A Form A is anhydrous within the lattice, but may contain some surface water.

[0231] Compound A Form A was prepared by slurrying free base and adipic acid in EtOAc at RT for 48 hours, then transferred to 5° C. for 24 hours to increase yield. The wet sample was dried under vacuum at RT for 3 hours. No morphological change was observed before and after drying. A solid was obtained in 62.2% yield. As per TGA and DSC, the sample showed a weight loss of 0.6% up to 100° C., and the DSC curve showed two endotherms at 56.0° C. and 168.7° C. (peak temperatures). Based on integration of the NMR spectrum, the stoichiometry of adipic acid:free base was determined to be 1.06. An EtOAc peak was observed. Approximately 0.07 moles of EtOAc (0.8 wt %) was detected, which was consistent with the TGA weight loss.

[0232] A disordered form of Compound A Form A, designated Compound A Form C, was identified by single crystal XRD, see Figure 7. Further description of this form and its interchangeability with Compound A Form A and Compound A Form D is provided below.

[0233] When Compound A Form A was exposed to an ambient humidity level of ≧40%, Compound A Form D was formed. Compound A Form D is a hemihydrate form of Compound A. Due to reversibility, Compound A Form D was dehydrated, whereby Compound A Form D formed Compound A Form C.

[0234] Another form of Compound A was obtained and named Form B. Compound A Form B was obtained by anti-solvent addition in DCM / toluene followed by transfer to 5° C. After air drying at RT overnight, no morphological change was observed. A weight loss of 2.2% up to 100° C. was observed in TGA, and two broad endotherms (peaks) at 55.7° C. and 109.6° C. and one small endotherm (peak) at 158.8° C. were observed in DSC. Based on integration, the stoichiometry of adipic acid:free base was determined to be 1.65.

[0235] VT-XRPD was performed on Compound A Form B for form identification. After heating to 90° C. under N2 protection, no form change was observed, indicating that the TGA weight loss was caused by surface water. Therefore, Compound A Form B was inferred to be anhydrous. No DCM peak was observed. To further confirm the stoichiometry, three batches of Compound A Form B were reprepared by anti-solvent addition in DCM / toluene followed by transfer to 5° C. Based on the NMR results, the adipic acid:free base stoichiometry of Compound A Form B ranged from 1.5 to 1.8.

[0236] Slurry competition between Compound A Forms A and B. A slurry competition experiment between Compound A Forms A and B was set up to determine the relationship between these two anhydrides. A saturated solution of Compound A Form A was obtained via slurrying Compound A Form A overnight at the target temperature. A mixture of Compound A Forms A+B was added to about 0.7 mL of a saturated solution of Compound A Form A and the suspension was observed. The suspension was stirred at a speed of 750 rpm and examined by XRPD in transmission mode. As summarized in Table 12, in toluene, after stirring a mixture of Compound A Forms A+B at 5° C., a mixture of Compound A Forms A+B was observed after 5 days. After transferring the sample to RT, Compound A Form A was observed after 18 days of slurrying at RT (the peak at about 18.1° was probably caused by the stirrer). In IPA, the mixture became Compound A Form A at both 5° C. and −20° C. [Table 13]

[0237] Two adipate salt forms, anhydrous Compound A Form A and Compound A Form B, were observed from the polymorph screening of adipate salts with Compound 1. It should be noted that while Compound A Form A was a monosalt, the acid / free base stoichiometry of different Compound A Form B batches varied from 1.5 to 2.1, suggesting that Compound A Form B could be a sesqui- or bis-salt. Slurry competition experiments between Compound A Forms A and B in toluene (RT) and IPA (5°C and -20°C) afforded Compound A Form A.

[0238] Reactive Crystallization with Adipic Acid. Starting from the free form of Compound 1, further steps were explored to determine whether additional forms of the adipate salt existed.

[0239] Compound 1 (30 mg) was weighed into HPLC vials equipped with a stirrer and dissolved at 50° C. A solution of adipic acid in THF (1 M, 1 or 1.5 equiv.) was added to each vial and an aliquot was taken if a solid formed. The solution or suspension was cooled to 40° C. at 0.5° C. / min and seeded with a very small amount of Compound A Form A. The sample was then further cooled to 5° C. overnight at 0.1° C. / min and if a precipitate formed it was filtered and analyzed by XRPD.

[0240] Reactive crystallization with adipic acid resulted primarily in Compound A Forms A / D or sticky material that was amorphous by XRPD. The results and observations of reactive crystallization with adipic acid are summarized in Table 13 below. [Table 14]

[0241] Example 3: Apparatus and method XRPD. A PANalytical X-ray powder diffractometer in reflection mode was used for XRPD analysis. The XRPD parameters are listed in the table below. [Table 15]

[0242] XRPD was also collected as follows: XRPD diffractograms were collected on a Bruker D8 diffractometer using CuKα radiation (40 kV, 40 mA) and a θ-2θ goniometer fitted with a Ge monochromator. The incident beam passes through a 2.0 mm divergence slit, followed by a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam passes through an 8.0 mm receiving slit with a 2.5° Soller slit, followed by a Lynxeye detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA, respectively.

[0243] Samples were run under ambient conditions as flat plate samples using the as-received powder. Samples were prepared on polished zero-background (510) silicon wafers by gently pressing onto a flat surface or filling into a cut cavity. The sample was rotated within its own plane.

[0244] Single crystal X-ray diffraction (SCXRD). Data were collected on a Rigaku Synergy Custom MM007-HF using a HyPix-6000 HPAD detector (The Woodlands, TX, USA). Data were collected in nitrogen gas flow at 90 K using Omega scanning. Data were integrated and scaled using CrysAlisPro (Rigaku Oxford Diffraction, 2021). WinGX was used for solving and refining the crystal structure. Solution by iterative methods (SHELXT-2014) produced a full heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by full matrix least squares (SHELXL-2018). All hydrogen atoms were placed using a riding model. Their positions were restrained relative to their parent atoms using the appropriate HFIX command in SHELXL-2018.

[0245] TGA / DSC. TGA data were collected using a TA Instruments TA Q5000 TGA or a TA Discovery TGA5500, and DSC was performed using a TA Instruments TA Discovery DSC2500. General parameters for TGA and DSC testing [Table 16]

[0246] Solution NMR. Solution NMR was collected on a Bruker 400M NMR spectrometer using DMSO-d6.

[0247] Example 4 - Compound A - Amorphous

[0248] Compound A (20 mg) was weighed into an HPLC vial and solvent was added in 10 volume aliquots (200 μl) on a stir plate at RT until the sample was dissolved or until a maximum of 50 volumes had been added, with observations made between additions. The resulting solution was frozen in a dry ice acetone bath and then placed in a freeze dryer under vacuum.

[0249] Amorphous materials of compound A (monoadipate salt) were successfully prepared by lyophilization. Characterization of the first batch of samples showed that they were all amorphous by XRPD and NMR contained adipic acid with varying amounts of residual solvent, approximately 1.1 equivalents, except for acetonitrile / water (1:1), which had no residual solvent. Purity was low, ranging from 85 to 89%, except for 1,4-dioxane, which had a very low purity of 57.5%. Static storage at 25 °C / 97% RH and 40 °C / 75% RH after 7 days showed that they all had deliquesced.

[0250] Liquid Asset Grinding (LAG) Screen: Amorphous material (25 mg) in an HPLC vial was treated with two ball bearings and solvent (5 μl, 0.2 vol) and ground for 2 h at 500 rpm on a Fritsch planetary mill fitted with an Automaxion adapter. Samples that went into solution upon solvent addition were allowed to slowly evaporate with a needle inserted into the cap. The solids obtained from the LAG were first analyzed by XRPD.

[0251] Example 4 - Compound A Form A Compound A Form A could be obtained in different solvent systems of acetone, THF and EtOAc from screening. Single crystal data of Compound A Form A indicates that Compound A Form A is anhydrous.

[0252] Compound A form A was obtained from THF system and the sample was air-dried at RT. No morphological change was observed before and after drying. TGA and DSC results showed a weight loss of 2.0% up to 100°C and two endotherms at 68.8°C and 169.1°C (peak temperatures). Based on the integration, the stoichiometry of adipic acid:free base was determined to be 1.06. A peak for THF was observed. Approximately 0.17 moles of THF (1.9 wt%) was detected, which was consistent with the TGA weight loss. The purity of Compound A form A was 98.30 area %. After heating the adipate salt type A to 100°C under N2 protection, cooling, and exposing to ambient conditions, negligible differences were observed before and after heating. A peak for THF was observed in the heated sample. Approximately 0.15 moles of THF (1.7 wt%) was still detected, suggesting that the organic solvent may be occluded in the crystalline form.

[0253] VH-XRPD analysis of compound A. The VH-XRPD analysis performed on compound A shows a small change between 44-46% RH, remaining up to 80% RH. The sample then returns to its original form upon reaching 30% RH. The sample appears to be a channel-like hydrate system that can exist in a range of occupancies from 0 to approximately 1 equivalent of water.

[0254] Single Crystal XRD. X-ray quality crystals were grown from saturated isopropanol solution followed by slow vapor diffusion of heptane to deposit the diffracting crystals. A colorless prism measuring 0.100 × 0.100 × 0.100 mm was mounted on a Cryoloop with paratone oil. Data were collected in a nitrogen gas stream at 90(2) K using phi and omega scanning. The crystal to detector distance was 40 mm and the exposure time was 0.2 seconds per frame using a scan width of 1.0°. Data collection was 99.9% complete up to 67.000° in θ. A total of 40537 reflections were collected covering indices -10<=h<=10, -15<=k<=15, -22<=l<=22. 12985 reflections had an R of 0.0345. int The structure was found to be symmetry independent, with a . Indexing and unit cell refinement indicated a simple triclinic lattice. The space group was found to be P1 (No.1). Data were integrated and scaled using CrysAlisPro 1.171.40.51a. Solution by iterative methods (SHELXT-2014) produced a full heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by full matrix least squares (SHELXL-2018). All hydrogen atoms were placed using a riding model. Their positions were restrained relative to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was unambiguously determined from the diffraction data. [Table 17] [Table 18] TIFF2025505655000037.tif212170 [Table 19] TIFF2025505655000039.tif249170TIFF2025505655000040.tif249170TIFF2025505655 000041.tif248170TIFF2025505655000042.tif249170TIFF2025505655000043.tif29170 [Table 20] TIFF2025505655000045.tif208170 [Table 21] TIFF2025505655000047.tif121170

[0255] Example 5 - Compound A Form D The crystal structure of Compound A Form D was determined using X-ray data collected at 100K on crystals isolated from the batch. The structure of Compound A Form D was solved and refined in the non-centrosymmetric monoclinic space group I2 with a final R1[I>2σ(I)]=3.54%. The asymmetric unit was found to contain one molecule of Compound A, one fully ordered adipate anion, one 50% occupied water molecule (O7) crystallographically arranged at a special position (2-fold axis), and one partially occupied water molecule (O8, 20% occupancy) that is disordered around a special position (2-fold axis). In this structure, the molecule also shows positional disorder in which the methylpyrrolidine ring is disordered over two sites, modeled in a ratio of 64.6:35.4. The absolute stereochemistry of the compound has been determined with stereocenters C6 and C25 in the S configuration. The Flack parameter for this structure is 0.007(8). The XRPD pattern simulated from the crystal structure data (collected at 100 K) matches the reference experimental diffractogram (collected at RT) of form D. The slight differences between the simulated and experimental diffractograms are due to lattice fluctuations due to temperature and preferred orientation.

[0256] Overlay with the calculated diffractogram of hydrated Form D shows that the calculated XRPDs of these two forms are similar, but with some differences. The simulated diffractogram matches the experimental VH diffractogram of Compound A Form A at 10% RH. The slight differences in the simulated and experimental diffractograms are due to lattice fluctuations due to temperature and preferred orientation.

[0257] Compound A forms A, C and D are structurally similar and rapidly interconvert depending on the ambient relative humidity, with the majority of water absorption occurring at 40-50% RH at 25 °C.

[0258] Morphological transition of compound A in various RH [Table 22]

[0259] Single Crystal Experiments. The single crystal X-ray structure of Compound A Form D was determined at 100 K using crystals grown by slow evaporation from THF. Crystals of sufficient size and quality for analysis by single crystal X-ray diffraction were isolated with approximate dimensions of 0.22 × 0.20 × 0.08 mm.

[0260] The crystals were monoclinic group I2 with final R1 = [I>2σ(I)] = 3.54%. The compound was confirmed as Compound A Form D. The asymmetric unit contained one molecule of Compound A Form D, one fully ordered adipate anion, one 50% occupied water molecule O7, present at the crystallographic special position (2-fold axis), and one partially occupied water molecule O8, disordered around the special position (2-fold axis). The refined atomic occupancy of O8 is 0.195 (approximately 20% water). The molecule also showed positional disorder at carbon C27 methylpyrrolidine ring, which is modeled across two sites in a ratio of 64.6:35.4. [Table 23] [Table 24] [Table 25] TIFF2025505655000052.tif235170TIFF2025505655000053.tif235170TIFF2025505655000054.tif235170TIFF2025505655000055.tif157170 [Table 26] [Table 27] [Table 28] TIFF2025505655000059.tif255170TIFF2025505655000060.tif19170

[0261] The single crystal structure of compound A form D is shown in Figure 20. C6 and C25 of compound A form D are in the S configuration. The Flack[2] parameter for this structure is 0.007(8). For the inverted structure, C6 and C25 in the R configuration, the Flack parameter is 0.996(8). Determination of the absolute structure using Bayesian statistics for the Bijvoet difference[3] reveals that the probability that the proposed absolute structure is correct is 1.000, while the probability of the absolute structure being a racemic twin or false are both 0.000. The Flack equivalent and its uncertainty are calculated through this program to be 0.011(6). The calculation was based on 3344 Bijvoet pairs with a coverage of 92%.

[0262] There are five intermolecular hydrogen bonds in the crystal structure of form D. A water molecule (O7) is present on the 2-fold axis and hydrogen-bonded to the two symmetry-related carbonyl oxygen atoms (O4). The carboxyl groups of the adipate form form a heterodimer through OH···N and O···HN intramolecular interactions with nitrogens N5 and N6 of the API molecule. The anime nitrogen atom N6 also participates in a hydrogen-bonding interaction with oxygen O3 of the adipate. In addition, nitrogen N7 of the disordered 1-methylpyrrolidine participates in one NH···O intermolecular interaction to oxygen O4 of the -COO- group of the adipate. Diagrams of the crystal packing within the unit cell can be seen in Figures 21 and 22. For clarity, all hydrogen atoms have been removed from the packing diagrams.

[0263] Overall Overview: Compound A was the most stable form of compound 1 for further development. The amorphous form is considered unstable for further development purposes. The adipate salt of compound A is not only much more stable than the other identified salt forms, but is also useful for crystallization and purification of the compound during large-scale synthesis.

[0264] Example 6 - Compound A Form C X-ray quality crystals were grown from saturated methyl ethyl ketone solutions slowly evaporated under ambient conditions. A colorless prism measuring 0.170 × 0.080 × 0.060 mm was mounted on a Cryoloop with paratone oil. Data were collected in a nitrogen gas stream at 90(2) K using phi and omega scanning. The crystal to detector distance was 40 mm and the exposure time was 0.05 seconds per frame using a scan width of 0.5°. Data collection was 100.0% complete up to 67.000° in θ. A total of 43859 reflections were collected covering indices -25<=h<=25, -10<=k<=10, -27<=l<=27. 7083 reflections had an R of 0.0360. intThe lattice structure was found to be symmetry independent, with a . Indexing and unit cell refinement indicated an I-centered monoclinic lattice. The space group was found to be I2 (No.5). Data were integrated and scaled using CrysAlisPro 1.171.41.76a. Solution by iterative methods (SHELXT-2014) produced a full heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by full matrix least squares (SHELXL-2018). All hydrogen atoms were placed using the riding model. Their positions were restrained relative to their parent atoms using the appropriate HFIX command in SHELXL-2018. [Table 29] [Table 30] [Table 31] TIFF2025505655000064.tif64170 [Table 32] TIFF2025505655000066.tif228170TIFF2025505655000067.tif228170TIFF2025505655 000068.tif228170TIFF2025505655000069.tif228170TIFF2025505655000070.tif59170 [Table 33] TIFF2025505655000072.tif64170 [Table 34] TIFF2025505655000074.tif55170

[0265] Similar to compound A form D, the carboxyl group of the adipate forms a heterodimer with the API molecule through intramolecular OH···N and O···HN interactions. Hydrogen H6A of the amine N6 forms one intermolecular NH···O bond to either the O3 or O3A oxygen atom of the positionally disordered -COO- group of the adipate anion (50 / 50). In addition, nitrogen atom N7 of one component of the positionally disordered 1-methylpyrrolidine is involved in one NH···O intermolecular interaction to oxygen O4 of the -COO- group of the adipate, also disordered. Nitrogen N7A of the second component is hydrogen bonded to the analogous oxygen O4A. There appear to be no further hydrogen-bonding interactions, and thus the crystal structure packing is further stabilized only by van der Waals interactions.

[0266] Diagrams of the crystal packing within the unit cell can be seen in Figures 23 and 24. A comparison of the crystal packing of Compound A Form C and Compound A Form D is shown in Figure 25. For clarity, all hydrogen atoms have been removed from the packing diagram.

[0267] Example 6 - Compound B Form A Compound B Form A was obtained from an acetone system and the sample was air-dried at RT. No morphological change was observed before and after drying (Figure 11). TGA and DSC results showed a weight loss of 0.7% up to 100°C and one endotherm at 53.8°C (peak temperature) before a possible overlapping peak at 156.3°C (Figure 12). Based on integration, the stoichiometry of fumaric acid:free base was determined to be 1.03. An acetone peak was observed and approximately 0.49 moles of acetone (4.4 wt%) was detected. The HPLC purity of Compound B Form A was determined to be 93.56 area %. After Compound B Form A was heated to 100°C under N2 protection, cooled, and exposed to ambient conditions, no morphological change was observed before and after heating. An acetone peak was observed in the heated sample. Approximately 0.39 moles of acetone (3.5 wt%) was still detected. The sample obtained after heating still observed overlapping peaks with an endotherm at 58.7° C. and a peak temperature at 157.1° C. The first endotherm may be caused by re-adsorption of water. Compound B Form A is expected to be an acetone / HO cosolvate since about 3.5 wt % acetone was still detected from NMR.

[0268] Example 7 - Compound C Form A Compound C Form A was obtained from EtOAc system and the sample was air-dried at RT. No morphological change was observed before and after drying (Figure 13). A weight loss of 8.6% was observed up to 100°C in TGA and two endotherms at 81.0°C and 149.2°C (peak temperatures) were observed in the DSC curve (Figure 14). The HPLC purity of Compound C Form A was determined to be 95.18 area %.

[0269] Example 8 - Compound D Form A: Compound D Form A was obtained from evaporation of an acetone / n-heptane (1:1, v / v) solution. The XRPD results are shown in Figure 15. A weight loss of 7.7% was observed in the TGA up to 170°C, and the DSC results (Figure 16) showed one endotherm at 75.8°C (peak temperature). Based on integration from the NMR analysis, the benzenesulfonic acid:free base stoichiometry was determined to be 1.03. An acetone peak was observed. Approximately 0.30 moles of acetone (2.7 wt%) was detected. The HPLC purity of Compound D Form A was determined to be 96.23 area %.

[0270] Example 9: Compound E Form A: Compound E Form A was obtained from the acetone system. The overlay of the XRPD spectra is shown in Figure 17. Limited solids were observed after stirring at 5°C. During the XRPD test, the sample was observed to have a tendency to absorb water and become liquid. The suspension was transferred to -20°C, but limited solids were still observed. Anti-solvent (n-heptane) was added and the sample was transferred to 5°C. However, a gel was obtained.

[0271] Example 10: Compound F Form A: Compound F Form A (810935-03-A2) was obtained by evaporation from acetone / n-heptane (1:1, v / v) system at RT (Figure 26).

[0272] TGA and DSC results showed a 9.0% weight loss up to 100° C. and two endotherms at 65.5° C. and 125.4° C. (peak temperatures) (FIG. 27).

[0273] Based on integration, the stoichiometry of acetic acid:free base was determined to be 0.69. An acetone peak was observed. Approximately 0.16 moles of acetone (1.5 wt%) was detected. The purity of Compound F Form A was 88.42 area %.

[0274] No morphological change was observed after compound F form A was heated to 100°C under N2 protection, cooled, and exposed to ambient conditions. Two broad DSC endotherms at 64.2°C and 124.2°C (peak temperatures) were still observed in the sample obtained after heating, suggesting re-adsorption of water. Since no morphological change was observed after heating, compound F form A is likely a hydrate. [Table 35]

[0275] Example 10 - Free Base Screening Procedure The solubility of the starting material was estimated in 20 solvents at RT. For each experiment, approximately 2 mg of sample was added to a 3 mL glass vial. Solvents from Table 32 were then added stepwise (50, 50, 200, 700 μL) to the vial until the solid was visibly dissolved or until a total volume of 1 mL was reached. The solubility results are summarized in Tables 5-11 and were used to guide solvent selection in salt screening and crystal form screening. [Table 36]

[0276] A total of 64 polymorph screening experiments were performed on free base Compound 1 using samples received as starting materials through different crystallization methods. The methods utilized and the crystalline forms identified are summarized in Table 33. As a result, Form A was obtained from the polymorph screening. [Table 37]

[0277] Slurry at RT Slurry conversion experiments were performed at RT in different solvent systems. Approximately 15-20 mg of the free base starting material (Compound 1) was suspended in 0.5 mL of solvent in an HPLC vial. After magnetic stirring at RT, the solid was isolated for XRPD analysis. The results summarized in Table 34 showed that Form A and amorphous were obtained. [Table 38]

[0278] Slurry at 5°. Slurry conversion experiments were performed at 5° C. in different solvent systems. Approximately 15-20 mg of the free base starting material (Compound 1) was suspended in 0.5 mL of solvent in an HPLC vial. After magnetic stirring at 5° C., the solid was isolated for XRPD analysis. The results summarized in Table 35 showed that Form A and amorphous were obtained. [Table 39]

[0279] Slurry at 50°. Slurry conversion experiments were performed in different solvent systems at 50°C. Approximately 20 mg of the free base starting material (compound 1) was suspended in 0.5 mL of solvent in an HPLC vial. After magnetic stirring at 50°C, the solid was isolated for XRPD analysis. The results summarized in Table 36 showed that an amorphous material was obtained. [Table 40]

[0280] Liquid vapor diffusion. Liquid vapor diffusion experiments were performed in different solvent systems. Approximately 20 mg of the free base starting material (compound 1) was dissolved in 0.3–1.5 mL of the corresponding solvent to obtain a clear solution in a 3 mL vial (if a suspension was observed, the sample was filtered through a PTFE filter with a pore size of 0.45 μm). This solution was then placed in a 20 mL vial containing 3 mL of the corresponding antisolvent. The 20 mL vial was sealed with a cap and kept at RT, allowing sufficient time for the organic vapor to interact with the solution. The precipitate was isolated for XRPD analysis. The results summarized in Table 37 indicated that Form A and amorphous were observed. [Table 41]

[0281] Slow evaporation. Slow evaporation experiments were performed under 10 conditions. Briefly, approximately 15-20 mg of free base starting material (810935-01-A) was dissolved in 0.5-1.0 mL of solvent in a 3 mL glass vial. The visually clear solution was allowed to evaporate at RT with the vial sealed with Parafilm®. The solid was isolated for XRPD analysis and the results summarized in Table 38 indicated that Form A and amorphous were obtained. [Table 42]

[0282] Antisolvent Addition A total of 12 antisolvent addition experiments were performed. Approximately 20 mg of free base starting material (compound 1) was dissolved in 0.5–1.5 mL of solvent to obtain a clear solution (if a suspension was observed, the sample was filtered through a PTFE filter with a pore size of 0.45 μm), the solution was magnetically stirred, and then antisolvent was added stepwise until a precipitate appeared or until the total amount of antisolvent reached 10.0 mL. The resulting precipitate was isolated for XRPD analysis. The results, summarized in Table 39, indicated that a poorly crystalline and amorphous Compound A Form A was produced. [Table 43]

[0283] Example 11 - Polymorph Screening of Compound A. The solubility of Compound A Form A (810935-33-A) was estimated at RT following a procedure similar to that described herein. The results summarized in Table 40 were used to guide the solvent selection in the polymorph screening of the adipate salt. The methods utilized and the crystalline forms identified are summarized in Table 41. [Table 44] [Table 45]

[0284] For Compound A, slurry at RT. Slurry conversion experiments were performed in different solvent systems at RT. Approximately 15 mg of Compound A Form A was suspended in 0.5 mL of solvent in an HPLC vial. After magnetic stirring at RT, the solid was isolated for XRPD analysis. The results summarized in Table 42 showed that adipate salt Type A was obtained. [Table 46]

[0285] Slurry at 50° C. for Compound A. Slurry conversion experiments were performed in different solvent systems at 50° C. Approximately 15 mg of Compound A Form A was suspended in 0.5 mL of solvent in an HPLC vial. After magnetic stirring at 50° C., the solid was isolated for XRPD analysis. The results summarized in Table 43 showed that Compound A Form A was obtained. [Table 47]

[0286] Liquid Vapor Diffusion Compound A. Liquid vapor diffusion experiments were performed in different solvent systems. Approximately 15 mg of Compound A Form A was dissolved in 0.5 mL of the corresponding solvent to obtain a clear solution in a 3 mL vial. This solution was then placed in a 20 mL vial containing 3 mL of the corresponding anti-solvent. The 20 mL vial was sealed with a cap and kept at RT to allow sufficient time for the organic vapor to interact with the solution. The precipitate was isolated for XRPD analysis. The results summarized in Table 44 indicated that an amorphous material was obtained. [Table 48]

[0287] Slow evaporation of Compound A. Slow evaporation experiments were performed under seven conditions. Briefly, approximately 15 mg of Compound A Form A was dissolved in 0.5-1.0 mL of solvent in a 3 mL glass vial. Visually clear solutions were allowed to evaporate at RT with the vial sealed by Parafilm® with a few pinholes. The results, summarized in Table 45, showed that only gels or clear solutions were obtained. [Table 49]

[0288] Solid Vapor Diffusion Compound A. Solid vapor diffusion experiments were performed using 12 different solvents. Approximately 15 mg of Compound A Form A (810935-40-A) was weighed into a 3 mL vial, which was placed into a 20 mL vial containing 2 mL of the corresponding solvent. The 20 mL vial was sealed with a cap and kept at RT to allow the solvent vapor to interact with the sample. The solid was tested by XRPD and the results summarized in Table 46 showed that Compound A Form A was obtained. [Table 50]

[0289] Antisolvent Addition Compound A A total of 14 antisolvent addition experiments were performed. Approximately 15 mg of Compound A Form A was dissolved in 0.5-1.5 mL of solvent to obtain a clear solution (if a suspension was observed, the sample was filtered through a PTFE filter with a pore size of 0.45 μm), the solution was magnetically stirred, and then antisolvent was added stepwise until a precipitate appeared or until the total amount of antisolvent reached 10.0 mL. The resulting precipitate was isolated for XRPD analysis. The results summarized in Table 47 indicated that Compound A Form A and Compound A Form B were produced. [Table 51]

[0290] Slow-cooling Compound A. Slow-cooling experiments were performed with four solvent systems. Approximately 15 mg of Compound A Form A was suspended in 1.0 mL of solvent in a 3 mL glass vial at RT. The suspension was then heated to 50° C., equilibrated for approximately 2 hours, and filtered into a new vial using a sealing membrane (PTFE, pore size 0.45 μm). The filtrate was slowly cooled to 5° C. at a rate of 0.1° C. / min. The resulting solid was kept isothermal at 5° C. and then isolated for XRPD analysis. The results summarized in Table 48 indicated that Compound A Form A was obtained. [Table 52]

[0291] All technical and scientific terms used herein have the same meaning. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0292] Throughout this specification and the claims, the words "comprise," "comprises," and "comprising" are used in their non-exclusive sense, unless the context otherwise requires. It is understood that the embodiments described herein include "consisting of" and / or "consisting essentially of" embodiments.

[0293] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is to be understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of the range and any other stated or intervening value in that stated range is included herein. The upper and lower limits of these smaller ranges that may be independently included in the smaller ranges are also included herein, subject to any specifically excluded limit in the stated range. Where one or both of the limits are included in the stated range, ranges excluding either or both of those included limits are also included herein.

[0294] Many modifications and other embodiments of the inventions described herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the invention is not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms have been employed herein, these terms are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. structure: A compound having the formula:

2. Compound A: and having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 9.6474, 11.0365, 15.4059, 16.4193, 18.7038 (±0.1° 2θ).

3. 3. The crystalline form of claim 2, wherein the crystalline form of Compound A has an X-ray powder diffraction pattern containing at least five characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 1.

4. 3. The crystalline form of claim 2, wherein the crystalline form of Compound A has an X-ray powder diffraction pattern containing at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 1.

5. 3. The crystalline form of claim 2, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern substantially as shown in FIG.

6. 3. The crystalline form of claim 2, wherein said crystalline form of Compound A has a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 2.

7. 3. The crystalline form of claim 2, wherein said crystalline form of Compound A has a corresponding DSC thermograph substantially as shown in Figure 2.

8. Compound A: and having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 5.2063, 14.63, 17.7161, 21.9253, 25.1335 (±0.1° 2θ).

9. 9. The crystalline form of claim 8, wherein the crystalline form of Compound A has an X-ray powder diffraction pattern containing at least five characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 2.

10. 9. The crystalline form of claim 8, wherein the crystalline form of Compound A has an X-ray powder diffraction pattern containing at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 2.

11. 9. The crystalline form of claim 8, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern substantially as shown in FIG.

12. Compound A: and having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 9.7745, 11.0487, 15.2452, 18.6477, 18.7908 (±0.1° 2θ).

13. 13. The crystalline form of claim 12, wherein the crystalline form of Compound A has an X-ray powder diffraction pattern containing at least five characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 3.

14. 13. The crystalline form of claim 12, wherein the crystalline form of Compound A has an X-ray powder diffraction pattern containing at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 3.

15. 13. The crystalline form of claim 12, wherein said crystalline form of Compound A has an X-ray powder diffraction pattern substantially as shown in Figure 8.

16. 13. The crystalline form of claim 12, wherein the crystalline form of Compound A has a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 10.

17. 13. The crystalline form of claim 12, wherein said crystalline form of Compound A has a corresponding DSC thermograph substantially as shown in Figure 9.

18. Compound B: and having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 6.6796, 14.9097, 15.2963, 19.4416, 23.7124 (±0.1° 2θ).

19. 19. The crystalline form of claim 18, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern containing at least five characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 4.

20. 19. The crystalline form of claim 18, wherein the crystalline form of Compound B has an X-ray powder diffraction pattern containing at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 4.

21. 19. The crystalline form of claim 18, wherein said crystalline form of Compound B has an X-ray powder diffraction pattern substantially as shown in FIG.

22. 19. The crystalline form of claim 18, wherein said crystalline form of Compound B has a corresponding DSC thermograph substantially as shown in Figure 12.

23. Compound C: and having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 12.5401, 17.5707, 16.834, 21.3525, 26.5569 (±0.1° 2θ).

24. 24. The crystalline form of claim 23, wherein the crystalline form of Compound C has an X-ray powder diffraction pattern containing at least five characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 5.

25. 24. The crystalline form of claim 23, wherein the crystalline form of Compound C has an X-ray powder diffraction pattern containing at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 5.

26. 24. The crystalline form of claim 23, wherein said crystalline form of Compound C has an X-ray powder diffraction pattern substantially as shown in FIG.

27. 24. The crystalline form of claim 23, wherein the crystalline form of Compound C has a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 14.

28. 24. The crystalline form of claim 23, wherein said crystalline form of Compound C has a corresponding DSC thermograph substantially as shown in Figure 14.

29. Compound D: and having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 7.3809, 10.7407, 14.654, 18.5979, 25.2558 (±0.1° 2θ).

30. 30. The crystalline form of claim 29, wherein the crystalline form of Compound D has an X-ray powder diffraction pattern containing at least five characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 6.

31. 30. The crystalline form of claim 29, wherein the crystalline form of Compound D has an X-ray powder diffraction pattern containing at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 6.

32. 30. The crystalline form of claim 29, wherein said crystalline form of Compound D has an X-ray powder diffraction pattern substantially as shown in Figure 15.

33. 30. The crystalline form of claim 29, wherein the crystalline form of Compound D has a TGA thermogram substantially corresponding to the representative TGA thermogram shown in Figure 16.

34. 30. The crystalline form of claim 29, wherein the crystalline form of Compound D has a corresponding DSC thermograph substantially as shown in Figure 16.

35. Compound E: and having a powder X-ray diffraction pattern including characteristic powder X-ray diffraction peaks using CuKα radiation at 5.9702, 6.2798, 12.4314, 18.9264, 20.6365 (±0.1° 2θ).

36. 36. The crystalline form of claim 35, wherein the crystalline form of Compound E has an X-ray powder diffraction pattern containing at least five characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 7.

37. 36. The crystalline form of claim 35, wherein the crystalline form of Compound E has an X-ray powder diffraction pattern containing at least 10 characteristic X-ray powder diffraction peaks using CuKα radiation as shown in Table 7.

38. 36. The crystalline form of claim 35, wherein the crystalline form of Compound E has an X-ray powder diffraction pattern substantially as shown in Figure 17.

39. A pharmaceutical composition comprising a solid form according to any one of claims 2 to 38 and at least one pharma- ceutically acceptable excipient.

40. 40. The pharmaceutical composition of claim 39, wherein the composition is formulated for oral administration.

41. 39. A method of treating a cancer comprising a KRasG12C mutation in a patient having cancer, comprising administering an effective amount of a compound of claim 1 or a crystalline form of any one of claims 2-38.

42. 1. A method for treating a cancer comprising a KRasG12C mutation in a patient having cancer, comprising: determining whether the patient has the mutation; and if said patient is determined to have said mutation, administering to said patient an effective amount of a compound of claim 1 or a crystalline form of any one of claims 2-38.

43. 43. The method of claim 41 or 42, wherein the cancer comprises lung cancer, colorectal cancer, or pancreatic cancer.

44. 43. The method of claim 41 or 42, wherein the cancer is lung cancer.

45. 45. The method of claim 44, wherein the lung cancer is non-small cell lung cancer (NSCLC).

46. 43. The method of claim 41 or 42, wherein the cancer is colorectal cancer.

47. 43. The method of claim 41 or 42, wherein the cancer is pancreatic cancer.

48. 39. A method for inhibiting proliferation of a cell population, said cell population comprising a KRasG12C mutation, said method comprising contacting said cell population with a compound of claim 1 or a crystalline form of any one of claims 2-38.

49. 40. A method for inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of claim 1 or a crystalline form of any one of claims 2-38.

50. 40. Use of a compound of claim 1 or a crystalline form of any one of claims 2 to 38 in the manufacture of a medicament for treating cancer.

51. 51. The use of claim 50, wherein the cancer comprises lung cancer, colorectal cancer, or pancreatic cancer.

52. A compound of claim 1 or a crystalline form of any one of claims 2 to 38 for use in a method of treating cancer.

53. 53. The compound of claim 52, wherein the cancer comprises lung cancer, colorectal cancer, or pancreatic cancer.

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