solid state

Abstract

A novel polymorph of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one is provided, which has advantages in formulation and manufacturing. [Solution] Crystalline and amorphous forms (e.g., several anhydrate, hydrate, and solvate forms, and solid forms thereof) of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one are provided, as well as pharmaceutical compositions and methods for treating diseases mediated by KRAS G12C inhibition.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 851,044, filed May 21, 2019, the specification of which is incorporated herein by reference in its entirety.

[0002] The present disclosure provides crystalline forms (e.g., crystalline forms of anhydrous forms, hydrate forms, several solvate forms, and physical forms thereof) of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (hereinafter "Compound 1"), pharmaceutical compositions, and methods of treating diseases mediated by KRAS G12C inhibition. [Background technology]

[0003] Compound 1 is a selective inhibitor of KRAS G12C useful for the treatment of cancer (e.g., the treatment of lung cancer, such as non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer). Compound 1 is disclosed in U.S. Patent Application Publication No. 2018 / 0334454A1, published November 22, 2018.

[0004] Many compounds can exist in various crystalline forms, or polymorphs, that exhibit different physical, chemical, and spectroscopic properties. For example, a particular polymorph of a compound may dissolve more quickly in a particular solvent, flow more quickly, or be more easily compressed than others. See, e.g., P. DiMartino, et al., J. Thermal. Anal., 48:447-458 (1997). In the case of drugs, certain solid forms may be more bioavailable than others, while others may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a regulatory perspective, because drugs are approved by agencies such as the U.S. Food and Drug Administration only if they meet strict purity and characterization standards. In practice, regulatory approval of one polymorph of a compound that exhibits certain solubility and physicochemical properties (including spectroscopic properties) typically does not imply immediate approval of other polymorphs of this same compound.

[0005] It is known in the pharmaceutical arts that polymorphic forms of a compound affect, for example, the solubility, stability, flowability, fractability, and compressibility of the compound, as well as the safety and efficacy of pharmaceuticals containing the compound. See, e.g., Knapman, K. Modern Drug Discoveries, 2000, 53. Thus, the discovery of new polymorphs of a drug can provide various advantages. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US Patent Application Publication No. 2018 / 0334454 [Non-patent literature]

[0007] [Non-Patent Document 1] P.DiMartino,et al.,J.Thermal.Anal.,48:447-458(1997) [Non-patent document 2] Knapman,K.Modern Drug Discoveries,2000,53 Summary of the Invention [Problem to be solved by the invention]

[0008] The present disclosure provides novel polymorphic forms of Compound 1 (e.g., several crystalline forms of anhydrous forms, hydrate forms, several solvate forms, and their physical forms), pharmaceutical compositions, and methods for treating diseases mediated by KRAS G12C inhibition. These novel polymorphic forms may advance the development of pharmaceuticals for the treatment of these chronic diseases and may offer numerous formulation, manufacturing, and therapeutic advantages. [Means for solving the problem]

[0009] The present disclosure provides crystalline and amorphous forms (e.g., several anhydrate, hydrate, and solvate forms and solid forms thereof) of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one, pharmaceutical compositions, and methods of treating diseases mediated by KRAS G12C inhibition. [Brief explanation of the drawings]

[0010] [Figure 1] Figure 1 shows XRPD data for the amorphous form of Compound 1. The powder X-ray pattern is characteristic of amorphous material with a broad amorphous halo and no clear compound-related diffraction peaks from 5-40° 2-theta. [Figure 2] 1 shows DSC data for the amorphous form of Compound 1. [Figure 3]1 shows TGA data for the amorphous form of Compound 1. [Figure 4] 1 shows the 19F solid state NMR (SSNMR) for the amorphous form of Compound 1. [Figure 5] 1 shows XRPD data for crystalline anhydrous Form I of Compound 1. The powder X-ray diffraction patterns of anhydrous Forms I-III of Compound 1 are characteristic of crystalline material with distinct diffraction peaks between 3° 2-theta and 40° 2-theta. [Figure 6] 1 shows DSC data for crystalline anhydrous Form I of Compound 1. [Figure 7] 1 shows TGA data for crystalline anhydrous Form I of Compound 1. [Figure 8] 1 shows 13C SSNMR data for crystalline anhydrous Form I of Compound 1. [Figure 9] 1 shows 19F SSNMR data for crystalline anhydrous Form I of Compound 1. [Figure 10] 1 shows XRPD data for crystalline anhydrous Form II of Compound 1. [Figure 11] 1 shows DSC data for crystalline anhydrous Form II of Compound 1. [Figure 12] 1 shows TGA data for crystalline anhydrous Form II of Compound 1. [Figure 13] 1 shows 13C SSNMR data for crystalline anhydrous Form II of Compound 1. [Figure 14] 1 shows 19F SSNMR data for crystalline anhydrous Form II of Compound 1. [Figure 15] 1 shows XRPD data for crystalline anhydrous Form III of Compound 1. [Figure 16] 1 shows DSC data for crystalline anhydrous Form III of Compound 1. [Figure 17] 1 shows TGA data for crystalline anhydrous Form III of Compound 1. [Figure 18] 1 shows XRPD data for the crystalline hydrate form of Compound 1. [Figure 19] 1 shows DSC data for the crystalline hydrate form of Compound 1. [Figure 20] 1 shows TGA data for the crystalline hydrate form of Compound 1. [Figure 21] 1 is overlaid XRPD data (top to bottom) for crystalline anhydrous Forms I, II, and III and the crystalline hydrate form of Compound 1. [Figure 22] 1 shows XRPD data for crystalline THF solvate Form I of Compound 1. [Figure 23] 1 shows DSC data for crystalline THF solvate Form I of Compound 1. [Figure 24] 1 shows TGA data for crystalline THF solvate Form I of Compound 1. [Figure 25] 1 shows XRPD data for crystalline MeCN solvate Form I of Compound 1. [Figure 26] 1 shows DSC data for crystalline MeCN solvate Form I of Compound 1. [Figure 27] 1 shows TGA data for crystalline MeCN solvate Form I of Compound 1. [Figure 28] 1 shows XRPD data for crystalline MEK solvate Form I of Compound 1. [Figure 29] 1 shows DSC data for crystalline MEK solvate Form I of Compound 1. [Figure 30] 1 shows TGA data for crystalline MEK solvate Form I of Compound 1. [Figure 31] 1 shows XRPD data for crystalline EtOAc solvate Form I of Compound 1. [Figure 32] 1 shows XRPD data for crystalline DMF solvate Form I of Compound 1. [Figure 33] 1 shows DSC data for crystalline DMF solvate Form I of Compound 1. [Figure 34] 1 shows TGA data for crystalline DMF solvate Form I of Compound 1. [Figure 35] 1 shows XRPD data for crystalline DCM solvate Form I of Compound 1. [Figure 36] 1 shows DSC data for crystalline DCM solvate Form I of Compound 1. [Figure 37] 1 shows TGA data for crystalline DCM solvate Form I of Compound 1. [Figure 38] 1 shows XRPD data for crystalline acetone solvate Form I of Compound 1. [Figure 39] 1 shows DSC data for crystalline acetone solvate Form I of Compound 1. [Figure 40] 1 shows TGA data for crystalline acetone solvate Form I of Compound 1. [Figure 41] 1 shows XRPD data for crystalline acetone solvate Form II of Compound 1. [Figure 42] 1 shows DSC data for crystalline acetone solvate Form II of Compound 1. [Figure 43] 1 shows TGA data for crystalline acetone solvate Form II of Compound 1. [Figure 44] 1 shows XRPD data for crystalline p-dioxane solvate Form I of Compound 1. [Figure 45] 1 shows DSC data for crystalline p-dioxane solvate Form I of Compound 1. [Figure 46] 1 shows TGA data for crystalline p-dioxane solvate Form I of Compound 1. [Figure 47] 1 shows XRPD data for crystalline MeOH solvate Form I of Compound 1. [Figure 48] 1 shows DSC data for crystalline MeOH solvate Form I of Compound 1. [Figure 49] 1 shows TGA data for crystalline MeOH solvate Form I of Compound 1. [Figure 50] 1 shows XRPD data for crystalline IPA solvate Form I of Compound 1. [Figure 51] 1 shows DSC data for crystalline IPA solvate Form I of Compound 1. [Figure 52] 1 shows TGA data for crystalline IPA solvate Form I of Compound 1. [Figure 53] 1 shows XRPD data for crystalline EtOH solvate Form I of Compound 1. [Figure 54] 1 shows DSC data for crystalline EtOH solvate Form I of Compound 1. [Figure 55] 1 shows TGA data for crystalline EtOH solvate Form I of Compound 1. [Figure 56] 1 is overlaid XRPD data for isostructural solvate forms of Compound 1 (top to bottom—THF, MeCN, MEK, DCM, acetone, MeOH, IPA, EtOH). DETAILED DESCRIPTION OF THE INVENTION

[0011] definition The term "Compound 1" means 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one. [ka]

[0012] Some of the compounds disclosed herein may exist as atropisomers, which are conformational stereoisomers that arise when rotation around a single bond in the molecule is hindered or very slow as a result of steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers, both as pure individual atropisomer preparations, as enriched preparations of each, or as unspecified mixtures of each. If the barrier to rotation around a single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of isomeric species may be possible. For example, compound 1 can be [ka] The M atropisomer of compound 1 is also known as AMG 510. Canon, J., et al., Nature 575(7781):217-223(2019), Figure 1a.

[0013] Alternatively, compound 1 may have the atropisomer P shown below, which exhibits restricted rotation. [ka]

[0014] Abbreviations: The following abbreviations may be used herein:

[0015] [Table 1]

[0016] [Table 2]

[0017] [Table 3]

[0018] In the context of this disclosure (particularly in the context of the claims), the use of the terms "a," "an," "the," and similar referents should be construed to encompass both the singular and the plural, unless otherwise indicated. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. The use of any and all examples or exemplary language (e.g., "e.g., "etc.") described herein is intended to better illustrate the invention and is not a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0019] The term "anhydrous form of Compound 1" refers to a form of Compound 1 that is substantially or completely free of water (especially water of crystallization). Those skilled in the art will recognize that the exact number of water molecules may vary slightly over time due to changes in temperature, pressure, and other environmental influences. All minor variations in the number of associated water molecules are contemplated within the scope of this disclosure.

[0020] The term "co-crystal" refers to a crystalline material at ambient temperature (20°C-25°C, preferably 20°C) comprising two or more compounds, at least two of which are held together by weak interactions, with at least one of the compounds being a co-crystal former and the other being compound 1. Weak interactions are defined as interactions that are neither ionic nor covalent, and include, for example, hydrogen bonding, van der Waals forces, and π-π interactions. The term "co-crystal" includes solvate forms.

[0021] The terms "non-crystalline form" or "non-crystalline" refer to a material that lacks long-range order and therefore does not exhibit distinct X-ray diffraction peaks (i.e., Bragg diffraction peaks). The XRPD pattern of an amorphous material is characterized by one or more amorphous halos.

[0022] The term "amorphous halo" refers to an approximately bell-shaped maximum in the X-ray powder pattern of an amorphous material.

[0023] The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient other than the active pharmaceutical ingredient (API), which is typically included in the formulation and / or administration to a patient.

[0024] The term "diseases mediated by KRAS G12C inhibition" refers to (i) cancer and (ii) solid tumors. KRAS is the most frequently mutated oncogene in cancer and encodes a critical signaling protein within tumors. Canon, J., et al., Nature 575(7781):217-223(2019), Abstract. The KRAS(G12C) mutant contains a cysteine ​​residue that has been exploited to design covalent inhibitors with promising preclinical activity. Ibid. A series of inhibitors were optimized using novel binding interactions to significantly enhance potency and selectivity. Ibid. This effort led to the discovery of AMG 510. Ibid. Preclinical analyses showed that treatment with AMG 510 significantly reduced KRAS activity. G12C Tumor regression and improved antitumor efficacy of chemotherapy and targeted agents. Id. In immunocompetent mice, treatment with AMG 510 resulted in a pro-inflammatory tumor microenvironment and led to durable cures, both alone and in combination with immune checkpoint inhibitors. Id. Cured mice were treated with isogenic KRAS G12D Rejection of tumor growth, suggesting adaptive immunity to a shared antigen. Id. Furthermore, in clinical trials, AMG 510 demonstrated antitumor activity in the initial administration cohort, representing a potentially novel treatment for patients lacking effective treatments. Id.

[0025] The term "cancer" refers to a hyperproliferative disorder in a mammal (e.g., a human) having a KRAS mutation, an HRAS mutation, or an NRAS G12C mutation, which can be treated, for example, by administering to the mammal a therapeutically effective amount of Compound 1 disclosed herein.In some embodiments, the cancer is, for example, acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder (CMD), or chronic myeloproliferative disorder (CRD). Reproductive disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), germinoma, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney Cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell neck cancer of occult primary, midline duct cancer, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, childhood anomaly cancer, urachal cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)).

[0026] The term "patient" refers to animals such as dogs, cats, cows, horses, sheep, and humans. Particular patients are mammals. The term patient includes males and females.

[0027] The term "therapeutically effective amount" refers to an amount of a compound that ameliorates, attenuates, or eliminates one or more symptoms of a particular disease or condition, or that prevents or delays the onset of one of the symptoms of a particular disease or condition.

[0028] The term "pharmaceutically acceptable" means that the referenced substance (e.g., a compound of the present disclosure, or a formulation containing a compound of the present disclosure, or a particular excipient) is suitable for administration to a patient.

[0029] As used herein, and unless otherwise indicated, the terms "polymorph" and "polymorphic form" refer to solid crystalline forms of a compound or complex. Different polymorphs of the same compound may exhibit different physical, chemical, and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., stability to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rate (which may affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more quickly when composed of one polymorph than when composed of another), or from changes in mechanical properties (e.g., a tablet crumbles during storage due to conversion of a kinetically favored polymorph to a thermodynamically more stable polymorph), or from both changes (e.g., tablets of one polymorph are more susceptible to decomposition at high humidity). The different physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates or may be more difficult to filter or wash free of impurities than another due, for example, to the shape or size distribution of particles of the polymorph.

[0030] Polymorphs of a molecule can be obtained by many methods known in the art, including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, evaporative diffusion, and sublimation. Polymorphs can be detected, identified, classified, and characterized using known techniques, such as, but not limited to, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy, solution calorimetry, solid-state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility, and dissolution rate.

[0031] When used herein to refer to spectra or data presented in a graphical format (e.g., XRPD, IR, Raman, and NMR spectra), and unless otherwise indicated, the term "peak" refers to a peak or other special feature that one of ordinary skill in the art would recognize as not being attributable to background noise.

[0032] As used herein, and unless otherwise indicated, the term "substantially pure," when used to describe a polymorph of a compound, means a solid form of the compound that contains the polymorph and is substantially free of other polymorphs of the compound. A representative substantially pure polymorph contains more than about 80% by weight of one polymorphic form of the compound and less than about 20% by weight of other polymorphic forms of the compound, more preferably more than about 90% by weight of one polymorphic form of the compound and less than about 10% by weight of other polymorphic forms of the compound, even more preferably more than about 95% by weight of one polymorphic form of the compound and less than about 5% by weight of other polymorphic forms of the compound, and most preferably more than about 97% by weight of one polymorphic form of the compound and less than about 3% by weight of other polymorphic forms of the compound.

[0033] The terms "treating," "treat," or "treatment," and the like, include preventative (e.g., prophylactic) and palliative treatment.

[0034] The term "variable hydrate" refers to a hydrate of Compound 1 that is associated with at least about 1, 2, 3, or 4 water molecules. In some embodiments, the hydrates of the present disclosure contain at least 1-10 associated water molecules. One of skill in the art will recognize that the exact number of associated water molecules may vary slightly over time due to changes in temperature, pressure, and other environmental influences. All slight variations in the number of associated water molecules are contemplated within the scope of the present disclosure.

[0035] In some embodiments, the treatment method is directed to the treatment of lung cancer, and the method comprises administering to a subject in need thereof an effective amount of any of the compounds described above (or a pharmaceutical composition comprising the compound). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In some embodiments, the lung cancer is small cell lung cancer. Other lung cancers treatable with the compounds of the present disclosure include, but are not limited to, ductal tumors, carcinoid tumors, and undifferentiated carcinomas. In one embodiment, the NSCLC is locally advanced or metastatic.

[0036] The compound of the present disclosure is administered to patients in a therapeutically effective amount.This compound can be administered alone or as part of a pharmaceutically acceptable composition or formulation.In addition, this compound or composition can be administered all at once, for example by bolus injection, or can be administered multiple times, for example by a series of tablets, or can be delivered substantially uniformly over a period of time, for example by using transdermal delivery.It should also be noted that the dose of this compound can vary over time.

[0037] In addition, the compounds of the present disclosure can be administered alone, in combination with other compounds of the present disclosure, or with other pharmaceutically active compounds. The other pharmaceutically active compounds may be intended to treat the same disease or condition as the compounds of the present disclosure, or may be intended to treat different diseases or conditions. When a patient is administered or has been administered multiple pharmaceutically active compounds, these compounds can be administered simultaneously or sequentially. For example, in the case of tablets, the active compounds may be found in one tablet or in separate tablets, and these separate tablets may be administered at the same time or sequentially in any order. In addition, it should be recognized that the compositions can be in various forms. For example, one or more compounds may be delivered by tablet, while another is administered by injection or orally as a syrup. All combinations, delivery methods, and administration sequences are contemplated.

[0038] It should also be noted that the solid forms of the present disclosure can be administered together. For example, a substantially pure crystalline anhydrous Form I of Compound 1 can be administered to a patient. Alternatively, about 90% by weight of crystalline anhydrous Form I of Compound 1 can be administered with the remainder of Compound 1 existing in other forms, such as amorphous forms of Compound 1. In another embodiment, 80% by weight of crystalline anhydrous Form I of Compound 1 can be administered with the remainder of Compound 1 existing in other forms, such as amorphous forms. All combinations are contemplated. In one embodiment of the present disclosure, Compound 1 is administered to a patient in a single substantially pure form. Those skilled in the art will recognize possible variations.

[0039] The compounds of the present disclosure may be used in the manufacture of a medicament for the treatment of diseases mediated by KRAS G12C inhibition, such as cancer (e.g., but not limited to, colorectal cancer, pancreatic cancer, and lung cancer (e.g., non-small cell lung cancer (NSCLC))).

[0040] In a further aspect, the present disclosure relates to the use of a salt, crystalline form, amorphous form, or co-crystal of Compound 1 for the preparation of a medicament useful for the treatment of cancer (e.g., colorectal cancer, pancreatic cancer, and lung cancer (e.g., non-small cell lung cancer (NSCLC))).

[0041] Because one aspect of the present disclosure contemplates treating a disease / condition with a combination of pharmaceutically active compounds that can be administered separately, the present disclosure further relates to combining separate pharmaceutical compositions in kit form. The kit includes two separate pharmaceutical compositions: a compound of the present disclosure and a second pharmaceutical compound. The kit includes containers (e.g., divided bottles or divided foil pouches) for housing the separate compositions. Further examples of containers include syringes, boxes, and bags. Typically, the kit includes instructions for use of the separate components. This kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosage intervals, or when the prescribing physician or veterinarian desires to titrate the individual components of the combination.

[0042] One example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. The tablets or capsules are then placed in the recesses, and the plastic foil is sealed with a sheet of relatively stiff material on the side of the foil opposite to the side in which the recesses were formed. As a result, the tablets or capsules are sealed within the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, thereby forming openings in the sheet at the locations of the recesses. The tablets or capsules can then be removed through the openings.

[0043] It may be desirable to have a memory aid in the form of numbers on the kit (e.g., next to the tablets or capsules), the numbers corresponding to the days of the regimen in which the tablets or capsules so designated should be taken. Another example of such a memory aid is a calendar printed on a card, for example, as follows: "Week 1, Monday, Tuesday, ... etc. ... Week 2, Monday, Tuesday, ..." etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or multiple pills or capsules to be taken on a particular day. Similarly, a daily dose of a compound of the present disclosure can consist of one tablet or capsule, while a daily dose of a second compound can consist of multiple tablets or capsules, or vice versa. The memory aid should reflect this and aid in the correct administration of the active agents.

[0044] In another specific embodiment of the present disclosure, a dispenser is provided that is designed to dispense the daily doses one at a time in the order of their intended use. Preferably, the dispenser is equipped with a memory aid to further facilitate compliance with the regimen. One example of such a memory aid is a mechanical counter that indicates the number of daily doses dispensed. Another example of such a memory aid is, for example, a battery-powered microchip memory with a liquid crystal readout or an audible reminder signal that reads the date the last daily dose was taken and / or reminds the user of the date the next dose should be taken.

[0045] The compounds of the present disclosure, and other pharmaceutically active compounds, may be administered to a patient orally, rectally, parenterally (e.g., intravenously, intramuscularly, or subcutaneously), intravesically, intravaginally, intraperitoneally, intravesically, topically (e.g., powders, ointments, or drops), or by oral or nasal spray, as needed. All methods used by those skilled in the art to administer pharmaceutically active agents are contemplated. In one embodiment, the compounds of the present disclosure, and other pharmaceutically active compounds, may be administered orally to a patient as needed.

[0046] Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0047] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Microbial contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents (e.g., sugars, sodium chloride, and the like). Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption (e.g., aluminum monostearate and gelatin).

[0048] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is dispersed in at least one inert conventional excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), or in a carrier containing at least one of: (a) fillers or extenders (e.g., starch, lactose, sucrose, mannitol, and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia); (c) humectants (e.g., glycerol); (d) disintegrants (e.g., agar, calcium carbonate, potato denaturant, etc.); The formulation may be mixed with any of the following additives: (a) starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (b) dissolution retardants (e.g., paraffin); (c) absorption accelerators (e.g., quaternary ammonium compounds); (d) wetting agents (e.g., cetyl alcohol and glycerol monostearate); (e.g., kaolin and bentonite); and (f) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate), or mixtures thereof. In the case of capsules and tablets, the dosage form may also contain a buffering agent. In one embodiment, the dosage form contemplated by the present disclosure is a solid dosage form (e.g., tablet) for oral administration.

[0049] Solid compositions of a similar type may also be employed as fillers in hard-filled gelatin capsules using such excipients as lactose, and high molecular weight polyethylene glycols and the like.

[0050] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, and others known in the art.These solid dosage forms can also contain opacifiers and can be of a composition that releases one or more active compounds in a certain part of the intestinal tract in a delayed manner.Examples of embedding compositions that can be used are polymeric substances and waxes.The active compound can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned additives.

[0051] Oral administration liquid dosage forms include, for example, pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir, for example, in soft filled gelatin capsule.In addition to active compound, this liquid dosage form can contain the inert diluent commonly used in this field, for example, water or other solvent, solubilizer and emulsifier, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, or the mixture of these substances and the like.

[0052] In addition to such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In addition to the active compounds, suspensions can contain suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, or mixtures of these substances, and the like.

[0053] Compositions for rectal administration are preferably suppositories which can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax; the suppositories are solid at normal room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active ingredient.

[0054] The dosage form for topical administration of the compound of the present disclosure includes ointments, powders, sprays and inhalants.The active compound or suitable compound is mixed with a physiologically acceptable carrier under sterile conditions, and preservatives, buffers or propellants that may be necessary.Ophthalmic preparations, eye ointments, powders and solutions are also contemplated within the scope of the present disclosure.

[0055] The compounds of the present disclosure may be administered to a patient at dosage levels ranging from about 0.1 to about 2000 mg per day (preferably 5 mg to 1000 mg per day). For a normal adult weighing approximately 70 kg, a dosage ranging from about 0.001 mg per kilogram to about 20 mg per kilogram of body weight is typically sufficient. The specific dosage and dosage range that may be used will depend on many factors, including the patient's requirements, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. Determination of dosage ranges and optimal dosages for a particular patient is within the ordinary skill of one in the art. In one embodiment, the total daily dose administered to a patient is 180 mg, 360 mg, 720 mg, or 960 mg. This total daily dose may be administered orally via multiple tablets containing, for example, 120 mg of Compound 1 (e.g., a total daily dose of 960 mg is administered via eight tablets of 120 mg each). In one embodiment, the total daily dose administered to a patient is 960 mg of Compound 1. In one embodiment, the total daily dose of 960 mg of Compound 1 is administered in eight tablets containing 120 mg of Compound 1.

[0056] Unless specifically stated otherwise, the compounds of the present disclosure can exist in unsolvated or solvated forms with pharmaceutically acceptable solvents such as water (hydrates), ethanol, and the like. The present disclosure contemplates and encompasses both solvated and unsolvated forms.

[0057] It is also possible that the compounds of the present disclosure may exist in various tautomeric forms. All tautomeric forms of the compounds of the present disclosure are contemplated. For example, all keto-enol forms of the compounds are included in the present disclosure.

[0058] Those skilled in the art will recognize that the compound names and structures contained herein may be based on a particular tautomer of the compound. Although the name or structure of only a particular tautomer may be used, it is intended that all tautomers are encompassed in the present disclosure unless otherwise stated.

[0059] Those skilled in the art will understand that the anhydrous free form, hydrates, salts, and co-crystals of Compound 1 may exist in one or more ionization states, typically as zwitterions. Although names or structures of only particular ionization states may be used, all ionization states are intended to be encompassed in this disclosure unless otherwise stated.

[0060] The present disclosure is also intended to encompass compounds that are synthesized in vitro using laboratory techniques such as those known to synthetic chemists, or that are synthesized using in vivo techniques such as by metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present disclosure may be synthesized using a combination of in vitro and in vivo techniques.

[0061] The present disclosure also includes isotopically labeled compounds, which are identical to those enumerated herein except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example: 2 H, 3 H, 13 C. 14 C. 15 N, 16 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Examples include Cl.

[0062] Compounds of the present disclosure that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. 3 H and 14 C) are useful in drug and / or substrate tissue distribution assays. 3 H isotopes, and carbon-14 isotopes (i.e. 14C isotopes) are particularly preferred due to their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H), may offer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability, and therefore may be preferable in some circumstances. Isotopically labeled compounds of the present disclosure may generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0063] All patents and other publications cited herein are incorporated by reference.

[0064] The examples and embodiments set forth below are illustrative of the invention disclosed herein and are not intended to limit the scope of the claims in any way.

[0065] Embodiment 1. In one embodiment, the present invention provides crystalline anhydrous Form I of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0066] 2. In another embodiment, the present disclosure provides crystalline anhydrous Form I of embodiment 1, wherein said anhydrous Form I is the M atropisomer.

[0067] 3. In another embodiment, the present disclosure provides crystalline anhydrous Form I of embodiment 1, characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 5.

[0068] 4. In another embodiment, the disclosure provides crystalline anhydrous Form I of embodiment 1, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2 theta degrees at about 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0.

[0069] 5. In another embodiment, the present disclosure provides crystalline anhydrous Form I of embodiment 1, characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles at about 9.0, 12.0, 12.6, and 19.0 degrees 2-theta.

[0070] 6. In another embodiment, the present disclosure provides crystalline anhydrous Form I of embodiment 1, wherein the crystalline anhydrous Form I has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 293°C.

[0071] 7. In another embodiment, the present disclosure provides crystalline anhydrous Form I of embodiment 1, wherein the crystalline anhydrous Form I has a thermogravimetric analysis thermogram comprising a weight loss of about 0.2% when heated from about 25° C. to about 275° C.

[0072] 8. In another embodiment, the present disclosure provides crystalline anhydrous Form I of embodiment 1, as shown in FIG. 13 Crystalline anhydrous Form I is provided as characterized by C solid-state NMR.

[0073] 9. In another embodiment, the present disclosure provides crystalline anhydrous Form I of embodiment 1, comprising peaks at about 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167.7, and 168 ppm. 13 Crystalline anhydrous Form I is provided as characterized by C solid-state NMR.

[0074] 10. In another embodiment, the present disclosure provides crystalline anhydrous Form I of embodiment 1, as shown in FIG. 19 Crystalline anhydrous Form I is provided as characterized by F solid-state NMR.

[0075] 11. In another embodiment, the present disclosure provides crystalline anhydrous Form I of embodiment 1, comprising peaks at about −49, −60, −79, −90, −109, −120, −138, −150, −168, and −179 ppm. 19 Crystalline anhydrous Form I is provided as characterized by F solid-state NMR.

[0076] 12. In another embodiment, the present disclosure provides crystalline anhydrous Form I of embodiment 1, wherein the crystalline anhydrous Form I is substantially pure.

[0077] 13. In another embodiment, the present disclosure provides a pharmaceutical composition comprising crystalline anhydrous Form I of embodiment 1 and a pharmaceutically acceptable excipient.

[0078] 14. In another embodiment, the present disclosure provides a pharmaceutical composition comprising crystalline anhydrous Form I of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, or a mixture thereof, and a pharmaceutically acceptable excipient.

[0079] 15. In another embodiment, the present disclosure provides the pharmaceutical composition of embodiment 14, which is a single dose.

[0080] 16. In another embodiment, the present disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and crystalline anhydrous Form I of embodiment 1.

[0081] 17. In another embodiment, the present disclosure provides a method of preparing crystalline anhydrous Form I of embodiment 1, comprising combining Form II of Compound 1 with a suitable solvent and removing the solvent to form crystalline anhydrous Form I of Compound 1.

[0082] 18. In another embodiment, the present disclosure provides the method of embodiment 17, wherein the suitable solvent is water.

[0083] 19. In another embodiment, the present disclosure provides a method of treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising crystalline anhydrous Form I of embodiment 1.

[0084] 20. In another embodiment, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of embodiment 14.

[0085] 21. In another embodiment, the present disclosure provides the method of embodiment 19, wherein the disease mediated by G12C inhibition is cancer.

[0086] 22. In another embodiment, the present disclosure provides the method of embodiment 21, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0087] 23. In another embodiment, the present disclosure provides the method of embodiment 22, wherein the cancer is lung cancer.

[0088] 24. In another embodiment, the present disclosure provides the method of embodiment 23, wherein the lung cancer is non-small cell lung cancer.

[0089] 25. In another embodiment, the present disclosure provides an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0090] 26. In another embodiment, the present disclosure provides an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one of embodiment 25, characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 1 .

[0091] 27. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, which is an M atropisomer.

[0092] 28. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, wherein the amorphous form has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 144°C.

[0093] 29. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, wherein the amorphous form has a thermogravimetric analysis thermogram comprising a weight loss of about 1.5% when heated from about 25°C to about 275°C.

[0094] 30. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, as shown in FIG. 19 Forms characterized by F solid-state NMR are provided.

[0095] 31. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, comprising peaks at about −86, −96, −116, −127, −146, and −156 ppm. 19 Forms characterized by F solid-state NMR are provided.

[0096] 32. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, wherein the amorphous form is substantially pure.

[0097] 33. In another embodiment, the present disclosure provides a pharmaceutical composition comprising the amorphous form of embodiment 25 and a pharmaceutically acceptable excipient.

[0098] 34. In another embodiment, the present disclosure provides a pharmaceutical composition comprising the amorphous form of any one of embodiments 25, 26, 27, 28, 29, 30, 31, 32, or 33, or a mixture thereof, and a pharmaceutically acceptable excipient.

[0099] 35. In another embodiment, the disclosure provides the pharmaceutical composition of embodiment 34, which is a single dose.

[0100] 36. In another embodiment, the present disclosure provides a method for preparing the amorphous form of embodiment 35, comprising dissolving Compound 1 and a suitable solvent to form the amorphous form of Compound 1.

[0101] 37. In another embodiment, the present disclosure provides the method of embodiment 36, wherein the suitable solvent is methanol.

[0102] 38. In another embodiment, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the amorphous form of embodiment 25.

[0103] 39. In another embodiment, the present disclosure provides the method of embodiment 38, wherein the disease mediated by G12C inhibition is cancer.

[0104] 40. In another embodiment, the present disclosure provides the method of embodiment 39, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0105] 41. In another embodiment, the present disclosure provides the method of embodiment 40, wherein the cancer is lung cancer.

[0106] 42. In another embodiment, the present disclosure provides the method of embodiment 41, wherein the lung cancer is non-small cell lung cancer.

[0107] 43. In another embodiment, the present disclosure provides crystalline anhydrous Form II of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0108] 44. In another embodiment, the present disclosure provides crystalline anhydrous Form II of embodiment 43, wherein the anhydrous Form II is the M atropisomer.

[0109] 45. In another embodiment, the present disclosure provides crystalline anhydrous Form II of embodiment 43, characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 10.

[0110] 46. ​​In another embodiment, the disclosure provides crystalline anhydrous Form II of Compound 1 of embodiment 43, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2 theta degrees at about 7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4.

[0111] 47. In another embodiment, the present disclosure provides crystalline anhydrous Form II of compound 1 of embodiment 43, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2 theta degrees at about 7.3, 9.8, 10.1, 11.3, 13.3, and 17.2.

[0112] 48. In another embodiment, the present disclosure provides crystalline anhydrous Form II of embodiment 43, wherein the crystalline anhydrous Form II has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 193°C.

[0113] 49. In another embodiment, the disclosure provides crystalline anhydrous Form II of embodiment 43, having a thermogravimetric analysis thermogram comprising a weight loss of about 1% to about 1.8% when heated from about 25°C to about 250°C.

[0114] 50. In another embodiment, the present disclosure provides crystalline anhydrous Form II of embodiment 43, as shown in FIG. 13 Forms characterized by C solid-state NMR are provided.

[0115] 51. In another embodiment, the present disclosure provides crystalline anhydrous Form II of embodiment 43, comprising peaks at about 16, 18, 19, 20, 23, 25, 31, 32, 38, 40, 43, 46, 51, 57, 105, 107, 110, 117, 120, 123, 124, 125, 128, 132, 149, 152, 155, 158, 159, 163, and 166 ppm. 13 Forms characterized by C solid-state NMR are provided.

[0116] 52. In another embodiment, the present disclosure provides crystalline anhydrous Form II of embodiment 43, as shown in FIG. 19 Forms characterized by F solid-state NMR are provided.

[0117] 53. In another embodiment, the present disclosure provides crystalline anhydrous Form II of embodiment 43, comprising peaks at about −59, −62, −89, −92, −119, −122, −148, −151, −179, and −181 ppm. 19 Forms characterized by F solid-state NMR are provided.

[0118] 54. In another embodiment, the present disclosure provides crystalline anhydrous Form II of embodiment 43, wherein the crystalline anhydrous Form II is substantially pure.

[0119] 55. In another embodiment, the present disclosure provides a pharmaceutical composition comprising the crystalline anhydrous Form II of embodiment 43 and a pharmaceutically acceptable excipient.

[0120] 56. In another embodiment, the present disclosure provides a pharmaceutical composition comprising crystalline anhydrous Form II of any one of embodiments 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55, or mixtures thereof, and a pharmaceutically acceptable excipient.

[0121] 57. In another embodiment, the disclosure provides the pharmaceutical composition of embodiment 56, which is a single dose.

[0122] 58. In another embodiment, the present disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and crystalline anhydrous Form II of embodiment 43.

[0123] 59. In another embodiment, the disclosure provides a method for preparing crystalline anhydrous Form II of embodiment 43, comprising combining an amorphous form of Compound 1 with a suitable solvent to form crystalline anhydrous Form II of Compound 1.

[0124] 60. In another embodiment, the present disclosure provides the method of embodiment 59, wherein the suitable solvent is methanol.

[0125] 61. In another embodiment, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the crystalline anhydrous Form II of embodiment 43.

[0126] 62. In another embodiment, the disclosure provides the method of embodiment 61, wherein the disease mediated by G12C inhibition is cancer.

[0127] 63. In another embodiment, the present disclosure provides the method of embodiment 62, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0128] 64. In another embodiment, the present disclosure provides the method of embodiment 63, wherein the cancer is lung cancer.

[0129] 65. In another embodiment, the present disclosure provides the method of embodiment 64, wherein the lung cancer is non-small cell lung cancer.

[0130] 66. In another embodiment, the present disclosure provides crystalline anhydrous Form III of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0131] 67. In another embodiment, the present disclosure provides crystalline anhydrous Form III of embodiment 66, wherein the anhydrous Form III is the M atropisomer.

[0132] 68. In another embodiment, the present disclosure provides crystalline anhydrous Form III of embodiment 66, characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 15.

[0133] 69. In another embodiment, the present disclosure provides crystalline anhydrous Form III of Compound 1 of embodiment 66, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2 theta degrees at about 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6.

[0134] 70. In another embodiment, the present disclosure provides crystalline anhydrous Form III of compound 1 of embodiment 66, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2 theta degrees at about 6.3, 8.4, 9.5, 15.5, and 16.0.

[0135] 71. In another embodiment, the present disclosure provides crystalline anhydrous Form III of embodiment 66, wherein the crystalline anhydrous Form III has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 194°C.

[0136] 72. In another embodiment, the present disclosure provides crystalline anhydrous Form III of embodiment 66, wherein the crystalline anhydrous Form III has a thermogravimetric analysis thermogram that exhibits negligible weight loss when heated from about 25°C to about 250°C.

[0137] 73. In another embodiment, the present disclosure provides crystalline anhydrous Form III of embodiment 66, wherein the crystalline anhydrous Form III is substantially pure.

[0138] 74. In another embodiment, the present disclosure provides a pharmaceutical composition comprising the crystalline anhydrous Form III of embodiment 66 and a pharmaceutically acceptable excipient.

[0139] 75. In another embodiment, the present disclosure provides a pharmaceutical composition comprising crystalline anhydrous Form III in any one of embodiments 66, 67, 68, 69, 70, 71, 72, 73, or 74, or a mixture thereof, and a pharmaceutically acceptable excipient.

[0140] 76. In another embodiment, the disclosure provides the pharmaceutical composition of embodiment 75, which is a single dose.

[0141] 77. In another embodiment, the present disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and crystalline anhydrous Form III of embodiment 66.

[0142] 78. In another embodiment, the disclosure provides a method for preparing crystalline anhydrous Form III of embodiment 66, comprising combining Compound 1 with a suitable solvent to form crystalline anhydrous Form III of Compound 1.

[0143] 79. In another embodiment, the present disclosure provides the method of embodiment 78, wherein the suitable solvent is acetone.

[0144] 80. In another embodiment, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the crystalline anhydrous Form III of embodiment 66.

[0145] 81. In another embodiment, the disclosure provides the method of embodiment 80, wherein the disease mediated by G12C inhibition is cancer.

[0146] 82. In another embodiment, the present disclosure provides the method of embodiment 81, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0147] 83. In another embodiment, the present disclosure provides the method of embodiment 82, wherein the cancer is lung cancer.

[0148] 84. In another embodiment, the present disclosure provides the method of embodiment 82, wherein the lung cancer is non-small cell lung cancer.

[0149] 85. In another embodiment, the present disclosure provides a crystalline hydrate form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0150] 86. In another embodiment, the present disclosure provides the crystalline hydrate form of embodiment 85, wherein the hydrate form is an M atropisomer.

[0151] 87. In another embodiment, the present disclosure provides the crystalline hydrate form of embodiment 85, wherein the crystalline hydrate form is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 18.

[0152] 88. In another embodiment, the disclosure provides a crystalline hydrate form of compound 1 of embodiment 85, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2 theta at about 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.2, 16.4, 16.6, 17.3, 17.4, 17.9, and 19.5.

[0153] 89. In another embodiment, the present disclosure provides a crystalline hydrate form of compound 1 of embodiment 85, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2 theta degrees of about 6.9, 8.0, 9.6, 12.4, and 13.1.

[0154] 90. In another embodiment, the present disclosure provides the crystalline hydrate form of embodiment 85, wherein the crystalline hydrate form has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 91°C.

[0155] 91. In another embodiment, the present disclosure provides the crystalline hydrate form of embodiment 85, wherein the crystalline hydrate form has a thermogravimetric analysis thermogram comprising a weight loss of about 11% when heated from about 39°C to about 160°C.

[0156] 92. In another embodiment, the present disclosure provides the crystalline hydrate form of embodiment 85, wherein the crystalline hydrate form is substantially pure.

[0157] 93. In another embodiment, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrate form of embodiment 85 and a pharmaceutically acceptable excipient.

[0158] 94. In another embodiment, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrate form of any one of embodiments 85, 86, 87, 88, 89, 90, 91, 92, or 93, or a mixture thereof, and a pharmaceutically acceptable excipient.

[0159] 95. In another embodiment, the disclosure provides the pharmaceutical composition of embodiment 94, which is a single dose.

[0160] 96. In another embodiment, the present disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the crystalline hydrate form of embodiment 85.

[0161] 97. In another embodiment, the present disclosure provides a method for preparing the crystalline hydrate form of embodiment 85, comprising combining Compound 1 with a suitable solvent in the presence of water to form the crystalline hydrate form of Compound 1.

[0162] 98. In another embodiment, the present disclosure provides the method of embodiment 78, wherein the suitable solvent is methanol.

[0163] 99. In another embodiment, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the crystalline hydrate form of embodiment 85.

[0164] 100. In another embodiment, the present disclosure provides the method of embodiment 99, wherein the disease mediated by G12C inhibition is cancer.

[0165] 101. In another embodiment, the present disclosure provides the method of embodiment 100, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0166] 102. In another embodiment, the present disclosure provides the method of embodiment 101, wherein the cancer is lung cancer.

[0167] 103. In another embodiment, the present disclosure provides the method of embodiment 102, wherein the lung cancer is non-small cell lung cancer.

[0168] 104. In another embodiment, the present disclosure provides a crystalline solvate form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0169] 105. In another embodiment, the disclosure provides the crystalline solvate form of embodiment 104, wherein the solvate form is a THF solvate form, a MeCN solvate form, a MEK solvate form, an EtOAc solvate form, a DCM solvate form, an acetone solvate form, a p-dioxane solvate form, a methanol solvate form, an isopropyl alcohol solvate form, or an ethanol solvate form.

[0170] 106. In another embodiment, the disclosure provides a pharmaceutical composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one, at least one crystalline form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one of any one of embodiments 1, 43, 66, 85, or 104, and a pharmaceutically acceptable excipient.

[0171] 107. In another aspect, the present disclosure provides the composition of embodiment 106, comprising more than about 50% by weight of crystalline 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0172] 108. In another embodiment, the present disclosure provides a pharmaceutical composition comprising at least one crystalline form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one of any one of embodiments 1, 43, 66, 85, or 104, and a pharmaceutically acceptable excipient.

[0173] Alternative Embodiments Provided herein as embodiment 1 is a compound that is a crystalline form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1), or an atropisomer thereof.

[0174] Provided herein as embodiment 2 is a compound of embodiment 1, which is the M atropisomer of compound 1.

[0175] Provided herein as embodiment 3 is a compound of embodiment 1 or 2, which is a crystalline anhydrous form of Compound 1.

[0176] Provided herein as Embodiment 4 is the compound of any one of Embodiments 1-3, characterized by a powder X-ray diffraction pattern comprising peaks at 9.0, 12.0, 12.6, and 19.0±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0177] As Embodiment 5, provided herein is the compound of any one of Embodiments 1-3, characterized by a powder X-ray diffraction pattern including at least three peaks selected from 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0178] As Embodiment 6, provided herein is the compound of any one of Embodiments 1-3, characterized by a powder X-ray diffraction pattern including at least five peaks selected from 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0179] As Embodiment 7, provided herein is the compound of any one of Embodiments 1-3, characterized by a powder X-ray diffraction pattern including at least seven peaks selected from 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0180] As Embodiment 8, provided herein is the compound of any one of Embodiments 1-3, characterized by a powder X-ray diffraction pattern including peaks at 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0181] Provided herein as Embodiment 9 is the compound of any one of Embodiments 1-3, characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 5, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0182] Provided herein as Embodiment 10 is the compound of any one of Embodiments 1-9, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 293° C.

[0183] Provided herein as Embodiment 11 is the compound of any one of Embodiments 1-10, characterized by a thermogravimetric analysis thermogram comprising a weight loss of about 0.2% when heated from about 25° C. to about 275° C.

[0184] As Embodiment 12, provided herein is the compound of any one of Embodiments 1-11, comprising at least three peaks selected from peaks at about 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm. 13 This compound is characterized by C solid-state NMR.

[0185] As embodiment 13, provided herein is the compound of any one of embodiments 1-11, comprising at least five peaks selected from peaks at about 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm. 13 This compound is characterized by C solid-state NMR.

[0186] Provided herein as Embodiment 14 is the compound of any one of Embodiments 1-11, comprising at least seven peaks selected from peaks at about 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm. 13 This compound is characterized by C solid-state NMR.

[0187] Provided herein as Embodiment 15 is the compound of any one of Embodiments 1-11, comprising peaks at about 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm. 13 This compound is characterized by C solid-state NMR.

[0188] Provided herein as embodiment 16 is a compound of any one of embodiments 1-11, substantially as shown in FIG. 13 This compound is characterized by C solid-state NMR.

[0189] Provided herein as embodiment 17 is the compound of any one of embodiments 1-16, comprising peaks at about -49, -60, -79, -90, -109, -120, -138, -150, -168, and -179 ppm. 19 This compound is characterized by F solid-state NMR.

[0190] Provided herein as embodiment 18 is a compound of any one of embodiments 1-16, substantially as shown in FIG. 19 This compound is characterized by F solid-state NMR.

[0191] Provided herein as embodiment 19 is the compound of any one of embodiments 1-18, wherein the compound is substantially pure.

[0192] Provided herein as embodiment 20 is a pharmaceutical composition comprising a compound of any one of embodiments 1-19 and a pharmaceutically acceptable excipient.

[0193] Provided herein as embodiment 21 is the pharmaceutical composition of embodiment 20, wherein the pharmaceutical composition is in a dosage form for oral administration.

[0194] Provided herein as embodiment 22 is the pharmaceutical composition of embodiment 20 or 21, wherein the dosage form is a solid dosage form.

[0195] Provided herein as embodiment 23 is the pharmaceutical composition of embodiment 22, wherein the solid dosage form is a tablet.

[0196] Provided herein as embodiment 24 is the pharmaceutical composition of any one of embodiments 20-23, comprising 120 mg of the compound.

[0197] Provided herein as embodiment 25 is a compound of any one of embodiments 1-19 or a pharmaceutical composition of any one of embodiments 20-24 for use as a medicament.

[0198] Provided herein as embodiment 26 is a compound of any one of embodiments 1-19 or a pharmaceutical composition of any one of embodiments 20-24 for use in treating cancer harboring a KRAS G12C mutation.

[0199] Provided herein as embodiment 27 is a compound or pharmaceutical composition for use in embodiment 26, wherein the cancer harboring a KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

[0200] Provided herein as embodiment 28 is a compound or pharmaceutical composition for use according to embodiment 26, wherein the cancer with a KRAS G12C mutation is non-small cell lung cancer.

[0201] Provided herein as embodiment 29 is a compound or pharmaceutical composition for use according to embodiment 26, wherein the cancer harboring the KRAS G12C mutation is pancreatic cancer.

[0202] Provided herein as embodiment 30 is a compound or pharmaceutical composition for use according to embodiment 26, wherein the cancer with a KRAS G12C mutation is colorectal cancer.

[0203] Provided herein as embodiment 31 is the use of a compound of any one of embodiments 1-19 or a pharmaceutical composition of any one of embodiments 20-24 in the preparation of a medicament for the treatment of cancer harboring a KRAS G12C mutation.

[0204] Provided herein as embodiment 32 is the use of embodiment 31, wherein the cancer harboring the KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

[0205] Provided herein as embodiment 33 is the use of embodiment 31, wherein the cancer harboring the KRAS G12C mutation is non-small cell lung cancer.

[0206] Provided herein as embodiment 34 is the use of embodiment 31, wherein the cancer harboring the KRAS G12C mutation is pancreatic cancer.

[0207] Provided herein as embodiment 35 is the use of embodiment 31, wherein the cancer harboring the KRAS G12C mutation is colorectal cancer.

[0208] Provided herein as embodiment 36 is a method of treating a cancer harboring a KRAS G12C mutation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of embodiments 1-19.

[0209] Provided herein as embodiment 37 is the method of embodiment 36, wherein the cancer harboring the KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

[0210] Provided herein as embodiment 38 is the method of embodiment 36, wherein the cancer with a KRAS G12C mutation is small cell lung cancer.

[0211] Provided herein as embodiment 39 is the method of embodiment 36, wherein the cancer with a KRAS G12C mutation is pancreatic cancer.

[0212] Provided herein as embodiment 40 is the method of embodiment 36, wherein the cancer with a KRAS G12C mutation is colorectal cancer.

[0213] Provided herein as embodiment 41 is the compound, use, or method of any one of embodiments 25 to 40, wherein the compound is administered at a total daily dose of 960 mg.

[0214] Provided herein as embodiment 42 is the compound, use, or method of any one of embodiments 25 to 41, wherein the compound is administered to an adult.

[0215] Provided herein as embodiment 43 is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern comprising peaks at 7.3, 9.8, 10.1, 11.3, 13.3, and 17.2±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0216] As embodiment 44, provided herein is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern comprising at least three peaks selected from 7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0217] As embodiment 45, provided herein is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern including at least five peaks selected from 7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0218] As embodiment 46, provided herein is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern including at least seven peaks selected from 7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0219] As embodiment 47, provided herein is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern comprising peaks at 7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0220] Provided herein as embodiment 48 is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 10 , as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0221] Provided herein as embodiment 49 is the compound of any one of embodiments 1-3 and 43-48, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 193°C.

[0222] Provided herein as embodiment 50 is the compound of any one of embodiments 1-3 and 43-49, characterized in that the compound has a thermogravimetric analysis thermogram comprising a weight loss of about 1% to about 1.8% when heated from about 25°C to about 250°C.

[0223] Provided herein as embodiment 51 is the compound of any one of embodiments 1-3 and 43-50, comprising peaks at about 16, 18, 19, 20, 23, 25, 31, 32, 38, 40, 43, 46, 51, 57, 105, 107, 110, 117, 120, 123, 124, 125, 128, 132, 149, 152, 155, 158, 159, 163, and 166 ppm. 13 This compound is characterized by C solid-state NMR.

[0224] Provided herein as embodiment 52 is a compound of any one of embodiments 1-3 and 43-50, substantially as shown in FIG. 13 This compound is characterized by C solid-state NMR.

[0225] Provided herein as embodiment 53 is the compound of any one of embodiments 1-3 and 43-52, comprising peaks at about -59, -62, -89, -92, -119, -122, -148, -151, -179, and -181 ppm. 19 This compound is characterized by F solid-state NMR.

[0226] Provided herein as embodiment 54 is a compound of any one of embodiments 1-3 and 43-52, substantially as shown in FIG. 19 This compound is characterized by F solid-state NMR.

[0227] Provided herein as embodiment 55 is the compound of any one of embodiments 43-54, which is substantially pure.

[0228] Provided herein as embodiment 56 is a pharmaceutical composition comprising a compound of any one of embodiments 43-55 and a pharmaceutically acceptable excipient.

[0229] Provided herein as embodiment 57 is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern comprising peaks at 6.3, 8.4, 9.5, and 16.0±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0230] As embodiment 58, provided herein is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern comprising at least three peaks selected from 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0231] As embodiment 59, provided herein is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern comprising at least five peaks selected from 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0232] As embodiment 60, provided herein is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern comprising at least seven peaks selected from 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0233] Provided herein as embodiment 61 is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern comprising peaks at 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0234] Provided herein as embodiment 62 is the compound of any one of embodiments 1-3, characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 15, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0235] Provided herein as Embodiment 63 is the compound of any one of Embodiments 1-3 and 57-62, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 194° C.

[0236] Provided herein as embodiment 64 is the compound of any one of embodiments 1-3 and 57-63, wherein the compound is characterized by substantially negligible weight loss when heated from about 25°C to about 250°C.

[0237] Provided herein as embodiment 65 is the compound of any one of embodiments 57-64, which is substantially pure.

[0238] Provided herein as embodiment 66 is a pharmaceutical composition comprising a compound of any one of embodiments 57-65 and a pharmaceutically acceptable excipient.

[0239] Provided herein as embodiment 67 is a compound of embodiment 1 or 2, which is a crystalline hydrate form of Compound 1.

[0240] Provided herein as embodiment 68 is the compound of any one of embodiments 1, 2, and 67, characterized by a powder X-ray diffraction pattern comprising peaks at 6.9, 8.0, 9.6, 12.4, and 13.1±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0241] Provided herein as embodiment 69 is the compound of any one of embodiments 1, 2, and 67, characterized by a powder X-ray diffraction pattern comprising at least three peaks selected from 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0242] Provided herein as embodiment 70 is the compound of any one of embodiments 1, 2, and 67, characterized by a powder X-ray diffraction pattern comprising at least five peaks selected from 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0243] Provided herein as Embodiment 71 is the compound of any one of Embodiments 1, 2, and 67, characterized by a powder X-ray diffraction pattern comprising at least seven peaks selected from 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0244] Provided herein as embodiment 72 is the compound of any one of embodiments 1, 2, and 67, characterized by a powder X-ray diffraction pattern comprising peaks at 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.2, 16.4, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0245] Provided herein as embodiment 73 is the compound of any one of embodiments 1, 2, and 67, characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 18, as determined by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0246] Provided herein as embodiment 74 is the compound of any one of embodiments 1, 2, and 67-73, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 91°C.

[0247] Provided herein as Embodiment 75 is the compound of any one of Embodiments 1, 2, and 67-74, characterized in that the compound has a thermogravimetric analysis thermogram comprising a weight loss of about 11% when heated from about 39° C. to about 160° C.

[0248] Provided herein as embodiment 76 is the compound of any one of embodiments 67-75, which is a substantially pure compound.

[0249] Provided herein as embodiment 77 is a pharmaceutical composition comprising a compound of any one of embodiments 67-76 and a pharmaceutically acceptable excipient.

[0250] Provided herein as embodiment 78 is a compound of embodiment 1 or 2, which is a crystalline solvate form of Compound 1.

[0251] Provided herein as embodiment 79 is a compound of embodiment 78 that is a solvate with tetrahydrofuran, acetonitrile, methyl ethyl ketone, ethyl acetate, dichloromethane, acetone, p-dioxane, methanol, isopropyl alcohol, or ethanol.

[0252] Provided herein as embodiment 80 is a compound, the compound being an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1), or an atropisomer thereof.

[0253] Provided herein as embodiment 81 is a compound of embodiment 80, which is the M atropisomer of compound 1.

[0254] Provided herein as embodiment 82 is the compound of embodiment 80 or 81, characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 5, as determined by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

[0255] Provided herein as Embodiment 83 is the compound of any one of Embodiments 80-82, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 144°C.

[0256] Provided herein as Embodiment 84 is the compound of any one of Embodiments 80-83, wherein the compound is characterized by a thermogravimetric analysis thermogram comprising a weight loss of about 1.5% when heated from about 25°C to about 275°C.

[0257] Provided herein as embodiment 85 is the compound of any one of embodiments 80-84, comprising peaks at about -86, -96, -116, -127, -146, and -156 ppm. 19 This compound is characterized by F solid-state NMR.

[0258] Provided herein as embodiment 86 is a compound of any one of embodiments 80-85, substantially as shown in FIG. 19 This compound is characterized by F solid-state NMR.

[0259] Provided herein as embodiment 87 is the compound of any one of embodiments 80-86, which is a substantially pure compound.

[0260] Provided herein as embodiment 88 is a pharmaceutical composition comprising a compound of any one of embodiments 80-87 and a pharmaceutically acceptable excipient.

[0261] Provided herein as embodiment 89 is a pharmaceutical composition comprising (1) a compound of any one of embodiments 4-18, (2) a compound of any one of embodiments 43-54, (3) a compound of any one of embodiments 57-64, (4) a compound of any one of embodiments 67-75, or (5) a compound of any one of embodiments 80-86, or any mixture thereof, and a pharmaceutically acceptable excipient.

[0262] Crystallization Method Anti-solvent precipitation Solutions of compounds of the present disclosure were prepared in various solvents, then an anti-solvent was added. The solids formed were isolated and analyzed.

[0263] Alternatively, solutions of compounds of the present disclosure were prepared in various solvents, then an anti-solvent was added and the samples were evaporated. The solids formed were isolated and analyzed.

[0264] Alternatively, solutions of compounds of the present disclosure were prepared in various solvents, then an anti-solvent was added and the samples were cooled to 2° C.-8° C. The solids that formed were isolated and analyzed.

[0265] Sonication Solutions or suspensions of compounds of the present disclosure were prepared in various solvents and sonicated in an ice bath for 90-180 minutes. The solids were isolated and analyzed.

[0266] Slow cooling Saturated solutions of compounds of the present disclosure were prepared in various solvents at ambient or elevated temperatures. Samples prepared at elevated temperatures were allowed to cool to ambient or 2-8° C. The solids formed were isolated and analyzed.

[0267] evaporation Solutions of compounds of the present disclosure were prepared in various solvents. Once complete dissolution was observed, the solvent was evaporated under reduced pressure at ambient or elevated temperature. The solids formed were isolated and analyzed.

[0268] Delayed evaporation Solutions of compounds of the present disclosure were prepared in various solvents. Upon observing complete dissolution, the solutions were allowed to evaporate ambiently in partially covered vials with or without a nitrogen gas blanket. The solids that formed were isolated and analyzed.

[0269] Alternatively, a solution of the disclosed compound was prepared and then sonicated for approximately 90 minutes. After sonication, the sample was evaporated. Experiments that produced a glass were reprocessed by slurrying the material with a 15-fold addition of antisolvent (hexane at 50°C or water at room temperature). Any resulting solids were isolated and analyzed.

[0270] Stress experiment Solutions or suspensions of compounds of the present disclosure were prepared in various solvents followed by sonication for 60 minutes. The samples were then stirred at 30°C for 24-72 hours, followed by stirring at 50°C for 24 hours. Samples were analyzed by XRPD at each stage before final isolation and analysis.

[0271] Slurry experiments A solution of the compound of the present disclosure is prepared by adding enough solid to a given solvent so that there is excess solid.All forms described below can be obtained from various solvents (for example, but not limited to, the specific solvents described in the Examples).The mixture is then stirred in a sealed vial at ambient or elevated temperature.After a predetermined time, the solid is isolated and analyzed by vacuum or centrifugal filtration.

[0272] Analysis method X-ray powder diffraction (XRPD) X-ray powder diffraction data were obtained using a Phillips X-ray automated powder diffractometer (X'Pert) equipped with a fixed slit and a real-time multistrip (RTMS) detector. The radiation was CuKα (1.54 Å), and the voltage and current were 45 kV and 40 mA, respectively. Data were collected at room temperature from 3.0 to 40.0 degrees 2-theta with a step size of 0.0167 degrees and a count time of 15.240 seconds. The stage was rotated with a rotation time of 1.0 seconds.

[0273] Alternatively, X-ray powder diffraction data were obtained using a PANalytical Empyrean automated powder diffractometer (X'Celerator) equipped with a solar slit, a beam stop, a short antiscatter extension, an antiscatter knife edge, and a scanning position-sensitive detector. The radiation was CuKα (1.54 Å). Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry.

[0274] Alternatively, X-ray powder diffraction data were obtained using a PANalytical X'Pert PRO X-ray diffraction system equipped with a programmable diverging slit and a real-time multistrip (RTMS) detector. The radiation was CuKα (1.54 Å), and the voltage and current were 45 kV and 40 mA, respectively. Data were collected at room temperature from 3.0 to 30.0 degrees 2-theta or from 5 to 45 degrees 2-theta with a step size of 0.0334 degrees. The stage was rotated with a rotation time of 2.0 seconds.

[0275] It should be noted that peak shifts of approximately ±0.2 degrees can occur in XRPD patterns and can be caused by factors such as sample preparation and instrument alignment.

[0276] Thermogravimetric analysis (TGA) Thermogravimetric analysis was performed on a TGA Discovery Series, TA Instruments. Samples were analyzed under nitrogen at a heating rate of 10°C / min over the temperature range of 25°C to 325°C.

[0277] Differential scanning calorimetry (DSC) Differential scanning calorimetry data were collected using standard DSC mode (Discovery Series, TA Instruments). A heating rate of 10 °C / min was employed over the temperature range of 25 °C to 350 °C. Analyses were performed under nitrogen, and samples were loaded into aluminum pans. Indium was used as the calibration standard.

[0278] solid state NMR Approximately 100 mg of sample was packed into a 4 mm ceramic rotor using a SSNMR packing tool. SSNMR spectra were acquired on a Bruker Avance III 500 MHz WB spectrometer. 19 F spectrum, 500MHz 1 The data were collected using a Bruker double-resonance MAS probe operating at the H resonance frequency. All experiments used a 4-mm H / F / X spinning probe operating at a spinning frequency of 14 kHz.19 F measurements were performed using a 4us pi / 2 pulse and a spinal 64 sequence. 1 H decoupling was performed. A recycle delay of 1.26*T1 was used for optimal S / N / time. [Example]

[0279] Example 1: Identification of solid forms of Compound 1 In the field of pharmaceutical research and development, the search for a suitable solid form has become an important step. The search for a solid form involves several determinations, primarily the search for amorphous, salt, or co-crystal forms, and the search for polymorphs of each amorphous, salt, or co-crystal. During a lead optimization program, several properties of the compound under investigation are optimized, and typically, one or several candidates are continued into an exploratory development program. Typically, the evaluation and optimization of physicochemical parameters during lead optimization focuses primarily on solubility. In this case, compound 1 has good solubility characteristics. In addition to solubility optimization, when salts are investigated, additional physicochemical parameters must be considered, such as (1) melting point, (2) thermal behavior, (3) hygroscopicity, (4) crystal habit, (5) polymorphic behavior or physical stability, (6) impurity profile, and (7) chemical stability of the anhydrate or salt form. The melting point of a drug, either as a free base, acid, or salt form, should be high relative to a certain threshold to enable processing steps such as drying or tableting. Assessment of thermal behavior, typically performed by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), also includes solid-solid phase transitions. This may be enantiotropic or monotropic and may relate to the conversion of one polymorph to another, or one pseudopolymorph to another pseudopolymorph (e.g., a lower solvate or hydrate), or to true polymorphism. Hygroscopicity plays an important role in the assessment of solid forms because this property is critically involved in many process steps (drying, storage, blending, granulation, to name just a few). Hygroscopicity can be investigated by dynamic vapor sorption (DVS). Briefly, this technique provides information on the amount of water taken up by a compound at a specific relative humidity level. The discussion of thermal behavior and hygroscopicity represents a link to another parameter to consider in the investigation of anhydrous or salt forms: manageable polymorphic behavior is required for continued drug development. Therefore, anhydrous or salt research procedures typically involve at least a brief assessment of polymorphism.In this sense, manageable polymorphic behavior is not equivalent to the presence of only one or two polymorphic forms, but rather provides a context for the conversion of unequal polymorphic forms. Crystal habit can influence anhydrous or salt investigations, and optimization often means transferring a drug in the form of needle-like crystals to, for example, platelets or cubic crystals, which exhibit better flow properties. Salt investigations can be a tool for improving the impurity profile of a drug, because pharmaceutical salts often exhibit crystal structures that are quite different from those of the corresponding free base or free acid.

[0280] Polymorph and Salt Screening Therefore, a polymorph and salt screen of Compound 1 was conducted. Crystalline chloride, phosphate, and mesylate salts, as well as crystalline anhydrous, hydrate, and solvate forms were identified. None of the identified salts appeared to exhibit particularly advantageous thermal properties or relatively low crystallinity based on DSC data. Of the several remaining free base polymorphs (e.g., hydrates and solvates), crystalline anhydrous Form I demonstrated surprising and unexpected advantages.

[0281] First, crystalline anhydrous Form I of Compound 1 is the most thermodynamically stable polymorph identified in the screening process. Crystalline anhydrous Forms II and III, described below, convert to crystalline anhydrous Form I upon heating or slurrying.

[0282] Specifically, crystalline anhydrous Form II converts to crystalline anhydrous Form I upon heating and recrystallization at 193°C. Crystalline anhydrous Form II converts to crystalline anhydrous Form I upon slurrying with water at 90°C for 1 hour. A mixture of crystalline anhydrous Form I and crystalline anhydrous Form II converts to crystalline anhydrous Form I upon slurrying with 90 / 10 volume / volume water / acetonitrile at RT for 7 days. A mixture of crystalline anhydrous Form I and crystalline anhydrous Form II converts to crystalline anhydrous Form I upon slurrying with heptane at 80°C for 1 day.

[0283] Crystalline anhydrous Form III melts at 180° C. Crystalline anhydrous Form III converts to crystalline anhydrous Form I upon melting and recrystallization at 220° C. A mixture of crystalline anhydrous Form I and crystalline anhydrous Form III converts to crystalline anhydrous Form I upon slurrying in ethanol at RT for 10 days. A mixture of crystalline anhydrous Form I and crystalline anhydrous Form III converts to crystalline anhydrous Form I upon slurrying in methanol at RT for 10 days.

[0284] The high melting point of crystalline anhydrous Form I is a further indication of its thermodynamic stability (DSC endotherm onset at about 293° C.).

[0285] Second, crystalline anhydrous Form I is less hygroscopic than crystalline anhydrous Forms II and III (Form I absorbed 0.5-1.0 wt. % water at 25°C and 0-90% RH, Form II absorbed 2-2.5 wt. % water at 25°C and 0-90% RH, and Form III absorbed 7.0 wt. % water at 25°C and 0-95% RH).

[0286] Furthermore, crystalline anhydrous Form I is physically and chemically stable in the solid state, exhibiting no decomposition peaks by HPLC or any changes in the solid state properties examined (e.g., XRPD, melting point onset and heat of fusion by DSC, and volatiles content by TGA) over 14 weeks at 25°C / 60% RH, 40°C / 75% RH, 40°C / ambient RH, and 60°C / ambient RH. Furthermore, crystalline anhydrous Form I was stable in an additive compatibility study with three prototype blends stored at 40°C / 75% RH for 4 weeks. Crystalline anhydrous Form I was also stable to ultraviolet and visible light in the solid state.

[0287] Thus, crystalline anhydrous Form I exhibits advantageous and unexpected overall properties, particularly when compared to the other forms and salts identified.

[0288] Polymorphism Screening A polymorphic screen to generate various solid forms of the M atropisomer of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1) was carried out as described below. For convenience, references to "Compound 1" in the Examples below should be understood to refer to the M atropisomer of Compound 1.

[0289] Example 1 Compound 1 may be prepared according to the procedures disclosed in U.S. Patent Application Publication No. 2018 / 0334454, published November 22, 2018, which is incorporated herein by reference in its entirety.

[0290] Amorphous Form I of Compound 1 was prepared by rotary evaporation from MeOH with secondary drying under reduced pressure at RT.

[0291] XRPD, TGA, DSC, and 19 The relative peak areas of the F SSNMR amorphous form are shown in Figures 1, 2, 3, and 4.

[0292] Differential scanning calorimetry (DSC) thermogram with an endotherm beginning at approximately 144°C.

[0293] Thermogravimetric analysis (TGA) thermogram showing a weight loss of about 1.5% when heated from about 25°C to about 275°C.

[0294] 19 F SSNMR: -86, -96, -116, -127, -146, and -156 ppm.

[0295] Many anhydrous and hydrate forms of Compound 1 were investigated (see Table 1 below). Further characterization of these crystalline forms (e.g., melting point, thermal behavior, hygroscopicity, crystal habit, particle size, polymorphic behavior, stability, and purity) was investigated. These forms were characterized by methods including XRPD, TGA, and DSC analysis. Rel. Int% is the percentage of relative intensity based on the highest peak.

[0296] FIG. 21 shows a superposition of crystalline anhydrous Forms I, II, III, and variable hydrate Form I of Compound 1 (Forms I-III and variable hydrate Form I are in top-to-bottom order).

[0297] [Table 4]

[0298] Example 2: Preparation of Crystalline Anhydrous Form I of Compound 1 Crystalline anhydrous Form I was prepared by adding 1.5 g of crystalline anhydrous Form II of Compound 1 to 10 mL of water to form a slurry. The slurry was heated to 90° C. for 2 hours and then stirred at RT overnight. The solid was filtered off, dried under reduced pressure, and identified as crystalline anhydrous Form I by XRPD. TGA included a DSC endotherm onset at about 292.6° C. and a weight loss of about 0.2% when heated from about 25° C. to about 275° C.

[0299] The crystalline anhydrous Form I prepared above has been shown to be stable by proton NMR, X-ray powder diffraction (XRPD) data (Figure 5), DSC (Figure 6), TGA (Figure 7), carbon-13 SSNMR (Figure 8), and 19 It was characterized by F SSNMR (Figure 9).

[0300] 1H NMR(400MHz,DMSO-d6)δ ppm 0.93(d,J=6.84Hz,3H)1.07(d,J=6.63Hz,3H)1.35(d,J=6.84Hz,3H)1.90(s,3H)2.66-2.75(m,1H)3.14(br t,J=11.20Hz,1H)3.59-3.75(m,2H)3.97-4.08(m,1H)4.08-4.22(m,1H)4.22-4.43(m,2H)4.90(br s,1H)5.74-5.79(m,1H)6.21(br d,J=17.00Hz,1H)6.65-6.75(m,2H)6.79-6.92(m,1H)7.18(d,J=4.98Hz,1 H)7.23-7.31(m,1H)8.22-8.33(m,1H)8.38(d,J=4.77Hz,1H)10.19(s,1H)

[0301] 13 C SSNMR: 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167.7, and 168 ppm.

[0302] 19 F SSNMR: -49, -60, -79, -90, -109, -120, -138, -150, -168, and -179 ppm.

[0303] [Table 5]

[0304] Example 3: Preparation of Anhydrous Form II of Compound 1 Crystalline anhydrous Form II of Compound 1 was prepared by adding 0.987 g of anhydrous Compound 1 to 15 mL of MeOH to form a slurry. The isolated solid was identified as crystalline anhydrous Form II by XRPD.

[0305] DSC onset at about 192.5°C, TGA with weight loss of about 1% to about 1.8% when heated from about 25°C to about 250°C.

[0306] The crystalline anhydrous Form II of Compound 1 prepared above has been shown to be stable by proton NMR, X-ray powder diffraction (XRPD) data (Figure 10), DSC (Figure 11), TGA (Figure 12), carbon-13 SSNMR (Figure 13), and 19 It was characterized by F SSNMR (Figure 14).

[0307] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.93(d,J=6.63Hz,4H)1.07(d,J=6.84Hz,4H)1.35(d,J=6.63Hz,4H)1.90(s,3H)2.60-2.76(m,1H)3.11-3.28(m,2H)3.68(br d,J=13.89Hz,2H)4.08(d,J=5.18Hz,2H)4.32(br d,J=13.68Hz,2H)4.90(br s,1H)5.74-5.79(m,1H)6.21(br d,J=16.17Hz,1H)6.65-6.76(m,2H)6.80-6.92(m,1H)7.18(d,J=4.98Hz,1H)7.23-7.31(m,1H)8.29(br d,J=9.33Hz,1H)8.38(d,J=4.98Hz,1H)10.19(s,1H).

[0308] 13 C SSNMR: 16, 18, 19, 20, 23, 25, 31, 32, 38, 40, 43, 46, 51, 57, 105, 107, 110, 117, 120, 123, 124, 125, 128, 132, 149, 152, 155, 158, 159, 163, and 166 ppm.

[0309] 19 F SSNMR: -59, -62, -89, -92, -119, -122, -148, -151, -179, and -181 ppm.

[0310] [Table 6]

[0311] Example 4: Preparation of Crystalline Anhydrous Form III of Compound 1 Crystalline anhydrous Form III of Compound 1 was prepared by drying acetone solvate Form I of Compound 1 under reduced pressure at about 65°C to 76°C. DSC endotherm onset at about 194°C, TGA with negligible weight loss upon heating from about 25°C to about 250°C.

[0312] The crystalline anhydrous Form III of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 15), DSC (Figure 16), and TGA (Figure 17).

[0313] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.93(d,J=6.82Hz,3H)1.07(d,J=6.61Hz,3H)1.35(d,J=6.61Hz,2H)1.90(s,2H)2.64-2.80(m,1H)3.14(br t,J=10.66Hz,1H)3.45-3.57(m,1H)3.58-3.76(m,1H)3.94-4.08(m,1H)4.14(br d,J=13.00Hz,1H)4.21-4.47(m,2H)4.90(br s,1H)5.76(dd,J=10.44,2.13Hz,1H)6.21(br d,J=16.84Hz,1H)6.55-6.78(m,2H)6.86(dt,J=16.20,11.29Hz,1H)7.13-7. 21(m,1H)7.21-7.33(m,1H)8.21-8.34(m,1H)8.39(d,J=4.90Hz,1H)10.20(br s,1H).

[0314] [Table 7]

[0315] Example 5: Preparation of Variable Hydrate Form I of Compound 1 The variable hydrate form I of compound 1 was prepared by dissolving compound 1 in MeOH at RT, polish filtering, and then adding aliquots of water as an antisolvent until precipitation occurred. After stirring at RT for 13 days, the solid was isolated.

[0316] DSC endotherm onset at about 91°C, TGA with about 11% weight loss (3.9 mol water) when heated from about 39°C to about 160°C.

[0317] Karl Fischer 10.63% (3.7 mol) water.

[0318] The crystalline mutated hydrate Form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 18), DSC (Figure 19), and TGA (Figure 20).

[0319] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.94(d,J=6.62Hz,3H)1.08(d,J=6.84Hz,3H)1.35(d,J=6.63Hz,3H)1.90(s,3H)2.61-2.79(m,1H)3.15(br t,J=11.01Hz,1H)3.40-3.58(m,2H)3.59-3.84(m,3H)3.86-4.09(m,1H)4.15(br d,J=12.39Hz,1H)4.21-4.47(m,3H)4.90(br s,2H)5.73-5.82(m,1H)6.15-6.21(m,1H)6.23(br d,J=4.92Hz,1H)6.63-6.77(m,3H)6.78-7.03(m,2H)7.14-7.31(m,3H)8.14-8.35(m,1H)8.39(d,J=4.92Hz,1H).

[0320] [Table 8]

[0321] Example 6: Preparation of Crystalline THF Solvate Form I of Compound 1 Crystalline THF solvate Form I of Compound 1 was prepared by placing amorphous Compound 1 in a small open vial, then placing this vial inside a larger vial containing THF, capping it, and steam-stressing the solid at RT for 4 days.

[0322] DSC endotherm onset at approximately 165°C, TGA showing a weight loss of approximately 13.4% when heated from approximately 130°C to approximately 160°C (1.2 mol THF).

[0323] NMR 1.1 mol THF

[0324] The crystalline THF solvate Form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 22), DSC (Figure 23), and TGA (Figure 24).

[0325] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.94(d,J=6.62Hz,3H)1.08(d,J=6.62Hz,3H)1.35(d,J=6.62Hz,3H)1.68-1.84(m,4H)1.90(s,3H)2.62-2.93(m,1H)3.15(br t,J=11.33Hz,1H)3.49-3.75(m,10H)3.87-4.09(m,1H)4.09-4.21(m,1H)4.22-4.47(m,4H)4.91(br s,2H)5.71-5.83(m,2H)6.21(br dd,J=16.88,4.70Hz,1H)6.64-6.78(m,3H)6.78-6.99(m,1H)7.14-7.22(m,1H) 7.28(td,J=8.33,7.05Hz,1H)8.18-8.35(m,1H)8.39(d,J=4.92Hz,1H)10.21(br s,1H)

[0326] [Table 9]

[0327] Example 7: Preparation of crystalline MeCN solvate Form I of Compound 1 Crystalline MeCN solvate Form I was prepared by slurrying Compound 1 in MeCN at RT for 14 days.

[0328] DSC endotherm onset at about 112° C., TGA with a weight loss of about 6.9% when heated from about 38° C. to about 170° C. (1 mol MeCN).

[0329] NMR 0.9 mol MeCN.

[0330] The crystalline MeCN solvate Form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 25), DSC (Figure 26), and TGA (Figure 27).

[0331] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.85-1.00(m,3H)1.07(d,J=6.82Hz,3H)1.35(d,J=6.82Hz,3H)1.90(s,3H)1.99-2.16(m,2H)2.52-2.78(m,1H)3.14(br s,1H)3.35-3.56(m,1H)3.57-3.84(m,2H)3.86-4.09(m,1H)4.09-4.19(m,1H)4.19-4.47(m,2H)4.90(br s,1H)5.66-5.80(m,1H)6.20(br dd,J=16.73,4.58Hz,1H)6.61-6.76(m,2H)6.78-6.94(m,1H)7.11-7.21( m,1H)7.21-7.31(m,1H)8.16-8.36(m,2H)8.39(d,J=4.69Hz,1H)10.21(br s,1H).

[0332] [Table 10]

[0333] Example 8: Preparation of Crystalline MEK Solvate Form I of Compound 1 Crystalline MEK solvate Form I was prepared by dissolving Compound 1 in MEK at RT, polish filtering, and then adding aliquots of heptane as an antisolvent until precipitation occurred. The solid was isolated after stirring at RT for 13 days. It was also prepared by slurrying amorphous Compound 1 in MEK at RT.

[0334] DSC endotherm onset at approximately 106°C, TGA showing a weight loss of approximately 10.7% when heated from approximately 39°C to approximately 197°C (0.9 mol MEK).

[0335] NMR 0.8 mol MEK.

[0336] The crystalline MEK solvate Form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 28), DSC (Figure 29), and TGA (Figure 30).

[0337] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.92(q,J=7.05Hz,5H)1.08(d,J=6.62Hz,3H)1.35(d,J=6.62Hz,3H)1.90(s,3H)2.04-2.10(m,2H)2.36-2.49(m,2H)2.60-2.93(m,1H)3.15(br s,1H)3.36-3.57(m,2H)3.57-3.84(m,4H)3.86-4.09(m,2H)4.15(br d,J=12.82Hz,1H)4.22-4.46(m,4H)4.91(br s,2H)5.72-5.83(m,2H)6.00-6.21(m,1H)6.23(br d,J=4.49Hz,1H)6.64-6.78(m,3H)6.78-7.00(m,2H)7.17-7.31(m,3H)8.16-8.35(m,1H)8.39(d,J=4.92Hz,1H)10.22(br s,1H).

[0338] [Table 11]

[0339] Example 9: Preparation of Crystalline EtOAc Solvate Form I of Compound 1 Crystalline EtOAc solvate Form I was prepared by slurrying Compound 1 in ethyl acetate (EtOAC) at RT for 24 hours.

[0340] The crystalline EtOAc solvate Form I prepared above was characterized by proton NMR and X-ray powder diffraction (XRPD) data (Figure 31).

[0341] [Table 12]

[0342] Example 10: Preparation of DMF solvate Form I of Compound 1 Crystalline DMF solvate Form I of Compound 1 was prepared by slurrying Compound 1 in DMF / water at RT for 24 hours.

[0343] The crystalline DMF solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 32), DSC (Figure 33), and TGA (Figure 34).

[0344] DSC endotherm onset at about 74°C, TGA with a weight loss of about 17% when heated from about 36°C to about 195°C.

[0345] NMR 1-2 mol DMF.

[0346] 1H NMR(500MHz,DMSO-d6)δ ppm 0.94(d,J=6.49Hz,4H)1.08(d,J=6.75Hz,4H)1.35(d,J=6.75Hz,4H)1.91(s,4H)2. 30(s,1H)2.55(t,J=5.58Hz,1H)2.73(s,6H)2.89(s,5H)3.00-3.21(m,1H)3.27(br d,J=13.49Hz,2H)3.34(br s,5H)3.60-3.74(m,2H)3.96-4.16(m,1H)4.32(br d,J=13.75Hz,2H)4.39(br s,1H)4.90(br s,1H)5.67-5.86(m,1H)6.20(br dd,J=16.61,7.27Hz,1H)6.64-6.77(m,2H)6.79-6.92(m,1H)7.17-7.32(m,2H)7.95(s,1H)8.28(br dd,J=16.22,9.21Hz,1H)8.40(d,J=4.93Hz,1H)10.19(d,J=1.30Hz,1H).

[0347] [Table 13]

[0348] Example 11: Preparation of Crystalline DCM Solvate Form I of Compound 1 Crystalline DCM solvate Form I of Compound 1 was prepared by dissolving Compound 1 in DCM at RT, polish filtering, and then adding aliquots of heptane as an antisolvent until precipitation occurred. After stirring at RT for 1 h, the solid was isolated.

[0349] 1H NMR(400MHz,DMSO-d6)δ ppm 0.84-1.02(m,2H)1.07(d,J=6.61Hz,2H)1.35(d,J=6.82Hz,2H)1.90(s,2H)2.64-2.80(m,1H)3.14(br t,J=11.19Hz,1H)3.45-3.57(m,1H)3.58-3.84(m,2H)3.86-4.09(m,1H)4.09-4.21(m,1H)4.21-4.46(m,2H)4.90(br s,1H)5.65-5.86(m,2H)6.08-6.28(m,1H)6.63-6.76(m,2H)6.86(dt,J=16.46,11.27Hz, 1H)7.12-7.21(m,1H)7.21-7.31(m,1H)8.16-8.36(m,2H)8.39(d,J=4.90Hz,1H)10.20(br s,1H).

[0350] The crystalline DCM solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 35), DSC (Figure 36), and TGA (Figure 37).

[0351] DSC endotherm onset at about 174°C, TGA with weight loss of about 7.2% when heated from about 40°C to about 200°C. (0.5 mol DCM) from 40 to 200°C.

[0352] NMR 0.5mol DCM

[0353] [Table 14]

[0354] Example 12: Preparation of Crystalline Acetone Solvate Form I of Compound 1 Crystalline acetone solvate Form I of Compound 1 was prepared by slurrying amorphous Compound 1 in acetone / water (50:50) at RT or in acetone / water (50:50) at 2-8°C for 15 days.

[0355] The crystalline acetone solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 38), DSC (Figure 39), and TGA (Figure 40).

[0356] DSC endotherm onset at about 72° C., TGA with a weight loss of about 21.4% when heated from about 38° C. to about 130° C. (0.7 mol acetone and 5.3 mol water).

[0357] NMR 0.7 mol acetone.

[0358] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.84-1.00(m,3H)1.07(d,J=6.61Hz,3H)1.34(d,J=6.61Hz,3H)1.90(s,3H)2. 05-2.12(m,3H)2.52-2.78(m,2H)3.08-3.21(m,1H)3.45-3.57(m,1H)3.67(br d,J=11.72Hz,2H)3.97-4.06(m,1H)4.08-4.21(m,1H)4.32(br d,J=13.85Hz,2H)4.90(br s,1H)5.54-5.80(m,2H)5.99-6.26(m,2H)6.52-6.75(m,2H)6.84(br s,1H)7.09-7.30(m,2H)8.12-8.36(m,3H)8.38(d,J=4.90Hz,1H)10.21(br s,1H).

[0359] [Table 15]

[0360] Example 13: Preparation of Crystalline Acetone Solvate Form II of Compound 1 Crystalline acetone solvate Form II of Compound 1 was prepared by slurrying Compound 1 in acetone at 2-8° C. for 15 days.

[0361] The crystalline acetone solvate Form II of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 41), DSC (Figure 42), and TGA (Figure 43).

[0362] DSC endotherm onset at about 137°C, TGA with a weight loss of about 7.3% when heated from about 100°C to about 200°C (0.8 mol acetone).

[0363] NMR 0.7 mol acetone

[0364] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.83-1.02(m,3H)1.07(d,J=6.82Hz,2H)1.35(d,J=6.61Hz,2H)1.90(s,2H)2.09(s,3H)2.52-2.77(m,1H)3.18(br s,1H)3.45-3.57(m,1H)3.66(br s,4H)3.96-4.08(m,1H)4.08-4.20(m,1H)4.32(br d,J=13.64Hz,3H)4.90(br s,2H)5.69-5.80(m,1H)6.15-6.26(m,1H)6.60-6.75(m,2H)6.79-6.94(m,1H)7.07-7.2 1(m,1H)7.27(td,J=8.31,7.03Hz,1H)8.20-8.36(m,2H)8.39(d,J=4.90Hz,1H)10.20(br s,1H).

[0365] [Table 16]

[0366] Example 14: Preparation of crystalline p-dioxane solvate Form I of Compound 1 Crystalline p-dioxane solvate Form I of Compound 1 was prepared by slurrying Compound 1 in p-dioxane at RT for 14 days.

[0367] The crystalline p-dioxane solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 44), DSC (Figure 45), and TGA (Figure 46).

[0368] DSC endotherm onset at approximately 112°C, TGA showing a weight loss of approximately 23.2% when heated from approximately 25°C to approximately 150°C (1.9 mol p-dioxane).

[0369] NMR 1.9 mol p-dioxane

[0370] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.84-1.00(m,3H)1.07(d,J=6.61Hz,3H)1.35(d,J=6.82Hz,3H)1.90(s,2H)2.52-2.77(m,2H)3.05-3.28(m,1H)3.32(s,4H)3.58-3.78(m, 3H)3.98-4.07(m,1H)4.09-4.20(m,1H)4.09-4.19(m,1H)4.15-4.43(m,1H)4.16-4.21(m,1H)4.22-4.45(m,1H)4.23-4.45(m,1H)4.90(br s,1H)5.61-5.80(m,1H)6.20(br dd,J=16.62,4.48Hz,1H)6.58-6.76(m,2H)6.79-6.93(m,1H)7.10-7.21( m,1H)7.21-7.31(m,1H)8.14-8.36(m,3H)8.39(d,J=4.90Hz,1H)10.20(br s,1H)

[0371] [Table 17]

[0372] Example 15: Preparation of Crystalline Methanol Solvate Form I of Compound 1 Crystalline MeOH solvate Form I of Compound 1 was prepared by placing Compound 1 in a small open vial, then placing this vial inside a larger vial containing methanol (MeOH), capping, and steam stressing the solid at RT for 4 days.

[0373] The crystalline MeOH solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 47), DSC (Figure 48), and TGA (Figure 49).

[0374] DSC endotherm onset at about 57°C, TGA with weight loss of about 5.2% when heated from about 38°C to about 220°C. (1.0 mol MeOH)

[0375] NMR 0.8mol MeOH

[0376] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.94(d,J=6.62Hz,3H)1.08(d,J=6.62Hz,3H)1.35(d,J=6.84Hz,3H)1.90(s,3H)2.64-2.80 (m,1H)3.18(d,J=4.92Hz,3H)3.48-3.76(m,2H)3.97-4.21(m,2H)4.21-4.47(m,2H)4.91(br s,1H)5.69-5.86(m,1H)6.21(br dd,J=16.67,4.49Hz,1H)6.63-6.79(m,2H)6.80-6.98(m,1H)7.17-7.31(m,2H)8.18-8.35(m,1H)8.39(d,J=4.92Hz,1H)10.22(br s,1H)

[0377] [Table 18]

[0378] Example 16: Preparation of Crystalline IPA Solvate Form I of Compound 1 Crystalline isopropanol (IPA) solvate Form I of Compound 1 was prepared by slurrying amorphous Compound 1 in IPA at RT for 5 days.

[0379] The crystalline IPA solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 50), DSC (Figure 51), and TGA (Figure 52).

[0380] DSC endotherm onset at approximately 56°C, TGA showing approximately 8.7% weight loss when heated from approximately 39°C to approximately 190°C (0.9 mol IPA).

[0381] NMR 2.3 mol IPA

[0382] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.94(d,J=6.62Hz,3H)1.02-1.06(m,1H)1.05(d,J=5.98Hz,14H)1.35(d,J=6.62Hz,3H)1.90(s,3H)2.72(br s,1H)3.10-3.21(m,1H)3.45-3.58(m,1H)3.78(td,J=6.09,4.06Hz,9H)3.98-4.09(m,1H)4.16(br s,1H)4.35(d,J=4.06Hz,8H)4.91(br d,J=0.85Hz,1H)5.73-5.83(m,2H)6.16-6.28(m,1H)6.66-6.93(m,5H)7.19 (dd,J=4.81,0.75Hz,2H)7.23-7.33(m,2H)8.39(d,J=4.92Hz,3H)10.21(br s,1H).

[0383] [Table 19]

[0384] Example 17: Preparation of Crystalline EtOH Solvate Form I of Compound 1 Crystalline EtOH solvate Form I of Compound 1 was prepared by slurrying amorphous Compound 1 in ethanol (EtOH) at RT for 10 days.

[0385] The crystalline EtOH solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 53), DSC (Figure 54), and TGA (Figure 55).

[0386] DSC endotherm onset at approximately 194°C, TGA showing approximately 5% weight loss when heated from approximately 36°C to approximately 195°C. (0.6 mol EtOH)

[0387] NMR 0.7 mol EtOH.

[0388] 1 H NMR(400MHz,DMSO-d6)δ ppm 0.84-1.02(m,5H)1.02-1.12(m,5H)1.35(d,J=6.82Hz,3H)1.90(s,3H)2.52-2.77(m,1H)3.14(br t,J=10.87Hz,1H)3.34-3.57(m,2H)3.58-3.84(m,2H)3.86-4.08(m,1H)4.09-4.21(m,1H)4.21-4.46(m,3H)4.90(br s,1H)5.51-5.80(m,1H)6.20(br dd,J=16.52,4.58Hz,1H)6.62-6.75(m,2H)6.86(dt,J=16.30,11.24Hz,1H)7.13-7.19 (m,1H)7.27(td,J=8.20,7.03Hz,1H)8.16-8.36(m,2H)8.39(d,J=4.90Hz,1H)10.20(br s,1H).

[0389] [Table 20]

[0390] While the invention has been described and illustrated with reference to certain specific embodiments thereof, those skilled in the art will recognize that various adaptations, changes, modifications, substitutions, deletions, or additions to procedures and protocols may be made without departing from the spirit and scope of the disclosure. It is therefore intended that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

1. A compound which is a crystalline form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1) or an atropisomer thereof.

2. The compound of claim 1 , wherein the compound is the M atropisomer of Compound 1.

3. 3. The compound of claim 1 or 2, wherein the compound is a crystalline anhydrous form of Compound 1.

4. 4. The compound of any one of claims 1 to 3, wherein the compound is characterized by a powder X-ray diffraction pattern comprising peaks at 9.0, 12.0, 12.6, and 19.0±0.2 degrees two-theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

5. 4. The compound of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern comprising at least three peaks selected from 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

6. 4. The compound of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern comprising at least five peaks selected from 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

7. 4. The compound of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern comprising at least seven peaks selected from 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

8. 4. The compound of any one of claims 1 to 3, wherein the compound is characterized by a powder X-ray diffraction pattern comprising peaks at 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees two-theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

9. 4. The compound of any one of claims 1 to 3, wherein the compound is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 5, when measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

10. 10. The compound of any one of claims 1 to 9, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 293°C.

11. 11. The compound of any one of claims 1 to 10, wherein the compound is characterized by a thermogravimetric analysis thermogram comprising a weight loss of about 0.2% when heated from about 25°C to about 275°C.

12. The compound comprises at least three peaks selected from peaks at about 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm. １３ The compound according to any one of claims 1 to 11, characterized by C solid state NMR.

13. The compound comprises at least five peaks selected from peaks at about 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm. １３ The compound according to any one of claims 1 to 11, characterized by C solid state NMR.

14. The compound includes at least seven peaks selected from peaks at about 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm. １３ The compound according to any one of claims 1 to 11, characterized by C solid state NMR.

15. The compounds include peaks at about 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm. １３ The compound according to any one of claims 1 to 11, characterized by C solid state NMR.

16. The compound has a structure substantially similar to that shown in FIG. 8 as determined by x-ray powder diffraction using an x-ray wavelength of 1.54 Å. １３ The compound according to any one of claims 1 to 11, characterized by C solid state NMR.

17. The compound includes peaks at about -49, -60, -79, -90, -109, -120, -138, -150, -168, and -179 ppm. １９ The compound of any one of claims 1 to 16, characterized by F solid state NMR.

18. The compound has a structure substantially similar to that shown in FIG. 9 as determined by x-ray powder diffraction using an x-ray wavelength of 1.54 Å. １９ The compound of any one of claims 1 to 16, characterized by F solid state NMR.

19. The compound of any one of claims 1 to 18, wherein the compound is substantially pure.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable excipient.

21. 21. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition is in a dosage form for oral administration.

22. 22. The pharmaceutical composition of claim 20 or 21, wherein the dosage form is a solid dosage form.

23. 23. The pharmaceutical composition of claim 22, wherein the solid dosage form is a tablet.

24. 24. The pharmaceutical composition of any one of claims 20 to 23, comprising 120 mg of the compound.

25. A compound according to any one of claims 1 to 19 or a pharmaceutical composition according to any one of claims 20 to 24 for use as a medicament.

26. A compound according to any one of claims 1 to 19 or a pharmaceutical composition according to any one of claims 20 to 24 for use in the treatment of cancers harboring a KRAS G12C mutation.

27. 27. The compound or pharmaceutical composition for use according to claim 26, wherein the cancer harboring the KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

28. 27. The compound or pharmaceutical composition for use according to claim 26, wherein the cancer harboring the KRAS G12C mutation is non-small cell lung cancer.

29. 27. The compound or pharmaceutical composition for use according to claim 26, wherein the cancer harboring the KRAS G12C mutation is pancreatic cancer.

30. 27. The compound or pharmaceutical composition for use according to claim 26, wherein the cancer harboring the KRAS G12C mutation is colorectal cancer.

31. Use of a compound according to any one of claims 1 to 19 or a pharmaceutical composition according to any one of claims 20 to 24 in the preparation of a medicament for the treatment of cancers harboring the KRAS G12C mutation.

32. 32. The use of claim 31, wherein the cancer harboring the KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

33. The use of claim 31 , wherein the cancer harboring the KRAS G12C mutation is non-small cell lung cancer.

34. The use of claim 31 , wherein the cancer harboring the KRAS G12C mutation is pancreatic cancer.

35. 32. The use of claim 31, wherein the cancer harboring the KRAS G12C mutation is colorectal cancer.

36. 20. A method of treating a cancer harboring a KRAS G12C mutation in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 19.

37. 37. The method of claim 36, wherein the cancer harboring the KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

38. 37. The method of claim 36, wherein the cancer harboring the KRAS G12C mutation is small cell lung cancer.

39. 37. The method of claim 36, wherein the cancer harboring the KRAS G12C mutation is pancreatic cancer.

40. 37. The method of claim 36, wherein the cancer harboring the KRAS G12C mutation is colorectal cancer.

41. 41. The compound, use or method of any one of claims 25 to 40, wherein the compound is administered in a total daily dose of 960 mg.

42. 42. The compound, use or method of any one of claims 25 to 41, wherein the compound is administered to an adult.

43. 4. The compound of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern comprising peaks at 7.3, 9.8, 10.1, 11.3, 13.3, and 17.2±0.2 degrees two-theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

44. 4. The compound of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern comprising at least three peaks selected from 7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2 degrees two-theta when measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

45. 4. The compound of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern comprising at least five peaks selected from 7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2 degrees two-theta when measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

46. 4. The compound of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern comprising at least seven peaks selected from 7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2 degrees two-theta when measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

47. 4. The compound of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern comprising peaks at 7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2 degrees two-theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

48. 4. The compound of any one of claims 1 to 3, wherein the compound is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 10, when measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

49. 49. The compound of any one of claims 1-3 and 43-48, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 193°C.

50. 50. The compound of any one of claims 1-3 and 43-49, wherein the compound has a thermogravimetric analysis thermogram comprising a weight loss of about 1% to about 1.8% when heated from about 25°C to about 250°C.

51. The compounds include peaks at about 16, 18, 19, 20, 23, 25, 31, 32, 38, 40, 43, 46, 51, 57, 105, 107, 110, 117, 120, 123, 124, 125, 128, 132, 149, 152, 155, 158, 159, 163, and 166 ppm. １３ The compound of any one of claims 1 to 3 and 43 to 50, characterized by C solid state NMR.

52. The compound is substantially as shown in FIG. １３ The compound of any one of claims 1 to 3 and 43 to 50, characterized by C solid state NMR.

53. The compound includes peaks at about -59, -62, -89, -92, -119, -122, -148, -151, -179, and -181 ppm. １９ 53. The compound of any one of claims 1 to 3 and 43 to 52, characterized by F solid state NMR.

54. The compound is substantially as shown in FIG. １９ 53. The compound of any one of claims 1 to 3 and 43 to 52, characterized by F solid state NMR.

55. 55. The compound of any one of claims 43 to 54, wherein the compound is substantially pure.

56. A pharmaceutical composition comprising a compound according to any one of claims 43 to 55 and a pharmaceutically acceptable excipient.

57. 4. The compound of any one of claims 1 to 3, wherein the compound is characterized by a powder X-ray diffraction pattern comprising peaks at 6.3, 8.4, 9.5, and 16.0±0.2 degrees two-theta as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

58. 4. The compound of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern comprising at least three peaks selected from 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees two-theta when measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

59. 4. The compound of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern comprising at least five peaks selected from 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees two-theta when measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

60. 4. The compound of any one of claims 1 to 3, characterized by a powder X-ray diffraction pattern comprising at least seven peaks selected from 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees two-theta when measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

61. 4. The compound of any one of claims 1 to 3, wherein the compound is characterized by a powder X-ray diffraction pattern comprising peaks at 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees two-theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

62. 4. The compound of any one of claims 1 to 3, wherein the compound is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 15, when measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

63. 63. The compound of any one of claims 1-3 and 57-62, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 194°C.

64. The compound according to any one of claims 1 to 3 and 57 to 63, characterized in that the compound undergoes negligible weight loss when heated from about 25°C to about 250°C.

65. 65. The compound of any one of claims 57 to 64, wherein the compound is substantially pure.

66. A pharmaceutical composition comprising a compound according to any one of claims 57 to 65 and a pharmaceutically acceptable excipient.

67. 3. The compound of claim 1 or 2, wherein the compound is a crystalline hydrate form of Compound 1.

68. 68. The compound of any one of claims 1, 2 and 67, wherein the compound is characterized by a powder X-ray diffraction pattern comprising peaks at 6.9, 8.0, 9.6, 12.4, and 13.1±0.2 degrees two-theta as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

69. 68. The compound of any one of claims 1, 2 and 67, characterized by a powder X-ray diffraction pattern comprising at least three peaks selected from 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees two-theta when measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

70. 68. The compound of any one of claims 1, 2 and 67, characterized by a powder X-ray diffraction pattern comprising at least five peaks selected from 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees two-theta, as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

71. 68. The compound of any one of claims 1, 2 and 67, characterized by a powder X-ray diffraction pattern comprising at least seven peaks selected from 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees two-theta when measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

72. 68. The compound of any one of claims 1, 2 and 67, wherein the compound is characterized by a powder X-ray diffraction pattern comprising peaks at 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.2, 16.4, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees two-theta as measured by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

73. 68. The compound of any one of claims 1, 2 and 67, wherein the compound is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 18, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

74. 74. The compound of any one of claims 1, 2, and 67-73, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 91°C.

75. 75. The compound of any one of claims 1, 2, and 67-74, wherein the compound has a thermogravimetric analysis thermogram comprising a weight loss of about 11% when heated from about 39°C to about 160°C.

76. 76. The compound of any one of claims 67 to 75, wherein the compound is substantially pure.

77. A pharmaceutical composition comprising a compound according to any one of claims 67 to 76 and a pharmaceutically acceptable excipient.

78. The compound of claim 1 or 2, wherein the compound is a crystalline solvate form of Compound 1.

79. 79. The compound of claim 78, wherein the compound is a solvate with tetrahydrofuran, acetonitrile, methyl ethyl ketone, ethyl acetate, dichloromethane, acetone, p-dioxane, methanol, isopropyl alcohol, or ethanol.

80. 1. A compound, which is an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1) or an atropisomer thereof.

81. 81. The compound of claim 80, wherein the compound is the M atropisomer of compound 1.

82. 82. The compound of claim 80 or 81, wherein the compound is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 5, as determined by x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

83. 83. The compound of any one of claims 80-82, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 144°C.

84. 84. The compound of any one of claims 80-83, wherein the compound is characterized by a thermogravimetric analysis thermogram comprising a weight loss of about 1.5% when heated from about 25°C to about 275°C.

85. The compound includes peaks at about -86, -96, -116, -127, -146, and -156 ppm. １９ 85. The compound of any one of claims 80 to 84, characterized by F solid state NMR.

86. The compound is substantially as shown in FIG. １９ 86. The compound of any one of claims 80 to 85, characterized by F solid state NMR.

87. 87. The compound of any one of claims 80 to 86, wherein the compound is substantially pure.

88. A pharmaceutical composition comprising a compound according to any one of claims 80 to 87 and a pharmaceutically acceptable excipient.

89. (1) A compound according to any one of claims 4 to 18, (2) a compound according to any one of claims 43 to 54, (3) a compound according to any one of claims 57 to 64, (4) a compound according to any one of claims 67 to 75, or (5) 87. A pharmaceutical composition comprising a compound according to any one of claims 80 to 86, or any mixture thereof, and a pharmaceutically acceptable excipient.

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