solid form

Abstract

The present disclosure provides crystalline and amorphous forms of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one, including several anhydrous, hydrate, and solvate forms, as well as solid state forms thereof; pharmaceutical compositions; and methods of treating diseases mediated by KRAS G12C inhibition.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 851,044, filed May 21, 2019, which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure provides crystalline forms (including anhydrous, hydrated, and several solvated crystalline forms) of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propyl)-3-pyridyl)-4-((2S)-2-methyl-4-(2-acryloyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (hereinafter referred to as "Compound 1"), as well as its physical form, pharmaceutical compositions, and methods for treating diseases mediated by KRAS G12C inhibition. Background Technology

[0004] Compound 1 is a selective inhibitor of KRAS G12C and can be used to treat cancers, including lung cancer (e.g., 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.

[0005] Many compounds can exist in different crystalline or polymorphic forms, which exhibit different physical, chemical, and spectroscopic properties. For example, some polymorphs of a compound may be more soluble in a particular solvent, may be more fluid, or may be more compressible than other polymorphs. See, for example, P. DiMartino et al., J. Thermal Anal., 48:447-458 (1997). In the case of pharmaceuticals, some solid forms may have higher bioavailability than others, while others may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a regulatory perspective, as pharmaceuticals are only approved by agencies such as the U.S. Food and Drug Administration if they meet stringent purity and characterization standards. In practice, regulatory approval of one polymorph of a compound (which exhibits certain solubility and physicochemical (including spectroscopic) properties) does not usually imply that other polymorphs of the same compound are likely to be approved.

[0006] Polymorphic forms of known compounds in the pharmaceutical arts affect, for example, the solubility, stability, flowability, fractability, and compressibility of the compound, as well as the safety and efficacy of pharmaceutical products containing it. See, e.g., Knapman, K. Modern Drug Discoveries [Modern Drug Discoveries], 2000, 53. Thus, the discovery of new polymorphic forms of a drug can provide a variety of advantages.

[0007] The present disclosure provides new polymorphic forms of Compound 1 (including anhydrous forms, hydrate forms, several crystalline forms of several solvate forms), as well as physical forms thereof, pharmaceutical compositions, and methods of treating diseases mediated by KRAS G12C inhibition. The new polymorphic forms can further develop formulations for the treatment of these chronic diseases and can produce many formulation, manufacturing, and therapeutic benefits. SUMMARY

[0008] The present disclosure provides crystalline and amorphous forms of 6-fluoro-7-(2-fluoro-6- hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l- piperazinyl)pyrido[2,3-d]pyrimidin-2(lH)-one (Compound 1) (including several anhydrous forms, hydrate forms, and solvated forms) and solid state forms thereof, pharmaceutical compositions, and methods of treating diseases mediated by KRAS G12C inhibition. BRIEF DESCRIPTION OF DRAWINGS

[0009] Figure 1 XRPD data for the amorphous form of Compound 1 is shown. The powder X-ray diffractogram is characterized by a broad amorphous halo for amorphous material at 5°-40° 2-theta and no significant compound-related diffraction peaks.

[0010] Figure 2 DSC data for the amorphous form of Compound 1 is shown.

[0011] Figure 3 TGA data for the amorphous form of Compound 1 is shown.

[0012] Figure 4 TGA data for the amorphous form of Compound 1 is shown. 19 F Solid-state NMR (SSNMR).

[0013] Figure 5 XRPD data for the crystalline anhydrous Form I of Compound 1 is shown. The powder X-ray diffractogram for the anhydrous Forms I-III of Compound 1 is characterized by crystalline material having significant diffraction peaks between 3° 2-theta to 40° 2-theta.

[0014] Figure 6 DSC data for crystalline anhydrous Form I of Compound 1 is shown.

[0015] Figure 7 TGA data for crystalline anhydrous Form I of Compound 1 is shown.

[0016] Figure 8 XRPD data for crystalline anhydrous Form I of Compound 1 is shown. 13 C SSNMR data for crystalline anhydrous Form I of Compound 1 is shown.

[0017] Figure 9 F SSNMR data for crystalline anhydrous Form I of Compound 1 is shown. 19 F SSNMR data for crystalline anhydrous Form I of Compound 1 is shown.

[0018] Figure 10 XRPD data for crystalline anhydrous Form II of Compound 1 is shown.

[0019] Figure 11 DSC data for crystalline anhydrous Form II of Compound 1 is shown.

[0020] Figure 12 TGA data for crystalline anhydrous Form II of Compound 1 is shown.

[0021] Figure 13 XRPD data for crystalline anhydrous Form II of Compound 1 is shown. 13 C SSNMR data for crystalline anhydrous Form II of Compound 1 is shown.

[0022] Figure 14 F SSNMR data for crystalline anhydrous Form II of Compound 1 is shown. 19 F SSNMR data for crystalline anhydrous Form II of Compound 1 is shown.

[0023] Figure 15 XRPD data for crystalline anhydrous Form III of Compound 1 is shown.

[0024] Figure 16 DSC data for crystalline anhydrous Form III of Compound 1 is shown.

[0025] Figure 17 TGA data for crystalline anhydrous Form III of Compound 1 is shown.

[0026] Figure 18 XRPD data for crystalline hydrate Form of Compound 1 is shown.

[0027] Figure 19 DSC data for crystalline hydrate Form of Compound 1 is shown.

[0028] Figure 20 TGA data for crystalline hydrate Form of Compound 1 is shown.

[0029] Figure 21 are superimposed XRPD data (from top to bottom) for crystalline anhydrous Forms I, II, and III and crystalline hydrate Forms of Compound 1.

[0030] Figure 22 XRPD data for crystalline THF solvate Form I of Compound 1 are shown.

[0031] Figure 23 DSC data for crystalline THF solvate Form I of Compound 1 are shown.

[0032] Figure 24 TGA data for crystalline THF solvate Form I of Compound 1 are shown.

[0033] Figure 25 XRPD data for crystalline MeCN solvate Form I of Compound 1 are shown.

[0034] Figure 26 DSC data for crystalline MeCN solvate Form I of Compound 1 are shown.

[0035] Figure 27 TGA data for crystalline MeCN solvate Form I of Compound 1 are shown.

[0036] Figure 28 XRPD data for crystalline MEK solvate Form I of Compound 1 are shown.

[0037] Figure 29 DSC data for crystalline MEK solvate Form I of Compound 1 are shown.

[0038] Figure 30 TGA data for crystalline MEK solvate Form I of Compound 1 are shown.

[0039] Figure 31 XRPD data for crystalline EtOAc solvate Form I of Compound 1 are shown.

[0040] Figure 32 XRPD data for crystalline DMF solvate Form I of Compound 1 are shown.

[0041] Figure 33 DSC data for crystalline DMF solvate Form I of Compound 1 are shown.

[0042] Figure 34 TGA data for crystalline DMF solvate Form I of Compound 1 are shown.

[0043] Figure 35 XRPD data for crystalline DCM solvate Form I of Compound 1 are shown.

[0044] Figure 36 DSC data for crystalline DCM solvate Form I of Compound 1 is shown.

[0045] Figure 37 TGA data for crystalline DCM solvate Form I of Compound 1 is shown.

[0046] Figure 38 XRPD data for crystalline acetone solvate Form I of Compound 1 is shown.

[0047] Figure 39 DSC data for crystalline acetone solvate Form I of Compound 1 is shown.

[0048] Figure 40 TGA data for crystalline acetone solvate Form I of Compound 1 is shown.

[0049] Figure 41 XRPD data for crystalline acetone solvate Form II of Compound 1 is shown.

[0050] Figure 42 DSC data for crystalline acetone solvate Form II of Compound 1 is shown.

[0051] Figure 43 TGA data for crystalline acetone solvate Form II of Compound 1 is shown.

[0052] Figure 44 XRPD data for crystalline dioxane solvate Form I of Compound 1 is shown.

[0053] Figure 45 DSC data for crystalline dioxane solvate Form I of Compound 1 is shown.

[0054] Figure 46 TGA data for crystalline dioxane solvate Form I of Compound 1 is shown.

[0055] Figure 47 XRPD data for crystalline MeOH solvate Form I of Compound 1 is shown.

[0056] Figure 48 DSC data for crystalline MeOH solvate Form I of Compound 1 is shown.

[0057] Figure 49 TGA data for crystalline MeOH solvate Form I of Compound 1 is shown.

[0058] Figure 50 XRPD data for crystalline IPA solvate Form I of Compound 1 is shown.

[0059] Figure 51 DSC data for crystalline IPA solvate Form I of Compound 1 is shown.

[0060] Figure 52 TGA data for crystalline IPA solvate Form I of Compound 1 is shown.

[0061] Figure 53 XRPD data for crystalline EtOH solvate Form I of Compound 1 is shown.

[0062] Figure 54 DSC data for crystalline EtOH solvate Form I of Compound 1 is shown.

[0063] Figure 55 TGA data for crystalline EtOH solvate Form I of Compound 1 is shown.

[0064] Figure 1 Superimposed XRPD data for isomorphous solvate forms of Compound 1 (top to bottom - THF, MeCN, MEK, DCM, acetone, MeOH, IPA, EtOH). DETAILED DESCRIPTION

[0065] DEFINITIONS

[0066] The term "Compound 1" means 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2- propanyl)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3- d]pyrimidin-2(1H)-one.

[0067]

[0068] Certain compounds disclosed herein can exist as atropisomers, which are conformational stereoisomers that arise when rotation about a single bond in the molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers as pure individual atropisomer preparations, enriched preparations of each, or unspecified mixtures of each. If the barrier to rotation about a single bond is high enough and the interconversion between conformations is slow enough, then separation and isolation of isomeric species can be permitted. For example, Compound 1 is the atropisomer M and can exhibit restricted rotation. The M-atropisomer of Compound 1 is also known as AMG 510. Canon, J., et al., Nature 575(7781): 217-223 (2019), Figure 5 a.

[0069] Alternatively, Compound 1 has the atropisomer P below, and can exhibit restricted rotation.

[0070]

[0071] Abbreviations: The following abbreviations can be used herein:

[0072]

[0073]

[0074]

[0075] The use of the terms “a” and “an” and “the” and similar referents in the context of the present disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or specifically contradicted by context. Recitation of a range 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 into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the present disclosure and does not pose a limitation on the scope of the present disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

[0076] The term “anhydrous form” of “Compound 1” refers to a form of Compound 1 that is substantially or completely free of water, in particular free of crystallization water. The skilled person will understand that the exact number of water molecules can vary slightly at any time with variable temperature, pressure, and other environmental influences. All minor variations in the number of associated water molecules are contemplated within the scope of the present disclosure.

[0077] The term “co-crystal” refers to a crystalline material comprising two or more compounds at ambient temperature (20-25 °C, preferably 20 °C), wherein at least two are bound together by weak interactions, wherein at least one of the compounds is a co-crystal former and the other is Compound 1. Weak interactions are defined as interactions that are neither ionic nor covalent, and include, for example: hydrogen bonds, van der Waals forces, and π-π interactions. The term “co-crystal” includes solvate forms.

[0078] The term “amorphous form” or “amorphous” refers to a material that lacks long-range order and therefore does not show distinct X-ray diffraction peaks (i.e., Bragg diffraction peaks). An XRPD pattern of an amorphous material is characterized by one or more amorphous halos.

[0079] The term "amorphous halo" is the approximately bell-shaped maximum in the X-ray powder pattern of amorphous material.

[0080] The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient other than the active pharmaceutical ingredient (API) that is typically incorporated for formulation and / or administration to a patient.

[0081] The term "disease mediated by KRAS G12C inhibition" refers to (i) cancer and (ii) solid tumors. KRAS is the most frequently mutated oncogene in cancer, encoding a key signal transduction protein in tumors. Canon, J., et al., Nature 575(7781): 217-223 (2019), abstract. KRAS (G12C) mutants have a cysteine residue that has been exploited to design covalent inhibitors with good preclinical activity. Id. Optimization of a series of inhibitors, using new binding interactions, significantly improved their potency and selectivity. Id. These efforts led to the discovery of AMG 510. Id. In preclinical analyses, AMG 510 treatment led to tumor regression and improved antitumor efficacy of chemotherapies and targeted agents. Id. In immunocompetent mice, treatment with AMG 510 produced a proinflammatory tumor microenvironment and produced durable cures, both alone and in combination with immune checkpoint inhibitors. Id. Cured mice rejected isogenic KRAS G12C tumors, suggesting adaptive immunity to shared antigens. Id. Moreover, in clinical trials, AMG 510 has shown antitumor activity in the first dosing cohort and represents a potential transformative therapy for patients lacking effective treatments. Id. G12D

[0082] ​The term "cancer" refers to a hyperproliferative disorder in a mammal, such as a human, having a KRAS, HRAS, or NRAS G12C mutation, which can be treated by, for example, 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 sarcoma), anal cancer, appendix cancer, astrocytic tumor, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem cell neuroglioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid tumor, embryoma, blastoma, primary lymphoma, cervical cancer, childhood cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic duct carcinoma in situ (DCIS), embryoma, CNS cancer, endometrial cancer, ependymal tumor, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial blastoma, extragonadal blastoma, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germinoma, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin 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 neck cancer with occult primary, midline carcinoma, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, 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 cancer, 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, renal pelvis and ureter transitional cell cancer, trophoblastic tumor, childhood cancer of rare type, urachal cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some embodiments, the method involves treating a non-cancerous hyperproliferative disorder, such as a benign proliferation of the skin (e.g., psoriasis), restenosis, or benign prostatic hyperplasia (e.g., benign prostatic hypertrophy (BPH)).

[0083] The term "patient" means an animal, such as a dog, cat, cow, horse, sheep, and human. A particular patient is a mammal. The term patient includes both male and female.

[0084] The term "therapeutically effective amount" means an amount of a compound that ameliorates, attenuates or eliminates one or more symptoms of, or prevents or delays the onset of, a particular disease or condition.

[0085] The term "pharmaceutically acceptable" means that the substance (e.g., a compound of the disclosure or a formulation containing a compound of the disclosure, or a particular excipient) is suitable for use in patients.

[0086] As used herein, unless otherwise noted, the terms "polymorph" and "polymorphic form" refer to a solid crystalline form of a compound or complex. Different polymorphs of the same compound can exhibit different physical, chemical, and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rate (which can affect bioavailability). Differences in stability can arise from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form composed of one polymorph fades more quickly than one composed of another) or mechanical characteristics (e.g., tablets break upon storage when the kinetically favored polymorph converts to the thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more prone to breakage under high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph can be more likely to form solvates than another due to, e.g., the shape or size distribution of particles of one polymorph, or can be more difficult to filter or wash free of impurities than another.

[0087] Polymorphs of a molecule can be obtained by a variety of methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Polymorphs can be detected, identified, classified, and characterized using well-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.

[0088] As used herein, reference to spectra or data (e.g., XRPD, IR, Raman, and NMR spectra) presented in graphical form, and unless otherwise indicated, the term "peak" refers to a peak or other distinctive feature that one of skill in the art would recognize as not attributable to background noise.

[0089] As used herein, unless otherwise indicated, the term "substantially pure" when used in reference to a polymorphic form of a compound means a solid form of the compound comprising the polymorphic form and being substantially free of other polymorphic forms of the compound. Representative substantially pure polymorphic forms comprise greater 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 greater 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 greater 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 greater 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.

[0090] The terms "treating", "treat" or "treatment" and the like, include preventative (e.g., prophylactic) and palliative treatment.

[0091] The term "variable hydrate" means a hydrate of Compound 1 having at least about one, two, three, or four associated water molecules. In some embodiments, the hydrates of the disclosure include at least one to ten associated water molecules. One of skill in the art will appreciate that the exact number of associated water molecules can vary slightly at any time with variable temperature, pressure, and other environmental influences. All slight variations in the number of associated water molecules are contemplated to be within the scope of the disclosure.

[0092] In some embodiments, the methods of treatment involve treating lung cancer, which methods comprise administering to a subject in need thereof an effective amount of any one of the above-described compounds (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 that can be treated with the disclosed compounds include, but are not limited to, adenomas, carcinoids, and undifferentiated carcinomas. In one embodiment, the NSCLC is locally advanced or metastatic.

[0093] The compounds of the disclosure are administered to a patient in a therapeutically effective amount. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. Further, the compounds or compositions can be administered simultaneously, e.g., by multiple bolus infusions, e.g., by a series of tablets, or delivered substantially uniformly over a period of time using, e.g., transdermal delivery. It is also noted that the dosage of the compound can vary over time.

[0094] Further, the compounds of the disclosure can be administered alone, in combination with other compounds of the disclosure, or in combination with other pharmaceutically active compounds. The other pharmaceutically active compounds can be intended to treat the same disease or disorder or a different disease or disorder as the compounds of the disclosure. If a patient will receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously or sequentially. For example, in the case of tablets, the active compounds can be found in one tablet or in multiple tablets that are separate or administered sequentially in any order, either all at once or sequentially. Further, it is recognized that the compositions can be in different forms. For example, one or more compounds can be delivered by tablet, while another compound is administered by injection or orally as a syrup. All combinations, delivery methods, and administration sequences are contemplated.

[0095] It is also noted that the solid state forms of the disclosure can be administered together. For example, 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 remaining Compound 1 in another form, such as an amorphous form of Compound 1. In another embodiment, about 80% by weight of crystalline anhydrous Form I of Compound 1 can be administered with the remaining Compound 1 in another form, such as an amorphous form. All combinations are contemplated. In one embodiment of the disclosure, Compound 1 is administered to a patient in one substantially pure form. The skilled artisan will appreciate the possible variations.

[0096] The compounds of the disclosure are useful in the manufacture of a medicament for the treatment of a disease mediated by KRAS G12C inhibition, such as a cancer, including but not limited to colorectal cancer, pancreatic cancer, and lung cancer, such as non-small cell lung cancer (NSCLC).

[0097] In yet another aspect, the disclosure relates to the use of a salt, crystalline form, amorphous form, or co-crystal of Compound 1 for the manufacture of a medicament for the treatment of a cancer, such as colorectal cancer, pancreatic cancer, and lung cancer, such as non-small cell lung cancer (NSCLC).

[0098] Since 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 the combination of the individual pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present disclosure and a second pharmaceutical compound. The kit comprises containers for containing the separate compositions, such as separate bottles or separate foil packets. Additional examples of containers include injections, boxes, and bags. Typically, the kit will contain directions for use of the separate components. The kit form is particularly advantageous when the separate components are supplied in different dosage forms (e.g., oral and parenteral), administered at different dosage intervals, or are otherwise intended to be administered at different times during the course of therapy.

[0099] An example of such a kit is the so-called "blister pack". Blister packs are well known in the packaging industry. The "blister pack" is a piece 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 that are to be packaged. The tablets or capsules are then placed in the recesses and the piece of relatively stiff material is heat sealed onto the plastic foil at the side opposite to the direction of the recesses. As a result the tablets or capsules are sealed in the recesses between the plastic foil and the piece of relatively stiff material. Preferably the strength of the piece is such that an opening can be formed in the piece at the recess by manually exerting pressure on the recess, so that the tablet or capsule can be removed from the blister pack through the opening. The tablet or capsule can then be removed through the opening.

[0100] It can be desirable to provide a memory aid on the kit, for example in the form of numbers next to the tablets or capsules, wherein the numbers correspond to the days of the regimen for which the tablets or capsules so designated should be taken. Another example of a memory aid is a calendar printed on a card, for example as follows: "week 1, Monday, Tuesday,... and so on... week 2, Monday, Tuesday... and so on". Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or a number of tablets or capsules to be taken on a given day. Also, 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 a number of tablets or capsules, and vice versa. The memory aid should reflect this and help in the correct administration of the active agents.

[0101] In another particular embodiment of the disclosure, a dispenser is provided which is designed to dispense one daily dose at a time in the order of its intended use. Preferably, the dispenser is equipped with a memory aid in order to further facilitate compliance with the regimen. One example of such a memory aid is a mechanical counter which indicates the number of daily doses which have been dispensed. Another example of such a memory aid is a battery-powered microchip memory which is coupled with a liquid crystal readout or an audible reminder signal which reads out, for example, the date of the last taken daily dose and / or reminds of the date of the next dose.

[0102] The compounds of the disclosure and other pharmaceutically active compounds can be administered to a patient orally, rectally, parenterally (e.g., intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, topically (e.g., as a powder, ointment or drop), or as a buccal or nasal spray, if desired. All methods known to those skilled in the art for administering a pharmaceutically active agent are contemplated. In one embodiment, the compounds of the disclosure and other pharmaceutically active compounds can be administered orally to a patient, if desired.

[0103] Compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating such as lecithin, by the maintenance of required particle size in the case of dispersion and by the use of surfactants.

[0104] These compositions also can contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the growth of microorganisms can be achieved by the inclusion of various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, and the like). It also can be desirable to include isotonic agents, for example, 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).

[0105] Solid dosage forms for oral administration include capsules, tablets, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically-acceptable excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders such as starches, lactose, sucrose, mannitol, and silicic acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retarders such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) moisturizing agents such as glycerol and sorbitol; (h) respiration agents such as kaolin and bentonite; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage form can also comprise buffering agents. In one embodiment, the dosage form contemplated in the present disclosure is a solid dosage form, such as a tablet for oral administration.

[0106] Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.

[0107] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art. They can also contain opacifying agents and can also be of such composition that they release the active compound or 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 compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0108] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs such as in soft-filled gelatin capsules. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butanediol, dimethylformamide, oils, in particular cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[0109] In addition to such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to active compounds, can contain suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

[0110] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ordinary room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active component.

[0111] Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalers. The active compound or compounds are mixed under sterile conditions with a physiologically acceptable carrier and any needed preservatives, buffers, or propellants as can be required. Ophthalmic formulations, eye ointments, powders, and solutions are contemplated as being within the scope of this disclosure.

[0112] The compounds of the disclosure can be administered to a patient at dosage levels from about 0.1 to about 2000 mg / day, preferably from 5 mg to 1000 mg / day. For a normal human adult having a body mass of about 70 kg, a dosage in the range of about 0.001 mg per kg of body weight to about 20 mg per kg of body weight is generally sufficient. The specific dosage and dosage range that can be used depends on a number of factors including the needs of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosages and optimum dosages for particular patients is within the ordinary skill in the art. In one embodiment, the total daily dose administered to a patient is 180 mg, 360 mg, 720 mg, or 960 mg. The total daily dose can be administered orally in multiple tablets including, for example, 120 mg of Compound 1 (e.g., a total daily dose of 960 mg is administered as 8 tablets of 120 mg Compound 1 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 as 8 tablets of 120 mg Compound 1 each.

[0113] Unless otherwise stated, the compounds of the disclosure can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrates), ethanol, and the like. The solvated forms of the disclosure are considered to be within the scope of the disclosure. The compounds of the disclosure can also exist in different tautomeric forms. All tautomers of the compounds of the disclosure are contemplated. For example, all keto-enol forms of the compounds are included in the disclosure.

[0114] The compounds of the disclosure can also exist in different tautomeric forms. All tautomers of the compounds of the disclosure are contemplated. For example, all keto-enol forms of the compounds are included in the disclosure.

[0115] Those skilled in the art will recognize that the compound names and structures contained herein can be based on the specific tautomer of the compound. While names or structures for only a specific tautomer can be used, unless otherwise indicated, the disclosure is intended to encompass all tautomers.

[0116] Those skilled in the art will understand that the anhydrous free forms, hydrates, salts, and co-crystals of Compound 1 can exist in one or more ionized states, which typically exist as zwitterions. While names or structures for only a specific ionized state can be used, unless otherwise indicated, the disclosure is intended to encompass all ionized states.

[0117] The present disclosure also is intended to encompass compounds that are synthesized in vitro using laboratory techniques such as those well known to synthetic chemists; or synthesized using in vivo techniques such as via metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present disclosure can be synthesized using a combination of in vitro and in vivo techniques.

[0118] The present disclosure also includes isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.

[0119] Compounds of the present disclosure containing the foregoing isotopes and / or other isotopes of atoms are within the scope of the disclosure. Certain isotopically-labeled compounds of the present disclosure, for example, those into which radioactive isotopes such as 3 H, and 14 C, are useful in drug and / or substrate tissue distribution assays. Because of the ease with which they can be prepared and detected, tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred. Further, heavier isotopes such as deuterium, i.e., 2H) Substitution can provide certain therapeutic advantages (e.g., extended half-life in vivo or reduced dosage requirements) that arise from greater metabolic stability, and thus is preferred in some instances. Isotopically-labeled compounds of the disclosure can generally be prepared by substituting one or more of the isotopically-labeled reagents for non-isotopically-labeled reagents in the synthesizing procedure.

[0120] All patents and other publications cited are incorporated herein by reference.

[0121] The examples and embodiments presented below are illustrative of the application disclosed herein and are not intended to limit the scope of the claims in any way.

[0122] EMBODIMENTS

[0123] 1. In one embodiment, the present application provides a crystalline anhydrous Form I of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3- d]pyrimidin-2(lH)-one (Compound 1).

[0124] 2. In another embodiment, the present disclosure provides the crystalline anhydrous Form I of embodiment 1, wherein the anhydrous Form I is the M atropisomer.

[0125] 3. In another embodiment, the present disclosure provides the crystalline anhydrous Form I of embodiment 1, wherein the crystalline anhydrous Form I is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 8

[0126] 4. In another embodiment, the present disclosure provides the crystalline anhydrous Form I of embodiment 1, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from a powder X-ray diffraction pattern comprising peaks at diffraction angles 2 theta degrees of 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.

[0127] 5. In another embodiment, the present disclosure provides the crystalline anhydrous Form I of embodiment 1, wherein the crystalline anhydrous Form I is characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2 theta degrees of about 9.0, 12.0, 12.6, and 19.0.

[0128] ​6. In another embodiment, the present disclosure provides the crystalline anhydrous Form I as described in embodiment 1 having a differential scanning calorimetry thermogram comprising an endotherm starting at about 293 °C.

[0129] 7. In another embodiment, the present disclosure provides the anhydrous crystalline form of embodiment 1 having a thermogravimetric analysis thermogram comprising a weight loss of about 0.2% when heated from about 25 °C to about 275 °C.

[0130] 8. In another embodiment, the present disclosure provides the crystalline anhydrous Form I as described in embodiment 1, wherein the crystalline anhydrous Form I is characterized by a Figure 9 13 C solid state NMR.

[0131] 9. In another embodiment, the present disclosure provides the crystalline anhydrous Form I as described in embodiment 1, wherein the crystalline anhydrous Form I is characterized by 13 C solid state NMR, the 13 C solid state NMR 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.

[0132] 10. In another embodiment, the present disclosure provides the crystalline anhydrous Form I as described in embodiment 1, wherein the crystalline anhydrous Form I is characterized by a Figure 1 19 F solid state NMR.

[0133] 11. In another embodiment, the present disclosure provides the crystalline anhydrous Form I as described in embodiment 1, wherein the crystalline anhydrous Form I is characterized by 19 F solid state NMR, the 19 F solid state NMR comprising peaks at about -49, -60, -79, -90, -109, -120, -138, -150, -168, and -179 ppm.

[0134] 12. In another embodiment, the present disclosure provides the crystalline anhydrous Form I as described in embodiment 1, which is substantially pure.

[0135] 13. In another embodiment, the present disclosure provides a pharmaceutical composition comprising the crystalline anhydrous Form I as described in embodiment 1, and a pharmaceutically acceptable excipient.

[0136] ​​14. In another embodiment, the present disclosure provides a pharmaceutical composition comprising crystalline anhydrous Form I or a mixture thereof as described in any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, and a pharmaceutically acceptable excipient.

[0137] 15. In another embodiment, the present disclosure provides a pharmaceutical composition as described in embodiment 14, wherein the composition is a single dose.

[0138] 16. In another embodiment, the present disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2- propanoyl)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3- d]pyrimidin-2(lH)-one and crystalline anhydrous Form I as described in embodiment 1.

[0139] 17. In another embodiment, the present disclosure provides a method of making crystalline anhydrous Form I as described in embodiment 1, the method comprising: combining Form II of Compound 1 and a suitable solvent and removing the solvent to form crystalline anhydrous Form I of Compound 1.

[0140] 18. In another embodiment, the present disclosure provides a method as described in embodiment 17, wherein the suitable solvent is water.

[0141] 19. In another embodiment, the present disclosure provides a method of treating a disease mediated by KRAS G12C inhibition, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising crystalline anhydrous Form I as described in embodiment 1.

[0142] 20. In another embodiment, the present disclosure provides a method of treating a disease mediated by KRAS G12C inhibition, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a pharmaceutical composition as described in embodiment 14.

[0143] 21. In another embodiment, the present disclosure provides a method as described in embodiment 19, wherein the disease mediated by G12C inhibition is a cancer.

[0144] 22. In another embodiment, the present disclosure provides a method as described in embodiment 21, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0145] 23. In another embodiment, the present disclosure provides a method as described in embodiment 22, wherein the cancer is lung cancer.

[0146] 24. In another embodiment, the present disclosure provides the method of embodiment 23, wherein the lung cancer is non-small cell lung cancer.

[0147] 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-pyridyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0148] 26. In another embodiment, the present disclosure provides the amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one of embodiment 25, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 4

[0149] 27. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, wherein the form is the M atropisomer.

[0150] 28. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, having a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 144 °C.

[0151] 29. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, having a thermogravimetric analysis thermogram comprising a weight loss of about 1.5% when heated from about 25 °C to about 275 °C.

[0152] 30. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, wherein the form is characterized by 19 F solid state NMR as shown in Figure 10 19 F solid state NMR as shown in 19 F solid state NMR comprising peaks at about -86, -96, -116, -127, -146, and -156 ppm.

[0153] 31. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, wherein the form is characterized by 19 F solid state NMR as shown in 19 F solid state NMR comprising peaks at about -86, -96, -116, -127, -146, and -156 ppm.

[0154] 32. In another embodiment, the present disclosure provides the amorphous form of embodiment 25, which is substantially pure.

[0155] 33. In another embodiment, the present disclosure provides a pharmaceutical composition comprising the amorphous form of any one of embodiments 25, and a pharmaceutically acceptable excipient.

[0156] 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.

[0157] 35. In another embodiment, the present disclosure provides the pharmaceutical composition of embodiment 34, wherein the composition is a single dose.

[0158] 36. In another embodiment, the present disclosure provides a method of preparing the amorphous form of embodiment 35, the method comprising dissolving Compound 1 and a suitable solvent to form the amorphous form of Compound 1.

[0159] 37. In another embodiment, the present disclosure provides the method of embodiment 36, wherein the suitable solvent is methanol.

[0160] 38. In another embodiment, the present disclosure provides a method of treating a disease mediated by KRAS G12C inhibition, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising the amorphous form of embodiment 25.

[0161] 39. In another embodiment, the present disclosure provides the method of embodiment 38, wherein the disease mediated by G12C inhibition is a cancer.

[0162] 40. In another embodiment, the present disclosure provides the method of embodiment 39, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0163] 41. In another embodiment, the present disclosure provides the method of embodiment 40, wherein the cancer is lung cancer.

[0164] 42. In another embodiment, the present disclosure provides the method of embodiment 41, wherein the lung cancer is non-small cell lung cancer.

[0165] 43. In another embodiment, the present disclosure provides a crystalline anhydrous Form II of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3- d]pyrimidin-2(lH)-one (Compound 1).

[0166] 44. In another embodiment, the present disclosure provides the crystalline anhydrous Form II of embodiment 43, wherein the crystalline anhydrous Form II is the M atropisomer.

[0167] 45. In another embodiment, the present disclosure provides the crystalline anhydrous Form II of embodiment 43, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 13

[0168] 46. In another embodiment, the present disclosure provides the crystalline anhydrous Form II of Compound 1 of embodiment 43, wherein the form is characterized by at least three peaks, at least five peaks, or at least seven peaks selected from a powder X-ray diffraction pattern comprising peaks at diffraction angles 2 theta degrees of 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.

[0169] 47. In another embodiment, the present disclosure provides the crystalline anhydrous Form II of Compound II of embodiment 43, wherein the form is characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2 theta degrees of about 7.3, 9.8, 10.1, 11.3, 13.3, and 17.2.

[0170] 48. In another embodiment, the present disclosure provides the crystalline anhydrous Form II of embodiment 43, having a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 193 °C.

[0171] 49. In another embodiment, the present disclosure provides the 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.

[0172] 50. In another embodiment, the present disclosure provides the crystalline anhydrous Form II of embodiment 43, wherein the form is characterized by a solid state NMR substantially as shown in Figure 14 13 C.

[0173] ​​51. In another embodiment, the present disclosure provides the crystalline anhydrous Form II of embodiment 43, wherein the Form is characterized by 13 C solid state NMR, the 13 C solid state NMR comprises 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.

[0174] 52. In another embodiment, the present disclosure provides the crystalline anhydrous Form II of embodiment 43, wherein the Form is characterized by Figure 15 as shown in 19 F solid state NMR.

[0175] 53. In another embodiment, the present disclosure provides the crystalline anhydrous Form II of embodiment 43, wherein the Form is characterized by 19 F solid state NMR, the 19 F solid state NMR comprises peaks at about -59, -62, -89, -92, -119, -122, -148, -151, -179, and -181 ppm.

[0176] 54. In another embodiment, the present disclosure provides the crystalline anhydrous Form II of embodiment 43, which is substantially pure.

[0177] 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.

[0178] 56. In another embodiment, the present disclosure provides a pharmaceutical composition comprising the crystalline anhydrous Form II of any one of embodiments 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55, or a mixture thereof, and a pharmaceutically acceptable excipient.

[0179] 57. In another embodiment, the present disclosure provides the pharmaceutical composition of embodiment 56, wherein the composition is a single dose.

[0180] 58. In another embodiment, the present disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3- pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin- 2(lH)-one and crystalline anhydrous Form II as described in Example 43.

[0181] 59. In another embodiment, the present disclosure provides a method of making crystalline anhydrous Form II as described in Example 43, the method comprising: combining an amorphous form of Compound 1 and a suitable solvent to form crystalline anhydrous Form II of Compound 1.

[0182] 60. In another embodiment, the present disclosure provides the method of Example 59, wherein the suitable solvent is methanol.

[0183] 61. In another embodiment, the present disclosure provides a method of treating a disease mediated by KRAS G12C inhibition, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a pharmaceutical composition comprising crystalline anhydrous Form II as described in Example 43.

[0184] 62. In another embodiment, the present disclosure provides the method of Example 61, wherein the disease mediated by G12C inhibition is a cancer.

[0185] 63. In another embodiment, the present disclosure provides the method of Example 62, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0186] 64. In another embodiment, the present disclosure provides the method of Example 63, wherein the cancer is lung cancer.

[0187] 65. In another embodiment, the present disclosure provides the method of Example 64, wherein the lung cancer is non-small cell lung cancer.

[0188] 66. In another embodiment, the present disclosure provides crystalline anhydrous Form III of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4- ((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin-2(lH)-one (Compound 1).

[0189] 67. In another embodiment, the present disclosure provides the crystalline anhydrous Form III of Example 66, wherein the crystalline anhydrous Form III is the M atropisomer.

[0190] 68. In another embodiment, the present disclosure provides crystalline anhydrous Form III as described in embodiment 66, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 18 FIG. 6.

[0191] 69. In another embodiment, the present disclosure provides crystalline anhydrous Form III of Compound 1 as described in embodiment 66, wherein the Form is characterized by at least three peaks, at least five peaks, or at least seven peaks selected from a powder X-ray diffraction pattern comprising peaks at diffraction angles 2 theta degrees of about 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6.

[0192] 70. In another embodiment, the present disclosure provides crystalline anhydrous Form III of Compound II as described in embodiment 66, wherein the Form is characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2 theta degrees of about 6.3, 8.4, 9.5, 15.5, and 16.0.

[0193] 71. In another embodiment, the present disclosure provides crystalline anhydrous Form III as described in embodiment 66, having a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 194 °C.

[0194] 72. In another embodiment, the present disclosure provides crystalline anhydrous Form III as described in embodiment 66, having a thermogravimetric analysis thermogram comprising a nearly negligible weight loss when heated from about 25 °C to about 250 °C.

[0195] 73. In another embodiment, the present disclosure provides crystalline anhydrous Form III as described in embodiment 66, which is substantially pure.

[0196] 74. In another embodiment, the present disclosure provides a pharmaceutical composition comprising crystalline anhydrous Form III as described in embodiment 66, and a pharmaceutically acceptable excipient.

[0197] 75. In another embodiment, the present disclosure provides a pharmaceutical composition comprising crystalline anhydrous Form III or a mixture thereof as described in any one of embodiments 66, 67, 68, 69, 70, 71, 72, 73, or 74, and a pharmaceutically acceptable excipient.

[0198] 76. In another embodiment, the present disclosure provides a pharmaceutical composition as described in embodiment 75, wherein the composition is a single dose.

[0199] 77. In another embodiment, the present disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3- pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin- 2(lH)-one and crystalline anhydrous Form III as described in Example 66.

[0200] 78. In another embodiment, the present disclosure provides a method of making crystalline anhydrous Form III as described in Example 66, comprising: combining Compound 1 and a suitable solvent to form crystalline anhydrous Form III of Compound 1.

[0201] 79. In another embodiment, the present disclosure provides the method of Example 78, wherein the suitable solvent is acetone.

[0202] 80. 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 pharmaceutically effective amount of a pharmaceutical composition comprising crystalline anhydrous Form III as described in Example 66.

[0203] 81. In another embodiment, the present disclosure provides the method of Example 80, wherein the disease mediated by G12C inhibition is a cancer.

[0204] 82. In another embodiment, the present disclosure provides the method of Example 81, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0205] 83. In another embodiment, the present disclosure provides the method of Example 82, wherein the cancer is lung cancer.

[0206] 84. In another embodiment, the present disclosure provides the method of Example 82, wherein the lung cancer is non-small cell lung cancer.

[0207] 85. In another embodiment, the present disclosure provides a crystalline hydrate form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2- methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin-2(lH)-one (Compound 1).

[0208] 86. In another embodiment, the present disclosure provides the crystalline hydrate form of Example 85, wherein the crystalline hydrate form is the M atropisomer.

[0209] 87. In another embodiment, the present disclosure provides a crystalline hydrate form of Compound 1 as described in embodiment 85, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 5

[0210] 88. In another embodiment, the present disclosure provides a crystalline hydrate form of Compound 1 as described in embodiment 85, wherein the form is characterized by at least three peaks, at least five peaks, or at least seven peaks selected from a powder X-ray diffraction pattern comprising peaks at diffraction angles 2 theta degrees of 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.

[0211] 89. In another embodiment, the present disclosure provides a crystalline hydrate form of Compound I as described in embodiment 85, wherein the form is 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.

[0212] 90. In another embodiment, the present disclosure provides a crystalline hydrate form as described in embodiment 85 having a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 91 °C.

[0213] 91. In another embodiment, the present disclosure provides a crystalline hydrate form as described in embodiment 85 having a thermogravimetric analysis thermogram comprising a weight loss of about 11% when heated from about 39 °C to about 160 °C.

[0214] 92. In another embodiment, the present disclosure provides a crystalline hydrate form as described in embodiment 85, which is substantially pure.

[0215] 93. In another embodiment, the present disclosure provides a pharmaceutical composition comprising a crystalline hydrate form as described in embodiment 85, and a pharmaceutically acceptable excipient.

[0216] 94. In another embodiment, the present disclosure provides a pharmaceutical composition comprising a crystalline hydrate form as described in any one of embodiments 85, 86, 87, 88, 89, 90, 91, 92, or 93, or a mixture thereof, and a pharmaceutically acceptable excipient.

[0217] ​95. In another embodiment, the present disclosure provides a pharmaceutical composition of embodiment 94, wherein the composition is a single dose.

[0218] 96. In another embodiment, the present disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3- pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin- 2(lH)-one and a crystalline hydrate form as described in embodiment 85.

[0219] 97. In another embodiment, the present disclosure provides a method of making the crystalline hydrate form of embodiment 85, comprising combining Compound 1 and a suitable solvent in the presence of water to form a crystalline hydrate form of Compound 1.

[0220] 98. In another embodiment, the present disclosure provides the method of embodiment 78, wherein the suitable solvent is methanol.

[0221] 99. 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 pharmaceutically effective amount of a pharmaceutical composition comprising the crystalline hydrate form of embodiment 85.

[0222] 100. In another embodiment, the present disclosure provides the method of embodiment 99, wherein the disease mediated by G12C inhibition is a cancer.

[0223] 101. In another embodiment, the present disclosure provides the method of embodiment 100, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0224] 102. In another embodiment, the present disclosure provides the method of embodiment 101, wherein the cancer is lung cancer.

[0225] 103. In another embodiment, the present disclosure provides the method of embodiment 102, wherein the lung cancer is non-small cell lung cancer.

[0226] 104. In another embodiment, the present disclosure provides a crystalline solvate form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2- methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin-2(lH)-one (Compound 1).

[0227] 105. In another embodiment, the present disclosure provides a crystalline solvate form of embodiment 104, wherein the solvate form is a THF, MeCN, MEK, EtOAc, DCM, acetone, p-dioxane, methanol, isopropanol, or ethanol solvate form.

[0228] 106. In another embodiment, the present disclosure provides a pharmaceutical composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3- pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin-2(lH)-one and at least one crystalline form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2- propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3- d]pyrimidin-2(lH)-one of any one of embodiments 1, 43, 66, 85, or 104, and a pharmaceutically acceptable excipient.

[0229] 107. In another embodiment, the present disclosure provides a composition of embodiment 106, comprising greater than about 50% by weight of crystalline 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin-2(lH)-one.

[0230] 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)-l-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin-2(lH)-one of any one of embodiments 1, 43, 66, 85, or 104, and a pharmaceutically acceptable excipient.

[0231] Alternative Embodiments

[0232] Provided herein as embodiment 1 is a compound, wherein the compound is a crystalline form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin-2(lH)-one (Compound 1) or an atropisomer thereof.

[0233] Provided herein as Example 2 is a compound according to Example 1, wherein the compound is the M atropisomer of Compound 1.

[0234] Provided herein as Example 3 is a compound according to Example 1 or 2, wherein the compound is a crystalline anhydrous form of Compound 1.

[0235] Provided herein as Example 4 is a compound according to any one of Examples 1-3, 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 2-theta as measured by x-ray powder diffraction using an x-ray wavelength of

[0236] Provided herein as Example 5 is a compound according to any one of Examples 1-3, wherein the compound is 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 2-theta as measured by x-ray powder diffraction using an x-ray wavelength of

[0237] Provided herein as Example 6 is a compound according to any one of Examples 1-3, wherein the compound is 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 2-theta as measured by x-ray powder diffraction using an x-ray wavelength of

[0238] Provided herein as Example 7 is a compound according to any one of Examples 1-3, wherein the compound is 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 2-theta as measured by x-ray powder diffraction using an x-ray wavelength of

[0239] ​​​​The compound provided herein as Example 8 is a compound according to any one of Examples 1-3, characterized in that the compound has a powder X-ray diffraction pattern comprising, as described by X-ray powder diffraction... The peaks were measured at 2θ at X-ray wavelengths of 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.

[0240] The compound provided herein as Example 9 is a compound according to any one of Examples 1-3, wherein the compound is characterized by being used as described by X-ray powder diffraction. The X-ray wavelength measurement is basically as follows Figure 8 The powder X-ray diffraction pattern shown.

[0241] The compound provided herein as Example 10 is a compound according to any one of Examples 1-9, wherein the compound is characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic start at about 293°C.

[0242] The compound provided herein as Example 11 is a compound according to any one of Examples 1-10, wherein the compound is characterized by a thermogravimetric analysis (TGA) heatmap showing a weight loss of about 0.2% when heated from about 25°C to about 275°C.

[0243] The compound provided herein as Example 12 is a compound according to any one of Examples 1-11, wherein the compound is characterized in that... 13 C solid-state NMR, 13 The solid-state NMR spectrum contains at least three peaks selected from the following: approximately 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.

[0244] The compound provided herein as Example 13 is a compound according to any one of Examples 1-11, wherein the compound is characterized in that... 13 C solid-state NMR, the 13The solid-state NMR spectrum contains at least five peaks selected from the following: approximately 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.

[0245] The compound provided herein as Example 14 is a compound according to any one of Examples 1-11, wherein the compound is characterized in that... 13 C solid-state NMR, the 13 The solid-state NMR spectrum contains at least seven peaks selected from the following: approximately 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.

[0246] The compound provided herein as Example 15 is a compound according to any one of Examples 1-11, wherein the compound is characterized in that... 13 C solid-state NMR, the 13 The solid-state NMR spectrum contains peaks at approximately 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.

[0247] The compound provided herein as Example 16 is a compound according to any one of Examples 1-11, wherein the compound is characterized in that it is substantially as follows: Figure 9 shown 13 C solid-state NMR.

[0248] The compound provided herein as Example 17 is a compound according to any one of Examples 1-16, wherein the compound is characterized in that... 19 F solid-state NMR, the 19 F solid-state NMR contains peaks at approximately -49, -60, -79, -90, -109, -120, -138, -150, -168, and -179 ppm.

[0249] The compound provided herein as Example 18 is a compound according to any one of Examples 1-16, wherein the compound is characterized in that it is substantially as follows: Figure 10 shown19 F Solid state NMR.

[0250] Provided herein as Example 19 is the compound according to any one of Examples 1-18, wherein the compound is substantially pure.

[0251] Provided herein as Example 20 is a pharmaceutical composition comprising the compound according to any one of Examples 1-19 and a pharmaceutically acceptable excipient.

[0252] Provided herein as Example 21 is the pharmaceutical composition according to Example 20, wherein the pharmaceutical composition is an orally administered dosage form.

[0253] Provided herein as Example 22 is the pharmaceutical composition according to Example 20 or 21, wherein the dosage form is a solid dosage form.

[0254] Provided herein as Example 23 is the pharmaceutical composition according to Example 22, wherein the solid dosage form is a tablet.

[0255] Provided herein as Example 24 is the pharmaceutical composition according to any one of Examples 20-23, wherein the pharmaceutical composition comprises 120 mg of the compound.

[0256] Provided herein as Example 25 is the compound according to any one of Examples 1-19 or the pharmaceutical composition according to any one of Examples 20-24 for use as a medicament.

[0257] Provided herein as Example 26 is the compound according to any one of Examples 1-19 or the pharmaceutical composition according to any one of Examples 20-24 for use in the treatment of a cancer having a KRAS G12C mutation.

[0258] Provided herein as Example 27 is the compound or pharmaceutical composition for use according to Example 26, wherein the cancer having a KRAS G12C mutation is a lung cancer, a pancreatic cancer, or a colorectal cancer.

[0259] Provided herein as Example 28 is the compound or pharmaceutical composition for use according to Example 26, wherein the cancer having a KRAS G12C mutation is a non-small cell lung cancer.

[0260] Provided herein as Example 29 is the compound or pharmaceutical composition for use according to Example 26, wherein the cancer having a KRAS G12C mutation is a pancreatic cancer.

[0261] Provided herein as Example 30 is a compound or pharmaceutical composition for use according to Example 26, wherein the cancer having a KRAS G12C mutation is colorectal cancer.

[0262] Provided herein as Example 31 is the use of a compound according to any one of Examples 1-19 or a pharmaceutical composition according to any one of Examples 20-24 in the manufacture of a medicament for treating a cancer having a KRAS G12C mutation.

[0263] Provided herein as Example 32 is the use according to Example 31, wherein the cancer having a KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

[0264] Provided herein as Example 33 is the use according to Example 31, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer.

[0265] Provided herein as Example 34 is the use according to Example 31, wherein the cancer having a KRAS G12C mutation is pancreatic cancer.

[0266] Provided herein as Example 35 is the use according to Example 31, wherein the cancer having a KRAS G12C mutation is colorectal cancer.

[0267] Provided herein as Example 36 is a method of treating a cancer having a KRAS G12C mutation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of Examples 1-19.

[0268] Provided herein as Example 37 is the method according to Example 36, wherein the cancer having a KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

[0269] Provided herein as Example 38 is the method according to Example 36, wherein the cancer having a KRAS G12C mutation is small cell lung cancer.

[0270] Provided herein as Example 39 is the method according to Example 36, wherein the cancer having a KRAS G12C mutation is pancreatic cancer.

[0271] Provided herein as Example 40 is the method according to Example 36, wherein the cancer having a KRAS G12C mutation is colorectal cancer.

[0272] Provided herein as Example 41 is the compound, use or method according to any one of Examples 25-40, wherein the compound is administered at a total daily dose of 960 mg.

[0273] Provided herein as Example 42 is the compound, use or method according to any one of Examples 25-41, wherein the compound is administered to an adult human.

[0274] Provided herein as Example 43 is the compound according to any one of Examples 1-3, wherein the compound is 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 2-theta, as measured by x-ray powder diffraction using an x-ray wavelength of

[0275] Provided herein as Example 44 is the compound according to any one of Examples 1-3, wherein the compound is 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 2-theta, as measured by x-ray powder diffraction using an x-ray wavelength of

[0276] Provided herein as Example 45 is the compound according to any one of Examples 1-3, wherein the compound is 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 2-theta, as measured by x-ray powder diffraction using an x-ray wavelength of

[0277] Provided herein as Example 46 is the compound according to any one of Examples 1-3, wherein the compound is 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 2-theta, as measured by x-ray powder diffraction using an x-ray wavelength of

[0278] Provided herein as Example 47 is the compound according to any one of Examples 1-3, wherein the compound is 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 2-theta, as measured by x-ray powder diffraction using an x-ray wavelength of​​​​ 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 2-theta, as measured by x-ray wavelength.

[0279] Provided herein as Example 48 is the compound according to any one of Examples 1-3, wherein the compound is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 13 Provided herein as Example 48 is the compound according to any one of Examples 1-3, wherein the compound is characterized by a powder X-ray diffraction pattern substantially as shown in

[0280] Provided herein as Example 49 is the compound according to any one of Examples 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.

[0281] Provided herein as Example 50 is the compound according to any one of Examples 1-3 and 43-49, wherein the compound is characterized by 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.

[0282] Provided herein as Example 51 is the compound according to any one of Examples 1-3 and 43-50, wherein the compound is characterized by a 13 C solid state NMR, which 13 C solid state NMR comprises 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.

[0283] Provided herein as Example 52 is the compound according to any one of Examples 1-3 and 43-50, wherein the compound is characterized by a Figure 14 13 C solid state NMR, which

[0284] Provided herein as Example 53 is the compound according to any one of Examples 1-3 and 43-52, wherein the compound is characterized by a 19 F solid state NMR, which 19 F solid state NMR comprises peaks at about -59, -62, -89, -92, -119, -122, -148, -151, -179, and -181 ppm. ​​

[0285] Provided herein as Example 54 is a compound according to any one of Examples 1-3 and 43-52, 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 2-theta, as measured using an x-ray wavelength of Figure 15 19 F Solid-state NMR.

[0286] Provided herein as Example 55 is a compound according to any one of Examples 43-54, wherein the compound is substantially pure.

[0287] Provided herein as Example 56 is a pharmaceutical composition comprising a compound according to any one of Examples 43-55 and a pharmaceutically acceptable excipient.

[0288] Provided herein as Example 57 is a compound according to any one of Examples 1-3, 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 2-theta, as measured using an x-ray wavelength of

[0289] Provided herein as Example 58 is a compound according to any one of Examples 1-3, wherein the compound is 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 2-theta, as measured using an x-ray wavelength of

[0290] Provided herein as Example 59 is a compound according to any one of Examples 1-3, wherein the compound is 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 2-theta, as measured using an x-ray wavelength of

[0291] Provided herein as Example 60 is a compound according to any one of Examples 1-3, wherein the compound is 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 2-theta, as measured using an x-ray wavelength of

[0292] ​​​​​Provided herein as Example 61 is a compound according to any one of Examples 1-3, 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 2-theta, as measured using an x-ray wavelength of 8.4 A.

[0293] Provided herein as Example 62 is a compound according to any one of Examples 1-3, wherein the compound is characterized by a powder X-ray diffraction pattern substantially as set forth in FIG. 8.4 A. Figure 18 Provided herein as Example 63 is a compound according to any one of Examples 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.

[0294] Provided herein as Example 64 is a compound according to any one of Examples 1-3 and 57-63, wherein the compound is characterized by having a nearly negligible weight loss when heated from about 25 °C to about 250 °C.

[0295] Provided herein as Example 65 is a compound according to any one of Examples 57-64, wherein the compound is substantially pure.

[0296] Provided herein as Example 66 is a pharmaceutical composition comprising a compound according to any one of Examples 57-65 and a pharmaceutically acceptable excipient.

[0297] Provided herein as Example 67 is a compound according to Example 1 or 2, wherein the compound is a crystalline hydrate form of Compound 1.

[0298] Provided herein as Example 68 is a compound according to any one of Examples 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 2-theta, as measured using an x-ray wavelength of 8.4 A.

[0299] Provided herein as Example 69 is a compound according to any one of Examples 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 2-theta, as measured using an x-ray wavelength of 8.4 A.

[0300] 8.4 A. 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 2-theta, as measured by x-ray powder diffraction using Cu K-alpha x- ray wavelength.

[0301] Provided herein as Example 70 is the compound according to any one of Examples 1, 2, and 67, wherein the compound is 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 2-theta, as measured by x-ray powder diffraction using Cu K-alpha x- ray wavelength.

[0302] Provided herein as Example 71 is the compound according to any one of Examples 1, 2, and 67, wherein the compound is 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 2-theta, as measured by x-ray powder diffraction using Cu K-alpha x- ray wavelength.

[0303] Provided herein as Example 72 is the compound according to any one of Examples 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 2-theta, as measured by x-ray powder diffraction using Cu K-alpha x- ray wavelength.

[0304] Provided herein as Example 73 is the compound according to any one of Examples 1, 2, and 67, wherein the compound is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 5

[0305] ​​​​​Provided herein as Example 74 is a compound according to any one of Examples 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.

[0306] Provided herein as Example 75 is a compound according to any one of Examples 1, 2, and 67-74, wherein the compound is characterized by a thermogravimetric analysis thermogram comprising a weight loss of about 11% when heated from about 39 °C to about 160 °C.

[0307] Provided herein as Example 76 is a compound according to any one of Examples 67-75, wherein the compound is substantially pure.

[0308] Provided herein as Example 77 is a pharmaceutical composition comprising a compound according to any one of Examples 67-76 and a pharmaceutically acceptable excipient.

[0309] Provided herein as Example 78 is a compound according to Example 1 or 2, wherein the compound is a crystalline solvate form of Compound 1.

[0310] Provided herein as Example 79 is a compound according to Example 78, wherein the compound is a solvate with tetrahydrofuran, acetonitrile, methyl ethyl ketone, ethyl acetate, dichloromethane, acetone, p-dioxane, methanol, isopropanol, or ethanol.

[0311] Provided herein as Example 80 is a compound, wherein the compound is an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3- pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin- 2(lH)-one (Compound 1) or a retro-inverso isomer thereof.

[0312] Provided herein as Example 81 is a compound according to Example 80, wherein the compound is the M retro-inverso isomer of Compound 1.

[0313] Provided herein as Example 82 is a compound according to Example 80 or 81, wherein the compound is characterized by a powder X-ray diffraction pattern substantially as shown in as measured by x-ray powder diffraction using an x-ray wavelength of Figure 4

[0314] ​Provided herein as Example 83 is the compound according to any one of Examples 80-82, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 144 °C.

[0315] Provided herein as Example 84 is the compound according to any one of Examples 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.

[0316] Provided herein as Example 85 is the compound according to any one of Examples 80-84, wherein the compound is characterized by 19 F solid state NMR, the 19 F solid state NMR comprises peaks at about -86, -96, -116, -127, -146, and -156 ppm.

[0317] Provided herein as Example 86 is the compound according to any one of Examples 80-85, wherein the compound is characterized by substantially as Figure 1 shown in 19 F solid state NMR.

[0318] Provided herein as Example 87 is the compound according to any one of Examples 80-86, wherein the compound is substantially pure.

[0319] Provided herein as Example 88 is a pharmaceutical composition comprising the compound according to any one of Examples 80-87 and a pharmaceutically acceptable excipient.

[0320] Provided herein as Example 89 is a pharmaceutical composition comprising (1) the compound according to any one of Examples 4-18, (2) the compound according to any one of Examples 43-54, (3) the compound according to any one of Examples 57-64, (4) the compound according to any one of Examples 67-75, or (5) the compound according to any one of Examples 80-86, or any mixture thereof; and a pharmaceutically acceptable excipient.

[0321] Crystallization techniques

[0322] Anti-solvent precipitation

[0323] Solutions of the compounds of the disclosure were prepared in various solvents and then an anti-solvent was added. The solids that formed were isolated and analyzed.

[0324] Alternatively, solutions of the compounds of the disclosure are prepared in various solvents, then an antisolvent is added and the sample is allowed to evaporate. The solid formed is isolated and analyzed.

[0325] Alternatively, solutions of the compounds of the disclosure are prepared in various solvents, then an antisolvent is added and the sample is cooled to 2-8°C. The solid formed is isolated and analyzed.

[0326] Ultrasonication

[0327] Solutions or suspensions of the compounds of the disclosure are prepared in various solvents and ultrasonicated in an ice bath for 90-180 minutes. The solid is isolated and analyzed.

[0328] Slow cooling

[0329] Saturated solutions of the compounds of the disclosure are prepared in various solvents at ambient or elevated temperature. Samples prepared at elevated temperature are allowed to cool to ambient or 2-8°C. The solid formed is isolated and analyzed.

[0330] Evaporation

[0331] Solutions of the compounds of the disclosure are prepared in various solvents. Once complete dissolution is observed, the solvent is evaporated under vacuum at ambient or heated temperature. The solid formed is isolated and analyzed.

[0332] Slow evaporation

[0333] Solutions of the compounds of the disclosure are prepared in various solvents. Once complete dissolution is observed, the solution is allowed to evaporate at ambient in a partially covered vial with or without a nitrogen blanket. The solid formed is isolated and analyzed.

[0334] Alternatively, solutions of the compounds of the disclosure are prepared, then ultrasonicated for about 90 minutes. After ultrasonication, the sample is allowed to evaporate. The experiment is repeated by slurrying the material with 15 volumes of antisolvent (hexane at 50°C or water at room temperature) and the experiment is repeated. Any solid produced is isolated and analyzed.

[0335] Pressure experiment

[0336] Solutions or suspensions of the compounds of the disclosure are prepared in various solvents, then ultrasonicated for 60 minutes. The sample is then stirred to 30°C for 24-72 hours, then stirred at 50°C for 24 hours. The sample is analyzed at each stage with XRPD prior to final isolation and analysis.

[0337] Slurry experiment

[0338] Solutions of the compounds of the disclosure are prepared by adding sufficient solid to a given solvent such that there is an excess of solid present. All of the forms described below can be obtained from a variety of solvents, including but not limited to the specific solvents described in the examples. The mixture is then stirred in a sealed vial at room temperature or at an elevated temperature. After a given amount of time, the solid is isolated by filtration under vacuum or centrifugation and analyzed.

[0339] Analytical techniques

[0340] X-ray powder diffraction (XRPD)

[0341] X-ray powder diffraction data are obtained using a Phillips X-ray automated powder diffractometer (X’Pert) equipped with a fixed slit and a real-time multiple strip (RTMS) detector. The radiation is Cu Ka at 45 kV and 40 mA, respectively. The data are collected from 3.0 to 40.0 degrees 2-theta at room temperature; the step size is 0.0167 degrees; and the counting time is 15.240 seconds. The platform is rotated with a rotation time of 1.0 second.

[0342] Alternatively, X-ray powder diffraction data are obtained using a PANalytical Empyrean automated powder diffractometer equipped with a Soller slits, beam block, short anti scatter extension, anti scatter vane, and scanning position sensitive detector (X’Celerator). The radiation is Cu Ka The sample is mounted in transmission geometry between 3 um thick films and analyzed.

[0343] Alternatively, X-ray powder diffraction data are obtained using a PANalytical X’Pert PRO X-ray diffractometer equipped with a programmable divergence slit and a real-time multiple strip (RTMS) detector. The radiation is Cu Ka at 45 kV and 40 mA, respectively. The data are collected from 3.0 to 30.0 or from 5 to 45 degrees 2-theta at room temperature; the step size is 0.0334 degrees. The platform is rotated with a rotation time of 2.0 seconds.

[0344] It is noted that a peak shift of approximately + / - 0.2 degrees can occur in the XRPD pattern and can be caused by factors such as sample preparation and instrument alignment.

[0345] Thermogravimetric analysis (TGA)

[0346] Thermogravimetric analysis is performed on a TGA Discovery Series TA instrument. The sample is analyzed under nitrogen at a heating rate of 10 °C / min over a temperature range of 25 °C to 325 °C.

[0347] Differential scanning calorimetry (DSC)

[0348] Differential scanning calorimetry data was collected using standard DSC mode (Discovery Series, TA Instruments). A heating rate of 10 °C / min was employed over a temperature range of 25 °C to 350 °C. Analysis was performed under nitrogen and samples were loaded into aluminum pans. Indium was used as a calibration standard.

[0349] Solid state NMR

[0350] Approximately 100 mg of sample was packed into a 4 mm ceramic rotor using SSNMR packing tool. SSNMR spectra were obtained on a Bruker Avance III 500 MHz WB spectrometer. 19 F spectra were collected using a Bruker double resonance MAS probe operating at 500 MHz 1 H resonance frequency. All experiments used a 4-mm H / F / X spinning probe operated at a 14 kHz spinning rate. For 19 F measurements, a 4us pi / 2 pulse was used and 1 H decoupling was performed using a spinal 64 sequence. A recycle delay of 1.26*T1 was used for optimal S / N / time.

[0351] Examples

[0352] Example 1: Identification of solid form Compound 1

[0353] In the field of drug research and development, the investigation of suitable solid state forms represents a key step. The investigation of solid state forms includes several decisions, mainly the investigation of anhydrous, salt or co-crystal forms and the investigation of the polymorphism of the respective anhydrous, salt or co-crystal form. During the lead optimization program several properties of the compound are optimized, typically leading to one or several candidates to continue into the exploratory development program. Usually, during the evaluation and optimization of the physicochemical parameters during lead optimization, the main focus is on the solubility. In the present case, Compound 1 has a good solubility profile. When investigating salts, in addition to the optimization of the solubility, other physicochemical parameters have to be considered, such as (1) the melting point, (2) the thermal behavior, (3) the hygroscopicity, (4) the crystal habit, (5) the polymorphic behavior or the physical stability, (6) the impurity profile and (7) the chemical stability of the anhydrous or salt form. The melting point of a drug (as free base, acid or salt form) should be above a certain threshold to allow processing steps such as drying or tableting. The evaluation of the thermal behavior, usually done by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), also includes solid-solid phase transitions. These can be enantiotropic or monotropic and can be associated with a conversion from one polymorph to another or from one pseudopolymorph, e.g. a lower solvate or hydrate, or true polymorph, to another. The hygroscopicity plays a key role in the evaluation of solid state forms, as this property is highly relevant to many process steps, such as drying, storage, blending, granulation, to name a few. The hygroscopicity can be investigated by dynamic vapor sorption (DVS). Basically, this technique generates information about the amount of water that a compound absorbs at certain relative humidity levels. The discussion of the thermal behavior and the hygroscopicity represents a link to another parameter that has to be considered in the investigation of anhydrous or salt forms: for an anhydrous or salt form to continue in drug development, a manageable polymorphic behavior is required. Therefore, usually at least a short evaluation of the polymorphic phenomena is performed in the anhydrous or salt investigation program. In this sense, a manageable polymorphic behavior does not equate to the presence of only one or two polymorphic forms, but rather to a situation where the polymorphic forms are not equally convertible. The crystal habit can influence the anhydrous or salt investigation and in many cases optimization means shifting the drug from a needle-like crystal form, for example, to a platelet or even a cubic crystal showing better flow properties. The investigation of salts can be a tool to improve the impurity profile of a drug, as drug salts often exhibit a crystal structure that is quite different from the structure of the corresponding free base or acid.

[0354] Polymorph and salt screening

[0355] Accordingly, a polymorph and salt screen of Compound 1 was performed. Crystalline chloride, phosphate and mesylate salts were identified, as well as crystalline anhydrate, hydrate and solvate forms. None of the identified salts showed particularly advantageous thermal characteristics or showed lower crystallinity based on DSC data. Of the remaining several polymorphs of the free base (including hydrates and solvates), crystalline anhydrate Form I showed surprising and unexpected advantages.

[0356] First, crystalline anhydrate Form I of Compound 1 is the most thermodynamically stable polymorph identified in the screening process. Upon heating or slurry, crystalline anhydrate Forms II and III described below convert to crystalline anhydrate Form I.

[0357] Specifically, upon heating at 193 °C and recrystallization, crystalline anhydrate Form II converts to crystalline anhydrate Form I. Upon slurry in water at 90 °C for 1 hour, crystalline anhydrate Form II converts to crystalline anhydrate Form I. Upon slurry in 90 / 10 v / v water / acetonitrile at room temperature for 7 days, a mixture of crystalline anhydrate Form I and crystalline anhydrate Form II converts to crystalline anhydrate Form I. Upon slurry in heptane at 80 °C for 1 day, a mixture of crystalline anhydrate Form I and crystalline anhydrate Form II converts to crystalline anhydrate Form I.

[0358] Crystalline anhydrate Form III melts at 180 °C. Upon melting and recrystallization at 220 °C, crystalline anhydrate Form III converts to crystalline anhydrate Form I. Upon slurry in ethanol at room temperature for 10 days, a mixture of crystalline anhydrate Form I and crystalline anhydrate Form III converts to crystalline anhydrate Form I. Upon slurry in methanol at room temperature for 10 days, a mixture of crystalline anhydrate Form I and crystalline anhydrate Form III converts to crystalline anhydrate Form I.

[0359] The high melting point of crystalline anhydrate Form I is a further indicator of its thermodynamic stability (DSC endotherm onset at about 293 °C).

[0360] Second, crystalline anhydrate Form I is less hygroscopic than crystalline anhydrate Forms II and III (Form I absorbs 0.5-1.0% wt water between 0 and 90% RH at 25 °C; Form II absorbs 2-2.5% wt water between 0 and 90% RH at 25 °C; Form III absorbs 7.0% wt water between 0 and 95% RH at 25 °C).

[0361] In addition, the crystalline anhydrous Form I was physically and chemically stable in the solid state at 25 °C / 60% RH, 40 °C / 75% RH, 40 °C / ambient RH, and 60 °C / ambient RH for 14 weeks, with no degradation peaks by HPLC or any changes in the solid state properties studied, including XRPD, DSC showing onset of melting point and heat of fusion, and TGA showing volatile content. In addition, the crystalline anhydrous Form I was stable in excipient compatibility studies of three prototype mixtures stored at 40 °C / 75% RH for 4 weeks. The crystalline anhydrous Form I was also stable to ultraviolet and visible light in the solid state.

[0362] Accordingly, the crystalline anhydrous Form I exhibits favorable and unexpected overall properties, particularly when compared to other forms and identified salts.

[0363] Polymorph screening

[0364] As described below, a polymorph screen was performed to generate different solid forms of the M atropisomer of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2- propanoyl)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3- d]pyrimidin-2(lH)-one (Compound 1). For convenience, reference to “Compound 1” in the examples below is understood to refer to the M atropisomer of Compound 1.

[0365] Example 1

[0366] Compound 1 can be prepared according to the procedures disclosed in U.S. Publication 2018 / 0334454, published November 22, 2018, which is incorporated by reference herein in its entirety.

[0367] Amorphous Form I of Compound 1 was prepared by rotary evaporation from MeOH, along with secondary drying under vacuum at room temperature.

[0368] XRPD, TGA, DSC, and 19 The relative peak areas of the amorphous Form by F SSNMR are represented in Figure 21 , 2 , 3, and 4.

[0369] Differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset at about 144 °C.

[0370] Thermogravimetric analysis (TGA) thermogram comprising a weight loss of about 1.5% when heated from about 25 °C to about 275 °C.

[0371] 19 F SSNMR: -86, -96, -116, -127, -146, and -156 ppm.

[0372] A number of anhydrous forms and hydrate forms of Compound 1 were investigated (see Table 1 below). Further characterization of these crystalline forms was investigated, such as melting point, thermal behavior, hygroscopicity, crystal habit, particle size, polymorphic behavior, stability, and purity. These forms were characterized by a variety of methods, including XRPD, TGA, and DSC analysis. The relative intensity % is based on the relative intensity percentage of the largest peak.

[0373] Figure 5 Overlays of crystalline anhydrous Forms I, II, III, and variable hydrate Form I of Compound 1 are shown (Forms I-III and variable hydrate Form I, from top to bottom, respectively).

[0374] Table 1. XRPD Distinctive Peaks

[0375]

[0376] Example 2: Preparation of crystalline anhydrous Form I of Compound 1

[0377] Crystalline anhydrous Form I was prepared by charging 1.5 g of crystalline anhydrous Form II of Compound 1 with 10 mL of water to form a slurry. The slurry was heated to 90 °C for 2 h, then stirred at room temperature overnight. The solids were filtered, vacuum dried, and identified as crystalline anhydrous Form I by XRPD. The DSC endotherm onset was at about 292.6 °C, and the TGA contained about 0.2% weight loss when heated from about 25 °C to about 275 °C.

[0378] The crystalline anhydrous Form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data ( Figure 6 ), DSC ( Figure 7 ), TGA ( Figure 8 ), carbon 13 SSNMR ( Figure 9 ), and 19 F SSNMR ( Figure 10 ).

[0379] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (d, J=6.84 Hz, 3 H) 1.07 (d, J=6.63 Hz, 3 H) 1.35 (d, J=6.84 Hz, 3 H) 1.90 (s, 3 H) 2.66 - 2.75 (m, 1 H) 3.14 (br t, J=11.20 Hz, 1 H) 3.59 - 3.75 (m, 2 H) 3.97 - 4.08 (m, 1 H) 4.08 - 4.22 (m, 1 H) 4.22 - 4.43 (m, 2 H) 4.90 (br s, 1 H) 5.74 - 5.79 (m, 1 H) 6.21 (br d, J=17.00 Hz, 1 H) 6.65 - 6.75 (m, 2 H) 6.79 - 6.92 (m, 1 H) 7.18 (d, J=4.98 Hz, 1 H) 7.23 - 7.31 (m, 1 H) 8.22 - 8.33 (m, 1 H) 8.38 (d, J=4.77 Hz, 1 H) 10.19 (s, 1 H)

[0380] 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.

[0381] 19 F SSNMR: -49, -60, -79, -90, -109, -120, -138, -150, -168, and -179 ppm.

[0382] Table 2: XRPD data for crystalline anhydrous Form I of Compound 1

[0383]

[0384]

[0385] Example 3: Preparation of anhydrous Form II of Compound 1

[0386] Crystalline anhydrous Form II of Compound 1 was prepared by charging 0.987 g of amorphous Compound 1 with 15 mL of MeOH to produce a slurry. The isolated solid was identified as crystalline anhydrous Form II by XRPD.

[0387] DSC onset at about 192.5 °C and TGA includes about 1% to about 1.8% weight loss when heated from about 25 °C to about 250 °C.

[0388] The crystalline anhydrous Form II of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data Figure 11 , DSC Figure 12 , TGA Figure 13 , carbon-13 SSNMR Figure 14 , and 19 fluorine-19 SSNMR Figure 15 .

[0389] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (d, J=6.63 Hz, 4 H) 1.07 (d, J=6.84 Hz, 4 H) 1.35 (d, J=6.63 Hz, 4 H) 1.90 (s, 3 H) 2.60 - 2.76 (m, 1 H) 3.11 - 3.28 (m, 2 H) 3.68 (br d, J=13.89 Hz, 2 H) 4.08 (d, J=5.18 Hz, 2 H) 4.32 (br d, J=13.68 Hz, 2 H) 4.90 (br s, 1 H) 5.74 - 5.79 (m, 1 H) 6.21 (br d, J=16.17 Hz, 1 H) 6.65 - 6.76 (m, 2 H) 6.80 - 6.92 (m, 1 H) 7.18 (d, J=4.98 Hz, 1 H) 7.23 - 7.31 (m, 1 H) 8.29 (br d, J=9.33 Hz, 1 H) 8.38 (d, J=4.98 Hz, 1 H) 10.19 (s, 1 H).

[0390] 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.

[0391] 19 F SSNMR: -59, -62, -89, -92, -119, -122, -148, -151, -179, and -181 ppm.

[0392] Table 3: XRPD data for crystalline anhydrous Form II of Compound 1

[0393]

[0394]

[0395] Example 4: Preparation of crystalline anhydrous Form III of Compound 1

[0396] Crystalline anhydrate Form III of Compound 1 was prepared by vacuum drying Compound 1 acetone solvate Form I at about 65-76 °C. DSC onset at about 194 °C, TGA contains almost negligible weight loss when heated from about 25 °C to about 250 °C.

[0397] Crystalline anhydrate Form III of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data, Figure 16 ), DSC( Figure 17 ), and TGA( Position [°2Θ] ).

[0398] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (d, J=6.82 Hz, 3 H) 1.07 (d, J=6.61 Hz, 3 H) 1.35 (d, J=6.61 Hz, 2 H) 1.90 (s, 2 H) 2.64 - 2.80 (m, 1 H) 3.14 (br t, J=10.66 Hz, 1 H) 3.45 - 3.57 (m, 1 H) 3.58 - 3.76 (m, 1 H) 3.94 - 4.08 (m, 1 H) 4.14 (br d, J=13.00 Hz, 1 H) 4.21 - 4.47 (m, 2 H) 4.90 (br s, 1 H) 5.76 (dd, J=10.44, 2.13 Hz, 1 H) 6.21 (br d, J=16.84 Hz, 1 H) 6.55 - 6.78 (m, 2 H) 6.86 (dt, J=16.20, 11.29 Hz, 1 H) 7.13 - 7.21 (m, 1 H) 7.21 - 7.33 (m, 1 H) 8.21 - 8.34 (m, 1 H) 8.39 (d, J=4.90 Hz, 1 H) 10.20 (br s, 1 H).

[0399] Table 4: XRPD data for anhydrate Form III of Compound 1

[0400] Relative intensity [%] Position [°2Θ] Relative intensity [%] Figure 18 6.3 14.11 25.4 10.81 8.4 63.06 25.9 5.35 9.5 84.68 26.7 17.58 10.4 12.93 26.8 5.18 12.8 6.80 27.2 10.38 13.0 6.79 27.5 12.87 13.7 4.59 27.9 4.42 14.9 12.72 28.3 7.66 15.4 45.73 28.6 15.70 15.5 69.05 29.3 3.10 16.0 79.08 29.7 1.70 16.6 8.35 30.2 1.02 17.6 100.00 31.4 2.93 18.2 9.32 32.2 3.52 18.7 37.73 32.5 3.97 19.2 16.82 33.1 2.31 20.0 36.44 33.7 1.35 20.6 13.07 34.6 4.91 20.8 9.52 35.5 3.74 21.7 3.50 35.8 2.54 21.7 16.74 36.7 1.18 22.7 5.52 37.3 1.65 23.0 13.50 38.0 2.18 23.2 4.81 39.0 1.57 24.2 11.39 24.9 3.83

[0401] Example 5: Preparation of variable hydrate Form I of Compound 1 Variable hydrate Form I of Compound 1 was prepared by dissolving Compound 1 in MeOH at room temperature, fine filtration, and then charging aliquots of water as antisolvent until precipitation occurred. The solids were isolated after stirring at room temperature for 13 days.

[0402] DSC first endotherm onset at about 91 °C, TGA contains about 11% weight loss when heated from about 39 °C to about 160 °C (3.9 mol water).

[0403] Karl Fischer 10.63% (3.7 mol) water.

[0404] The crystalline polymorph Form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data, Figure 19 ), DSC( Figure 20 ), and TGA( Figure 22 ).

[0405] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (d, J=6.62 Hz, 3 H) 1.08 (d, J=6.84 Hz, 3 H) 1.35 (d, J=6.63 Hz, 3 H) 1.90 (s, 3 H) 2.61 - 2.79 (m, 1 H) 3.15 (br t, J=11.01 Hz, 1 H) 3.40 - 3.58 (m, 2 H) 3.59 - 3.84 (m, 3 H) 3.86 - 4.09 (m, 1 H) 4.15 (br d, J=12.39 Hz, 1 H) 4.21 - 4.47 (m, 3 H) 4.90 (br s, 2 H) 5.73 - 5.82 (m, 1 H) 6.15 - 6.21 (m, 1 H) 6.23 (br d, J=4.92 Hz, 1 H) 6.63 - 6.77 (m, 3 H) 6.78 - 7.03 (m, 2 H) 7.14 - 7.31 (m, 3 H) 8.14 - 8.35 (m, 1 H) 8.39 (d, J=4.92 Hz, 1 H).

[0406] Table 5: XRPD data for crystalline polymorph Form I of Compound 1

[0407]

[0408]

[0409] Example 6: Preparation of crystalline THF solvate Form I of Compound 1

[0410] The crystalline THF solvate Form I of Compound 1 was prepared by placing amorphous Compound 1 in a small open vial, then placing the vial in a larger vial containing THF and capping to subject the solid to vapor stress at room temperature for 4 days.

[0411] DSC endotherm onset at about 165 °C, TGA contains about 13.4% weight loss when heated from about 130 °C to about 160 °C. (1.2 mol THF)

[0412] NMR 1.1 mol THF

[0413] The crystalline THF solvate Form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data Figure 23 , DSC Figure 24 , and TGA Figure 25 .

[0414] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (d, J=6.62 Hz, 3 H) 1.08 (d, J=6.62 Hz, 3 H) 1.35 (d, J=6.62 Hz, 3 H) 1.68 - 1.84 (m, 4 H) 1.90 (s, 3 H) 2.62 - 2.93 (m, 1 H) 3.15 (br t, J=11.33 Hz, 1 H) 3.49 - 3.75 (m, 10 H) 3.87 - 4.09 (m, 1 H) 4.09 - 4.21 (m, 1 H) 4.22 - 4.47 (m, 4 H) 4.91 (br s, 2 H) 5.71 - 5.83 (m, 2 H) 6.21 (br dd, J=16.88, 4.70 Hz, 1 H) 6.64 - 6.78 (m, 3 H) 6.78 - 6.99 (m, 1 H) 7.14 - 7.22 (m, 1 H) 7.28 (td, J=8.33, 7.05 Hz, 1 H) 8.18 - 8.35 (m, 1 H) 8.39 (d, J=4.92 Hz, 1 H) 10.21 (br s, 1 H)

[0415] Table 6: XRPD data for the crystalline THF solvate Form I of Compound 1 XRPD peak table:

[0416]

[0417]

[0418]

[0419] Example 7: Preparation of the crystalline MeCN solvate Form I of Compound 1

[0420] The crystalline MeCN solvate Form I was prepared by slurrying Compound 1 in MeCN at room temperature for 14 days.

[0421] DSC endotherm onset at about 112 °C, TGA comprises about 6.9% weight loss when heated from about 38 °C to about 170 °C. (1 mol MeCN).

[0422] NMR 0.9 mol MeCN.

[0423] The crystalline THF solvate Form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data Figure 26), DSC Figure 27 ) and TGA ( Figure 28 The crystalline MeCN solvate form I prepared above was characterized.

[0424] 1 H NMR(400MHz, DMSO-d6)δppm 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).

[0425] Table 7: XRPD data for the crystalline MeCN solvate form I of compound 1. XRPD peak table:

[0426]

[0427]

[0428] Example 8: Preparation of the crystalline MEK solvate form I of compound 1

[0429] Crystalline MEK solvate form I was prepared by dissolving compound 1 in MEK at room temperature, fine filtration, and then adding an equal amount of heptane as an antisolvent until precipitation occurred. The solid was separated after stirring at room temperature for 13 days. It was also prepared by a slurry of amorphous compound 1 in MEK at room temperature.

[0430] The endothermic reaction of DSC begins at approximately 106 °C, and TGA includes a weight loss of approximately 10.7% when heated from approximately 39 °C to approximately 197 °C (0.9 mol MEK).

[0431] NMR 0.8 mol MEK.

[0432] Data from proton NMR and X-ray powder diffraction (XRPD) Figure 29 ), DSC Figure 30) and TGA Figure 31 The crystalline MEK solvate Form I prepared above was characterized by proton NMR and X-ray powder diffraction (XRPD) data

[0433] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (q, J=7.05 Hz, 5 H) 1.08 (d, J=6.62 Hz, 3 H) 1.35 (d, J=6.62 Hz, 3 H) 1.90 (s, 3 H) 2.04 - 2.10 (m, 2 H) 2.36 - 2.49 (m, 2 H) 2.60 - 2.93 (m, 1 H) 3.15 (br s, 1 H) 3.36 - 3.57 (m, 2 H) 3.57 - 3.84 (m, 4 H) 3.86 - 4.09 (m, 2 H) 4.15 (br d, J=12.82 Hz, 1 H) 4.22 - 4.46 (m, 4 H) 4.91 (br s, 2 H) 5.72 - 5.83 (m, 2 H) 6.00 - 6.21 (m, 1 H) 6.23 (br d, J=4.49 Hz, 1 H) 6.64 - 6.78 (m, 3 H) 6.78 - 7.00 (m, 2 H) 7.17 - 7.31 (m, 3 H) 8.16 - 8.35 (m, 1 H) 8.39 (d, J=4.92 Hz, 1 H) 10.22 (br s, 1 H).

[0434] Table 8: XRPD data for the crystalline MEK solvate Form I of Compound 1: XRPD Peak Table:

[0435]

[0436]

[0437]

[0438] Example 9: Preparation of the crystalline EtOAc solvate Form I of Compound 1

[0439] The crystalline EtOAc solvate Form I was prepared by slurry of Compound 1 with ethyl acetate (EtOAc) at room temperature for 24 h.

[0440] The crystalline EtOAc solvate Form I prepared above was characterized by proton NMR and X-ray powder diffraction (XRPD) data Figure 32

[0441] Table 9: XRPD data for the crystalline EtOAc solvate Form I of Compound 1: XRPD Peak Table:

[0442]

[0443] ​

[0444] Example 10: Preparation of DMF solvate Form I of Compound 1

[0445] Crystalline DMF solvate Form I of Compound 1 was prepared by slurry of Compound 1 in DMF / water at room temperature for 24 h.

[0446] The crystalline DMF solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data Figure 33 ), DSC Figure 34 ), and TGA Position [°2Θ] .

[0447] The DSC endotherm starts at about 74 °C and the TGA contains about 17% weight loss when heated from about 36 °C to about 195 °C.

[0448] NMR 1-2 mol DMF.

[0449] 1 H NMR (500 MHz, DMSO-d6) δ ppm 0.94 (d, J=6.49 Hz, 4 H) 1.08 (d, J=6.75 Hz, 4 H) 1.35 (d, J=6.75 Hz, 4 H) 1.91 (s, 4 H) 2.30 (s, 1 H) 2.55 (t, J=5.58 Hz, 1 H) 2.73 (s, 6 H) 2.89 (s, 5 H) 3.00 - 3.21 (m, 1 H) 3.27 (br d, J=13.49 Hz, 2 H) 3.34 (br s, 5 H) 3.60 - 3.74 (m, 2 H) 3.96 - 4.16 (m, 1 H) 4.32 (br d, J=13.75 Hz, 2 H) 4.39 (br s, 1 H) 4.90 (br s, 1 H) 5.67 - 5.86 (m, 1 H) 6.20 (br dd, J=16.61, 7.27 Hz, 1 H) 6.64 - 6.77 (m, 2 H) 6.79 - 6.92 (m, 1 H) 7.17 - 7.32 (m, 2 H) 7.95 (s, 1 H) 8.28 (br dd, J=16.22, 9.21 Hz, 1 H) 8.40 (d, J=4.93 Hz, 1 H) 10.19 (d, J=1.30 Hz, 1 H).

[0450] Table 10: XRPD data for crystalline DMF solvate Form I of Compound 1 XRPD Peak Table:

[0451] Relative intensity [%] Position [°2Θ] Relative intensity [%] Figure 35 7.8 100.0 24.3 12.6 8.1 60.0 24.9 11.5 9.0 19.1 25.4 12.7 12.4 17.5 26.8 17.8 13.3 7.5 27.3 11.1 14.4 25.9 28.3 30.4 15.0 7.4 28.6 38.6 16.1 11.4 29.4 12.3 16.8 26.5 30.4 6.0 17.3 17.5 31.6 6.2 18.9 12.3 34.0 3.3 19.9 58.6 35.7 1.9 20.8 38.6 37.9 2.6 21.8 11.0 42.2 2.2 23.3 17.0

[0452] Example 11: Preparation of crystalline DCM solvate Form I of Compound 1

[0453] Crystalline DCM solvate Form I of Compound 1 was prepared by dissolving Compound 1 in DCM at room temperature, fine filtered, and then charging equal portions of heptane as antisolvent until precipitation occurred. The solid was isolated after stirring at room temperature for 1 h.

[0454] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.84 - 1.02 (m, 2 H) 1.07 (d, J=6.61 Hz, 2 H) 1.35 (d, J=6.82 Hz, 2 H) 1.90 (s, 2 H) 2.64 - 2.80 (m, 1 H) 3.14 (br t, J=11.19 Hz, 1 H) 3.45 - 3.57 (m, 1 H) 3.58 - 3.84 (m, 2 H) 3.86 - 4.09 (m, 1 H) 4.09 - 4.21 (m, 1 H) 4.21 - 4.46 (m, 2 H) 4.90 (br s, 1 H) 5.65 - 5.86 (m, 2 H) 6.08 - 6.28 (m, 1 H) 6.63 - 6.76 (m, 2 H) 6.86 (dt, J=16.46, 11.27 Hz, 1 H) 7.12 - 7.21 (m, 1 H) 7.21 - 7.31 (m, 1 H) 8.16 - 8.36 (m, 2 H) 8.39 (d, J=4.90 Hz, 1 H) 10.20 (br s, 1 H).

[0455] The crystalline DCM solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data, Figure 36 , DSC, Figure 37 , and TGA, Figure 38 .

[0456] DSC endotherm onset at about 174 °C, TGA contains about 7.2% weight loss when heated from about 40 °C to about 200 °C. (0.5 mol DCM), from 40°-200°.

[0457] NMR 0.5 mol DCM

[0458] Table 11: XRPD data for crystalline DCM solvate Form I of Compound 1

[0459]

[0460]

[0461] Example 12: Preparation of crystalline acetone solvate Form I of Compound 1

[0462] Crystalline acetone solvate Form I of Compound 1 was prepared by slurrying amorphous Compound 1 in acetone / water (50:50) at room temperature or Compound 1 in acetone / water (50:50) at 2-8 °C for 15 days.

[0463] Crystalline acetone solvate Form I of Compound 1 prepared as above was characterized by proton NMR, X-ray powder diffraction (XRPD) data, Figure 39 ), DSC( Figure 40 ), and TGA( Figure 41 ).

[0464] The DSC endotherm starts at about 72 °C and the TGA contains about 21.4% weight loss when heated from about 38 °C to about 130 °C. (0.7 mol acetone and 5.3 mol water).

[0465] NMR 0.7 mol acetone.

[0466] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.84 - 1.00 (m, 3 H) 1.07 (d, J=6.61 Hz, 3 H) 1.34 (d, J=6.61 Hz, 3 H) 1.90 (s, 3 H) 2.05 - 2.12 (m, 3 H) 2.52 - 2.78 (m, 2 H) 3.08 - 3.21 (m, 1 H) 3.45 - 3.57 (m, 1 H) 3.67 (br d, J=11.72 Hz, 2 H) 3.97 - 4.06 (m, 1 H) 4.08 - 4.21 (m, 1 H) 4.32 (br d, J=13.85 Hz, 2 H) 4.90 (br s, 1 H) 5.54 - 5.80 (m, 2 H) 5.99 - 6.26 (m, 2 H) 6.52 - 6.75 (m, 2 H) 6.84 (br s, 1 H) 7.09 - 7.30 (m, 2 H) 8.12 - 8.36 (m, 3 H) 8.38 (d, J=4.90 Hz, 1 H) 10.21 (br s, 1 H).

[0467] Table 12: XRPD data for crystalline acetone solvate Form I of Compound 1

[0468]

[0469]

[0470] 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.

[0471] The crystalline acetone solvate Form II of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data Figure 42 , DSC Figure 43 , and TGA Figure 44 .

[0472] The DSC endotherm starts at about 137 °C and the TGA contains about 7.3% weight loss when heated from about 100 °C to about 200 °C. (0.8 mol acetone).

[0473] NMR 0.7 mol acetone

[0474] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.83 - 1.02 (m, 3 H) 1.07 (d, J=6.82 Hz, 2 H) 1.35 (d, J=6.61 Hz, 2 H) 1.90 (s, 2 H) 2.09 (s, 3 H) 2.52 - 2.77 (m, 1 H) 3.18 (br s, 1 H) 3.45 - 3.57 (m, 1 H) 3.66 (br s, 4 H) 3.96 - 4.08 (m, 1 H) 4.08 - 4.20 (m, 1 H) 4.32 (br d, J=13.64 Hz, 3 H) 4.90 (br s, 2 H) 5.69 - 5.80 (m, 1 H) 6.15 - 6.26 (m, 1 H) 6.60 - 6.75 (m, 2 H) 6.79 - 6.94 (m, 1 H) 7.07 - 7.21 (m, 1 H) 7.27 (td, J=8.31, 7.03 Hz, 1 H) 8.20 - 8.36 (m, 2 H) 8.39 (d, J=4.90 Hz, 1 H) 10.20 (br s, 1 H).

[0475] Table 13: XRPD data for the crystalline acetone solvate Form II of Compound 1

[0476]

[0477]

[0478] Example 14: Preparation of the crystalline p-dioxane solvate Form I of Compound 1

[0479] The crystalline p-dioxane solvate Form I of Compound 1 was prepared by slurrying Compound 1 in p-dioxane at room temperature for 14 days.

[0480] The crystalline p-dioxane solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data Figure 45 , DSC Figure 46 , and TGA Figure 47The crystalline p-dioxane solvate Form I of Compound 1 prepared above was characterized.

[0481] DSC endotherm onset at about 112 °C, TGA comprising about 23.2% weight loss when heated from about 25 °C to about 150 °C. (1.9 mol p-dioxane)

[0482] NMR 1.9 mol p-dioxane

[0483] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.84 - 1.00 (m, 3 H) 1.07 (d, J=6.61 Hz, 3 H) 1.35 (d, J=6.82 Hz, 3 H) 1.90 (s, 2 H) 2.52 - 2.77 (m, 2 H) 3.05 - 3.28 (m, 1 H) 3.32 (s, 4 H) 3.58 - 3.78 (m, 3 H) 3.98 - 4.07 (m, 1 H) 4.09 - 4.20 (m, 1 H) 4.09 - 4.19 (m, 1 H) 4.15 - 4.43 (m, 1 H) 4.16 - 4.21 (m, 1 H) 4.22 - 4.45 (m, 1 H) 4.23 - 4.45 (m, 1 H) 4.90 (br s, 1 H) 5.61 - 5.80 (m, 1 H) 6.20 (br dd, J=16.62, 4.48 Hz, 1 H) 6.58 - 6.76 (m, 2 H) 6.79 - 6.93 (m, 1 H) 7.10 - 7.21 (m, 1 H) 7.21 - 7.31 (m, 1 H) 8.14 - 8.36 (m, 3 H) 8.39 (d, J=4.90 Hz, 1 H) 10.20 (br s, 1 H)

[0484] Table 14: XRPD data for crystalline p-dioxane solvate Form I of Compound 1

[0485]

[0486]

[0487] Example 15: Preparation of crystalline methanol solvate Form I of Compound 1

[0488] Crystalline MeOH solvate Form I of Compound 1 was prepared by placing Compound 1 in a small open vial, then placing the vial in a larger vial containing methanol (MeOH) and capping to subject the solid to vapor stress at room temperature for 4 days.

[0489] The crystalline MeOH solvate Form I of Compound 1 was characterized by proton NMR, X-ray powder diffraction (XRPD) data Figure 48 , DSC Figure 49 , and TGAFigure 50 The crystalline MeOH solvate Form I of Compound 1 prepared above was characterized.

[0490] DSC endotherm onset at about 57 °C, TGA contains about 5.2% weight loss when heated from about 38 °C to about 220 °C. (1.0 mol MeOH)

[0491] NMR 0.8 mol MeOH

[0492] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (d, J=6.62 Hz, 3 H) 1.08 (d, J=6.62 Hz, 3 H) 1.35 (d, J=6.84 Hz, 3 H) 1.90 (s, 3 H) 2.64 - 2.80 (m, 1 H) 3.18 (d, J=4.92 Hz, 3 H) 3.48 - 3.76 (m, 2 H) 3.97 - 4.21 (m, 2 H) 4.21 - 4.47 (m, 2 H) 4.91 (br s, 1 H) 5.69 - 5.86 (m, 1 H) 6.21 (br dd, J=16.67, 4.49 Hz, 1 H) 6.63 - 6.79 (m, 2 H) 6.80 - 6.98 (m, 1 H) 7.17 - 7.31 (m, 2 H) 8.18 - 8.35 (m, 1 H) 8.39 (d, J=4.92 Hz, 1 H) 10.22 (br s, 1 H)

[0493] Table 15: XRPD data for crystalline MeOH solvate Form I of Compound 1

[0494]

[0495]

[0496] Example 16: Preparation of crystalline IPA solvate Form I of Compound 1

[0497] The crystalline IPA solvate Form I of Compound 1 was prepared by slurry of amorphous Compound 1 in isopropyl alcohol (IPA) at room temperature for 5 days.

[0498] The crystalline IPA solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data ( Figure 51 ), DSC ( Figure 52 ), and TGA ( Figure 53 ).

[0499] DSC endotherm onset at about 56 °C, TGA comprising about 8.7% weight loss when heated from about 39 °C to about 190 °C. (0.9 mol IPA)

[0500] NMR 2.3 mol IPA

[0501] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (d, J=6.62 Hz, 3 H) 1.02 - 1.06 (m, 1 H) 1.05 (d, J=5.98 Hz, 14 H) 1.35 (d, J=6.62 Hz, 3 H) 1.90 (s, 3 H) 2.72 (br s, 1 H) 3.10 - 3.21 (m, 1 H) 3.45 - 3.58 (m, 1 H) 3.78 (td, J=6.09, 4.06 Hz, 9 H) 3.98 - 4.09 (m, 1 H) 4.16 (br s, 1 H) 4.35 (d, J=4.06 Hz, 8 H) 4.91 (br d, J=0.85 Hz, 1 H) 5.73 - 5.83 (m, 2 H) 6.16 - 6.28 (m, 1 H) 6.66 - 6.93 (m, 5 H) 7.19 (dd, J=4.81, 0.75 Hz, 2 H) 7.23 - 7.33 (m, 2 H) 8.39 (d, J=4.92 Hz, 3 H) 10.21 (br s, 1 H).

[0502] Table 16: XRPD data for crystalline MeOH solvate Form I of Compound 1

[0503]

[0504]

[0505] Example 17: Preparation of crystalline EtOH solvate Form I of Compound 1

[0506] Crystalline EtOH solvate Form I of Compound 1 was prepared by slurry of amorphous Compound 1 in ethanol (EtOH) at room temperature for 10 days.

[0507] Crystalline EtOH solvate Form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data Figure 54 , DSC Figure 55 , and TGA ​ .

[0508] DSC endotherm onset at about 194 °C, TGA comprising about 5% weight loss when heated from about 36 °C to about 195 °C. (0.6 mol EtOH)

[0509] NMR 0.7 mol EtOH.

[0510] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.84 - 1.02 (m, 5 H) 1.02 - 1.12 (m, 5 H) 1.35 (d, J=6.82 Hz, 3 H) 1.90 (s, 3 H) 2.52 - 2.77 (m, 1 H) 3.14 (br t, J=10.87 Hz, 1 H) 3.34 - 3.57 (m, 2 H) 3.58 - 3.84 (m, 2 H) 3.86 - 4.08 (m, 1 H) 4.09 - 4.21 (m, 1 H) 4.21 - 4.46 (m, 3 H) 4.90 (br s, 1 H) 5.51 - 5.80 (m, 1 H) 6.20 (br dd, J=16.52, 4.58 Hz, 1 H) 6.62 - 6.75 (m, 2 H) 6.86 (dt, J=16.30, 11.24 Hz, 1 H) 7.13 - 7.19 (m, 1 H) 7.27 (td, J=8.20, 7.03 Hz, 1 H) 8.16 - 8.36 (m, 2 H) 8.39 (d, J=4.90 Hz, 1 H) 10.20 (br s, 1 H).

[0511] Table 17: XRPD data for crystalline EtOH solvate Form I of Compound 1

[0512]

[0513]

[0514] While the application has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will understand that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols can be made without departing from the spirit and scope of the disclosure. It is intended, therefore, that the application be defined by the scope of the following claims as reasonably and justly interpreted at the time such claims are made, with all equivalents to be included therein as is permitted by law.

Claims

1. A crystalline form of a compound, wherein the compound is the M atropisomer of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin-2(lH)-one, wherein the compound is characterized by a powder x-ray diffraction pattern comprising peaks, as measured by x-ray powder diffraction using an x-ray wavelength of 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 2-theta.

2. The crystalline form of claim 1, wherein the compound is characterized by a powder x-ray diffraction pattern as shown in Figure 5.

3. A crystalline form of a compound, wherein the compound is the M atropisomer of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin-2(lH)-one, wherein the compound is characterized by 13 C solid state NMR, the 13 C solid state NMR comprises 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.

4. The crystalline form of claim 3, wherein the compound is characterized by the XRPD pattern as shown in Figure 8. 13 C Solid state NMR.

5. A crystalline form of a compound, wherein the compound is 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, wherein the compound is characterized by 19 F solid state NMR, the 19 F solid state NMR comprises peaks at about -49, -60, -79, -90, -109, -120, -138, -150, -168, and -179 ppm as measured at 14 kHz spinning frequency.

6. The crystalline form of claim 5, wherein the compound is characterized by the XRPD pattern of Figure 9. 19 F Solid state NMR.

7. The crystalline form of any one of claims 1-6, wherein the compound is characterized by a differential scanning calorimetry thermogram comprising an endotherm with an onset at 293 °C.

8. The crystalline form of any one of claims 1-7, wherein the compound is characterized by a thermogravimetric analysis thermogram comprising a weight loss of 0.2% when heated from 25 °C to 275 °C.

9. The crystalline form of any one of claims 1-6, wherein the compound is substantially pure.

10. A pharmaceutical composition comprising the crystalline form of any one of claims 1-6 and a pharmaceutically acceptable excipient.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is an orally administered dosage form.

12. The pharmaceutical composition of claim 11, wherein the dosage form is a solid dosage form.

13. The pharmaceutical composition of claim 12, wherein the solid dosage form is a tablet.

14. The pharmaceutical composition of any one of claims 10-13, wherein the pharmaceutical composition comprises 120 mg of the compound.

15. Use of the crystalline form of any one of claims 1-6 in the manufacture of a medicament for the treatment of a cancer having a KRAS G12C mutation.

16. The use of claim 15, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, endometrial cancer, pancreatic cancer, skin cancer, gastric cancer, nasal cavity cancer, or cholangiocarcinoma.

17. The use of claim 15, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer.

18. The use of claim 15, wherein the cancer having a KRAS G12C mutation is pancreatic cancer.

19. The use of claim 15, wherein the cancer having a KRAS G12C mutation is colorectal cancer.

20. The use of any one of claims 16-19, wherein the compound is administered at a total daily dose of 5 mg-1000 mg.

21. The use of any one of claims 16-19, wherein the compound is administered at a total daily dose of 960 mg.

22. The use of any one of claims 16-19, wherein the compound is administered to an adult human.

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