Solid state forms

Abstract

To provide compounds and pharmaceutical compositions for use in the treatment of cancer having a KRAS G12C mutation.SOLUTION: A compound is provided which is a crystalline hydrochloride salt form of an M atropisomer of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 851,049, filed May 21, 2019, which is incorporated herein by reference in its entirety.

[0002] The present disclosure provides at least one crystalline salt form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (hereinafter "Compound 1"), including several crystalline forms of the hydrochloride, phosphate, and mesylate salts, pharmaceutical compositions, and methods of treating diseases mediated by KRAS G12C inhibition. [Background technology]

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

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

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

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

[0007] [Non-Patent Document 1] P.DiMartino,et al.,J.Thermal Anal.,48:447-458(1997) [Non-patent document 2] Knapman,K.Modern Drug Discoveries,2000,53 Summary of the Invention [Means for solving the problem]

[0008] This disclosure provides novel polymorphic forms of Compound 1, including several crystalline salt forms and their physical forms, pharmaceutical compositions, and methods of treating diseases mediated by KRAS G12C inhibition. These novel polymorphic forms may advance the development of pharmaceuticals for treating these chronic diseases and may offer numerous formulation, manufacturing, and therapeutic advantages.

[0009] The present disclosure provides stable crystalline salt forms of Compound 1, including several crystalline salt forms, their physical forms and mesylate forms, pharmaceutical compositions and methods of treating diseases mediated by KRAS G12C inhibition. [Brief explanation of the drawings]

[0010] [Figure 1] 1 shows XRPD data for hydrochloride salt Form I of Compound 1. The powder X-ray diffraction patterns of hydrochloride salt Forms I-VII of Compound 1 are characteristic of crystalline material with distinct diffraction peaks between 3° 2θ and 40° 2θ. [Figure 2] 1 shows DSC data for the hydrochloride salt Form I of Compound 1. [Figure 3] 1 shows TGA data for the hydrochloride salt Form I of Compound 1. [Figure 4] 1 shows XRPD data for crystalline hydrochloride salt Form II of Compound 1. [Figure 5] 1 shows DSC data for crystalline hydrochloride salt Form II of Compound 1. [Figure 6] 1 shows TGA data for crystalline hydrochloride salt Form II of Compound 1. [Figure 7] 1 shows XRPD data for crystalline hydrochloride salt Form III of Compound 1. [Figure 8]1 shows DSC data for crystalline hydrochloride salt Form III of Compound 1. [Figure 9] 1 shows TGA data for crystalline hydrochloride salt Form III of Compound 1. [Figure 10] 1 shows XRPD data for crystalline hydrochloride salt Form IV of Compound 1. [Figure 11] 1 shows DSC data for crystalline hydrochloride salt Form IV of Compound 1. [Figure 12] 1 shows TGA data for crystalline hydrochloride salt Form IV of Compound 1. [Figure 13] 1 shows XRPD data for crystalline hydrochloride salt Form V of Compound 1. [Figure 14] 1 shows DSC data for crystalline hydrochloride salt Form V of Compound 1. [Figure 15] 1 shows TGA data for crystalline hydrochloride salt Form V of Compound 1. [Figure 16] 1 shows XRPD data for crystalline hydrochloride salt Form VI of Compound 1. [Figure 17] 1 shows DSC data for crystalline hydrochloride salt Form VI of Compound 1. [Figure 18] 1 shows TGA data for crystalline hydrochloride salt Form VI of Compound 1. [Figure 19] 1 shows XRPD data for crystalline hydrochloride salt Form VII of Compound 1. [Figure 20] 1 shows DSC data for crystalline hydrochloride salt Form VII of Compound 1. [Figure 21] 1 shows TGA data for crystalline hydrochloride salt Form VII of Compound 1. [Figure 22] 1 shows XRPD data for crystalline phosphate salt Form I of Compound 1. [Figure 23] 1 shows DSC data for crystalline phosphate salt Form I of Compound 1. [Figure 24] 1 shows TGA data for crystalline phosphate salt Form I of Compound 1. [Figure 25] 1 shows XRPD data for crystalline mesylate Form I of Compound 1. [Figure 26] 1 shows DSC data for crystalline mesylate Form I of Compound 1. [Figure 27] 1 shows TGA data for crystalline mesylate salt Form I of Compound 1. [Figure 28] 1 shows an overlay of XRPD data for the HCl salt of Compound 1 (Forms I-VII from top to bottom). DETAILED DESCRIPTION OF THE INVENTION

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

[0012] Certain compounds disclosed herein may exist as atropisomers, which are conformational isomers that arise when rotation around a single bond in the molecule is hindered or very slow as a result of steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers, both as pure individual atropisomer preparations, as concentrated preparations of each, or as unspecified mixtures of each. If the rotation barrier around a single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of isomeric species may be possible. For example, compound 1 may be [ka] The M atropisomer of compound 1 is atropisomer M, which may 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 1a.

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

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

[0015] [Table 1]

[0016] [Table 2]

[0017] [Table 3]

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

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

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

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

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

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

[0024] The term "diseases mediated by KRAS G12C inhibition" refers to (i) cancer and (ii) solid tumors. KRAS is the most frequently mutated oncogene in cancer and encodes a critical signaling protein within tumors. See abstract in Canon, J., et al., Nature 575(7781):217-223 (2019). The KRAS(G12C) mutant contains a cysteine ​​residue that has been exploited to design covalent inhibitors with promising preclinical activity. Id. A series of inhibitors were optimized using novel binding interactions to significantly enhance potency and selectivity. Id. This effort led to the discovery of AMG510. Id. Preclinical analyses showed that treatment with AMG510 inhibited KRAS G12C inhibition. G12C Tumor regression and improved antitumor efficacy of chemotherapy and targeted agents. Id. In immunocompetent mice, treatment with AMG510 resulted in a pro-inflammatory tumor microenvironment and led to durable cures, both alone and in combination with immune checkpoint inhibitors. Id. Cured mice were treated with isogenic KRAS G12D The tumor growth was rejected, suggesting adaptive immunity to a shared antigen. Id. Furthermore, in clinical trials, AMG510 demonstrated antitumor activity in the initial dosing cohort, representing a potentially novel treatment for patients lacking effective treatments. Id.

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

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

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

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

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

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

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

[0032] As used herein and unless otherwise indicated, the term "substantially pure," when used to describe a polymorph of a compound, means a solid form of the compound that contains the polymorph and is substantially free of other polymorphs of the compound. A representative substantially pure polymorph contains greater than about 80% by weight of a given 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 a given 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 a given 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 a given polymorphic form of the compound and less than about 3% by weight of other polymorphic forms of the compound.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0055] The compounds of the present disclosure may be administered to a patient at dosage levels ranging from about 0.1 to about 2,000 mg per day (preferably 5 mg to 1,000 mg per day). For a normal adult weighing approximately 70 kg, a dosage ranging from about 0.001 mg per kilogram of body weight to about 20 mg per kilogram of body weight is typically sufficient. The specific dosage and dosage range that may be used will depend on many factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular patient is within the ordinary skill of one in the art.

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

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

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

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

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

[0061] The present disclosure also includes isotopically labeled compounds, which are identical to those enumerated herein except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, 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 Examples include Cl.

[0062] Compounds of the present disclosure that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. 3 H and 14 1C) are useful in drug and / or substrate tissue distribution assays. 3 H isotopes and carbon-14 isotopes (i.e. 14 C isotopes) are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e. 2 Substitution with heavier isotopes such as H can offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred. Isotopically labeled compounds of the present disclosure may generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

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

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

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

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

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

[0068] 4. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride Form I of Compound I of claim 1, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ degrees of about 6.6, 8.9, 10.9, 13.7, 14.2, 15.1, 16.8, 18.0, 19.0, and 21.1.

[0069] 5. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride Form I of Compound I of claim 1, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ degrees of about 8.9, 10.9, and 14.2.

[0070] 6. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form I of Compound 1 of claim 1, wherein the crystalline hydrochloride salt Form I has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 192°C.

[0071] 7. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form I of Compound 1 of claim 1, wherein the crystalline hydrochloride salt Form I has a thermogravimetric analysis thermogram comprising a weight loss of about 0.2% to about 5.3% when heated from about 30°C to about 150°C.

[0072] 8. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form I of claim 1, wherein the crystalline hydrochloride salt Form I is substantially pure.

[0073] 9. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrochloride salt Form I of claim 1 and a pharmaceutically acceptable excipient.

[0074] 10. In another embodiment of the disclosure, the disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the hydrochloride salt Form I of claim 1.

[0075] 11. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrochloride salt Form I according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or a mixture thereof and a pharmaceutically acceptable excipient.

[0076] 12. In another embodiment of the present disclosure, the present disclosure provides the pharmaceutical composition of claim 11, wherein the pharmaceutical composition is in a single dose.

[0077] 13. In another embodiment of the disclosure, the disclosure provides a method for preparing crystalline hydrochloride salt Form I of claim 1, comprising combining 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, hydrochloric acid, and a suitable solvent to form crystalline hydrochloride salt Form I of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0078] 14. In another embodiment of the present disclosure, the present disclosure provides the method of claim 12, wherein the suitable solvent is ethyl acetate.

[0079] 15. In another embodiment of the present disclosure, 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 hydrochloride Form I of claim 1.

[0080] 16. In another embodiment of the present disclosure, the present disclosure provides the method of claim 15, wherein the disease mediated by KRAS G12C inhibition is cancer.

[0081] 17. In another embodiment of the present disclosure, the present disclosure provides the method of claim 16, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0082] 18. In another embodiment of the present disclosure, the present disclosure provides the method of claim 17, wherein the cancer is lung cancer.

[0083] 19. In another embodiment of the present disclosure, the present disclosure is the method of claim 18, wherein the lung cancer is non-small cell lung cancer.

[0084] 20. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form II of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0085] 21. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form II of Compound 1 of claim 20, wherein 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one is the M atropisomer.

[0086] 22. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form II of claim 20, characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 4.

[0087] 23. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride Form II of Compound I of claim 20, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° at about 6.0, 6.3, 8.2, 10.6, 11.2, 12.7, 13.6, 14.3, 16.1, 16.5, 17.2, 21.6, and 21.4.

[0088] 24. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride Form II of Compound I of claim 20, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of about 6.3, 8.2, 10.6, and 16.1.

[0089] 25. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form II of Compound 1 of claim 20, wherein the crystalline hydrochloride salt Form II has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 114°C.

[0090] 26. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form II of Compound 1 of claim 20, wherein the crystalline hydrochloride salt Form II has a thermogravimetric analysis thermogram comprising a weight loss of about 9% when heated from about 20°C to about 90°C.

[0091] 27. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form II of claim 20, wherein the crystalline hydrochloride salt Form II is substantially pure.

[0092] 28. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrochloride salt Form II of claim 20 and a pharmaceutically acceptable excipient.

[0093] 29. In another embodiment of the disclosure, the disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the hydrochloride salt Form II of claim 20.

[0094] 30. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrochloride salt Form II according to any one of claims 20, 21, 22, 23, 24, 25, 26, 27, 28 and 29 or a mixture thereof and a pharmaceutically acceptable excipient.

[0095] 31. In another embodiment of the present disclosure, the present disclosure provides the pharmaceutical composition of claim 30, wherein the pharmaceutical composition is in a single dose.

[0096] 32. In another embodiment of the disclosure, the disclosure provides a method for preparing the crystalline hydrochloride salt Form II of claim 20, comprising combining 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, HCl, and a suitable solvent to form crystalline hydrochloride salt Form II of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0097] 33. In another embodiment of the present disclosure, the present disclosure provides the method of claim 32, wherein the suitable solvent is methanol.

[0098] 34. In another embodiment of the present disclosure, 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 hydrochloride Form II of claim 20.

[0099] 35. In another embodiment of the present disclosure, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of claim 30.

[0100] 36. In another embodiment of the present disclosure, the present disclosure provides the method of claim 35, wherein the disease mediated by KRAS G12C inhibition is cancer.

[0101] 37. In another embodiment of the present disclosure, the present disclosure provides the method of claim 36, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0102] 38. In another embodiment of the present disclosure, the present disclosure provides the method of claim 37, wherein the cancer is lung cancer.

[0103] 39. In another embodiment of the present disclosure, the present disclosure is the method of claim 38, wherein the lung cancer is non-small cell lung cancer.

[0104] 40. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form III of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0105] 41. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form III of Compound 1 of claim 40, wherein 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one is the M atropisomer.

[0106] 42. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form III of claim 40, characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 7.

[0107] 43. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride Form III of Compound 1 of claim 40, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° at about 6.4, 8.4, 11.0, 11.2, 12.7, 13.6, 13.9, 15.0, 15.6, 16.6, 16.7, 16.8, and 21.2.

[0108] 44. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride Form III of Compound I of claim 40, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of about 6.4, 8.4, 11.0, or 15.6.

[0109] 45. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form III of Compound 1 of claim 40, wherein the crystalline hydrochloride salt Form III has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 129°C.

[0110] 46. ​​In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form III of Compound 1 of claim 40, wherein the crystalline hydrochloride salt Form III has a thermogravimetric analysis thermogram comprising a weight loss of about 8% when heated from about 20°C to about 200°C.

[0111] 47. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form III of claim 40, wherein the crystalline hydrochloride salt Form III is substantially pure.

[0112] 48. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrochloride salt Form III of claim 40 and a pharmaceutically acceptable excipient.

[0113] 49. In another embodiment of the disclosure, the disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the crystalline hydrochloride salt Form III of claim 1.

[0114] 50. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrochloride salt Form III of any one of claims 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49 or a mixture thereof and a pharmaceutically acceptable excipient.

[0115] 51. In another embodiment of the present disclosure, the present disclosure provides the pharmaceutical composition of claim 50, wherein the pharmaceutical composition is in a single dose.

[0116] 52. In another embodiment of the disclosure, the disclosure provides a method for preparing the crystalline hydrochloride salt Form III of claim 40, comprising combining 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, HCl, and a suitable solvent to form crystalline hydrochloride salt Form III of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0117] 53. In another embodiment of the present disclosure, the present disclosure provides the method of claim 52, wherein the suitable solvent is dichloromethane, ethanol, ethanol / water, or n-butanol.

[0118] 54. In another embodiment of the present disclosure, the present disclosure provides a method, wherein the solvent is dichloromethane.

[0119] 55. In another embodiment of the present disclosure, the present disclosure provides the method of claim 53, wherein the solvent is ethanol.

[0120] 56. In another embodiment of the present disclosure, the present disclosure provides the method of claim 53, wherein the solvent is ethanol / water.

[0121] 57. In another embodiment of the present disclosure, the present disclosure provides the method of claim 53, wherein the solvent is n-butanol.

[0122] 58. In another embodiment of the present disclosure, 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 hydrochloride Form III of claim 40.

[0123] 59. In another embodiment of the present disclosure, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of claim 50.

[0124] 60. In another embodiment of the present disclosure, the present disclosure provides the method of claim 58, wherein the disease mediated by KRAS G12C inhibition is cancer.

[0125] 61. In another embodiment of the present disclosure, the present disclosure provides the method of claim 60, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0126] 62. In another embodiment of the present disclosure, the present disclosure provides the method of claim 61, wherein the cancer is lung cancer.

[0127] 63. In another embodiment of the present disclosure, the present disclosure is the method of claim 62, wherein the lung cancer is non-small cell lung cancer.

[0128] 64. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form IV of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0129] 65. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form IV of Compound 1 of claim 64, wherein 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one is the M atropisomer.

[0130] 66. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form IV of claim 64, characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 10.

[0131] 67. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride Form IV of Compound 1 of claim 64, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° at about 5.6, 6.5, 8.5, 11.3, 12.8, 13.6, 14.0, 14.1, 15.0, 16.7, 17.8, and 18.4.

[0132] 68. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride Form IV of Compound I of claim 46, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of about 5.6, 6.5, and 8.5.

[0133] 69. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form IV of Compound 1 of claim 64, wherein the crystalline hydrochloride salt Form IV has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 223°C.

[0134] 70. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form IV of Compound 1 of claim 64, wherein the crystalline hydrochloride salt Form IV has a thermogravimetric analysis thermogram comprising a weight loss of about 4.4% when heated from about 25°C to about 200°C.

[0135] 71. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form IV of claim 64, wherein the crystalline hydrochloride salt Form IV is substantially pure.

[0136] 72. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrochloride salt Form IV of claim 64 and a pharmaceutically acceptable excipient.

[0137] 73. In another embodiment of the disclosure, the disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the crystalline hydrochloride salt Form IV of claim 64.

[0138] 74. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrochloride salt Form IV according to any one of claims 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73, or a mixture thereof, and a pharmaceutically acceptable excipient.

[0139] 75. In another embodiment of the present disclosure, the present disclosure provides a method for preparing crystalline hydrochloride salt Form IV of claim 64, comprising combining 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, HCl, and a suitable solvent to form crystalline hydrochloride salt Form IV of Compound 1.

[0140] 76. In another embodiment of the present disclosure, the present disclosure provides the method of claim 75, wherein the suitable solvent is MeCN or ethanol.

[0141] 77. In another embodiment of the disclosure, the disclosure provides a method, wherein the solvent is MeCN.

[0142] 78. In another embodiment of the present disclosure, the present disclosure provides the method of claim 76, wherein the solvent is ethanol.

[0143] 79. In another embodiment of the present disclosure, 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 hydrochloride salt Form IV 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.

[0144] 80. In another embodiment of the present disclosure, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of claim 74.

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

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

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

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

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

[0150] 86. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form V of Compound 1 of claim 85, wherein 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one is the M atropisomer.

[0151] 87. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form V of claim 85, characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 13.

[0152] 88. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form V of Compound 1 of claim 85, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° at about 6.0, 7.9, 9.1, 9.9, 12.0, 12.4, 12.7, 13.2, 13.8, 14.7, 15.4, 15.7, and 18.9.

[0153] 89. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form V of Compound I of claim 85, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of about 7.9, 9.9, 13.8, and 15.7.

[0154] 90. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form V of Compound 1 of claim 85, wherein the crystalline hydrochloride salt Form V has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 266°C.

[0155] 91. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form V of Compound 1 of claim 85, wherein the crystalline hydrochloride salt Form V has a thermogravimetric analysis thermogram comprising a weight loss of about 1.1% when heated from about 25°C to about 200°C.

[0156] 92. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form V of claim 85, wherein the crystalline hydrochloride salt Form V is substantially pure.

[0157] 93. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrochloride salt Form V of claim 85 and a pharmaceutically acceptable excipient.

[0158] 94. In another embodiment of the present disclosure, the present disclosure provides a composition comprising an amorphous form of Compound 1 and crystalline hydrochloride Form V of Compound 1 of claim 85.

[0159] 95. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising crystalline hydrochloride salt Form V according to any one of claims 85, 86, 87, 88, 89, 90, 91, 92, 93 or 94 or a mixture thereof and a pharmaceutically acceptable excipient.

[0160] 96. In another embodiment of the present disclosure, the present disclosure provides the pharmaceutical composition of claim 95, wherein the pharmaceutical composition is in a single dose.

[0161] 97. In another embodiment of the present disclosure, the present disclosure provides a method for preparing crystalline hydrochloride salt Form V of claim 85, comprising combining 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, HCl, and a suitable solvent to form crystalline hydrochloride salt Form V of Compound 1.

[0162] 98. In another embodiment of the present disclosure, the present disclosure provides the method of claim 97, wherein the suitable solvent is acetone, isopropyl alcohol (IPA), ethanol, MeCN, MeOH, or Et2O.

[0163] 99. In another embodiment of the present disclosure, the present disclosure provides the method of claim 98, wherein the suitable solvent is acetone.

[0164] 100. In another embodiment of the present disclosure, the present disclosure provides the method of claim 98, wherein the suitable solvent is isopropyl alcohol.

[0165] 101. In another embodiment of the present disclosure, the present disclosure provides the method of claim 98, wherein the suitable solvent is ethanol.

[0166] 102. In another embodiment of the present disclosure, the present disclosure provides the method of claim 98, wherein the suitable solvent is MeCN.

[0167] 103. In another embodiment of the present disclosure, the present disclosure provides the method of claim 98, wherein the suitable solvent is MeOH.

[0168] 104. In another embodiment of the present disclosure, the present disclosure provides the method of claim 98, wherein the suitable solvent is Et2O.

[0169] 105. In another embodiment of the present disclosure, 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 hydrochloride Form V of claim 85.

[0170] 106. In another embodiment of the present disclosure, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of claim 95.

[0171] 107. In another embodiment of the present disclosure, the present disclosure provides the method of claim 105, wherein the disease mediated by KRAS G12C inhibition is cancer.

[0172] 108. In another embodiment of the present disclosure, the present disclosure provides the method of claim 107, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0173] 109. In another embodiment of the present disclosure, the present disclosure provides the method of claim 107, wherein the cancer is lung cancer.

[0174] 110. In another embodiment of the present disclosure, the present disclosure provides the method of claim 107, wherein the lung cancer is non-small cell lung cancer.

[0175] 111. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form VI of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0176] 112. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form VI of Compound 1 of claim 111, wherein 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one is the M atropisomer.

[0177] 113. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form VI of claim 111, characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 16.

[0178] 114. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form VI of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one of claim 111, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ degrees of about 6.0, 7.7, 10.0, 12.1, 12.5, 13.7, 14.5, 15.2, 15.9, 18.1, 19.0, and 20.9.

[0179] 115. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride Form VI of Compound 1 of claim 111, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of about 7.7, 10.0, and 15.9.

[0180] 116. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form VI of Compound 1 of claim 111, wherein the crystalline hydrochloride salt Form VI has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 273°C.

[0181] 117. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form VI of Compound 1 of claim 111, wherein the crystalline hydrochloride salt Form VI has a thermogravimetric analysis thermogram comprising a weight loss of about 4% when heated from about 25°C to about 250°C.

[0182] 118. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form VI of claim 111, wherein the crystalline hydrochloride salt Form VI is substantially pure.

[0183] 119. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrochloride salt Form VI of claim 111 and a pharmaceutically acceptable excipient.

[0184] 120. In another embodiment of the disclosure, the disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and crystalline hydrochloride Form VI of Compound 1 of claim 111.

[0185] 121. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising crystalline hydrochloride salt Form VI according to any one of claims 111, 112, 113, 114, 115, 116, 117, 118, 119 or 120 or a mixture thereof and a pharmaceutically acceptable excipient.

[0186] 122. In another embodiment of the present disclosure, the present disclosure provides the pharmaceutical composition of claim 121, wherein the pharmaceutical composition is in a single dose.

[0187] 123. In another embodiment of the disclosure, the disclosure provides a method for preparing crystalline hydrochloride salt Form VI of claim 111, comprising combining 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, HCl, and a suitable solvent to form crystalline hydrochloride salt Form VI 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.

[0188] 124. In another embodiment of the present disclosure, the present disclosure provides the method of claim 123, wherein the suitable solvent is p-dioxane.

[0189] 125. In another embodiment of the present disclosure, 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 hydrochloride Form VI of claim 111.

[0190] 126. In another embodiment of the present disclosure, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of claim 121.

[0191] 127. In another embodiment of the present disclosure, the present disclosure provides the method of claim 126, wherein the disease mediated by KRAS G12C inhibition is cancer.

[0192] 128. In another embodiment of the present disclosure, the present disclosure provides the method of claim 127, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0193] 129. In another embodiment of the present disclosure, the present disclosure provides the method of claim 128, wherein the cancer is lung cancer.

[0194] 130. In another embodiment of the present disclosure, the present disclosure provides the method of claim 129, wherein the lung cancer is non-small cell lung cancer.

[0195] 131. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form VII of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0196] 132. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form VII of Compound 1 of claim 131, wherein 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one is the M atropisomer.

[0197] 133. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form VII of claim 131, characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 19.

[0198] 134. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride Form VII of Compound 1 of claim 131, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ degrees at about 6.0, 7.8, 9.0, 9.9, 12.0, 12.6, 13.2, 13.8, 14.6, 15.4, 15.8, 15.9, 18.9, 20.1, 20.6, and 20.9.

[0199] 135. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form VII of Compound 1 of claim 131, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° at about 7.8, 9.9, 13.2, and 14.6.

[0200] 136. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form VII of Compound 1 of claim 131, wherein the crystalline hydrochloride salt Form VII has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 259°C.

[0201] 137. In another embodiment of the disclosure, the disclosure provides crystalline hydrochloride salt Form VII of Compound 1 of claim 131, wherein the crystalline hydrochloride salt Form VII has a thermogravimetric analysis thermogram comprising approximately a small weight loss when heated from about 25°C to about 250°C.

[0202] 138. In another embodiment of the present disclosure, the present disclosure provides crystalline hydrochloride salt Form VII of claim 131, wherein the crystalline hydrochloride salt Form VII is substantially pure.

[0203] 139. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline hydrochloride salt Form VII of claim 131 and a pharmaceutically acceptable excipient.

[0204] 140. In another embodiment of the disclosure, the disclosure provides a composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and crystalline hydrochloride salt Form VII of claim 131.

[0205] 141. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising crystalline hydrochloride salt Form VII according to any one of claims 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140, or a mixture thereof, and a pharmaceutically acceptable excipient.

[0206] 142. In another embodiment of the present disclosure, the present disclosure provides the pharmaceutical composition of claim 141, wherein the pharmaceutical composition is in a single dose.

[0207] 143. In another embodiment of the disclosure, the disclosure provides a method for preparing crystalline hydrochloride salt Form VII of claim 131, comprising combining 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, HCl, and a suitable solvent to form crystalline hydrochloride salt Form VII 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.

[0208] 144. In another embodiment of the present disclosure, the present disclosure provides the method of claim 143, wherein the suitable solvent is ethanol.

[0209] 145. In another embodiment of the present disclosure, 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 hydrochloride salt Form VII of claim 131.

[0210] 146. In another embodiment of the present disclosure, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of claim 141.

[0211] 147. In another embodiment of the present disclosure, the present disclosure provides the method of claim 145, wherein the disease mediated by KRAS G12C inhibition is cancer.

[0212] 148. In another embodiment of the present disclosure, the present disclosure provides the method of claim 147, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0213] 149. In another embodiment of the present disclosure, the present disclosure provides the method of claim 148, wherein the cancer is lung cancer.

[0214] 150. In another embodiment of the present disclosure, the present disclosure provides the method of claim 149, wherein the lung cancer is non-small cell lung cancer.

[0215] 151. In another embodiment of the disclosure, the disclosure provides crystalline phosphate salt Form I of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0216] 152. In another embodiment of the disclosure, the disclosure provides crystalline phosphate salt Form I of Compound 1 of claim 151, wherein 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one is the M atropisomer.

[0217] 153. In another embodiment of the present disclosure, the present disclosure provides crystalline phosphate Form I of claim 151, characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 22.

[0218] 154. In another embodiment of the disclosure, the disclosure provides crystalline phosphate Form I of Compound 1 of claim 151, 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 2θ° at about 6.0, 8.7, 10.9, 11.8, 13.7, 14.5, 15.1, 17.2, 19.1, 19.6, 21.4, 24.0, 25.6, 26.3, 26.7, and 27.4.

[0219] 155. In another embodiment of the disclosure, the disclosure provides crystalline phosphate Form I of Compound 1 of claim 151, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° at about 8.7, 13.7, 14.5, 17.2, and 19.1.

[0220] 156. In another embodiment of the disclosure, the disclosure provides crystalline phosphate salt Form I of Compound 1 of claim 151, wherein the crystalline hydrochloride salt Form I has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 217°C.

[0221] 157. In another embodiment of the disclosure, the disclosure provides crystalline phosphate Form I of Compound 1 of claim 151, wherein the crystalline phosphate Form I has a thermogravimetric analysis thermogram comprising a weight loss of about 2.5% when heated from about 25°C to about 200°C.

[0222] 158. In another embodiment of the present disclosure, the present disclosure provides crystalline phosphate Form I of claim 151, wherein the crystalline phosphate Form I is substantially pure.

[0223] 159. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising the crystalline phosphate salt Form I of claim 151 and a pharmaceutically acceptable excipient.

[0224] 160. In another embodiment of the disclosure, the disclosure provides a composition comprising an amorphous form and crystalline phosphate Form I of Compound 1 of claim 151.

[0225] 161. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising crystalline phosphate salt Form I according to any one of claims 151, 152, 153, 154, 155, 156, 157, 158, 159, or 160, or a mixture thereof, and a pharmaceutically acceptable excipient.

[0226] 162. In another embodiment of the present disclosure, the present disclosure provides the pharmaceutical composition of claim 161, wherein the pharmaceutical composition is in a single dose.

[0227] 163. In another embodiment of the disclosure, the disclosure provides a method for preparing crystalline phosphate salt Form I of claim 151, comprising combining 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, HPO, and a suitable solvent to form crystalline phosphate salt Form I of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0228] 164. In another embodiment of the present disclosure, the present disclosure provides the method of claim 163, wherein the suitable solvent is methyl ethyl ketone (MEK).

[0229] 165. In another embodiment of the present disclosure, 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 phosphate Form I of claim 151.

[0230] 166. In another embodiment of the present disclosure, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of claim 161.

[0231] 167. In another embodiment of the present disclosure, the present disclosure provides the method of claim 165, wherein the disease mediated by KRAS G12C inhibition is cancer.

[0232] 168. In another embodiment of the present disclosure, the present disclosure provides the method of claim 167, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0233] 169. In another embodiment of the present disclosure, the present disclosure provides the method of claim 168, wherein the cancer is lung cancer.

[0234] 170. In another embodiment of the present disclosure, the present disclosure provides the method of claim 169, wherein the lung cancer is non-small cell lung cancer.

[0235] 171. In another embodiment of the present disclosure, the present disclosure provides crystalline mesylate Form I of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0236] 172. In another embodiment of the disclosure, the disclosure provides crystalline mesylate Form I of Compound 1 of claim 171, wherein 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one is the M atropisomer.

[0237] 173. In another embodiment of the present disclosure, the present disclosure provides crystalline mesylate Form I of claim 171, characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 25.

[0238] 174. In another embodiment of the present disclosure, the present disclosure provides crystalline mesylate Form I of Compound I of claim 171, 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 2θ° at about 7.6, 8.7, 9.8, 14.6, 15.2, 15.8, 19.0, 19.6, 20.5, and 23.1.

[0239] 175. In another embodiment of the present disclosure, the present disclosure provides crystalline mesylate Form I of Compound 1 of claim 171, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of about 7.6, 9.8, 15.8, 19.6, and 20.5.

[0240] 176. In another embodiment of the disclosure, the disclosure provides crystalline mesylate Form I of Compound 1 of claim 171, wherein the crystalline mesylate Form I has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 242°C.

[0241] 177. In another embodiment of the present disclosure, the present disclosure provides crystalline mesylate Form I of Compound 1 of claim 171, wherein the crystalline mesylate Form I has a thermogravimetric analysis thermogram comprising a weight loss of about 0.8% when heated from about 25°C to about 200°C.

[0242] 178. In another embodiment of the present disclosure, the present disclosure provides crystalline mesylate Form I of Compound 1 of claim 171, wherein the crystalline mesylate Form I is substantially pure.

[0243] 179. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising crystalline mesylate Form I of Compound 1 of claim 171 and a pharmaceutically acceptable excipient.

[0244] 180. In another embodiment of the disclosure, the disclosure provides a composition comprising an amorphous form and crystalline mesylate Form I of Compound 1 of claim 171.

[0245] 181. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising crystalline mesylate Form I according to any one of claims 171, 172, 173, 174, 175, 176, 177, 178, 179 or 180 or a mixture thereof and a pharmaceutically acceptable excipient.

[0246] 182. In another embodiment of the present disclosure, the present disclosure provides the pharmaceutical composition of claim 181, wherein the pharmaceutical composition is in a single dose.

[0247] 183. In another embodiment of the disclosure, the disclosure provides a method for preparing crystalline mesylate salt Form I of claim 171, comprising combining 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, methanesulfonic acid, and a suitable solvent to form crystalline mesylate salt Form I of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0248] 184. In another embodiment of the present disclosure, the present disclosure provides the method of claim 183, wherein the suitable solvent is ethyl acetate.

[0249] 185. In another embodiment of the present disclosure, 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 mesylate Form I of claim 171.

[0250] 186. In another embodiment of the present disclosure, the present disclosure provides a method for treating a disease mediated by KRAS G12C inhibition, comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of claim 181.

[0251] 187. In another embodiment of the present disclosure, the present disclosure provides the method of claim 185, wherein the disease mediated by KRAS G12C inhibition is cancer.

[0252] 188. In another embodiment of the present disclosure, the present disclosure provides the method of claim 187, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

[0253] 189. In another embodiment of the present disclosure, the present disclosure provides the method of claim 188, wherein the cancer is lung cancer.

[0254] 190. In another embodiment of the present disclosure, the present disclosure provides the method of claim 189, wherein the lung cancer is non-small cell lung cancer.

[0255] 191. In another embodiment of the present disclosure, the present disclosure provides 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]pyrimidine according to any one of claims 1, 20, 40, 64, 85, 111, 131, 151, or 171. The present invention provides a pharmaceutical composition comprising an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one, at least one crystalline form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one, and a pharmaceutically acceptable excipient.

[0256] 192. In another embodiment of the present disclosure, the present disclosure provides the composition of claim 191, comprising greater than about 50% by weight of crystalline 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0257] 193. In another embodiment of the present disclosure, the present disclosure provides a pharmaceutical composition comprising at least one crystalline form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one of any one of claims 1, 20, 40, 64, 85, 111, 131, 151, or 171 and a pharmaceutically acceptable excipient.

[0258] Alternative Embodiments Provided herein as embodiment 1 is a compound that is the crystalline hydrochloride salt form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1), or an atropisomer thereof.

[0259] Provided herein as embodiment 2 is a compound of embodiment 1, wherein the compound is the M atropisomer.

[0260] Provided herein as Embodiment 3 is a compound of Embodiment 1 or Embodiment 2, characterized by a powder X-ray diffraction pattern substantially as shown in FIG.

[0261] Provided herein as Embodiment 4 is the compound of Embodiment 1 or Embodiment 2, characterized by at least three peaks, at least five peaks, at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ degrees of 6.6, 8.9, 10.9, 13.7, 14.2, 15.1, 18.0, 19.0, and 21.1±0.2 degrees 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0262] Provided herein as Embodiment 5 is a compound of Embodiment 1 or Embodiment 2, characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 8.9, 10.9, and 14.2±0.2° 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0263] Provided herein as Embodiment 6 is the compound of Embodiment 1 or Embodiment 2, characterized by a powder X-ray diffraction pattern substantially as shown in FIG.

[0264] Provided herein as Embodiment 7 is a compound of Embodiment 1 or Embodiment 2 characterized by at least three peaks, at least five peaks, at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ degrees of 6.0, 6.3, 8.2, 10.6, 11.2, 12.7, 13.6, 14.3, 16.1, 16.5, 17.2, 21.6, and 21.4±0.2 degrees 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0265] Provided herein as Embodiment 8 is a compound of Embodiment 1 or Embodiment 2, characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 6.3, 8.2, 10.6, and 16.1±0.2 degrees 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0266] Provided herein as Embodiment 9 is the compound of Embodiment 1 or Embodiment 2, characterized by a powder X-ray diffraction pattern substantially as shown in FIG.

[0267] Provided herein as Embodiment 10 is the compound of Embodiment 1 or Embodiment 2, characterized by at least three peaks, at least five peaks, at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 6.4, 8.4, 11.0, 11.2, 12.7, 13.6, 13.9, 15.0, 15.6, 16.6, 16.7, 16.8, and 21.2±0.2° 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0268] Provided herein as Embodiment 11 is a compound of Embodiment 1 or Embodiment 2, characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 6.4, 8.4, 11.0, and 15.6±0.2° 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0269] Provided herein as Embodiment 12 is a compound of Embodiment 1 or Embodiment 2, characterized by a powder X-ray diffraction pattern substantially as shown in FIG.

[0270] Provided herein as Embodiment 13 is a compound of Embodiment 1 or Embodiment 2, characterized by at least three peaks, at least five peaks, at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ degrees of 5.6, 6.5, 8.5, 11.3, 12.8, 13.6, 14.0, 14.1, 15.0, 16.7, 17.8, and 18.4±0.2 degrees 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0271] Provided herein as Embodiment 14 is a compound of Embodiment 1 or Embodiment 2, characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 5.6, 6.5, and 8.5±0.2° 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0272] Provided herein as Embodiment 15 is the compound of Embodiment 1 or Embodiment 2, characterized by a powder X-ray diffraction pattern substantially as shown in FIG.

[0273] Provided herein as Embodiment 16 is a compound of Embodiment 1 or Embodiment 2, characterized by at least three peaks, at least five peaks, at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 6.0, 7.9, 9.1, 9.9, 12.0, 12.4, 12.7, 13.2, 13.8, 14.7, 15.4, 15.7, and 18.9±0.2° 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0274] Provided herein as Embodiment 17 is a compound of Embodiment 1 or Embodiment 2, characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 7.9, 9.9, 13.8, and 15.7±0.2° 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0275] Provided herein as Embodiment 18 is a compound of Embodiment 1 or Embodiment 2, characterized by a powder X-ray diffraction pattern substantially as shown in FIG.

[0276] Provided herein as Embodiment 19 is the compound of Embodiment 1 or Embodiment 2, characterized by at least three peaks, at least five peaks, at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ degrees of 6.0, 7.7, 10.0, 12.1, 12.5, 13.7, 14.5, 15.2, 15.9, 18.1, 19.0, and 20.9±0.2 degrees 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0277] Provided herein as Embodiment 20 is a compound of Embodiment 1 or Embodiment 2, characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 7.7, 10.0, and 15.9±0.2° 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0278] Provided herein as Embodiment 21 is a compound of Embodiment 1 or Embodiment 2, characterized by a powder X-ray diffraction pattern substantially as shown in FIG.

[0279] Provided herein as Embodiment 22 is a compound of Embodiment 1 or Embodiment 2, characterized by at least three peaks, at least five peaks, at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ degrees of 6.0, 7.8, 9.0, 9.9, 12.0, 12.6, 13.2, 13.8, 14.6, 15.4, 15.8, 15.9, 18.9, 20.1, 20.6, and 20.9±0.2 degrees 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0280] Provided herein as Embodiment 23 is a compound of Embodiment 1 or Embodiment 2, characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 7.8, 9.9, 13.2, and 14.6±0.2 degrees 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0281] Provided herein as Embodiment 24 is a compound that is a crystalline phosphate salt form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1), or an atropisomer thereof.

[0282] Provided herein as embodiment 25 is a compound of embodiment 24, which is the M atropisomer.

[0283] Provided herein as Embodiment 26 is a compound of Embodiment 24 or Embodiment 25, characterized by a powder X-ray diffraction pattern substantially as shown in FIG.

[0284] Provided herein as Embodiment 27 is a compound of Embodiment 24 or Embodiment 25, characterized by at least three peaks, at least five peaks, at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ degrees of 6.0, 8.7, 10.9, 11.8, 13.7, 14.5, 15.1, 17.2, 19.1, 19.6, 21.4, 24.0, 25.6, 26.3, 26.7, and 27.4±0.2 degrees 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0285] Provided herein as Embodiment 28 is a compound of Embodiment 24 or Embodiment 25, characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 8.7, 13.7, 14.5, 17.2, and 19.1±0.2 degrees 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0286] Provided herein as embodiment 29 is a compound that is a crystalline mesylate salt form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1), or an atropisomer thereof.

[0287] Provided herein as embodiment 30 is a compound of embodiment 29, which is the M atropisomer.

[0288] Provided herein as Embodiment 31 is the compound of Embodiment 29 or Embodiment 30, characterized by a powder X-ray diffraction pattern substantially as shown in FIG.

[0289] Provided herein as Embodiment 32 is the compound of Embodiment 29 or Embodiment 30, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ degrees of 7.6, 9.8, 14.6, 15.2, 15.8, 19.0, 19.6, 20.5, and 23.2±0.2 degrees 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0290] Provided herein as Embodiment 33 is a compound of Embodiment 29 or Embodiment 30, characterized by an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 7.6, 9.8, 15.8, 19.6, and 20.5±0.2° 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

[0291] Provided herein as embodiment 34 is a pharmaceutical composition comprising a compound of any one of embodiments 1-33 and a pharmaceutically acceptable excipient.

[0292] Provided herein as embodiment 35 is a compound of any one of embodiments 1-33 or a pharmaceutical composition of embodiment 34 for use as a medicament.

[0293] Provided herein as embodiment 36 is a compound of any one of embodiments 1-33 or a pharmaceutical composition of embodiment 34 for use in treating cancer with a KRAS G12C mutation.

[0294] Provided herein as embodiment 37 is a compound or pharmaceutical composition for use according to embodiment 36, wherein the cancer harboring the KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

[0295] Provided herein as embodiment 38 is a compound or pharmaceutical composition for use according to embodiment 36, wherein the cancer harboring the KRAS G12C mutation is non-small cell lung cancer.

[0296] Provided herein as embodiment 39 is a compound or pharmaceutical composition for use according to embodiment 36, wherein the cancer harboring the KRAS G12C mutation is pancreatic cancer.

[0297] Provided herein as embodiment 40 is a compound or pharmaceutical composition for use according to embodiment 36, wherein the cancer harboring the KRAS G12C mutation is colorectal cancer.

[0298] Provided herein as embodiment 41 is the use of a compound of any one of embodiments 1 to 33 or a pharmaceutical composition of embodiment 34 in the preparation of a medicament for treating cancer harboring a KRAS G12C mutation.

[0299] Provided herein as embodiment 42 is the use of embodiment 41, wherein the cancer harboring the KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

[0300] Provided herein as embodiment 43 is the use of embodiment 41, wherein the cancer harboring the KRAS G12C mutation is non-small cell lung cancer.

[0301] Provided herein as embodiment 44 is the use of embodiment 41, wherein the cancer harboring the KRAS G12C mutation is pancreatic cancer.

[0302] Provided herein as embodiment 45 is the use of embodiment 41, wherein the cancer harboring the KRAS G12C mutation is colorectal cancer.

[0303] Provided herein as embodiment 46 is a method of treating a cancer harboring a KRAS G12C mutation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of embodiments 1-33.

[0304] Provided herein as embodiment 47 is the method of embodiment 46, wherein the cancer harboring the KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

[0305] Provided herein as embodiment 48 is the method of embodiment 46, wherein the cancer harboring the KRAS G12C mutation is small cell lung cancer.

[0306] Provided herein as embodiment 49 is the method of embodiment 46, wherein the KRAS G12C mutated cancer is pancreatic cancer.

[0307] Provided herein as embodiment 50 is the method of embodiment 46, wherein the cancer harboring the KRAS G12C mutation is colorectal cancer.

[0308] Crystallization Technology Anti-solvent precipitation Solutions of compounds of the present disclosure were prepared in various solvents, followed by the addition of an anti-solvent, and the solids formed were isolated and analyzed.

[0309] Instead, solutions of compounds of the present disclosure were prepared in various solvents, then an anti-solvent was added and the samples were evaporated. The solids formed were isolated and analyzed.

[0310] Alternatively, solutions of compounds of the present disclosure were prepared in various solvents, then an anti-solvent was added and the samples were cooled to 2° C.-8° C. The solids that formed were isolated and analyzed.

[0311] Sonication Solutions or suspensions of compounds of the present disclosure were prepared in various solvents and sonicated in an ice bath for 90-180 minutes. The solids were isolated and analyzed.

[0312] Slow cooling Saturated solutions of compounds of the present disclosure were prepared in various solvents at ambient or elevated temperatures. Samples prepared at elevated temperatures were allowed to cool to ambient temperature or 2-8° C. The solids formed were isolated and analyzed.

[0313] evaporation Solutions of compounds of the present disclosure were prepared in various solvents. Once complete dissolution was observed, the solvent was evaporated by vacuum at ambient or elevated temperature. The solids formed were isolated and analyzed.

[0314] Slow evaporation Solutions of compounds of the present disclosure were prepared in various solvents. Once complete dissolution was observed, the solutions were allowed to evaporate at ambient temperature in partially shielded vials with or without a nitrogen gas blanket. The solids formed were isolated and analyzed.

[0315] Instead, a solution of the disclosed compound was prepared and then sonicated for approximately 90 minutes. After sonication, the sample was evaporated. The glass-forming experiment was repeated by slurrying the material with 15 times the amount of antisolvent (hexane at 50°C or water at room temperature). Any resulting solids were isolated and analyzed.

[0316] Stress experiment Solutions or suspensions of compounds of the present disclosure were prepared in various solvents followed by 60 minutes of sonication. The samples were then stirred at 30°C for 24-72 hours, followed by 24 hours at 50°C. Samples were analyzed by XRPD at each stage before final isolation and analysis.

[0317] Slurry experiments Solutions of the compounds of the present disclosure were prepared by adding enough solid to a given solvent so that there was excess solid. All forms described below can be obtained from various solvents, including, but not limited to, the specific solvents described in the examples. This mixture was then stirred in a sealed vial at ambient or elevated temperature. After a predetermined time, the solid was isolated by vacuum or centrifugal filtration and analyzed.

[0318] analysis technology X-ray powder diffraction (XRPD) X-ray powder diffraction data were obtained using a Phillips X-ray automated powder diffractometer (X'Pert) equipped with a fixed slit and real-time multistrip (RTMS) detector. The radiation was CuKα (1.54 Å), and the voltage and current were 45 kV and 40 mA, respectively. Data were collected at room temperature from 3.0 to 40.0° 2θ; the step size was 0.0167°, and the count time was 15.240 s. The stage was rotated with a rotation time of 1.0 s.

[0319] Alternatively, X-ray powder diffraction data were obtained using a PANalytical Empyrean automated powder diffractometer (X'Celerator) equipped with a solar slit, a beam stop, a short antiscatter extension, an antiscatter knife edge, and a scanning position sensitive detector. The radiation was CuKα (1.54 Å). Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry.

[0320] Alternatively, X-ray powder diffraction data were obtained using a PANalytical X'Pert PRO X-ray diffraction system equipped with a programmable diverging slit and a real-time multistrip (RTMS) detector. The radiation was CuKα (1.54 Å), and the voltage and current were 45 kV and 40 mA, respectively. Data were collected at room temperature from 3.0 to 30.0° 2θ or from 5 to 45° 2θ with a step size of 0.0334°. The stage was rotated with a rotation time of 2.0 seconds.

[0321] It should be noted that peak shifts of approximately ±0.2° can occur in XRPD patterns and can be caused by factors such as sample preparation and instrument alignment.

[0322] Thermogravimetric analysis (TGA) Thermogravimetric analysis was performed on a TGA Discovery Series, TA Instruments. Samples were analyzed under nitrogen at a heating rate of 10°C / min over the temperature range of 25°C to 325°C.

[0323] Differential scanning calorimetry (DSC) Differential scanning calorimetry data were collected using standard DSC mode (Discovery Series, TA Instruments). A heating rate of 10 °C / min was employed over the temperature range of 25 °C to 350 °C. Analyses were performed under nitrogen, and samples were loaded into aluminum pans. Indium was used as a calibration standard. [Example]

[0324] Example 1: Identification of solid forms of Compound 1 In the field of pharmaceutical research and development, the search for a suitable solid form is an important step. The search for a solid form involves several determinations, primarily the search for amorphous, salt, or co-crystal forms, and the search for polymorphs of each amorphous, salt, or co-crystal. During a lead optimization program, several properties of the compound under investigation are optimized, typically leading to one or several candidates for an exploratory development program. Typically, the evaluation and optimization of physicochemical parameters during lead optimization focuses primarily on solubility. In this case, compound 1 has good solubility characteristics. In addition to solubility optimization, when salts are investigated, additional physicochemical parameters must be considered, such as (1) melting point, (2) thermal behavior, (3) hygroscopicity, (4) crystal habit, (5) polymorphic behavior or physical stability, (6) impurity profile, and (7) chemical stability of the anhydrate or salt form. The melting point of the drug, whether as a free base, acid, or salt form, must be high compared to a certain threshold to enable processing steps such as drying or tableting. The evaluation of thermal behavior, typically performed by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), also includes solid-solid phase transitions. This can be either enantiotropic or monotropic and can relate to the conversion of one polymorph to another, or one pseudopolymorph to another pseudopolymorph (e.g., a lower solvate or hydrate), or to true polymorphism. Hygroscopicity plays an important role in the evaluation of solid forms because this property is highly relevant to many process steps (drying, storage, blending, granulation, to name just a few). Hygroscopicity can be investigated by dynamic vapor sorption (DVS). Essentially, this technique provides information on the amount of water taken up by a compound at a given relative humidity level. The discussion of thermal behavior and hygroscopicity represents a link to another parameter that must be considered in the investigation of anhydrous or salt forms: manageable polymorphic behavior is required for continued drug development in anhydrous or salt forms. Therefore, an anhydrous or salt research procedure typically involves at least a brief evaluation of polymorphism. In this sense, manageable polymorphic behavior does not equate to the presence of only one or two polymorphic forms, but rather provides a situation of unequal polymorphic form conversion.Crystal habit can affect anhydrous or salt studies, and optimization often means transitioning a drug in needle-like crystalline form to, for example, platelets or cubic crystals, which exhibit better flow properties. Salt studies can be a tool for improving a drug's impurity profile, since pharmaceutical salts often exhibit crystal structures that are quite different from those of the corresponding free base or acid.

[0325] Polymorph and Salt Screening For convenience, references to "Compound 1" in the Examples below should be understood to refer to the M atropisomer of Compound 1.

[0326] Polymorph and salt screening to generate various solid forms of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1) was performed as described below for each form.

[0327] A number of hydrochloride salt Forms I, II, III, IV, V, VI, and VII of Compound 1 were investigated. Further characterization of these crystalline forms, including melting point, thermal behavior, hygroscopicity, crystal habit, particle size, polymorphic behavior, stability, and purity, was investigated, including XRPD, TGA, and DSC analyses. Rel.Int% is the percentage of relative intensity based on the highest peak.

[0328] Figure 28 illustrates an overlay of XRPD data for hydrochloride salt Forms I, II, III, IV, V, VI, and VII of Compound 1. Table A (below) shows the XRPD suggested peaks for hydrochloride salt Forms I-VII.

[0329] [Table 4]

[0330] Example 1 Hydrochloride salt Form I of Compound 1 was prepared by charging Compound 1 (25 mg) with 3.71 μL of HCl (1:1 mol / mol) and 1.25 mL of EtOAc; then stirred at room temperature for 24 hours.

[0331] The relative peak areas of the hydrochloride salt Form I from XRPD, TGA and DSC are shown in Figures 1, 2 and 3.

[0332] DSC starts at about 192°C, and TGA includes weight loss of about 0.2% to about 5.3% when heated from about 30°C to about 150°C. NMR: 1 H NMR(500MHz,DMSO-d6)δ ppm 0.97-1.13(m,4H)1.13-1.28(m,4H)1.35(d,J=6.75Hz,3H)1.95-2.01(m,1H)2.07(br s,2H)2.82-3.03(m,1H)3.03-3.21(m,1H)3.27(br d,J=8.56Hz,1H)3.36-3.58(m,1H)3.59-3.71(m,1H)3.94-4.09(m,2H)4.15(br d,J=12.46Hz,2H)4.23-4.44(m,5H)4.94(br s,2H)5.69-5.82(m,2H)6.10-6.27(m,2H)6.64-6.79(m,3H)6.79-6.96(m,2H)7.18-7.36(m,2H)7.62(br s,1H)8.23-8.37(m,1H)8.58(br s,1H)9.07-9.29(m,1H)9.37(br s,1H)10.29(br s,1H)

[0333] [Table 5]

[0334] Example 2: Preparation of Crystalline Hydrochloride Salt Form II of Compound 1 Crystalline hydrochloride salt Form II was prepared by evaporation under ambient conditions from a concentrated solution of Compound 1 and HCl in MeOH. Crystalline hydrochloride salt Form II was also prepared from slow cooling of a concentrated solution of Compound 1 in 20:80 (vol / vol) MeOH / HO to 60-5°C.

[0335] Endotherm begins: Endotherm at approximately 114-203°C.

[0336] TGA: Contains approximately 9% weight loss when heated from about 20°C to about 90°C.

[0337] The crystalline form of hydrochloride salt Form II prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 4), DSC (Figure 5), and TGA (Figure 6). NMR: 1 H NMR(400MHz,DMSO-d6)δ ppm 1.00-1.11(m,2H)1.11-1.29(m,3H)1.35(d,J=6.82Hz,2H)2.00-2.17(m,2H)2.94(br s,1H)3.03-3.21(m,1H)3.27(br d,J=10.87Hz,1H)3.52(br d,J=13.00Hz,2H)3.64(br d,J=11.29Hz,3H)3.90-4.09(m,4H)4.09-4.22(m,2H)4.23-4.45(m,5H)4.94(br s,2H)5.65-5.86(m,2H)6.09-6.26(m,2H)6.65-6.92(m,2H)6.79-6.95(m,1H)7.28(td,J=8.20,7.03Hz,2H)7.65(br s,2H)8.25-8.42(m,2H)8.51-8.70(m,2H)10.31(br s,1H).

[0338] [Table 6]

[0339] [Table 7]

[0340] Example 3: Preparation of Hydrochloride Salt Form III (Trihydrate) of Compound 1 Hydrochloride Form III of Compound 1 was prepared by drying hydrochloride Form I under vacuum at room temperature for 2 days. Hydrochloride Form III (trihydrate) of Compound 1 was also prepared by adding HCl to a concentrated solution of Compound 1 in dichloromethane, precipitating from the HCl salt. Hydrochloride Form III (trihydrate) of Compound 1 was also prepared by evaporation under ambient conditions from a concentrated solution of Compound 1 and HCl in EtOH (1:2 EtOH / HO). Additionally, hydrochloride Form III (trihydrate) of Compound 1 was also prepared by crash precipitation from a solution of Compound 1 and HCl in 1-BuOH containing the anti-solvent heptane.

[0341] DSC: Endothermic at approximately 129-213°C.

[0342] TGA: Contains approximately 8% weight loss when heated from about 20°C to about 200°C.

[0343] The hydrochloride salt Form III of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 7), DSC (Figure 8), and TGA (Figure 9). NMR: 1 H NMR(400MHz,DMSO-d6)δ ppm 0.99-1.10(m,2H)1.11-1.28(m,3H)1.35(d,J=6.82Hz,2H)2.00-2.14(m,3H)2.93(br s,2H)3.03-3.21(m,1H)3.27(br d,J=10.23Hz,1H)3.38-3.52(m,2H)3.53-3.72(m,6H)3.90-4.09(m,2H)4.09-4.22(m,2H)4.23-4.39(m,3H)4.94(br s,3H)5.65-5.87(m,2H)6.06-6.35(m,2H)6.59-6.79(m,3H)6.86(dt,J=16.30,10.71Hz,1H)7.28(td,J=8.31,7.03Hz,2H)7.62(br s,1H)8.23-8.42(m,2H)8.50-8.70(m,2H)10.29(br s,1H)

[0344] [Table 8]

[0345] [Table 9]

[0346] Example 4: Preparation of Hydrochloride Salt Form IV (Sesquihydrate) of Compound 1 Crystalline hydrochloride salt Form IV of Compound 1 was prepared by adding HCl to a concentrated solution of Compound 1 in MeCN, followed by precipitation from the HCl salt. Crystalline hydrochloride salt Form IV of Compound 1 was also prepared by evaporation under ambient conditions from a concentrated solution of Compound 1 and HCl in EtOH.

[0347] The crystalline form of hydrochloride salt Form IV prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 10), DSC (Figure 11), and TGA (Figure 12).

[0348] DSC: Endotherm at approximately 223°C.

[0349] TGA: Contains a weight loss of about 4.4% when heated from about 25°C to about 95°C. 1H NMR(400MHz,DMSO-d6)δ ppm 1.00-1.10(m,2H)1.19(br d,J=6.82Hz,2H)1.35(d,J=6.82Hz,2H)2.07(br d,J=1.70Hz,2H)2.81-3.03(m,1H)3.03-3.22(m,1H)3.22-3.40(m,1H)3.40-3.58(m,1H)3.58-3.68(m,1H)3.90-4.09(m,3H)4.15(br d,J=13.64Hz,1H)4.23-4.39(m,2H)4.94(br s,1H)5.66-5.88(m,1H)6.07-6.34(m,2H)6.63-6.78(m,2H)6.86(dt,J=16.57,10.68Hz,1H)7.28(td,J=8.31,7.03Hz,1H)7.62(br s,1H)8.23-8.50(m,1H)8.59(br d,J=5.11Hz,1H)10.29(br s,1H).

[0350] [Table 10]

[0351] [Table 11]

[0352] Example 5: Preparation of Hydrochloride Salt Form V of Compound 1 Crystalline forms of hydrochloride salt Form V were prepared by slurrying Compound 1 and HCl in acetone or IPA. Crystalline forms of hydrochloride salt Form V were also prepared by evaporation under ambient conditions from concentrated solutions of Compound 1 and HCl in EtOH. Crystalline forms of hydrochloride salt Form V were also prepared by crash precipitation from solutions of Compound 1 and HCl in MeCN or MeOH with the anti-solvent EtO.

[0353] DSC: Endotherm at approximately 266°C.

[0354] TGA: Contains a weight loss of about 1.1% when heated from about 25°C to about 200°C.

[0355] The crystalline form of hydrochloride salt Form V prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 13), DSC (Figure 14) and TGA (Figure 15). NMR: 1 H NMR(400MHz,DMSO-d6)δ ppm 0.98-1.13(m,2H)1.13-1.26(m,2H)1.35(d,J=6.61Hz,2H)2.00-2.16(m,2H)2.82-3.03 (m,1H)3.03-3.22(m,1H)3.22-3.38(m,1H)3.39-3.58(m,1H)3.58-3.68(m,1H)4.04(br d,J=13.85Hz,3H)4.15(br d,J=12.57Hz,2H)4.23-4.39(m,3H)4.94(br s,2H)5.66-5.88(m,2H)6.07-6.31(m,2H)6.65-6.92(m,4H)7.27(td,J=8.26,7.14Hz,2H)7.64(br s,1H)8.22-8.42(m,2H)8.48-8.71(m,2H)10.30(br s,1H).

[0356] [Table 12]

[0357] Example 6: Preparation of crystalline hydrochloride salt Form VI Crystalline hydrochloride salt Form VI was prepared by slurrying Compound 1 and HCl in p-dioxane at various temperatures.

[0358] DSC: Endotherm at approximately 273°C.

[0359] TGA: Contains approximately 4% weight loss when heated from about 25°C to about 250°C.

[0360] The crystalline hydrochloride salt Form VI prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 16), DSC (Figure 17), and TGA (Figure 18). NMR: 1H NMR(400MHz,DMSO-d6)δ ppm 1.01-1.15(m,3H)1.22(d,J=6.82Hz,3H)1.35(d,J=6.82Hz,3H)2.10(s,2H)2.83-3.04(m,1H)3.04-3.21(m,1H)3.27(br d,J=11.51Hz,1H)3.44-3.56(m,1H)3.87-4.09(m,2H)4.15(br d,J=13.21Hz,1H)4.22-4.47(m,3H)4.95(br s,1H)5.64-5.87(m,1H)6.21(br d,J=16.84Hz,1H)6.65-6.92(m,3H)7.27(td,J=8.31,7.03Hz,1H)7.69(br s,1H)8.22-8.48(m,1H)8.49-8.67(m,1H)10.32(br s,1H).

[0361] [Table 13]

[0362] Example 7: Preparation of crystalline hydrochloride salt form FORM VII (isostructural EtOH hemisolvate) of Compound 1 Crystalline hydrochloride salt Form VII of Compound 1 was prepared by crash precipitation from a solution of Compound 1 and HCl in EtOH containing the anti-solvent heptane or MTBE.

[0363] DSC endotherm at approximately 259°C.

[0364] TGA: Contains negligible weight loss when heated from about 25°C to about 250°C.

[0365] The crystalline hydrochloride salt Form VII of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 19), DSC (Figure 20), and TGA (Figure 21). 1H NMR(400MHz,DMSO-d6)δ ppm 1.00-1.13(m,2H)1.21(br d,J=6.82Hz,2H)1.35(d,J=6.61Hz,2H)2.09(br s,2H)2.82-3.04(m,1H)3.04-3.22(m,1H)3.22-3.36(m,1H)3.36-3.58(m,2H)3.58-3.68(m,1H)3.90-4.09(m,2H)4.15(br d,J=13.43Hz,1H)4.22-4.47(m,2H)4.94(br s,1H)5.68-5.81(m,1H)6.21(br d,J=16.84Hz,1H)6.65-6.92(m,3H)7.15-7.40(m,1H)7.67(br s,1H)8.15-8.40(m,1H)8.61(br d,J=5.33Hz,1H)10.31(br s,1H).

[0366] [Table 14]

[0367] Example 8: Preparation of Crystalline Phosphate Salt Form I of Compound 1 Crystalline phosphate salt Form I was prepared by charging Compound 1 and H3PO4 (0.9:1.0 mol / mol) with 4 mL of MEK, followed by slurrying at 55°C for 24 hours.

[0368] DSC: 217°C; TGA: Contains a weight loss of about 2.5% when heated from about 25°C to about 200°C.

[0369] The crystalline form of phosphate salt Form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 22), DSC (Figure 23), and TGA (Figure 24). 1H NMR(500MHz,DMSO-d6)δ ppm 0.88-0.97(m,2H)1.07(d,J=6.75Hz,2H)1.34(d,J=6.75Hz,2H)1.90(s,2H)2.67-2.76(m,1H)3.14(br t,J=10.90Hz,1H)3.36-3.59(m,1H)3.59-3.67(m,1H)3.94-4.08(m,1H)4.08-4.22(m,1H)4.22-4.36(m,2H)4.40(br d,J=13.23Hz,1H)4.90(br s,1H)5.67-5.85(m,1H)6.20(br dd,J=16.48,7.14Hz,1H)6.64-6.77(m,2H)6.78-6.93(m,1H)7.13-7.21(m,1H) 7.27(td,J=8.30,7.01Hz,1H)8.20-8.34(m,1H)8.38(d,J=4.67Hz,1H)10.17(br s,1H)

[0370] [Table 15]

[0371] Example 9: Preparation of Crystalline Mesylate Salt Form I of Compound 1 Crystalline mesylate Form I was prepared by charging 100 mg of Compound 1 with 1 equivalent of methanesulfonic acid in 4 mL of EtOAc, followed by slurrying at room temperature for 24 hours.

[0372] The crystalline form of mesylate salt Form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 25), DSC (Figure 26), and TGA (Figure 27).

[0373] DSC: onset about 242°C; TGA: contains about 0.8% weight loss when heated from about 25°C to about 200°C. 1H NMR(500MHz,DMSO-d6)δ ppm 0.95-1.10(m,4H)1.10-1.25(m,4H)1.35(d,J=6.75Hz,3H)2.07(br s,3H)2.30-2.36(m,3H)2.93(br s,1H)3.15(br t,J=11.03Hz,1H)3.27(br d,J=10.38Hz,1H)3.41-3.58(m,1H)3.58-3.69(m,1H)3.73(br s,1H)3.88-4.09(m,1H)4.10-4.22(m,1H)4.22-4.52(m,3H)4.70-5.39(m,2H)5.39-6.1 3(m,3H)6.13-6.26(m,1H)6.65-6.77(m,3H)6.78-6.93(m,1H)7.23-7.32(m,1H)7.62(br s,1H)8.23-8.37(m,1H)8.60(br s,1H)10.24(br s,1H).

[0374] [Table 16]

[0375] While the invention has been described and illustrated with reference to certain embodiments thereof, those skilled in the art will recognize that various adaptations, changes, modifications, substitutions, deletions, or additions to the procedures and protocols may be made without departing from the spirit and scope of the present disclosure. It is therefore intended that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

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

2. The compound of claim 1 which is an M atropisomer.

3. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern substantially as shown in FIG.

4. 3. The compound of claim 1 or 2, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 6.6, 8.9, 10.9, 13.7, 14.2, 15.1, 18.0, 19.0, and 21.1±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

5. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of 8.9, 10.9, and 14.2±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

6. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 4.

7. 3. The compound of claim 1, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 6.0, 6.3, 8.2, 10.6, 11.2, 12.7, 13.6, 14.3, 16.1, 16.5, 17.2, 21.6, and 21.4±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

8. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of 6.3, 8.2, 10.6, and 16.1±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

9. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 7.

10. 3. The compound of claim 1, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 6.4, 8.4, 11.0, 11.2, 12.7, 13.6, 13.9, 15.0, 15.6, 16.6, 16.7, 16.8, and 21.2±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

11. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of 6.4, 8.4, 11.0, and 15.6±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

12. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 10.

13. 3. The compound of claim 1, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 5.6, 6.5, 8.5, 11.3, 12.8, 13.6, 14.0, 14.1, 15.0, 16.7, 17.8, and 18.4±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

14. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of 5.6, 6.5, and 8.5±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

15. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 13.

16. 3. The compound of claim 1, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 6.0, 7.9, 9.1, 9.9, 12.0, 12.4, 12.7, 13.2, 13.8, 14.7, 15.4, 15.7, and 18.9±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

17. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of 7.9, 9.9, 13.8, and 15.7±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

18. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 16.

19. 3. The compound of claim 1, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 6.0, 7.7, 10.0, 12.1, 12.5, 13.7, 14.5, 15.2, 15.9, 18.1, 19.0, and 20.9±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

20. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of 7.7, 10.0, and 15.9±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

21. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 19.

22. 3. The compound of claim 1, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 6.0, 7.8, 9.0, 9.9, 12.0, 12.6, 13.2, 13.8, 14.6, 15.4, 15.8, 15.9, 18.9, 20.1, 20.6, and 20.9±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

23. 3. The compound of claim 1 or 2, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of 7.8, 9.9, 13.2, and 14.6±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

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

25. 25. The compound of claim 24, which is the M atropisomer.

26. 26. The compound of claim 24 or 25, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 22.

27. 26. The compound of claim 24 or 25, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 6.0, 8.7, 10.9, 11.8, 13.7, 14.5, 15.1, 17.2, 19.1, 19.6, 21.4, 24.0, 25.6, 26.3, 26.7, and 27.4±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

28. 26. The compound of claim 24 or 25, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of 8.7, 13.7, 14.5, 17.2, and 19.1±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

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

30. 30. The compound of claim 29, which is the M atropisomer.

31. 31. The compound of claim 29 or 30, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 25.

32. 31. The compound of claim 29 or 30, characterized by at least three peaks, at least five peaks, or at least seven peaks selected from an X-ray powder diffraction pattern comprising peaks at diffraction angles 2θ° of 7.6, 9.8, 14.6, 15.2, 15.8, 19.0, 19.6, 20.5, and 23.2±0.2° 2θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

33. 31. The compound of claim 29 or 30, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ° of 7.6, 9.8, 15.8, 19.6, and 20.5±0.2° 2θ as measured by X-ray powder diffraction using an X-ray wavelength of 1.54 Å.

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 and a pharmaceutically acceptable excipient.

35. A compound according to any one of claims 1 to 33 or a pharmaceutical composition according to claim 34 for use as a medicament.

36. A compound according to any one of claims 1 to 33 or a pharmaceutical composition according to claim 34 for use in the treatment of cancer harboring a KRAS G12C mutation.

37. 37. The compound or pharmaceutical composition for use according to claim 36, wherein the cancer harboring a KRAS G12C mutation is lung cancer, pancreatic cancer or colorectal cancer.

38. 37. The compound or pharmaceutical composition for use according to claim 36, wherein the cancer harboring a KRAS G12C mutation is non-small cell lung cancer.

39. 37. The compound or pharmaceutical composition for use according to claim 36, wherein the cancer harboring a KRAS G12C mutation is pancreatic cancer.

40. 37. The compound or pharmaceutical composition for use according to claim 36, wherein the cancer harboring a KRAS G12C mutation is colorectal cancer.

41. Use of a compound according to any one of claims 1 to 33 or a pharmaceutical composition according to claim 34 in the preparation of a medicament for treating cancers harboring a KRAS G12C mutation.

42. 42. The use of claim 41, wherein the cancer harboring the KRAS G12C mutation is lung cancer, pancreatic cancer or colorectal cancer.

43. 42. The use of claim 41, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer.

44. 42. The use of claim 41, wherein the cancer having a KRAS G12C mutation is pancreatic cancer.

45. 42. The use of claim 41, wherein the cancer harboring the KRAS G12C mutation is colorectal cancer.

46. 34. A method of treating a cancer harboring a KRAS G12C mutation in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 33.

47. 47. The method of claim 46, wherein the cancer harboring a KRAS G12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

48. 47. The method of claim 46, wherein the cancer harboring a KRAS G12C mutation is small cell lung cancer.

49. 47. The method of claim 46, wherein the cancer having a KRAS G12C mutation is pancreatic cancer.

50. 47. The method of claim 46, wherein the cancer having a KRAS G12C mutation is colorectal cancer.

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