Solid state forms

Abstract

The present invention provides crystalline and amorphous forms of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propane)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenyl)-1-piperyl)pyrido[2,3-d]pyrimidin-2(1H)-one, including several anhydrous, hydrated and solvated forms, as well as their solid forms, pharmaceutical compositions, and methods for treating diseases mediated by KRAS G12C inhibition.

Description

Technical Field

[0001] The present invention provides crystalline forms (including anhydrous forms, hydrate forms, and several crystalline forms of several solvated 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 (hereinafter referred to as "Compound 1"), as well as its physical forms, pharmaceutical compositions, and methods for treating diseases mediated by KRAS G12C inhibition. Prior Art

[0002] Compound 1 is a selective inhibitor of KRAS G12C and can be used to treat cancers, including treating lung cancer (such as non-small cell lung cancer (NSCLC)), pancreatic cancer, and colorectal cancer. U.S. Patent Application Publication No. 2018 / 0334454 A1, published on November 22, 2018, discloses Compound 1.

[0003] Many compounds can exist in different crystal forms or polymorphs, and these different crystal forms or polymorphs exhibit different physical, chemical, and spectroscopic properties. For example, certain polymorphs of a compound may be more soluble in a particular solvent, may flow more easily, or may be more compressible than other polymorphs. See, for example, P. DiMartino et al., J. Thermal Anal. [Journal of Thermal Analysis], 48:447-458 (1997). In the case of drugs, certain solid forms may have higher bioavailability than other solid forms, while other solid forms may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a regulatory perspective because drugs are only approved by agencies such as the U.S. Food and Drug Administration if they meet strict purity and characterization standards. In fact, regulatory approval of one polymorph of a compound (which exhibits certain solubility and physicochemical (including spectroscopic) properties) generally does not mean easy approval of other polymorphs of the same compound. The polymorphic forms of known compounds in the pharmaceutical field affect, for example, the solubility, stability, fluidity, fractability, and compressibility of the compound, as well as the safety and efficacy of drug products containing it. See, for example, Knapman, K. Modern Drug Discoveries, 2000, 53. Therefore, the discovery of new polymorphs of drugs can provide various advantages.

[0004] The present invention provides new polymorphic forms of Compound 1 (including anhydrous forms, hydrate forms, and several crystalline forms of several solvate forms), as well as its physical forms, pharmaceutical compositions, and methods for treating diseases mediated by KRAS G12C inhibition. The new polymorphic forms can be further developed for formulations for treating such chronic diseases and can confer many formulation benefits, manufacturing benefits, and therapeutic benefits. Summary of the Invention

[0005] The present invention provides crystalline and amorphous 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 (including several anhydrous forms, hydrate forms, and solvated forms), as well as its solid forms, pharmaceutical compositions, and methods for treating diseases mediated by KRAS G12C inhibition. Brief Description of the Drawings

[0006] [Figure 1] shows the XRPD data of the amorphous form of Compound 1. The powder X-ray pattern is characteristic of an amorphous material having a broad amorphous halo at 5° - 40° 2-θ and no distinct compound-related diffraction peaks.

[0007] [Figure 2] shows the DSC data of the amorphous form of Compound 1.

[0008] [Figure 3] shows the TGA data of the amorphous form of Compound 1.

[0009] [Figure 4] shows the 19F solid-state NMR (SSNMR) of the amorphous form of Compound 1.

[0010] [Figure 5] shows the XRPD data of the crystalline anhydrous Form I of Compound 1. The powder X-ray diffraction patterns of the anhydrous Forms I - III of Compound 1 are characteristic of crystalline materials having distinct diffraction peaks between 3° 2-θ and 40° 2-θ.

[0011] [Figure 6] shows the DSC data of the crystalline anhydrous Form I of Compound 1.

[0012] [Figure 7] shows the TGA data of the crystalline anhydrous Form I of Compound 1.

[0013] [Figure 8] shows the 13C SSNMR data of the crystalline anhydrous form I of Compound 1.

[0014] [Figure 9] shows the 19F SSNMR data of the crystalline anhydrous form I of Compound 1.

[0015] [Figure 10] shows the XRPD data of the crystalline anhydrous form II of Compound 1.

[0016] [Figure 11] shows the DSC data of the crystalline anhydrous form II of Compound 1.

[0017] [Figure 12] shows the TGA data of the crystalline anhydrous form II of Compound 1.

[0018] [Figure 13] shows the 13C SSNMR data of the crystalline anhydrous form II of Compound 1.

[0019] [Figure 14] shows the 19F SSNMR data of the crystalline anhydrous form II of Compound 1.

[0020] [Figure 15] shows the XRPD data of the crystalline anhydrous form III of Compound 1.

[0021] [Figure 16] shows the DSC data of the crystalline anhydrous form III of Compound 1.

[0022] [Figure 17] shows the TGA data of the crystalline anhydrous form III of Compound 1.

[0023] [Figure 18] shows the XRPD data of the crystalline hydrate form of Compound 1.

[0024] [Figure 19] shows the DSC data of the crystalline hydrate form of Compound 1.

[0025] [Figure 20] shows the TGA data of the crystalline hydrate form of Compound 1.

[0026] [Figure 21] is the superimposed XRPD data of the crystalline anhydrous forms I, II, and III and the crystalline hydrate form of Compound 1.

[0027] [Figure 22] shows the XRPD data of the crystalline THF solvate Form I of Compound 1.

[0028] [Figure 23] shows the DSC data of the crystalline THF solvate Form I of Compound 1.

[0029] [Figure 24] shows the TGA data of the crystalline THF solvate Form I of Compound 1.

[0030] [Figure 25] shows the XRPD data of the crystalline MeCN solvate Form I of Compound 1.

[0031] [Figure 26] shows the DSC data of the crystalline MeCN solvate Form I of Compound 1.

[0032] [Figure 27] shows the TGA data of the crystalline MeCN solvate Form I of Compound 1.

[0033] [Figure 28] shows the XRPD data of the crystalline MEK solvate Form I of Compound 1.

[0034] [Figure 29] shows the DSC data of the crystalline MEK solvate Form I of Compound 1.

[0035] [Figure 30] shows the TGA data of the crystalline MEK solvate Form I of Compound 1.

[0036] [Figure 31] shows the XRPD data of the crystalline EtOAc solvate Form I of Compound 1.

[0037] [Figure 32] shows the XRPD data of the crystalline DMF solvate Form I of Compound 1.

[0038] [Figure 33] shows the DSC data of the crystalline DMF solvate Form I of Compound 1.

[0039] [Figure 34] shows the TGA data of the crystalline DMF solvate Form I of Compound 1.

[0040] [Figure 35] shows the XRPD data of the crystalline DCM solvate Form I of Compound 1.

[0041] [Figure 36] shows the DSC data of the crystalline DCM solvate form I of Compound 1.

[0042] [Figure 37] shows the TGA data of the crystalline DCM solvate form I of Compound 1.

[0043] [Figure 38] shows the XRPD data of the crystalline acetone solvate form I of Compound 1.

[0044] [Figure 39] shows the DSC data of the crystalline acetone solvate form I of Compound 1.

[0045] [Figure 40] shows the TGA data of the crystalline acetone solvate form I of Compound 1.

[0046] [Figure 41] shows the XRPD data of the crystalline acetone solvate form II of Compound 1.

[0047] [Figure 42] shows the DSC data of the crystalline acetone solvate form II of Compound 1.

[0048] [Figure 43] shows the TGA data of the crystalline acetone solvate form II of Compound 1.

[0049] [Figure 44] shows the XRPD data of the crystalline p-xylene solvate form I of Compound 1.

[0050] [Figure 45] shows the DSC data of the crystalline p-xylene solvate form I of Compound 1.

[0051] [Figure 46] shows the TGA data of the crystalline p-xylene solvate form I of Compound 1.

[0052] [Figure 47] shows the XRPD data of the crystalline MeOH solvate form I of Compound 1.

[0053] [Figure 48] shows the DSC data of the crystalline MeOH solvate form I of Compound 1.

[0054] [Figure 49] shows the TGA data of the crystalline MeOH solvate Form I of Compound 1.

[0055] [Figure 50] shows the XRPD data of the crystalline IPA solvate Form I of Compound 1.

[0056] [Figure 51] shows the DSC data of the crystalline IPA solvate Form I of Compound 1.

[0057] [Figure 52] shows the TGA data of the crystalline IPA solvate Form I of Compound 1.

[0058] [Figure 53] shows the XRPD data of the crystalline EtOH solvate Form I of Compound 1.

[0059] [Figure 54] shows the DSC data of the crystalline EtOH solvate Form I of Compound 1.

[0060] [Figure 55] shows the TGA data of the crystalline EtOH solvate Form I of Compound 1.

[0061] [Figure 56] is the overlaid XRPD data of the isomorphous solvates of Compound 1 (from top to bottom - THF, MeCN, MEK, DCM, acetone, MeOH, IPA, EtOH). Embodiment

[0062] [] [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-piperidinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0063] Certain compounds disclosed herein can exist as atropisomers, which are conformational stereoisomers that arise when rotation around a single bond in a molecule is prevented or greatly slowed due to spatial interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers as pure individual atropisomer preparations, enriched preparations of each, or non-specific mixtures of each. If the rotational barrier around the single bond is high enough and the interconversion between conformations is slow enough, separation and isolation of the isomeric species can be tolerated. For example, Compound 1 is an atropisomer [, M , ] and can exhibit restricted rotation.

[0064] Alternatively, Compound 1 has the following atropisomers [, P , ], and can exhibit restricted rotation. . Abbreviations: The following abbreviations may be used herein: AcOH acetic acid aq or aq. aqueous DCM dichloromethane DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide eq or eq. or equiv. equivalent ESI or ES electrospray ionization Et ethyl Et 2O diethyl ether EtOAc ethyl acetate EtOH ethanol g gram h hour HPLC high performance liquid chromatography IPA Isopropyl alcohol iPr Isopropyl iPr 2NEt or DIPEA N - ethyldiisopropylamine (Hünig's base) LC MS, LCMS, LC - MS or LC / MS Liquid chromatography - mass spectrometry LG Leaving group (e.g., halogen, mesylate, triflate) m / z Mass - to - charge ratio Me Methyl MeCN Acetonitrile MeOH Methanol MEK Methyl ethyl ketone Met Metal species for cross - coupling (e.g., MgX, ZnX, SnR 3, SiR 3, B(OR) 2) mg Milligram min Minute mL Milliliter MS Mass spectrometry NaHMDS Sodium bis(trimethylsilyl)amide NBS N - Bromosuccinimide n - BuLi n - Butyllithium NCS N - Chlorosuccinimide NMR Nuclear magnetic resonance Pd 2(dba) 3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl 2·DCM, Pd(dppf)Cl 2 Dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) complexed with dichloromethane Tetrakis(triphenylphosphine)palladium(0) Tetrakis(triphenylphosphine)palladium(0) Phenyl Phenyl Parts per million Parts per million PR or PG or Prot. group Protecting group Round-bottom flask Round-bottom flask Reversed-phase high performance liquid chromatography Reversed-phase high performance liquid chromatography Room temperature Room temperature Saturated Saturated Supercritical fluid chromatography Supercritical fluid chromatography (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate Solid state NMR Solid state NMR Tetra-n-butylammonium fluoride Tetra-n-butylammonium fluoride N,N,N',N'-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate N,N,N',N'-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate tert-Butanol tert-Butanol Triethylamine Triethylamine Trifluoroacetic acid Trifluoroacetic acid Tetrahydrofuran Tetrahydrofuran Ultraviolet Ultraviolet

[0065] Unless otherwise indicated, in the context of describing the present invention (especially in the context of the claims), the use of the terms "a", "the", and similar references shall be construed to cover both the singular and the plural. Unless otherwise indicated herein, statements herein regarding ranges of values are merely intended to be a shorthand method of individually referring to each separate value within the range, and each separate value is incorporated into the specification as if it were individually recited herein. Any and all examples, or use of exemplary language (such as "for example"), provided herein are intended to better illustrate the invention and are not a limitation on the scope of the invention, unless otherwise required. No language in this specification should be construed as indicating any non-required element as essential for the practice of the invention.

[0066] The term "anhydrous form" of "Compound 1" refers to a form of Compound 1 that is substantially or completely free of water, especially free of water of crystallization. Those skilled in the art will understand that the exact number of water molecules can vary slightly at any given time depending on variable temperature, pressure, and other environmental influences. All minor variations in the amount of associated water molecules are contemplated within the scope of the present invention.

[0067] The term "cocrystal" refers to a crystalline material containing two or more compounds at ambient temperature (20°C to 25°C, preferably 20°C), wherein at least two are bound together by weak interactions, at least one of the compounds being a cocrystal former and the other being Compound 1. Weak interactions are defined as interactions that are neither ionic nor covalent and include, for example: hydrogen bonds, van der Waals forces, and π-π interactions. The term "cocrystal" includes solvate forms.

[0068] The term "amorphous form" or "amorphous" refers to a material that lacks long-range order and thus 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.

[0069] The term "amorphous halo" is the approximate bell-shaped maximum in the X-ray powder pattern of an amorphous substance.

[0070] The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient other than the active pharmaceutical ingredient (API), which is typically incorporated for formulating and / or administering to a patient.

[0071] The term "diseases mediated by KRAS G12C inhibition" refers to (i) cancers and (ii) solid tumors. KRAS is the most frequently mutated oncogene in human cancers and encodes a key signaling protein in tumors. The KRAS G12C mutant bears a cysteine that has been exploited to design covalent inhibitors with promising preclinical activity. We have optimized a series of inhibitors with novel binding interactions and significantly enhanced potency and selectivity. These efforts led to the discovery of compound 1, the first KRAS G12C inhibitor in clinical development. Treatment with preclinical compound 1 can cause regression of KRAS p.G12C tumors and significantly enhance the antitumor efficacy of chemotherapy and targeted drugs. In immunocompetent mice, treatment with compound 1 generates a pro-inflammatory tumor microenvironment and, in combination with immune checkpoint inhibition, results in durable cures. Cured mice reject the growth of syngeneic KRAS p.G12D tumors, indicating adaptive immunity to shared antigens. Compound 1 demonstrated preliminary evidence of clinical antitumor activity in the first-in-human cohort and represents a potential transformative therapy for patients lacking effective treatments.

[0072] The term "cancer" refers to the treatment of a KRAS, HRAS, or NRAS G12C mutation identified in a hyperproliferative disorder in a mammal, the treatment including administering to the mammal a therapeutically effective amount of Compound 1 as disclosed herein. In some embodiments, the method involves treating a subject with cancer, the cancer being, for example, acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioblastoma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid rhabdoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS) of the extrahepatic ducts, embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal glioma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, osteofibrous histiocytoma, 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 lymphoma, hypopharyngeal cancer, uveal melanoma, insulinoma, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplasia / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal 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, rare childhood cancer, urachal cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some embodiments, the method relates to treating non-cancerous hyperproliferative disorders, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or the prostate (e.g., benign prostatic hyperplasia (BPH)).

[0073] The term "patient" refers to an animal, such as a dog, cat, cow, horse, sheep, and a human. A particular patient is a mammal. The term patient includes male and female.

[0074] The term "therapeutically effective amount" means an amount of a compound that improves, attenuates, or eliminates one or more symptoms of a particular disease or disorder or prevents or delays the onset of one or more symptoms of a particular disease or disorder.

[0075] The term "patient in need" refers to a patient having a GlyT1-mediated disease or disorder or at risk of having a GlyT1-mediated disease or disorder (e.g., a cognitive disorder, such as schizophrenia).

[0076] The term "pharmaceutically acceptable" means that the substance mentioned (e.g., a compound of the present invention or a formulation containing a compound of the present invention, or a particular excipient) is suitable for administration to a patient.

[0077] As used herein, unless otherwise specified, the terms "polymorph" and "polymorphic form" refer to the solid crystalline forms of a compound or complex. Different polymorphs of the same compound can exhibit different physical, chemical, and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., stability to heat or light), compressibility, and density (important in formulation and product manufacture), and dissolution rate (which can affect bioavailability). Differences in stability can be caused by changes in chemical reactivity (e.g., differential oxidation, such that a dosage form fades faster when composed of one polymorph than when composed of another), or mechanical characteristics (e.g., tablets break during storage when the kinetically favored polymorph converts to the thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are more likely to crack at high humidity). The different physical properties of polymorphs can affect their processing. For example, due to, e.g., the shape or size distribution of the particles of one polymorph, that polymorph may be more likely to form a solvate than another polymorph, or may be more difficult to filter or wash free of impurities than another polymorph.

[0078] Polymorphs of a molecule can be obtained by a variety of methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Well-known techniques can be used to detect, identify, classify, and characterize polymorphs, such techniques including, but not limited to, differential scanning calorimetry (DSC), thermogravimetry (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.

[0079] As used herein, when referring to spectra or data presented in graphical form (e.g., XRPD, IR, Raman, and NMR spectra), and unless otherwise indicated, the term "peak" refers to a peak or other distinctive feature that one of ordinary skill in the art would recognize as not attributable to background noise. The term "prominent peak" refers to a peak in a spectrum or data that is at least the median size (e.g., height) of other peaks, or at least 1.5, 2, or 2.5 times the median size of other peaks in the spectrum or data.

[0080] As used herein, unless otherwise specified, when used to describe a polymorph of a compound, the term "substantially pure" means a solid form of the compound that contains the polymorph and is substantially free of other polymorphs of the compound. Representative substantially pure polymorphs contain greater than about 80 weight % of one polymorphic form of the compound and less than about 20 weight % of other polymorphic forms of the compound, more preferably greater than about 90 weight % of one polymorphic form of the compound and less than about 10 weight % of other polymorphic forms of the compound, even more preferably greater than about 95 weight % of one polymorphic form of the compound and less than about 5 weight % of other polymorphic forms of the compound, and most preferably greater than about 97 weight % of one polymorphic form of the compound and less than about 3 weight % of other polymorphic forms of the compound.

[0081] The terms "treating", "treat", or "treatment" and the like include prophylactic (e.g., preventative) and palliative treatment.

[0082] The term "variable hydrate" means a hydrate of Compound 1 having at least about one, two, three, or four associated water molecules. In some embodiments, the hydrates of the present invention include at least one to ten associated water molecules. Those skilled in the art will understand that the exact number of associated water molecules can vary slightly at any given time with variable temperature, pressure, and other environmental influences. All minor variations in the number of associated water molecules are contemplated within the scope of the present invention.

[0083] In some embodiments, the treatment methods relate to treating lung cancer, and the methods include administering to a subject in need thereof an effective amount of any of the above-described compounds (or a pharmaceutical composition comprising the compound). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In some embodiments, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, adenoma, carcinoid tumor, and undifferentiated carcinoma.

[0084] The compounds of the present invention are administered to a patient in a therapeutically effective amount. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. Additionally, the compounds or compositions can be administered simultaneously (e.g., by a series of tablets) by multiple rapid infusions or delivered substantially uniformly over a period of time using, for example, transdermal delivery. It should also be noted that the dosage of the compound can vary over time.

[0085] Furthermore, the compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or in combination with other pharmaceutically active compounds. The other pharmaceutically active compounds can be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If a patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously or sequentially. For example, in the case of tablets, the active compounds can be found in one tablet or in separate tablets, and the tablets can be administered all at once or sequentially in any order. Additionally, it should be recognized that the compositions can be in different forms. For example, one or more compounds can be delivered by tablets, while another compound is administered by injection or orally as a syrup. All combinations, delivery methods, and orders of administration are encompassed.

[0086] It should also be noted that the solid forms of the present invention 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 together with the remaining Compound 1 present in other forms, such as the amorphous form of Compound I. In another embodiment, about 80% by weight of crystalline anhydrous form I of Compound 1 can be administered together with the remaining Compound 1 present in other forms, such as the amorphous form. All combinations are contemplated. In one embodiment of the present invention, Compound 1 is administered to a patient in a substantially pure form. Those skilled in the art will understand the possible variations.

[0087] The compounds of the present invention can be used to manufacture a medicament for treating diseases mediated by KRAS G12C inhibition, such as cancer, including but not limited to colorectal cancer, pancreatic cancer, and lung cancer, such as non-small cell lung cancer (NSCLC).

[0088] In another aspect, the present invention relates to the use of a salt, crystalline form, amorphous form, or co-crystal of Compound 1 for the preparation of a medicament for treating cancer, such as colorectal cancer, pancreatic cancer, and lung cancer, such as non-small cell lung cancer (NSCLC).

[0089] Since one aspect of the present invention contemplates treating a disease / condition with a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to a combination of individual pharmaceutical compositions in the form of a kit. The kit contains two individual pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit contains containers for holding the individual compositions, such as separate bottles or separate foil pouches. Other examples of containers include syringes, cartridges, and bags. Generally, the kit contains instructions for using the individual components. The kit form is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosage intervals, or when titration of the individual components in the combination is required by the prescribing physician or veterinarian.

[0090] An example of such a kit is the so-called blister packaging. Blister packaging is well-known in the packaging industry and is widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packaging typically consists of a sheet of a relatively rigid material, which sheet is covered with a foil, preferably a transparent plastic material. During the packaging process, depressions are formed in the plastic foil. The depressions have the size and shape of the tablets or capsules to be packaged. Then, the tablets or capsules are placed in the depressions, and the sheet of relatively rigid material is sealed onto the plastic foil on the side of the foil opposite to the direction in which the depressions are formed. As a result, the tablets or capsules are sealed in the depressions between the plastic foil and the sheet. Preferably, the strength of the sheet is such that an opening can be formed in the sheet at the depression by manually applying pressure on the depression, so that the tablets or capsules can be removed from the blister packaging. The tablets or capsules can then be removed through this opening.

[0091] It may be necessary to provide a memory aid on the kit, for example in the form of numbers next to the tablets or capsules, where the numbers correspond to the number of days of a regimen in which the so-designated tablets or capsules are to be ingested. Another example of such a memory aid is a calendar printed on a card, for example, as follows: "First week, Monday, Tuesday,... etc... Second week, Monday, Tuesday..." etc. Other variations of the memory aid will be readily understood. The "daily dose" can be a single tablet or capsule or several pills or capsules taken on a given day. Moreover, the daily dose of the compound of the present invention can consist of one tablet or capsule, while the daily dose of a second compound can consist of several tablets or capsules, and vice versa. The memory aid should reflect this and assist in the correct administration of the active agent.

[0092] In another specific embodiment of the present invention, a dispenser is provided which is designed to dispense a daily dose once at a time in the order of its intended use. Preferably, the dispenser is equipped with a memory aid to further promote compliance with the regimen. An example of such a memory aid is a mechanical counter which indicates the number of daily doses that have been dispensed. Another example of such a memory aid is a battery-powered microchip memory which is coupled to a liquid crystal reading or an audible reminder signal, for example, which reads the date of the last administration of the daily dose and / or reminds of the date of the next administration.

[0093] If desired, the compounds of the present invention and other pharmaceutically active compounds can be administered to a patient orally, rectally, parenterally (e.g., intravenously, intramuscularly or subcutaneously), intrathecally, vaginally, intraperitoneally, intravesically, topically (e.g., as a powder, an ointment or a drop), or as a buccal or nasal spray. All methods used by those skilled in the art to administer pharmaceutically active agents are contemplated.

[0094] Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstituting 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 (such as olive oil) and injectable organic esters (such as ethyl oleate). Appropriate fluidity can be maintained, for example, by using coatings such as lecithin, in the case of dispersions, by maintaining the required particle size and by using surfactants.

[0095] 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 (such as parabens, chlorobutanol, phenol, sorbic acid, etc.). It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical compositions can be achieved by using agents that delay absorption (such as aluminum monostearate and gelatin).

[0096] Solid dosage forms for oral administration include capsules, tablets, powders and granules. In such solid dosage forms, the active compound is admixed with: at least one inert conventional excipient (or carrier) such as sodium citrate or dibasic calcium phosphate, or (a) fillers or extenders such as starch, lactose, sucrose, mannitol and silicic acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants such as glycerol; (d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retardants such as paraffin; (f) absorption promoters such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol, and glyceryl monostearate; (h) adsorbents such as kaolin and bentonite; and (i) lubricants such as 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.

[0097] Similar types of solid compositions can also be used as fillers in hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0098] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other forms well known in the art. They may also contain opacifying agents and may also have compositions such that they release one or more active compounds in a delayed manner in certain parts of the intestine. Examples of embedding compositions that can be used are polymeric substances and waxes. If appropriate, the active compounds can also be in the form of microencapsulation with one or more of the above excipients.

[0099] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, for example in soft-filled gelatin capsules. In addition to the active compound, the liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures of such substances, etc.

[0100] In addition to such inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents. In addition to the active compound, the suspensions may also contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, and tragacanth, or mixtures of such substances, etc.

[0101] Compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at ordinary room temperature but liquid at body temperature and will thus melt in the rectal or vaginal cavity and release the active ingredient.

[0102] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, sprays, and inhalants. The active compound or compounds suitable are mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also considered to be within the scope of the present invention.

[0103] The compounds of the present invention can be administered to a patient at a dosage level in the range of about 0.1 to about 2000 mg / day, preferably in the range of 5 mg to 1000 mg / day. For a normal adult of about 70 kg body weight, a dosage in the range of about 0.001 mg / kg body weight to about 20 mg / kg body weight is usually sufficient. The specific dosages and dosage ranges that can be used depend on many factors, including the needs of the patient, the severity of the disorder or disease being treated, and the pharmacological activity of the compound being administered. Determination of the dosage range and the optimal dosage for a particular patient is within the skill of the art.

[0104] Unless otherwise specifically stated, the compounds of the present invention can exist in unsolvated form as well as in solvated forms with pharmaceutically acceptable solvents (such as water (hydrates), ethanol, etc.). The present invention contemplates and encompasses both solvated and unsolvated forms.

[0105] The compounds of the present invention can also exist in different tautomeric forms. All tautomers of the compounds of the present invention are encompassed. For example, all keto-enol forms of the compounds are included in the present invention.

[0106] Those skilled in the art will recognize that the compound names and structures contained herein can be based on the specific tautomers of the compounds. Although names or structures specific to only one particular tautomer can be used, the present invention is intended to encompass all tautomers unless otherwise stated.

[0107] Those skilled in the art will understand that the anhydrous free form, hydrates, salts, and co-crystals of Compound 1 can exist in one or more ionized states, which generally exist as zwitterions. Although names or structures specific to only one particular ionized state can be used, the present invention is intended to encompass all ionized states unless otherwise stated.

[0108] The present invention also intends to encompass compounds synthesized in vitro using laboratory techniques (such as those well known to synthetic chemists); or compounds synthesized in vivo using in vivo techniques (such as via metabolism, fermentation, digestion, and the like). It is also contemplated that the compounds of the present invention can be synthesized using a combination of in vitro and in vivo techniques.

[0109] The present invention also includes isotopically labeled compounds, which are the same as those herein, but due to the fact that one or more atoms are replaced with atoms 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 the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 16O, 17O, 31P, 32P, 35S, 18F, and 36Cl.

[0110] Compounds of the present invention containing the foregoing isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention (such as those incorporating radioactive isotopes such as 3H and 14C) can be used for drug and / or substrate tissue distribution assays. Tritium, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred because of their ease of preparation and detection. Further, replacement with heavier isotopes (such as deuterium, i.e., 2H) can provide certain therapeutic advantages (such as, extended in vivo half-life or reduced dosage requirements) resulting from higher metabolic stability, and are thus preferred in some cases. Isotopically labeled compounds of the present invention can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents.

[0111] All patents and other publications cited herein are incorporated herein by reference.

[0112] The examples presented below illustrate specific embodiments of the present invention. These examples are representative and are not intended to limit the scope of the claims in any way. [Embodiments] []

[0113] 1. In one embodiment, the present invention provides a crystalline anhydrous Form I of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0114] 2. In another embodiment, the present invention provides the crystalline anhydrous Form I as in Embodiment 1, wherein the anhydrous Form I is the M configurational isomer.

[0115] 3. In another embodiment, the present invention provides the crystalline anhydrous Form I as in Embodiment 1, wherein the crystalline anhydrous Form I is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 5.

[0116] 4. In another embodiment, the present invention provides the crystalline anhydrous Form I as in Embodiment 1, the crystalline anhydrous Form I being characterized by at least three peaks, at least five peaks or at least seven peaks selected from a powder X-ray diffraction pattern, the powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ degrees of about 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9 and 25.0.

[0117] 5. In another embodiment, the present invention provides the crystalline anhydrous Form I as in Embodiment 1, wherein the crystalline anhydrous Form I is characterized by a powder X-ray diffraction pattern, the powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ degrees of about 9.0, 12.0, 12.6 and 19.0.

[0118] 6. In another embodiment, the present invention provides the crystalline anhydrous Form I as in Embodiment 1, the crystalline anhydrous Form I having a differential scanning calorimetry thermogram, the differential scanning calorimetry thermogram comprising an endotherm starting at about 293 °C.

[0119] 7. In another embodiment, the present invention provides the crystalline anhydrous form as in Embodiment 1, the crystalline anhydrous form having a thermogravimetric analysis thermogram, the thermogravimetric analysis thermogram comprising a weight loss of about 0.2% when heated from about 25 °C to about 275 °C.

[0120] 8. In another embodiment, the present invention provides the crystalline anhydrous Form I as in Embodiment 1, wherein the crystalline anhydrous Form I is characterized by 13C solid state NMR as shown in FIG. 8.

[0121] 9. In another embodiment, the present invention provides a crystalline anhydrous form as in Embodiment 1, wherein the crystalline anhydrous Form I is characterized by 13C solid-state NMR, and the 13C solid-state NMR includes peaks at about 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167.7 and 168 ppm.

[0122] 10. In another embodiment, the present invention provides a crystalline anhydrous form as in Embodiment 1, wherein the crystalline anhydrous Form I is characterized by 19F solid-state NMR as shown in Figure 9.

[0123] 11. In another embodiment, the present invention provides a crystalline anhydrous form as in Embodiment 1, wherein the crystalline anhydrous Form I is characterized by 19F solid-state NMR, and the 19F solid-state NMR includes peaks at about 49, 60, 79, 90, 109, 120, 138, 150, 168 and 179 ppm.

[0124] 12. In another embodiment, the present invention provides a crystalline anhydrous form as in Embodiment 1, and the crystalline anhydrous form is substantially pure.

[0125] 13. In another embodiment, the present invention provides a pharmaceutical composition, which comprises the crystalline anhydrous Form I as in Embodiment 1 and a pharmaceutically acceptable excipient.

[0126] 14. In another embodiment, the present invention provides a pharmaceutical composition, which comprises the crystalline anhydrous Form I or a mixture thereof as in any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 and a pharmaceutically acceptable excipient.

[0127] 15. In another embodiment, the present invention provides a pharmaceutical composition as in Embodiment 14, wherein the composition is a single dose.

[0128] 16. In another embodiment, the present invention 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-piperidinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the crystalline anhydrous Form I as in Embodiment 1.

[0129] 17. In another embodiment, the present invention provides a method for preparing the crystalline anhydrous Form I as in Embodiment 1, the method comprising: combining Form II of Compound 1 with a suitable solvent and removing the solvent to form the crystalline anhydrous Form I of Compound 1.

[0130] 18. In another embodiment, the present invention provides the method as in Embodiment 17, wherein the suitable solvent is water.

[0131] 19. In another embodiment, the present invention provides a method for treating a disease mediated by KRAS G12C inhibition, the method comprising administering to a patient in need a pharmaceutically effective amount of a pharmaceutical composition comprising the crystalline anhydrous Form I as in Embodiment 1.

[0132] 20. In another embodiment, the present invention provides a method for treating a disease mediated by KRAS G12C inhibition, the method comprising administering to a patient in need a pharmaceutically effective amount of the pharmaceutical composition as in Embodiment 14.

[0133] 21. In another embodiment, the present invention provides the method as in Embodiment 19, wherein the disease mediated by G12C inhibition is cancer.

[0134] 22. In another embodiment, the present invention provides the method as in Embodiment 21, wherein the cancer is lung cancer, pancreatic cancer or colorectal cancer.

[0135] 23. In another embodiment, the present invention provides the method as in Embodiment 22, wherein the cancer is lung cancer.

[0136] 24. In another embodiment, the present invention provides the method as in Embodiment 23, wherein the lung cancer is non-small cell lung cancer.

[0137] 25. In another embodiment, the present invention provides an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

[0138] 26. In another embodiment, the present invention provides an amorphous form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one as in embodiment 25, which is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 1.

[0139] 27. In another embodiment, the present invention provides an amorphous form as in embodiment 25, wherein the form is the M configurational isomer.

[0140] 28. In another embodiment, the present invention provides an amorphous form as in embodiment 25, the amorphous form having a differential scanning calorimetry thermogram that includes an endotherm starting at about 144 °C.

[0141] 29. In another embodiment, the present invention provides an amorphous form as in embodiment 25, the amorphous form having a thermogravimetric analysis thermogram that includes a weight loss of about 1.5% when heated from about 25 °C to about 275 °C.

[0142] 30. In another embodiment, the present invention provides an amorphous form as in embodiment 25, wherein the form is characterized by 19F solid state NMR as shown in FIG. 4.

[0143] 31. In another embodiment, the present invention provides an amorphous form as in embodiment 25, wherein the form is characterized by 19F solid state NMR, the 19F solid state NMR including peaks at about 86, 96, 116, 127, 146 and 156 ppm.

[0144] 32. In another embodiment, the present invention provides an amorphous form as in embodiment 25, which amorphous form is substantially pure.

[0145] 33. In another embodiment, the present invention provides a pharmaceutical composition comprising the amorphous form as in embodiment 25 and a pharmaceutically acceptable excipient.

[0146] 34. In another embodiment, the present invention provides a pharmaceutical composition comprising the amorphous form or a mixture thereof as in any one of embodiments 25, 26, 27, 28, 29, 30, 31, 32 or 33 and a pharmaceutically acceptable excipient.

[0147] 35. In another embodiment, the present invention provides a pharmaceutical composition as in embodiment 34, wherein the composition is a single dose.

[0148] 36. In another embodiment, the present invention provides a method for preparing the amorphous form as in embodiment 35, the method comprising dissolving compound 1 and a suitable solvent to form the amorphous form of compound 1.

[0149] 37. In another embodiment, the present invention provides a method as in embodiment 36, wherein the suitable solvent is methanol.

[0150] 38. In another embodiment, the present invention provides a method for treating a disease mediated by KRAS G12C inhibition, the method comprising administering to a patient in need a pharmaceutically effective amount of a pharmaceutical composition comprising the amorphous form as in embodiment 25.

[0151] 39. In another embodiment, the present invention provides a method as in embodiment 38, wherein the disease mediated by G12C inhibition is cancer.

[0152] 40. In another embodiment, the present invention provides a method as in embodiment 39, wherein the cancer is lung cancer, pancreatic cancer or colorectal cancer.

[0153] 41. In another embodiment, the present invention provides a method as in embodiment 40, wherein the cancer is lung cancer.

[0154] 42. In another embodiment, the present invention provides a method as in embodiment 41, wherein the lung cancer is non-small cell lung cancer.

[0155] 43. In another embodiment, the present invention provides the crystalline anhydrous form II of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0156] 44. In another embodiment, the present invention provides the crystalline anhydrous form II as in embodiment 43, wherein the crystalline anhydrous form II is the M-configuration isomer.

[0157] 45. In another embodiment, the present invention provides the crystalline anhydrous form II as in embodiment 43, which is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 10.

[0158] 46. In another embodiment, the present invention provides the crystalline anhydrous form II of Compound 1 as in embodiment 43, wherein the form is characterized by at least three peaks, at least five peaks or at least seven peaks selected from the powder X-ray diffraction pattern, the powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ degrees of about 7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2 and 18.4.

[0159] 47. In another embodiment, the present invention provides the crystalline anhydrous form II of Compound II as in embodiment 43, wherein the form is characterized by a powder X-ray diffraction pattern, the powder X-ray diffraction pattern comprising peaks at diffraction angles 2θ degrees of about 7.3, 9.8, 10.1, 11.3, 13.3 and 17.2.

[0160] 48. In another embodiment, the present invention provides the crystalline anhydrous form II as in embodiment 43, the crystalline anhydrous form II having a differential scanning calorimetry thermogram, the differential scanning calorimetry thermogram comprising an endotherm starting at about 193 °C.

[0161] 49. In another embodiment, the present invention provides the crystalline anhydrous Form II as in Embodiment 43, which has a thermogravimetric analysis thermogram that includes a weight loss of about 1% to about 1.8% when heated from about 25 °C to about 250 °C.

[0162] 50. In another embodiment, the present invention provides the crystalline anhydrous Form II as in Embodiment 43, wherein the form is characterized by 13C solid-state NMR as shown in Figure 13.

[0163] 51. In another embodiment, the present invention provides the crystalline anhydrous Form II as in Embodiment 43, wherein the form is characterized by 13C solid-state NMR, and the 13C solid-state NMR includes peaks at about 16, 18, 19, 20, 23, 25, 31, 32, 38, 40, 43, 46, 51, 57, 105, 107, 110, 117, 120, 123, 124, 125, 128, 132, 149, 152, 155, 158, 159, 163 and 166 ppm.

[0164] 52. In another embodiment, the present invention provides the crystalline anhydrous Form II as in Embodiment 43, wherein the form is characterized by 19F solid-state NMR as shown in Figure 14.

[0165] 53. In another embodiment, the present invention provides the crystalline anhydrous Form II as in Embodiment 43, wherein the form is characterized by 19F solid-state NMR, and the 19F solid-state NMR includes peaks at about 59, 62, 89, 92, 119, 122, 148, 151, 178 and 181 ppm.

[0166] 54. In another embodiment, the present invention provides the crystalline anhydrous Form II as in Embodiment 43, and the crystalline anhydrous Form II is substantially pure.

[0167] 55. In another embodiment, the present invention provides a pharmaceutical composition that includes the crystalline anhydrous Form II as in Embodiment 43 and a pharmaceutically acceptable excipient.

[0168] 56. In another embodiment, the present invention provides a pharmaceutical composition comprising the crystalline anhydrous form II or a mixture thereof as described in any one of embodiments 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55, and a pharmaceutically acceptable excipient.

[0169] 57. In another embodiment, the present invention provides the pharmaceutical composition as described in embodiment 56, wherein the composition is a single dose.

[0170] 58. In another embodiment, the present invention provides a composition comprising the 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 anhydrous form II as described in embodiment 43.

[0171] 59. In another embodiment, the present invention provides a method for preparing the crystalline anhydrous form II as described in embodiment 43, the method comprising: combining the amorphous form of compound 1 and a suitable solvent to form the crystalline anhydrous form II of compound 1.

[0172] 60. In another embodiment, the present invention provides the method as described in embodiment 59, wherein the suitable solvent is methanol.

[0173] 61. In another embodiment, the present invention provides a method for treating a disease mediated by KRAS G12C inhibition, the method comprising administering to a patient in need a pharmaceutically effective amount of a pharmaceutical composition comprising the crystalline anhydrous form II as described in embodiment 43.

[0174] 62. In another embodiment, the present invention provides the method as described in embodiment 61, wherein the disease mediated by G12C inhibition is cancer.

[0175] 63. In another embodiment, the present invention provides the method as described in embodiment 62, wherein the cancer is lung cancer, pancreatic cancer or colorectal cancer.

[0176] 64. In another embodiment, the present invention provides a method as in embodiment 63, wherein the cancer is lung cancer.

[0177] 65. In another embodiment, the present invention provides a method as in embodiment 64, wherein the lung cancer is non-small cell lung cancer.

[0178] 66. In another embodiment, the present invention provides the crystalline anhydrous form III of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0179] 67. In another embodiment, the present invention provides the crystalline anhydrous form III as in embodiment 66, wherein the crystalline anhydrous form III is the M-configuration isomer.

[0180] 68. In another embodiment, the present invention provides the crystalline anhydrous form III as in embodiment 66, which is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 15.

[0181] 69. In another embodiment, the present invention provides the crystalline anhydrous form III of Compound 1 as in embodiment 66, wherein the form is characterized by at least three peaks, at least five peaks or at least seven peaks selected from the powder X-ray diffraction pattern, and the powder X-ray diffraction pattern includes peaks at diffraction angles 2θ degrees of about 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0 and 17.6.

[0182] 70. In another embodiment, the present invention provides the crystalline anhydrous form III of Compound II as in embodiment 66, wherein the form is characterized by a powder X-ray diffraction pattern that includes peaks at diffraction angles 2θ degrees of about 6.3, 8.4, 9.5, 15.5 and 16.0.

[0183] 71. In another embodiment, the present invention provides the crystalline anhydrous form III as in embodiment 66, and the crystalline anhydrous form III has a differential scanning calorimetry thermogram that includes an endotherm starting at about 194 °C.

[0184] 72. In another embodiment, the present invention provides the crystalline anhydrous Form III as in Embodiment 66, which has a thermogravimetric analysis thermogram comprising a negligibly small weight loss when heated from about 25 °C to about 250 °C.

[0185] 73. In another embodiment, the present invention provides the crystalline anhydrous Form III as in Embodiment 66, which is substantially pure.

[0186] 74. In another embodiment, the present invention provides a pharmaceutical composition comprising the crystalline anhydrous Form III as in Embodiment 66 and a pharmaceutically acceptable excipient.

[0187] 75. In another embodiment, the present invention provides a pharmaceutical composition comprising the crystalline anhydrous Form III or a mixture thereof as in any one of Embodiments 66, 67, 68, 69, 70, 71, 72, 73 or 74 and a pharmaceutically acceptable excipient.

[0188] 76. In another embodiment, the present invention provides the pharmaceutical composition as in Embodiment 75, wherein the composition is a single dose.

[0189] 77. In another embodiment, the present invention 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 anhydrous Form III as in Embodiment 66.

[0190] 78. In another embodiment, the present invention provides a method for preparing the crystalline anhydrous Form III as in Embodiment 66, the method comprising: combining Compound 1 and a suitable solvent to form the crystalline anhydrous Form III of Compound 1.

[0191] 79. In another embodiment, the present invention provides the method as in Embodiment 78, wherein the suitable solvent is acetone.

[0192] 80. In another embodiment, the present invention provides a method for treating a disease mediated by KRAS G12C inhibition, the method comprising administering to a patient in need a pharmaceutically effective amount of a pharmaceutical composition comprising the crystalline anhydrous form III as in embodiment 66.

[0193] 81. In another embodiment, the present invention provides the method as in embodiment 80, wherein the disease mediated by G12C inhibition is cancer.

[0194] 82. In another embodiment, the present invention provides the method as in embodiment 81, wherein the cancer is lung cancer, pancreatic cancer or colorectal cancer.

[0195] 83. In another embodiment, the present invention provides the method as in embodiment 82, wherein the cancer is lung cancer.

[0196] 84. In another embodiment, the present invention provides the method as in embodiment 82, wherein the lung cancer is non-small cell lung cancer.

[0197] 85. In another embodiment, the present invention provides a crystalline hydrate form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0198] 86. In another embodiment, the present invention provides the crystalline hydrate form as in embodiment 85, wherein the crystalline hydrate form is the M-configuration isomer.

[0199] 87. In another embodiment, the present invention provides the crystalline hydrate form as in embodiment 85, which is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 18.

[0200] 88. In another embodiment, the present invention provides a crystalline hydrate form of Compound 1 as in Embodiment 85, wherein the form is characterized by at least three peaks, at least five peaks, or at least seven peaks selected from the powder X-ray diffraction pattern, and the powder X-ray diffraction pattern includes peaks at diffraction angles 2θ degrees of about 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.2, 16.4, 16.6, 17.3, 17.4, 17.9, and 19.5.

[0201] 89. In another embodiment, the present invention provides a crystalline hydrate form of Compound I as in Embodiment 85, wherein the form is characterized by a powder X-ray diffraction pattern that includes peaks at diffraction angles 2θ degrees of about 6.9, 8.0, 9.6, 12.4, and 13.1.

[0202] 90. In another embodiment, the present invention provides a crystalline hydrate form as in Embodiment 85, and the crystalline hydrate form has a differential scanning calorimetry thermogram that includes an endotherm starting at about 91 °C.

[0203] 91. In another embodiment, the present invention provides a crystalline hydrate form as in Embodiment 85, and the crystalline hydrate form has a thermogravimetric analysis thermogram that includes a weight loss of about 11% when heated from about 39 °C to about 160 °C.

[0204] 92. In another embodiment, the present invention provides a crystalline hydrate form as in Embodiment 85, and the crystalline hydrate form is substantially pure.

[0205] 93. In another embodiment, the present invention provides a pharmaceutical composition that includes a crystalline hydrate form as in Embodiment 85 and a pharmaceutically acceptable excipient.

[0206] 94. In another embodiment, the present invention provides a pharmaceutical composition that includes a crystalline hydrate form or a mixture thereof as in any one of Embodiments 85, 86, 87, 88, 89, 90, 91, 92, or 93 and a pharmaceutically acceptable excipient.

[0207] 95. In another embodiment, the present invention provides a pharmaceutical composition as in embodiment 94, wherein the composition is a single dose.

[0208] 96. In another embodiment, the present invention 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 a crystalline hydrate form as in embodiment 85.

[0209] 97. In another embodiment, the present invention provides a method for preparing the crystalline hydrate form as in embodiment 85, the method comprising: combining compound 1 and a suitable solvent in the presence of water to form the crystalline hydrate form of compound 1.

[0210] 98. In another embodiment, the present invention provides the method as in embodiment 78, wherein the suitable solvent is methanol.

[0211] 99. In another embodiment, the present invention provides a method for treating a disease mediated by KRAS G12C inhibition, the method comprising administering to a patient in need a pharmaceutically effective amount of a pharmaceutical composition comprising the crystalline hydrate form as in embodiment 85.

[0212] 100. In another embodiment, the present invention provides the method as in embodiment 99, wherein the disease mediated by G12C inhibition is cancer.

[0213] 101. In another embodiment, the present invention provides the method as in embodiment 100, wherein the cancer is lung cancer, pancreatic cancer or colorectal cancer.

[0214] 102. In another embodiment, the present invention provides the method as in embodiment 101, wherein the cancer is lung cancer.

[0215] 103. In another embodiment, the present invention provides the method as in embodiment 102, wherein the lung cancer is non-small cell lung cancer.

[0216] 104. In another embodiment, the present invention provides a crystalline solvate form of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).

[0217] 105. In another embodiment, the present invention provides the crystalline solvate form as in embodiment 104, wherein the solvate form is a THF, MeCN, MEK, EtOAc, DCM, acetone, p-xylene, methanol, isopropanol or ethanol solvate form.

[0218] 106. In another embodiment, the present invention provides a pharmaceutical composition, which comprises 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 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 as in any one of embodiments 1, 43, 66, 85 or 104, and a pharmaceutically acceptable excipient.

[0219] 107. In another embodiment, the present invention provides the composition as in embodiment 106, which comprises 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.

[0220] 108. In another embodiment, the present invention provides a pharmaceutical composition, which comprises 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 as in any one of embodiments 1, 43, 66, 85 or 104, and a pharmaceutically acceptable excipient. [Crystallization technology] [] [Anti-solvent precipitation] []

[0221] Prepare a solution of the compound of the present invention in various solvents, and then add an anti-solvent. The formed solid is separated and analyzed.

[0222] Alternatively, prepare a solution of the compound of the present invention in various solvents, then add an anti-solvent and evaporate the sample. The formed solid is separated and analyzed.

[0223] Alternatively, prepare a solution of the compound of the present invention in various solvents, then add an anti-solvent, and cool the sample to 2°C to 8°C. The formed solid is separated and analyzed. [Ultrasonic treatment] []

[0224] Prepare a solution or suspension of the compound of the present invention in various solvents and ultrasonically treat it in an ice bath for 90 - 180 minutes. The solid is separated and analyzed. [Slow cooling] []

[0225] Prepare a saturated solution of the compound of the present invention in various solvents at ambient temperature or high temperature. The sample prepared at high temperature is allowed to cool to ambient temperature or 2°C - 8°C. The formed solid is separated and analyzed. [Evaporation] []

[0226] Prepare a solution of the compound of the present invention in various solvents. Once complete dissolution is observed, evaporate the solvent under vacuum at ambient temperature or heating temperature. The formed solid is separated and analyzed. [Slow evaporation] []

[0227] Prepare a solution of the compound of the present invention in various solvents. Once complete dissolution is observed, allow the solution to evaporate under ambient conditions in a vial partially covered with or without a nitrogen layer. The formed solid is separated and analyzed.

[0228] Alternatively, prepare a solution of the compound of the invention, and then sonicate for about 90 minutes. After sonication, allow the sample to evaporate. The material is slurried by adding 15-fold antisolvent (hexane at 50 °C or water at room temperature), and the experiment producing the glassy material is repeated. Any resulting solid is separated and analyzed. [Pressure experiment] []

[0229] Prepare a solution or suspension of the compound of the invention in various solvents, and then sonicate for 60 minutes. Then stir the sample to 30 °C and hold for 24 - 72 hours, and then stir at 50 °C for 24 hours. Before the final separation and analysis, analyze the sample at each stage with XRPD. [Slurry experiment] []

[0230] Prepare a solution of the compound of the invention by adding sufficient solid to a given solvent such that there is an excess of solid. All forms described below are obtainable from various solvents, including but not limited to the specific solvents described in the examples. Then stir the mixture in a sealed vial at room temperature or elevated temperature. After a given amount of time, separate the solid by vacuum or centrifugal filtration and analyze. [Analytical techniques] [] [X-] [Ray powder diffraction] [(XRPD)]

[0231] X-ray powder diffraction data were obtained using a Phillips X-ray automatic powder diffractometer (X'Pert) equipped with a fixed slit and a real-time multiple strip (RTMS) detector. The radiation was CuKα (1.54 Å), and the voltage and current were 45 kV and 40 mA, respectively. Data were collected from 3.0 to 40.0 degrees 2-θ at room temperature; the step size was 0.0167 degrees; the counting time was 15.240 seconds. The stage rotated with a rotation time of 1.0 second.

[0232] Alternatively, X-ray powder diffraction data was obtained using a PANalytical Empyrean automatic powder diffractometer equipped with a Soler slit, beam stopper, short anti-scatter extension, anti-scatter blade, and a scanning position sensitive detector (X'Celerator). The radiation was CuKα (1.54 Å). The specimen of the sample was sandwiched between 3-μm-thick films and analyzed in transmission geometry.

[0233] Alternatively, X-ray powder diffraction data was obtained using a PANalytical X'Pert PRO X-ray diffraction system equipped with a programmable divergence slit and a real-time multiple strip (RTMS) detector. The radiation was CuKα (1.54 Å), and the voltage and current were 45 kV and 40 mA, respectively. Data was collected from 3.0 to 30.0 or from 5 to 45 degrees 2-θ at room temperature; the step size was 0.0334 degrees. The stage rotated with a rotation time of 2.0 seconds.

[0234]

[0235] It should be noted that a peak shift of approximately + / - 0.2 degrees can occur in the XRPD pattern and may be caused by factors such as sample preparation and instrument alignment. [Thermogravimetric analysis] [(TGA)]

[0236] Thermogravimetric analysis was performed on a TGA Discovery series TA instrument. The sample was analyzed in the temperature range of 25 °C to 325 °C at a heating rate of 10 °C / min under nitrogen. [Differential scanning calorimetry] [(DSC)]

[0237] Differential scanning calorimetry data was collected using the 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. Analysis was carried out under nitrogen, and the sample was loaded into an aluminum pan. Indium was used as the calibration standard. [Examples] [] [Examples] [1] [Identification of the anhydrous or hydrate form with commercial interest] []

[0238] In the field of drug research and development, the study of suitable solid forms represents a key step. The study of solid forms involves several decisions, mainly the study of anhydrous forms, salt forms or co-crystal forms and the study of corresponding polymorphs of anhydrous forms, salt forms or co-crystal forms. During the lead optimization program, several properties of the compound under study are optimized, typically leading to one or several candidates proceeding to the exploratory development program. Usually, during the evaluation and optimization of physicochemical parameters during lead optimization, the main focus is on solubility. In this case, Compound 1 has good solubility characteristics. When studying salts, in addition to the optimization of solubility, other physicochemical parameters must also 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 anhydrous form or salt form. The melting point of a drug (as a free base, acid or salt form) should be higher than a certain threshold to allow processing steps such as drying or tableting. The evaluation of thermal behavior, usually done by thermogravimetry (TGA) and differential scanning calorimetry (DSC), also includes solid-solid phase transitions. These can be enantiotropic or monotropic and can be related to the conversion of one polymorph to another or the conversion of one pseudopolymorph to another - for example, lower solvent化物 or hydrate - or the conversion to a true polymorph. Hygroscopicity plays a key role in the evaluation of solid forms because this property is highly relevant to many process steps such as drying, storage, blending, granulation (to name just a few). Hygroscopicity can be studied by dynamic vapor sorption (DVS). Basically, this technique generates information about the amount of moisture absorbed by the compound at a certain relative humidity level. Discussing thermal behavior and hygroscopicity represents a link to another parameter that must be considered in anhydrous or salt studies: for the anhydrous form or salt form to proceed in drug development, manageable polymorphic behavior is required. Therefore, a short assessment of polymorphism is usually carried out at least in the anhydrous or salt study procedure. In this sense, manageable polymorphic behavior does not mean the existence of only one or two polymorphic forms, but rather a situation where polymorphic forms with non-equivalent conversions are presented. Crystal habit can affect anhydrous or salt studies, and in many cases optimization means moving the drug in the form of needle-shaped crystals towards, for example, lamellar or even cubic crystals that show better flowability. The study of salts can be a tool for improving the impurity profile of a drug because drug salts usually exhibit crystal structures that are very different from those of the corresponding free base or acid.

[0239] Polymorph screening

[0240] As described below, polymorph screening was performed for each form to generate different 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). [Example] [1]

[0241] Compound 1 can be prepared according to the procedures disclosed in U.S. Publication 2018 / 0334454, published November 22, 2018, which is incorporated herein by reference in its entirety.

[0242] The amorphous form I of Compound 1 was prepared by rotary evaporation from MeOH followed by secondary drying under vacuum at room temperature.

[0243] The relative peak areas of the amorphous form in XRPD, TGA, DSC, and 19F SSNMR are shown in Figures 1, 2, 3, and 4.

[0244] Differential scanning calorimetry (DSC) thermogram, including an endotherm starting at about 144 °C.

[0245] Thermogravimetric analysis (TGA) thermogram, including a weight loss of about 1.5% when heated from about 25 °C to about 275 °C.

[0246] 19F SSNMR: 86, 96, 116, 127, 146, and 156 ppm.

[0247] Many anhydrous and hydrate forms of Compound 1 were studied (see Table 1 below). Further characterization of these crystalline forms was studied, such as melting point, thermal behavior, hygroscopicity, crystal habit, particle size, polymorphic behavior, stability, and purity. These forms were characterized by a variety of methods, including XRPD, TGA, and DSC analysis. The relative intensity % is based on the relative intensity percentage of the maximum peak.

[0248] Figure 21 shows the superposition of the anhydrous forms I, II, III, and variable hydrate form I of Compound 1 (forms I - III and variable hydrate form I from top to bottom in sequence). [Table 1]. XRPD Distinguishing Peaks Free base form Peaks unique to each form (KA1°) Form I 9.0 12.0 12.6 19.0 - - Form II 7.3 9.8 10.1 11.3 13.3 17.2 Form III 6.3 8.4 9.5 16.0 - - Hydrate form I 6.9 8.0 9.6 12.4 13.1 - [Example] [2] [: Compound] [1] [of the crystalline anhydrous form] [I] [Preparation of] []

[0249] The crystalline anhydrous form I was prepared by charging 1.5 g of the anhydrous form II of Compound 1 together with 10 mL of water to form a slurry. The slurry was heated to 90 °C for 2 h and then stirred overnight at room temperature. The solid was filtered, dried in vacuo, and identified as anhydrous form I by XRPD. The DSC endothermic onset was approximately 292.6 °C and the TGA contained a weight loss of approximately 0.2% when heated from approximately 25 °C to approximately 275 °C.

[0250] The crystalline form of the anhydrous Form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 5), DSC (Figure 6), TGA (Figure 7), carbon-13 SSNMR (Figure 8), and 19F SSNMR (Figure 9).

[0251] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (d, J = 6.84 Hz, 3 H) 1.07 (d, J = 6.63 Hz, 3 H) 1.35 (d, J = 6.84 Hz, 3 H) 1.90 (s, 3 H) 2.66 - 2.75 (m, 1 H) 3.14 (br t, J = 11.20 Hz, 1 H) 3.59 - 3.75 (m, 2 H) 3.97 - 4.08 (m, 1 H) 4.08 - 4.22 (m, 1 H) 4.22 - 4.43 (m, 2 H) 4.90 (br s, 1 H) 5.74 - 5.79 (m, 1 H) 6.21 (br d, J = 17.00 Hz, 1 H) 6.65 - 6.75 (m, 2 H) 6.79 - 6.92 (m, 1 H) 7.18 (d, J = 4.98 Hz, 1 H) 7.23 - 7.31 (m, 1 H) 8.22 - 8.33 (m, 1 H) 8.38 (d, J = 4.77 Hz, 1 H) 10.19 (s, 1 H) 13C SSNMR: 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167.7, and 168 ppm. 19F SSNMR: 49, 60, 79, 90, 109, 120, 138, 150, 168, and 179 ppm. [Table 2]: XRPD data of the crystalline anhydrous Form I of Compound 1 XRPD peak table: Position [°2θ] Relative intensity [%] Position [°2θ] Relative intensity [%] 8.8 72.02 26.6 12.27 9.0 32.38 26.8 8.19 10.8 89.48 27.3 7.42 12.0 17.57 27.8 3.31 12.6 5.21 28.0 11.20 12.8 7.83 28.5 3.83 13.6 70.38 28.8 8.53 13.9 8.16 29.1 2.01 14.2 64.52 29.4 13.68 14.3 15.98 29.7 9.66 15.0 54.34 30.2 13.60 15.4 34.78 30.9 1.84 15.5 11.84 31.3 1.53 17.4 10.60 31.5 5.71 17.6 11.10 31.7 3.54 18.0 22.28 31.9 1.13 18.6 20.76 32.3 1.55 18.7 41.59 32.6 1.69 19.0 100.00 32.8 2.47 19.2 13.83 33.0 2.11 19.9 34.21 33.6 3.23 20.0 20.81 33.9 5.14 20.2 2.92 34.2 3.90 20.9 8.05 34.7 0.67 21.2 2.59 34.9 1.76 21.7 14.40 35.0 1.62 22.0 9.77 35.4 1.10 22.2 16.27 35.8 2.43 22.5 18.45 36.5 0.59 22.9 21.27 37.0 4.04 23.1 14.15 37.0 2.30 23.7 15.87 37.3 0.80 23.9 10.39 37.7 0.66 25.0 19.32 38.0 1.27 25.3 4.26 38.3 2.60 25.6 1.90 38.4 4.02 25.8 6.05 39.1 0.51 26.1 7.93 39.4 1.88 26.3 4.28 39.8 0.90 [Example] [3] [: Compound] [1] [anhydrous form] [II] [Preparation of] []

[0252] The anhydrous form II of Compound 1 was prepared by charging 0.987 g of amorphous Compound 1 together with 15 mL of MeOH to produce a slurry. The isolated solid was identified as anhydrous form II by XRPD.

[0253] The DSC onset was approximately 192.5 °C and the TGA showed a weight loss of approximately 1% to approximately 1.8% when heated from approximately 25 °C to approximately 250 °C.

[0254] The anhydrous form II of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 10), DSC (Figure 11), TGA (Figure 12), carbon-13 SSNMR (Figure 13), and 19F SSNMR (Figure 14).

[0255] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (d, J = 6.63 Hz, 4 H) 1.07 (d, J = 6.84 Hz, 4 H) 1.35 (d, J = 6.63 Hz, 4 H) 1.90 (s, 3 H) 2.60 - 2.76 (m, 1 H) 3.11 - 3.28 (m, 2 H) 3.68 (br d, J = 13.89 Hz, 2 H) 4.08 (d, J = 5.18 Hz, 2 H) 4.32 (br d, J = 13.68 Hz, 2 H) 4.90 (br s, 1 H) 5.74 - 5.79 (m, 1 H) 6.21 (br d, J = 16.17 Hz, 1 H) 6.65 - 6.76 (m, 2 H) 6.80 - 6.92 (m, 1 H) 7.18 (d, J = 4.98 Hz, 1 H) 7.23 - 7.31 (m, 1 H) 8.29 (br d, J = 9.33 Hz, 1 H) 8.38 (d, J = 4.98 Hz, 1 H) 10.19 (s, 1 H)

[0256] 13C SSNMR: 16, 18, 19, 20, 23, 25, 31, 32, 38, 40, 43, 46, 51, 57, 105, 107, 110, 117, 120, 123, 124, 125, 128, 132, 149, 152, 155, 158, 159, 163 and 166 ppm.

[0257] 19F SSNMR: 59, 62, 89, 92, 119, 122, 148, 151, 178 and 181 ppm. [Table 3]: XRPD data of the crystalline anhydrous form II of Compound 1 Position [°2θ] Relative intensity [%] Position [°2θ] Relative intensity [%] 7.3 55.69 27.1 9.80 9.8 22.74 27.3 12.94 10.1 13.34 27.9 2.58 10.4 26.87 28.3 6.04 11.3 100.00 28.5 7.17 11.5 38.51 28.9 7.06 11.9 17.55 29.4 4.82 13.3 19.19 29.6 6.76 14.3 37.78 30.7 4.35 14.7 63.63 31.2 4.41 14.9 20.80 31.5 1.70 15.8 1.24 31.9 0.83 17.2 47.51 32.6 2.54 18.1 9.48 33.3 1.23 18.4 37.17 34.0 0.53 18.6 6.86 34.6 1.58 19.2 31.06 35.0 1.66 19.8 5.10 35.4 2.35 20.4 11.69 36.2 2.20 20.9 10.16 36.8 1.47 21.1 10.57 37.2 1.73 21.4 3.78 38.0 2.55 21.7 3.26 38.4 4.75 22.1 18.04 38.8 2.68 22.4 12.23 22.6 4.78 23.1 20.56 23.8 9.50 24.3 17.04 24.7 3.75 25.6 6.63 26.2 6.15 [Example] [4] [:Compound] [1] [Crystallized anhydrous form] [III] [Preparation] []

[0258] The crystalline anhydrous Form III of Compound 1 was prepared by vacuum drying the acetone solvate Form I of Compound 1 at about 65 °C - 76 °C. The DSC onset is about 194 °C and the TGA shows a nearly negligible weight loss when heated from about 25 °C to about 250 °C.

[0259] The crystalline form of the anhydrous Form III prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 15), DSC (Figure 16), and TGA (Figure 17).

[0260] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (d, J = 6.82 Hz, 3 H) 1.07 (d, J = 6.61 Hz, 3 H) 1.35 (d, J = 6.61 Hz, 2 H) 1.90 (s, 2 H) 2.64 - 2.80 (m, 1 H) 3.14 (br t, J = 10.66 Hz, 1 H) 3.45 - 3.57 (m, 1 H) 3.58 - 3.76 (m, 1 H) 3.94 - 4.08 (m, 1 H) 4.14 (br d, J = 13.00 Hz, 1 H) 4.21 - 4.47 (m, 2 H) 4.90 (br s, 1 H) 5.76 (dd, J = 10.44, 2.13 Hz, 1 H) 6.21 (br d, J = 16.84 Hz, 1 H) 6.55 - 6.78 (m, 2 H) 6.86 (dt, J = 16.20, 11.29 Hz, 1 H) 7.13 - 7.21 (m, 1 H) 7.21 - 7.33 (m, 1 H) 8.21 - 8.34 (m, 1 H) 8.39 (d, J = 4.90 Hz, 1 H) 10.20 (br s, 1 H) [Table 4]: XRPD data of anhydrous Form III of Compound 1 Position [°2θ] Relative Intensity [%] Position [°2θ] Relative Intensity [%] 6.3 14.11 25.4 10.81 8.4 63.06 25.9 5.35 9.5 84.68 26.7 17.58 10.4 12.93 26.8 5.18 12.8 6.80 27.2 10.38 13.0 6.79 27.5 12.87 13.7 4.59 27.9 4.42 14.9 12.72 28.3 7.66 15.4 45.73 28.6 15.70 15.5 69.05 29.3 3.10 16.0 79.08 29.7 1.70 16.6 8.35 30.2 1.02 17.6 100.00 31.4 2.93 18.2 9.32 32.2 3.52 18.7 37.73 32.5 3.97 19.2 16.82 33.1 2.31 20.0 36.44 33.7 1.35 20.6 13.07 34.6 4.91 20.8 9.52 35.5 3.74 21.7 3.50 35.8 2.54 21.7 16.74 36.7 1.18 22.7 5.52 37.3 1.65 23.0 13.50 38.0 2.18 23.2 4.81 39.0 1.57 24.2 11.39 24.9 3.83 [Example] [5] [:Compound] [1] [Variable hydrate form] [I] [Preparation] []

[0261] The variable hydrate form I of Compound 1 was prepared by dissolving Compound 1 in MeOH at room temperature, filtering it, and then loading aliquots of water as an antisolvent until precipitation occurred. The solid was separated after stirring for 13 days at room temperature.

[0262] The first endothermic onset of DSC was approximately at 91 °C, and TGA included a weight loss of approximately 11% (3.9 mol water) when heated from approximately 39 °C to approximately 160 °C.

[0263] Karl Fischer 10.63% (3.7 mol) water.

[0264] The crystalline form of the variable hydrate form I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 18), DSC (Figure 19), and TGA (Figure 20).

[0265] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (d, J = 6.62 Hz, 3 H) 1.08 (d, J = 6.84 Hz, 3 H) 1.35 (d, J = 6.63 Hz, 3 H) 1.90 (s, 3 H) 2.61 - 2.79 (m, 1 H) 3.15 (br t, J = 11.01 Hz, 1 H) 3.40 - 3.58 (m, 2 H) 3.59 - 3.84 (m, 3 H) 3.86 - 4.09 (m, 1 H) 4.15 (br d, J = 12.39 Hz, 1 H) 4.21 - 4.47 (m, 3 H) 4.90 (br s, 2 H) 5.73 - 5.82 (m, 1 H) 6.15 - 6.21 (m, 1 H) 6.23 (br d, J = 4.92 Hz, 1 H) 6.63 - 6.77 (m, 3 H) 6.78 - 7.03 (m, 2 H) 7.14 - 7.31 (m, 3 H) 8.14 - 8.35 (m, 1 H) 8.39 (d, J = 4.92 Hz, 1 H) [Table 5]: XRPD Data of the Crystalline Variable Hydrate Form I of Compound 1 XRPD Peak Table: Position [°2θ] Relative Intensity [%] Position [°2θ] Relative Intensity [%] Position [°2θ] Relative Intensity [%] 4.0 10.00 16.6 29.36 25.3 31.05 4.4 12.08 17.3 54.43 25.8 35.64 4.8 17.94 17.4 68.45 26.4 35.12 6.9 12.94 17.9 16.60 26.7 28.61 8.0 100.00 18.1 30.16 27.8 31.13 8.8 8.55 18.6 5.51 28.7 25.99 9.6 26.66 19.3 27.13 29.2 25.20 10.8 10.41 19.5 35.91 30.6 14.61 11.3 13.06 19.8 13.20 31.5 19.08 12.4 36.89 20.4 8.31 32.2 8.81 13.0 43.60 20.8 20.25 32.7 8.36 13.1 41.65 21.0 21.40 36.7 2.96 14.2 5.04 21.5 43.72 37.2 4.34 14.6 35.20 22.8 14.71 14.9 38.07 23.0 13.61 15.2 40.25 23.6 14.15 15.7 7.44 24.1 28.65 16.2 40.04 24.6 20.05 16.4 17.22 25.1 28.24 [Example] [6] [: Compound] [1] [Crystal] [THF] [Solvate form] [I] [Preparation] []

[0266] The crystalline THF solvate form I of Compound 1 was prepared by placing the amorphous Compound 1 in a small open vial, then placing the vial in a larger vial containing THF, and capping to subject the solid to vapor stress at room temperature for 4 days.

[0267] The DSC endothermic onset was approximately 165 °C, and the TGA included a weight loss of approximately 13.4% when heated from approximately 130 °C to approximately 160 °C. (1.2 mol THF)

[0268] NMR 1.1 mol THF

[0269] The crystalline form of the above-prepared THF solvate I was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 22), DSC (Figure 23), and TGA (Figure 24).

[0270] 1H NMR (400 MHz, DMSO- d 6) δ ppm 0.94 (d, J=6.62 Hz, 3 H) 1.08 (d, J=6.62 Hz, 3 H) 1.35 (d, J=6.62 Hz, 3 H) 1.68 - 1.84 (m, 4 H) 1.90 (s, 3 H) 2.62 - 2.93 (m, 1 H) 3.15 (br t, J=11.33 Hz, 1 H) 3.49 - 3.75 (m, 10 H) 3.87 - 4.09 (m, 1 H) 4.09 - 4.21 (m, 1 H) 4.22 - 4.47 (m, 4 H) 4.91 (br s, 2 H) 5.71 - 5.83 (m, 2 H) 6.21 (br dd, J=16.88, 4.70 Hz, 1 H) 6.64 - 6.78 (m, 3 H) 6.78 - 6.99 (m, 1 H) 7.14 - 7.22 (m, 1 H) 7.28 (td, J=8.33, 7.05 Hz, 1 H) 8.18 - 8.35 (m, 1 H) 8.39 (d, J=4.92 Hz, 1 H) 10.21 (br s, 1 H) [Table 6]: XRPD data of the crystalline THF solvent compound Form I of Compound 1 XRPD peak table: Position [°2θ] Relative strength [%] Position [°2θ] Relative strength [%] 7.0 54.90 26.9 1.62 9.0 100.00 27.3 2.20 9.8 46.41 27.5 7.64 10.3 5.55 27.6 9.42 10.5 99.74 28.1 1.43 10.9 11.45 28.4 13.20 11.2 5.67 28.7 3.64 11.8 5.10 28.9 5.81 13.7 24.35 29.2 5.97 14.0 9.45 29.5 2.80 14.1 59.90 29.8 3.78 14.7 6.49 30.0 4.57 16.6 52.03 30.2 5.86 17.0 37.49 30.6 3.73 17.3 56.50 31.1 1.64 18.0 3.30 31.6 3.62 18.3 16.05 31.9 1.07 18.7 41.48 32.5 1.55 18.8 54.81 33.1 5.45 19.1 31.94 33.3 1.71 19.4 8.97 33.7 0.66 19.7 25.38 34.1 2.01 20.0 4.56 34.3 2.49 20.4 7.31 35.4 1.19 20.6 11.11 35.7 1.20 20.8 6.26 36.2 4.29 21.1 22.76 36.3 4.30 21.2 34.92 36.5 2.51 22.1 5.75 36.9 1.70 22.3 18.70 37.1 1.30 22.5 33.36 37.5 2.10 22.8 36.37 38.0 1.09 23.0 10.85 38.2 1.05 23.2 2.20 38.9 3.39 23.6 3.63 39.4 1.73 24.0 9.03 24.4 9.86 24.7 3.54 24.8 3.71 25.2 32.94 25.6 20.13 25.8 21.45 26.0 7.67 26.6 8.01 [Example] [7] [Compound] [1] [crystal] [MECN] [solvate form] [I] [Preparation of] []

[0271] The crystalline MeCN solvate form I was prepared by slurrying Compound 1 in MeCN at room temperature for 14 days.

[0272] The DSC endothermic onset was approximately 112 °C and the TGA included a weight loss of approximately 6.9% when heated from approximately 38 °C to approximately 170 °C. (1 mol MeCN).

[0273] NMR 0.9 mol MeCN.

[0274] The crystalline form of the MeCN solvate I prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 25), DSC (Figure 26), and TGA (Figure 27).

[0275] 1H NMR (400 MHz, DMSO- d 6) δ ppm 0.85 - 1.00 (m, 3 H) 1.07 (d, J=6.82 Hz, 3 H) 1.35 (d, J=6.82 Hz, 3 H) 1.90 (s, 3 H) 1.99 - 2.16 (m, 2 H) 2.52 - 2.78 (m, 1 H) 3.14 (br s, 1 H) 3.35 - 3.56 (m, 1 H) 3.57 - 3.84 (m, 2 H) 3.86 - 4.09 (m, 1 H) 4.09 - 4.19 (m, 1 H) 4.19 - 4.47 (m, 2 H) 4.90 (br s, 1 H) 5.66 - 5.80 (m, 1 H) 6.20 (br dd, J=16.73, 4.58 Hz, 1 H) 6.61 - 6.76 (m, 2 H) 6.78 - 6.94 (m, 1 H) 7.11 - 7.21 (m, 1 H) 7.21 - 7.31 (m, 1 H) 8.16 - 8.36 (m, 2 H) 8.39 (d, J=4.69 Hz, 1 H) 10.21 (br s, 1 H). [Table 7]: XRPD data of crystalline MeCN solvate form I of compound 1 XRPD peak table: Position [°2θ] Relative strength [%] Position [°2θ] Relative strength [%] 7.2 72.45 25.3 10.74 9.9 52.43 25.7 13.79 10.0 37.15 26.5 21.93 10.2 8.87 26.8 9.15 10.5 2.74 27.0 26.55 11.2 91.77 27.4 8.80 11.3 15.89 27.5 12.09 11.6 8.89 28.0 11.68 13.2 4.06 28.4 12.41 13.7 3.17 28.6 11.67 14.2 25.71 28.8 8.71 14.5 100.00 29.1 10.79 15.7 1.02 29.7 3.00 16.6 15.62 30.1 3.21 16.9 66.32 30.5 13.17 17.2 2.44 30.8 5.66 17.4 4.61 31.0 9.44 18.0 14.01 31.2 3.79 18.2 53.02 31.9 1.38 18.7 56.63 32.2 5.20 18.9 49.31 32.3 7.29 19.8 3.70 33.5 2.46 20.1 21.31 34.0 1.40 20.4 16.05 34.4 2.91 20.8 4.63 34.9 3.17 21.0 5.42 35.2 3.57 21.7 73.71 35.4 2.40 22.3 5.02 36.2 0.94 22.5 5.69 36.6 2.12 22.7 34.41 37.0 4.21 23.0 6.77 37.7 3.05 23.4 15.57 37.9 5.41 23.6 15.11 38.0 3.75 24.1 37.36 38.5 2.87 25.0 8.92 38.9 3.18 [Example] [8] [: Compound] [1] [Crystal] [MEK] [Solvate Form] [I] [Preparation] []

[0276] The crystalline MEK solvate form I was prepared by dissolving Compound 1 in MEK at room temperature, filtering it, and then charging an equal portion of heptane as an antisolvent until precipitation occurred. The solid was separated after stirring at room temperature for 13 days. It was also prepared from the amorphous Compound 1 in a slurry in MEK at room temperature.

[0277] The DSC endothermic onset was approximately 106 °C, and the TGA included a weight loss of approximately 10.7% when heated from approximately 39 °C to approximately 197 °C. (0.9 mol MEK)

[0278] NMR 0.8 mol MEK.

[0279] The crystalline form of the above-prepared MEK solvate I was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 28), DSC (Figure 29), and TGA (Figure 30).

[0280] 1H NMR (400 MHz, DMSO- d 6) δ ppm 0.92 (q, J=7.05 Hz, 5 H) 1.08 (d, J=6.62 Hz, 3 H) 1.35 (d, J=6.62 Hz, 3 H) 1.90 (s, 3 H) 2.04 - 2.10 (m, 2 H) 2.36 - 2.49 (m, 2 H) 2.60 - 2.93 (m, 1 H) 3.15 (br s, 1 H) 3.36 - 3.57 (m, 2 H) 3.57 - 3.84 (m, 4 H) 3.86 - 4.09 (m, 2 H) 4.15 (br d, J=12.82 Hz, 1H) 4.22 - 4.46 (m, 4 H) 4.91 (br s, 2 H) 5.72 - 5.83 (m, 2 H) 6.00 - 6.21 (m, 1 H) 6.23 (br d, J=4.49 Hz, 1 H) 6.64 - 6.78 (m, 3 H) 6.78 - 7.00 (m, 2 H) 7.17 - 7.31 (m, 3 H) 8.16 - 8.35 (m, 1 H) 8.39 (d, J=4.92 Hz, 1 H) 10.22 (br s, 1 H). [Table 8]: XRPD data of crystalline MEK solvent compound Form I of Compound 1 XRPD peak table: Position [°2θ] Relative strength [%] Position [°2θ] Relative strength [%] 7.0 47.52 25.8 25.93 8.8 70.25 26.3 8.43 9.8 56.17 26.8 6.92 10.4 100.00 27.0 2.12 10.9 22.80 27.2 3.88 11.2 11.60 27.4 8.69 11.8 9.64 27.6 7.15 13.6 31.04 27.9 1.14 14.1 78.89 28.2 6.71 14.7 19.18 28.3 13.70 16.6 79.53 28.6 8.63 16.8 30.39 29.0 18.29 17.0 26.79 29.6 7.09 17.2 47.48 30.1 14.00 17.5 3.12 30.3 2.13 18.1 5.01 30.7 3.85 18.4 23.39 31.3 3.80 18.7 35.48 31.71 4.92 18.9 65.12 32.0 0.54 19.2 48.49 32.5 0.62 19.4 10.83 32.8 4.00 19.7 46.72 33.2 2.69 20.4 6.72 33.5 5.80 20.7 15.78 34.1 5.30 20.9 6.30 34.7 1.61 21.2 80.14 35.0 0.76 22.1 8.83 35.5 2.20 22.4 32.98 36.0 5.55 22.6 48.82 36.2 7.66 22.7 34.64 36.6 1.43 22.9 13.33 37.0 0.51 23.7 9.34 37.5 3.76 24.1 18.80 38.1 1.54 24.5 27.07 38.4 1.60 24.8 11.35 38.7 2.93 25.0 28.12 39.3 0.73 25.3 17.14 39.6 4.20 25.7 36.16 [Example] [9] [:Compound] [1] [Crystal of] [ETOAC] [Solvent form] [I] [Preparation] []

[0281] The crystalline EtOAc solvent compound Form I was prepared by slurry of compound 1 with ethyl acetate (EtOAc) at room temperature for 24 h.

[0282] The crystalline form of the MEK solvate I prepared above was characterized by proton NMR and X-ray powder diffraction (XRPD) data ( FIG. 31 ). [Table 9]: XRPD Data of the Crystalline EtOAc Solvate Form I of Compound 1: XRPD Peak Table: Position [°2θ] Relative Intensity [%] Position [°2θ] Relative Intensity [%] Position [°2θ] Relative Intensity [%] 7.1 8.9 23.1 14.8 34.3 4.0 9.0 55.8 23.8 9.9 34.8 1.2 9.8 36.0 24.1 8.2 35.4 2.4 10.5 100.0 24.5 19.9 35.7 1.8 11.0 19.6 24.8 11.5 35.9 3.9 11.3 5.6 25.1 35.4 36.3 10.9 11.9 1.9 25.4 11.8 36.8 2.9 12.5 2.2 25.8 35.3 37.0 2.7 13.7 21.3 26.0 24.8 37.3 1.9 14.2 48.6 26.6 17.1 37.9 2.7 14.7 11.8 27.0 2.0 38.1 3.0 16.7 51.6 27.5 9.1 39.1 4.3 17.0 39.5 27.7 4.7 39.7 3.3 17.4 40.6 28.0 4.2 40.1 3.1 18.1 4.6 28.6 13.0 40.4 3.6 18.3 10.5 29.0 10.6 41.2 2.5 18.9 38.1 29.2 10.9 41.6 3.6 19.2 23.2 29.7 5.0 42.0 1.3 19.5 11.8 30.2 4.8 42.5 2.2 19.7 30.5 30.9 5.5 43.2 4.1 20.0 2.9 31.3 3.2 43.5 3.4 20.4 3.8 31.7 4.5 43.8 2.2 20.7 12.9 32.1 3.4 44.1 2.6 21.3 59.1 32.6 1.8 44.4 2.3 22.1 3.7 33.1 6.8 22.6 30.7 33.6 5.2 22.8 34.2 34.0 2.9 [Example]

[10] [: Compound] [1] [of] [DMF] [solvate form] [I] [Preparation of] []

[0283] The crystalline DMF solvate form I of Compound 1 was prepared by slurrying Compound 1 in DMF / water at room temperature for 24 h.

[0284] The crystalline DMF solvate form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 32), DSC (Figure 33), and TGA (Figure 34).

[0285] The DSC endothermic onset was approximately 74 °C, and the TGA included a weight loss of approximately 17% when heated from approximately 36 °C to approximately 195 °C.

[0286] NMR 1 - 2 mol DMF.

[0287] 1H NMR (500 MHz, DMSO- d 6) δ ppm 0.94 (d, J=6.49 Hz, 4 H) 1.08 (d, J=6.75 Hz, 4 H) 1.35 (d, J=6.75 Hz, 4 H) 1.91 (s, 4 H) 2.30 (s, 1 H) 2.55 (t, J=5.58 Hz, 1 H) 2.73 (s, 6 H) 2.89 (s, 5 H) 3.00 - 3.21 (m, 1 H) 3.27 (br d, J=13.49 Hz, 2 H) 3.34 (br s, 5 H) 3.60 - 3.74 (m, 2 H) 3.96 - 4.16 (m, 1 H) 4.32 (br d, J=13.75 Hz, 2 H) 4.39 (br s, 1 H) 4.90 (br s, 1 H) 5.67 - 5.86 (m, 1 H) 6.20 (br dd, J=16.61, 7.27 Hz, 1 H) 6.64 - 6.77 (m, 2 H) 6.79 - 6.92 (m, 1 H) 7.17 - 7.32 (m, 2 H) 7.95 (s, 1 H) 8.28 (br dd, J=16.22, 9.21 Hz, 1 H) 8.40 (d, J=4.93 Hz, 1 H) 10.19 (d, J=1.30 Hz, 1H). [Table 10]: XRPD data of crystalline DMF solvent compound Form I of Compound 1 XRPD peak table: Position [°2θ] Relative strength [%] Position [°2θ] Relative strength [%] 7.8 100.0 24.3 12.6 8.1 60.0 24.9 11.5 9.0 19.1 25.4 12.7 12.4 17.5 26.8 17.8 13.3 7.5 27.3 11.1 14.4 25.9 28.3 30.4 15.0 7.4 28.6 38.6 16.1 11.4 29.4 12.3 16.8 26.5 30.4 6.0 17.3 17.5 31.6 6.2 18.9 12.3 34.0 3.3 19.9 58.6 35.7 1.9 20.8 38.6 37.9 2.6 21.8 11.0 42.2 2.2 23.3 17.0 [Example]

[11] [:Compound] [1] [Crystal of] [DCM] [Solvate Form] [I] [Preparation of] []

[0288] The crystalline DCM solvate form I of Compound 1 was prepared by dissolving Compound 1 in DCM at room temperature, filtering it finely, and then charging an equal portion of heptane as an anti-solvent until precipitation occurred. The solid was separated after stirring for 1 h at room temperature.

[0289] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.84 - 1.02 (m, 2 H) 1.07 (d, J = 6.61 Hz, 2 H) 1.35 (d, J = 6.82 Hz, 2 H) 1.90 (s, 2 H) 2.64 - 2.80 (m, 1 H) 3.14 (br t, J = 11.19 Hz, 1 H) 3.45 - 3.57 (m, 1 H) 3.58 - 3.84 (m, 2 H) 3.86 - 4.09 (m, 1 H) 4.09 - 4.21 (m, 1 H) 4.21 - 4.46 (m, 2 H) 4.90 (br s, 1 H) 5.65 - 5.86 (m, 2 H) 6.08 - 6.28 (m, 1 H) 6.63 - 6.76 (m, 2 H) 6.86 (dt, J = 16.46, 11.27 Hz, 1 H) 7.12 - 7.21 (m, 1 H) 7.21 - 7.31 (m, 1 H) 8.16 - 8.36 (m, 2 H) 8.39 (d, J = 4.90 Hz, 1 H) 10.20 (br s, 1 H).

[0290] The crystalline DCM solvate form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 35), DSC (Figure 36), and TGA (Figure 37).

[0291] The DSC endothermic onset was approximately 174 °C, and the TGA included a weight loss of approximately 7.2% when heated from approximately 40 °C to approximately 200 °C. (0.5 mol DCM), from 40° - 200°.

[0292] NMR 0.5mol DCM [Table 11]: XRPD Data of the Crystalline DCM Solvate Form I of Compound 1 XRPD Peak Table Position [°2θ] Relative Intensity [%] Position [°2θ] Relative Intensity [%] Position [°2θ] Relative Intensity [%] 7.1 53.6 21.3 16.8 29.3 9.3 9.5 100.0 21.4 65.3 29.5 5.3 10.1 64.3 21.8 33.6 29.9 6.6 10.9 95.6 22.8 74.2 30.1 8.7 11.7 9.1 23.2 12.1 30.4 17.3 11.6 3.4 23.5 23.7 30.8 6.6 13.8 12.2 23.6 43.1 31.3 3.7 14.0 26.5 23.9 10.5 31.7 4.0 14.3 95.5 24.4 11.9 32.3 7.2 14.6 12.7 25.0 17.6 32.5 7.7 15.2 7.2 25.2 12.8 33.0 2.4 16.6 23.7 25.8 21.9 33.5 1.9 16.8 97.7 26.2 58.2 34.2 8.3 17.6 36.1 26.5 18.3 34.8 2.8 17.8 86.9 26.7 19.1 35.7 2.3 18.6 35.9 27.2 14.4 36.9 2.4 18.9 65.9 27.3 13.4 37.3 6.5 19.1 88.3 27.7 14.8 37.8 9.6 19.8 6.0 28.0 14.5 38.8 2.4 20.2 31.9 28.3 22.0 39.1 3.6 20.7 16.3 28.7 12.6 21.0 13.2 29.0 9.0 [Example]

[12] [:Compound] [1] [Crystallized acetone solvent form] [I] [Preparation] []

[0293] The crystalline DCM solvent compound Form I of Compound 1 was prepared by slurry of amorphous Compound 1 in acetone / water (50:50) at room temperature or slurry of Compound 1 in acetone / water (50:50) at 2°C-8°C for 15 days.

[0294] The crystalline acetone solvate Form I of the above-prepared Compound 1 was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 38), DSC (Figure 39), and TGA (Figure 40).

[0295] The DSC endotherm starts at about 72 °C and the TGA shows a weight loss of about 21.4% when heated from about 38 °C to about 130 °C. (0.7 mol acetone and 5.3 mol water).

[0296] NMR 0.7 mol acetone.

[0297] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.84 - 1.00 (m, 3 H) 1.07 (d, J = 6.61 Hz, 3 H) 1.34 (d, J = 6.61 Hz, 3 H) 1.90 (s, 3 H) 2.05 - 2.12 (m, 3 H) 2.52 - 2.78 (m, 2 H) 3.08 - 3.21 (m, 1 H) 3.45 - 3.57 (m, 1 H) 3.67 (br d, J = 11.72 Hz, 2 H) 3.97 - 4.06 (m, 1 H) 4.08 - 4.21 (m, 1 H) 4.32 (br d, J = 13.85 Hz, 2 H) 4.90 (br s, 1 H) 5.54 - 5.80 (m, 2 H) 5.99 - 6.26 (m, 2 H) 6.52 - 6.75 (m, 2 H) 6.84 (br s, 1 H) 7.09 - 7.30 (m, 2 H) 8.12 - 8.36 (m, 3 H) 8.38 (d, J = 4.90 Hz, 1 H) 10.21 (br s, 1 H). [Table 12]: XRPD data of the crystalline acetone solvate Form I of Compound 1 XRPD peak table Position [°2θ] Relative intensity [%] Position [°2θ] Relative intensity [%] 5.6 1.4 24.0 17.6 7.8 100.0 24.7 11.9 8.1 38.3 25.0 10.8 9.0 13.1 25.6 15.7 11.2 2.3 26.1 11.1 12.4 22.1 26.6 10.6 12.6 4.9 26.9 22.9 13.2 36.5 27.1 17.5 14.3 78.7 27.8 5.7 14.9 10.7 28.1 22.0 15.0 10.1 28.4 8.6 15.7 4.7 28.8 16.2 16.4 20.2 29.1 13.0 16.6 7.7 29.4 10.9 16.8 12.4 30.2 13.5 16.9 19.6 30.9 6.5 17.0 9.4 31.3 7.7 17.3 11.5 31.6 7.3 17.5 10.8 31.9 5.6 18.0 2.1 32.6 4.9 18.8 26.4 33.2 2.9 19.8 16.6 33.6 7.3 20.1 32.6 34.5 6.2 20.2 24.2 35.0 3.8 20.5 37.7 35.4 3.7 20.7 17.3 35.8 3.3 21.4 5.0 36.6 2.9 21.6 14.4 36.9 3.8 22.6 2.7 37.3 5.3 23.1 4.1 37.8 4.0 23.2 6.4 38.7 4.5 23.4 7.3 39.3 3.2 23.9 12.0 [Example]

[13] [: Compound] [1] [in the crystalline acetone solvate form] [II] [Preparation] []

[0298] The crystalline acetone solvate form II of Compound 1 was prepared by slurrying Compound 1 in acetone at 2 °C - 8 °C for 15 days.

[0299] The crystalline DCM solvate form II of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 41), DSC (Figure 42), and TGA (Figure 43).

[0300] The DSC endothermic onset was approximately 137 °C, and the TGA included a weight loss of approximately 7.3% when heated from approximately 100 °C to approximately 200 °C. (0.8 mol acetone).

[0301] NMR 0.7 mol acetone

[0302] 1H NMR (400 MHz, DMSO- d 6) δ ppm 0.83 - 1.02 (m, 3 H) 1.07 (d, J=6.82 Hz, 2 H) 1.35 (d, J=6.61 Hz, 2 H) 1.90 (s, 2 H) 2.09 (s, 3 H) 2.52 - 2.77 (m, 1 H) 3.18 (br s, 1 H) 3.45 - 3.57 (m, 1 H) 3.66 (br s, 4 H) 3.96 - 4.08 (m, 1 H) 4.08 - 4.20 (m, 1 H) 4.32 (br d, J=13.64 Hz, 3 H) 4.90 (br s, 2 H) 5.69 - 5.80 (m, 1 H) 6.15 - 6.26 (m, 1 H) 6.60 - 6.75 (m, 2 H) 6.79 - 6.94 (m, 1 H) 7.07 - 7.21 (m, 1 H) 7.27 (td, J=8.31, 7.03 Hz, 1 H) 8.20 - 8.36 (m, 2 H) 8.39 (d, J=4.90 Hz, 1 H) 10.20 (br s, 1 H). [Table 13]: XRPD data of crystalline acetone solvent form II of compound 1 XRPD Peak Table Position [°2θ] Relative strength [%] Position [°2θ] Relative strength [%] 7.1 60.1 25.5 17.5 9.1 38.0 25.8 29.5 9.9 47.8 26.1 13.0 10.3 15.8 26.8 4.9 10.6 56.1 27.0 12.0 10.9 13.4 27.3 4.9 11.3 15.8 27.8 13.6 11.8 8.7 28.2 9.8 12.7 1.1 28.6 12.5 13.8 27.0 28.8 5.9 14.0 17.3 29.2 11.7 14.2 59.6 29.5 4.8 14.7 13.0 29.7 5.9 16.7 60.7 29.9 3.7 16.9 26.6 30.3 7.0 17.1 14.3 30.7 7.2 17.4 29.3 30.7 4.2 17.7 7.9 31.4 5.2 18.2 12.6 31.7 6.6 18.5 17.5 32.0 4.5 18.7 33.6 33.1 2.9 19.0 100.0 33.3 7.6 19.6 4.7 34.3 4.9 19.9 32.0 35.4 0.8 20.3 3.3 35.7 2.3 20.8 29.1 36.2 1.7 21.3 46.3 36.5 6.2 22.3 37.3 37.0 2.4 22.7 50.5 37.4 1.0 23.0 32.6 37.7 2.8 23.7 5.9 37.9 4.2 24.1 16.5 38.6 2.1 24.6 17.2 39.1 2.8 24.9 5.0 39.7 3.8 25.3 18.9 [Example]

[14] [: Compound] [1] [crystalline p-xylene solvate] [𠮿] [solvate form] [I] [Preparation] []

[0303] [The crystalline p-xylene solvate form I of Compound 1 was prepared by slurrying Compound 1 in p-xylene at room temperature for 14 days.]

[0304] [The crystalline p-xylene solvate form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 44), DSC (Figure 45), and TGA (Figure 46).]

[0305] [The DSC endothermic onset was approximately 112 °C, and the TGA included a weight loss of approximately 23.2% when heated from approximately 25 °C to approximately 150 °C. (1.9 mol p-xylene)]

[0306] [NMR 1.9 mol p-xylene]

[0307] 1H NMR (400 MHz, DMSO- d 6) δ ppm 0.84 - 1.00 (m, 3 H) 1.07 (d, J=6.61 Hz, 3 H) 1.35 (d, J=6.82 Hz, 3 H) 1.90 (s, 2 H) 2.52 - 2.77 (m, 2 H) 3.05 - 3.28 (m, 1 H) 3.32 (s, 4 H) 3.58 - 3.78 (m, 3 H) 3.98 - 4.07 (m, 1 H) 4.09 - 4.20 (m, 1 H) 4.09 - 4.19 (m, 1 H) 4.15 - 4.43 (m, 1 H) 4.16 - 4.21 (m, 1 H) 4.22 - 4.45 (m, 1 H) 4.23 - 4.45 (m, 1 H) 4.90 (br s, 1 H) 5.61 - 5.80 (m, 1 H) 6.20 (br dd, J=16.62, 4.48 Hz, 1 H) 6.58 - 6.76 (m, 2 H) 6.79 - 6.93 (m, 1 H) 7.10 - 7.21 (m, 1 H) 7.21 - 7.31 (m, 1 H) 8.14 - 8.36 (m, 3 H) 8.39 (d, J=4.90 Hz, 1 H) 10.20 (br s, 1 H) [Table 14]: XRPD data of the crystalline diisocyanate solvent compound Form I of Compound 1 XRPD Peak Table Position [°2θ] Relative strength [%] Position [°2θ] Relative strength [%] 7.8 94.7 24.1 55.3 9.5 83.9 24.3 8.5 9.6 55.6 25.0 25.5 10.2 7.1 25.9 21.9 11.0 59.4 26.6 26.6 11.3 30.2 27.0 20.1 11.8 1.0 27.3 7.1 12.9 71.9 27.4 9.2 13.2 1.6 27.7 10.6 13.7 6.4 28.0 6.4 14.3 13.0 28.1 5.0 15.8 81.2 28.6 20.8 16.4 4.8 28.8 6.5 16.6 4.5 29.1 6.3 17.7 81.5 29.2 5.9 18.1 49.0 29.6 6.6 18.3 40.0 30.0 7.1 18.6 85.4 30.4 4.6 18.8 100.0 30.5 8.0 19.0 63.4 31.0 12.2 19.2 94.1 31.5 3.3 19.8 88.2 32.0 8.6 20.0 73.8 32.3 5.4 20.4 13.1 32.7 1.2 20.5 42.2 33.3 9.4 20.9 13.0 34.3 3.1 21.2 41.5 34.9 4.0 21.6 22.5 35.5 4.3 21.7 20.6 35.9 5.3 22.0 34.7 36.3 1.1 22.4 6.1 36.8 2.8 22.7 8.0 37.0 5.2 23.0 3.2 37.4 1.0 23.3 14.6 37.8 1.7 23.6 32.9 38.9 3.1 23.7 47.2 39.5 3.6 [Example]

[15] [: Compound] [1] [in the crystalline methanol solvate form] [I] [Preparation of] []

[0308] The crystalline MeOH solvate form I of Compound 1 was prepared by placing Compound 1 in a small open vial, then placing the vial in a larger vial containing methanol (MeOH), and capping to subject the solid to vapor stress at room temperature for 4 days.

[0309] The crystalline MeOH solvate form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 47), DSC (Figure 48), and TGA (Figure 49).

[0310] The DSC endothermic onset was approximately 57 °C, and the TGA included a weight loss of approximately 5.2% when heated from approximately 38 °C to approximately 220 °C. (1.0 mol MeOH)

[0311] NMR 0.8 mol MeOH

[0312] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (d, J = 6.62 Hz, 3 H) 1.08 (d, J = 6.62 Hz, 3 H) 1.35 (d, J = 6.84 Hz, 3 H) 1.90 (s, 3 H) 2.64 - 2.80 (m, 1 H) 3.18 (d, J = 4.92 Hz, 3 H) 3.48 - 3.76 (m, 2 H) 3.97 - 4.21 (m, 2 H) 4.21 - 4.47 (m, 2 H) 4.91 (br s, 1 H) 5.69 - 5.86 (m, 1 H) 6.21 (br dd, J = 16.67, 4.49 Hz, 1 H) 6.63 - 6.79 (m, 2 H) 6.80 - 6.98 (m, 1 H) 7.17 - 7.31 (m, 2 H) 8.18 - 8.35 (m, 1 H) 8.39 (d, J = 4.92 Hz, 1 H) 10.22 (br s, 1 H) [Table 15]: XRPD data of the crystalline MeOH solvate Form I of Compound 1 XRPD peak table Position [°2θ] Relative intensity [%] Position [°2θ] Relative intensity [%] 7.2 22.9 26.3 21.1 9.0 30.8 26.8 12.1 9.7 42.7 27.5 5.2 10.3 13.3 27.8 4.5 10.6 100.0 28.1 3.8 11.2 44.1 28.5 7.3 12.1 4.1 28.7 15.9 13.7 26.4 29.0 9.4 14.1 10.9 29.2 7.1 14.4 91.4 29.9 6.5 14.9 43.3 30.3 3.7 16.0 0.9 31.1 3.3 16.8 91.1 31.4 10.8 17.0 18.4 31.5 9.2 17.2 5.0 32.2 1.4 17.4 37.0 32.4 1.3 17.6 15.5 33.4 1.3 17.8 22.7 33.6 1.7 18.1 8.0 33.8 2.2 18.7 35.3 34.1 1.6 18.9 4.5 34.4 3.6 19.1 3.6 34.9 3.1 19.5 74.7 34.9 3.9 20.0 1.7 35.5 1.8 20.3 1.6 35.7 2.4 20.6 4.7 36.1 1.7 21.1 21.9 36.7 5.1 21.3 2.9 37.3 1.9 21.7 68.4 37.9 2.2 22.0 5.9 38.1 2.8 22.5 17.1 38.8 1.6 22.7 9.7 39.7 2.6 23.0 17.7 39.9 3.0 23.3 4.1 24.2 8.2 24.3 12.9 24.6 40.5 25.1 22.7 25.4 5.6 25.9 35.7 [Example]

[16] [: Compound] [1] [crystal] [IPA] [solvated form] [I] [preparation of] []

[0313] The crystalline IPA solvate form I of Compound 1 was prepared by slurrying amorphous Compound 1 in isopropyl alcohol (IPA) at room temperature for 5 days.

[0314] The crystalline IPA solvate form I of Compound 1 prepared above was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 50), DSC (Figure 51), and TGA (Figure 52).

[0315] The DSC endothermic onset is approximately 56 °C, and the TGA includes a weight loss of approximately 8.7% when heated from approximately 39 °C to approximately 190 °C. (0.9 mol IPA)

[0316] NMR 2.3 mol IPA

[0317] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (d, J = 6.62 Hz, 3 H) 1.02 - 1.06 (m, 1 H) 1.05 (d, J = 5.98 Hz, 14 H) 1.35 (d, J = 6.62 Hz, 3 H) 1.90 (s, 3 H) 2.72 (br s, 1 H) 3.10 - 3.21 (m, 1 H) 3.45 - 3.58 (m, 1 H) 3.78 (td, J = 6.09, 4.06 Hz, 9 H) 3.98 - 4.09 (m, 1 H) 4.16 (br s, 1 H) 4.35 (d, J = 4.06 Hz, 8 H) 4.91 (br d, J = 0.85 Hz, 1 H) 5.73 - 5.83 (m, 2 H) 6.16 - 6.28 (m, 1 H) 6.66 - 6.93 (m, 5 H) 7.19 (dd, J = 4.81, 0.75 Hz, 2 H) 7.23 - 7.33 (m, 2 H) 8.39 (d, J = 4.92 Hz, 3 H) 10.21 (br s, 1 H). [Table 16]: XRPD data of the crystalline MeOH solvate form I of Compound 1 XRPD peak table: Position [°2θ] Relative intensity [%] Position [°2θ] Relative intensity [%] 7.1 84.1 26.6 5.6 9.2 73.8 27.0 11.0 9.8 47.9 27.7 15.1 10.2 4.2 27.8 8.3 10.6 89.1 28.2 8.7 11.2 17.2 28.5 10.5 11.7 5.1 28.7 18.2 13.7 38.9 29.0 2.9 14.1 82.0 29.3 2.6 14.6 7.5 29.5 6.7 14.8 1.8 29.9 9.8 16.6 90.0 30.2 6.2 16.8 30.3 30.4 7.9 17.2 20.0 30.9 4.5 17.5 52.1 31.2 5.0 18.0 23.3 31.7 4.2 18.2 15.9 31.8 4.8 18.6 38.1 32.7 3.4 18.8 100.0 32.9 6.2 18.9 75.5 33.0 5.8 19.2 10.6 33.5 6.0 19.7 52.3 34.1 5.5 20.4 27.0 34.7 2.3 21.0 21.5 35.2 3.0 21.3 65.6 35.5 0.8 22.0 28.6 35.9 2.1 22.2 14.3 36.2 2.5 22.5 50.5 36.5 4.4 22.9 19.9 36.6 3.5 23.1 27.1 36.9 2.7 23.3 8.6 37.0 2.6 23.5 8.8 37.4 5.7 23.8 11.3 38.1 1.2 24.2 19.0 38.3 1.0 24.8 12.0 38.7 1.2 25.0 16.1 39.1 4.9 25.4 37.9 39.5 2.1 25.5 45.3 26.1 16.0 [Example]

[17] [:Compound] [1] [Crystal of] [EtOH] [Solvent form] [I] [Preparation] []

[0318] The crystalline EtOH solvent Form I of Compound 1 was prepared by slurry of amorphous Compound 1 in ethanol (EtOH) at room temperature for 10 days.

[0319] The crystalline EtOH solvate Form I of the above-prepared Compound 1 was characterized by proton NMR, X-ray powder diffraction (XRPD) data (Figure 53), DSC (Figure 54), and TGA (Figure 55).

[0320] The DSC endothermic onset is approximately 194 °C, and the TGA includes a weight loss of approximately 5% when heated from approximately 36 °C to approximately 195 °C. (0.6 mol EtOH)

[0321] NMR 0.7 mol EtOH.

[0322] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.84 - 1.02 (m, 5 H) 1.02 - 1.12 (m, 5 H) 1.35 (d, J = 6.82 Hz, 3 H) 1.90 (s, 3 H) 2.52 - 2.77 (m, 1 H) 3.14 (br t, J = 10.87 Hz, 1 H) 3.34 - 3.57 (m, 2 H) 3.58 - 3.84 (m, 2 H) 3.86 - 4.08 (m, 1 H) 4.09 - 4.21 (m, 1 H) 4.21 - 4.46 (m, 3 H) 4.90 (br s, 1 H) 5.51 - 5.80 (m, 1 H) 6.20 (br dd, J = 16.52, 4.58 Hz, 1 H) 6.62 - 6.75 (m, 2 H) 6.86 (dt, J = 16.30, 11.24 Hz, 1 H) 7.13 - 7.19 (m, 1 H) 7.27 (td, J = 8.20, 7.03 Hz, 1 H) 8.16 - 8.36 (m, 2 H) 8.39 (d, J = 4.90 Hz, 1 H) 10.20 (br s, 1 H). [Table 17]: XRPD data of the crystalline EtOH solvate Form I of Compound 1 XRPD peak table: Position [°2θ] Relative intensity [%] Position [°2θ] Relative intensity [%] 7.2 63.3 25.6 27.2 9.3 42.8 25.7 24.1 9.8 35.9 26.2 5.4 10.2 6.1 26.5 14.6 10.8 100.0 27.3 8.6 11.2 13.4 27.8 8.2 11.9 5.3 28.7 11.6 12.7 0.9 29.0 7.1 13.8 28.1 29.3 1.6 14.4 91.3 29.9 4.9 14.7 14.3 30.3 1.8 16.8 77.0 30.5 3.0 17.1 21.3 31.0 6.1 17.3 19.5 31.3 2.3 17.8 34.9 31.8 2.1 17.9 14.9 32.3 1.7 18.2 3.0 32.7 0.1 18.8 40.0 33.5 2.4 19.1 31.5 34.1 4.1 19.7 25.4 34.7 1.7 20.5 8.9 35.0 1.6 20.8 3.3 35.7 1.1 21.0 8.2 36.5 1.3 21.6 54.2 37.1 4.8 22.6 26.1 38.0 3.2 23.0 9.5 39.5 1.4 23.4 16.6 39.8 1.8 23.9 7.1 24.4 11.8 24.9 11.5

[0323] Although the present invention has been described and illustrated with reference to certain specific embodiments thereof, those skilled in the art will understand that various adaptations, changes, modifications, substitutions, deletions, or additions can be made to the procedures and schemes without departing from the spirit and scope of the present invention. Accordingly, it is intended that the present invention be defined by the scope of the appended claims, and that such claims be construed reasonably broadly.

Claims

1. A compound, wherein the compound is in the amorphous form of the M-configuration isomer of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propyl)-3-pyridyl)-4-((2S)-2-methyl-4-(2-propenyl)-1-piperyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 1), wherein the compound is characterized by 19F solid-state NMR containing peaks at about -116 and -127 ppm.

2. The compound of claim 1, wherein the compound is characterized by 19F solid-state NMR, the 19F solid-state NMR containing peaks at about -86, -96, -116, -127, -146 and -156 ppm.

3. The compound of claim 1 or 2, wherein the compound is characterized by a differential scanning calorimetry thermogram containing an endothermic start at about 144°C.

4. The compound of claim 1 or 2, wherein the compound is characterized by a thermogravimetric analysis thermogram that includes a weight loss of about 1.5% when heated from about 25°C to about 275°C.

5. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 4, and a pharmaceutically acceptable excipient.

6. The pharmaceutical composition as claimed in item 5, wherein the pharmaceutical composition is a dosage form for oral administration.

7. The pharmaceutical composition as claimed in item 6, wherein the dosage form is a solid dosage form.

8. The pharmaceutical composition of claim 7, wherein the solid dosage form is a tablet.

9. Use of a compound as claimed in any one of claims 1 to 4, for the preparation of a medicament for treating cancers with KRAS G12C mutations.

10. As claimed in claim 9, wherein the cancer with the KRAS G12C mutation is non-small cell lung cancer, small intestinal cancer, appendix cancer, colorectal cancer, endometrial cancer, pancreatic cancer, skin cancer, gastric cancer, nasal cancer, or bile duct cancer.

11. As claimed in claim 10, wherein the cancer with the KRAS G12C mutation is non-small cell lung cancer.

12. As claimed in claim 10, wherein the cancer with the KRAS G12C mutation is pancreatic cancer.

13. As claimed in claim 10, wherein the cancer with the KRAS G12C mutation is colorectal cancer.

14. The use as claimed in any of claims 10 to 13, wherein the compound is administered at a total daily dose of 5 mg to 1000 mg.

15. The use of any one of claims 10 to 13, wherein the compound is administered to an adult.

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