Crystalline forms of AKR1C3 dependent KARS inhibitors

Abstract

The present application relates to crystalline forms of an AKR1C3 dependent KARS inhibitor. (Formula I) # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0002] The present disclosure also relates to pharmaceutical compositions comprising the crystalline form, as well as methods for obtaining such crystalline forms and methods of using such crystalline forms in the treatment of diseases and disorders that are typically improved by inhibiting AKR1C3-dependent KARS. Such diseases and disorders may include cancers with genetic alterations in the NRF2 / KEAP1 pathway, such as solid tumors, non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). Background Art

[0003] Polymorphism refers to the existence of more than one crystalline form of a substance.

[0004] The solid state form of the active pharmaceutical ingredient (API) of a particular drug is often an important determinant of the drug's ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and in vivo bioavailability. When the same composition of matter crystallizes in different lattice arrangements, crystalline forms occur, resulting in different thermodynamic properties and stability specific to a particular crystalline form. Crystal forms may also include different hydrates or solvates of the same compound. In deciding which crystalline form is preferred, many properties of the crystalline form are compared and the preferred crystalline form is selected based on many physical property variables. In some cases where it is believed that certain aspects (such as ease of preparation, stability, etc.) are critical, it is entirely possible that one crystalline form may be preferred. In other cases, another different crystalline form may be preferred due to a greater dissolution rate and / or superior bioavailability.

[0005] Therefore, the ability of a chemical substance to crystallize in more than one crystalline form can have a profound impact on the shelf life, solubility, formulation characteristics, and processing characteristics of a drug. In addition, the action of a drug may be affected by the polymorphic form of the drug molecule. Different polymorphs may have different uptake rates in the body, resulting in lower or higher biological activity than desired. In extreme cases, undesirable polymorphs may even show toxicity. The appearance of unknown crystalline forms during the manufacturing process may have a significant impact.

[0006] It is not possible to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in therapeutic compositions, or which polymorphs will display such desired properties. However, knowing which crystalline forms a drug may occur in certain circumstances enables researchers to maximize the desired properties of a compound, such as solubility, formulation characteristics, processing characteristics, and shelf life. Knowing these factors early in the development of a new drug may mean a drug that is more active, more stable, or less expensive to manufacture.

[0007] Therefore, there is a need to provide solid-state forms of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide whose physicochemical properties allow for the reliable production of safe and effective pharmaceutical products containing 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0008] Example 40 of WO 2021 / 005586 published on January 14, 2021 discloses 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0009] 6'-Fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide has the structure of formula (I):

[0010]

[0011] 6'-Fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide is converted by AKR1C3 to the lysine t-RNA synthetase (KARS) inhibitor (R)-6'-fluoro-N-(4-fluorobenzyl)-4'-hydroxy-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide in the presence of NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate). Example 152 of WO2021 / 005586 discloses (R)-6'-fluoro-N-(4-fluorobenzyl)-4'-hydroxy-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, which has a structure of formula (II):

[0012]

[0013] Lysine t-RNA synthetase is a ubiquitous enzyme essential for protein synthesis that is part of a multi-tRNA synthetase complex. AKR1C3 (also known as type 2 3α(17β)-hydroxysteroid dehydrogenase) is a NADP(H)-dependent ketosteroid reductase and a member of the aldo-keto reductase (AKR) superfamily that plays a role in steroid hormone metabolism and signaling and xenobiotic detoxification.

[0014] However, WO 2021 / 005586 does not provide information on the crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0015] A crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide has been discovered for use in treating diseases typically ameliorated by inhibiting AKR1C3-dependent KARS. Such diseases and conditions include cancers such as solid tumors, non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). Summary of the invention

[0016] In one aspect, the present invention provides a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide in free form (ie, non-salt form). In a specific embodiment, the free form is an anhydrous form of a compound of formula (I). In an embodiment, the crystalline form includes the crystalline form designated herein as Form A.

[0017] Preferably, Form A is substantially pure. More preferably, Form A is substantially phase pure.

[0018] The designation "Form A" is a name used herein to identify a particular crystalline form and should not be considered a limitation to any other material having similar or identical physical and chemical characteristics, but rather it should be understood that these designations are merely identifiers that should be interpreted in light of the characterization information also presented herein.

[0019] In one aspect, the present invention also provides a pharmaceutical composition comprising: (a) a therapeutically effective amount of crystalline Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide; and (b) at least one pharmaceutically acceptable carrier.

[0020] In one aspect, the present invention also provides a method for preparing Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, the method comprising the following steps:

[0021] a) reacting 6'-fluoro-1'H-spiro[piperidin-4,2'-quinolin]-4'(3'H)-one with 4-fluorobenzyl isocyanate in a chlorinated solvent, optionally in the presence of a base; and

[0022] b) isolating the solid formed.

[0023] In another aspect, the present invention also provides a method for preparing crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, the method comprising the following steps:

[0024] a) dissolving a certain amount of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (especially D form) in a solvent;

[0025] b) adding seed crystals of Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide; and

[0026] c) isolating the solid formed.

[0027] In one aspect, the present invention also provides a method for treating or preventing a disease or condition that can be treated by an AKR1C3-dependent KARS inhibitor, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of crystalline Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0028] In one aspect, the present invention also provides the use of the crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide for preparing drugs.

[0029] In one aspect, the present invention also provides the use of crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide for preparing a medicament for treating a disorder that can be treated by an AKR1C3-dependent KARS inhibitor.

[0030] In one aspect, the present invention also provides Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide for use in treating a disorder treatable by an AKR1C3-dependent KARS inhibitor.

[0031] Thus, the crystalline form A of the compound of formula (I) as described herein can be used to treat cancer, in particular wherein the cancer is selected from solid tumors, non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS).

[0032] Crystalline forms of the compound of formula (I) are particularly useful in the treatment of non-small cell lung cancer (NSCLC).

[0033] Also described herein are additional crystalline forms of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, designated Form B, Form C, Form D, Form E, and Form H. A These crystal forms can also be used directly or indirectly in drug preparation.

[0034] In another aspect, the present invention also provides 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide selected from A, B, C, D, E and hydrate H A Use of a crystalline form of the present invention or a mixture thereof for preparing a spray-dried composition. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 An illustrative XRPD spectrum of an anhydrous crystalline form of the compound of Formula (I), designated herein as Form A, is provided, showing degrees 2θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0036] Figure 2 An illustrative DSC of an anhydrous crystalline form of the compound of formula (I), designated herein as Form A, is provided.

[0037] Figure 3 An illustrative TGA of an anhydrous crystalline form of the compound of formula (I), designated herein as Form A, is provided.

[0038] Figure 4An illustrative XRPD spectrum of an anhydrous crystalline form of the compound of Formula (I), designated herein as Form B, is provided, showing degrees 2θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0039] Figure 5 An illustrative DSC of an anhydrous crystalline form of the compound of formula (I), designated herein as Form B, is provided.

[0040] Figure 6 An illustrative TGA of an anhydrous crystalline form of the compound of formula (I), designated herein as Form B, is provided.

[0041] Figure 7 An illustrative XRPD spectrum of an anhydrous crystalline form of the compound of Formula (I), designated herein as Form C, is provided, showing degrees 2θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0042] Figure 8 An illustrative DSC of an anhydrous crystalline form of the compound of formula (I), designated herein as Form C, is provided.

[0043] Fig. 9 An illustrative TGA of an anhydrous crystalline form of the compound of formula (I), designated herein as Form C, is provided.

[0044] Fig.10 An illustrative XRPD spectrum of an anhydrous crystalline form of the compound of Formula (I), designated herein as Form D, is provided, showing degrees 2θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0045] Fig.11 An illustrative DSC of an anhydrous crystalline form of the compound of formula (I), designated herein as Form D, is provided.

[0046] Fig.12 An illustrative TGA of an anhydrous crystalline form of the compound of formula (I), designated herein as Form D, is provided.

[0047] Fig.13 An illustrative XRPD spectrum of an anhydrous crystalline form of the compound of Formula (I), designated herein as Form E, is provided, showing degrees 2θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0048] Fig.14 An illustrative DSC of an anhydrous crystalline form of the compound of formula (I), designated herein as Form E, is provided.

[0049] Fig.15 An expansion of the DSC graph of the anhydrous crystalline form of the compound of formula (I), designated herein as Form E, is provided.

[0050] Fig.16 Provided is a crystalline anhydride form of a compound of formula (I) (designated herein as Hydrate H A An illustrative XRPD spectrum of (type ) showing 2θ (2-θ) degrees on the X-axis and relative intensity on the Y-axis.

[0051] Fig.17 Provided is a crystalline anhydride form of a compound of formula (I) (designated herein as Hydrate H A Illustrative DSC of (type).

[0052] Fig.18 Provided is a crystalline anhydride form of a compound of formula (I) (designated herein as Hydrate H A Illustrative TGA of (type).

[0053] A more detailed list of XRPD peaks for each of these crystalline forms is listed in Tables 1-5 herein, wherein relative intensity % (I / I0 x 100) is also provided. It should be understood that, due to, for example, instrumental variations (including differences between instruments), there is inherent variability in the values ​​measured in 2θ degrees (°2θ) in the X-ray powder diffraction spectrum or X-ray powder diffraction pattern. Likewise, it should be understood that there is a variability of up to ± 0.2°2θ in the XRPD peak measurements, however, such peaks will still be considered to represent a specific solid-state form of the crystalline material described herein. It should also be understood that, due to, for example, sample preparation and / or storage and / or environmental conditions, other measurements from XRPD experiments and DSC / TGA experiments (such as relative intensity and water content) may vary, however, these measurements will still be considered to represent a specific solid-state form of the crystalline material described herein. DETAILED DESCRIPTION

[0054] definition

[0055] As used herein, the terms "about" and "substantially" indicate that for features such as endotherms, endothermic peaks, exotherms, baseline shifts, etc., their values ​​may vary. With respect to X-ray diffraction peak positions, "about" or "substantially" means taking into account typical peak position and intensity variability. For example, it will be appreciated by those skilled in the art that peak positions (2θ) may show variability between certain devices, typically up to 0.2°. Occasionally, variability may be higher than 0.2°, depending on differences in device calibration. In addition, it will be appreciated by those skilled in the art that relative peak intensity will show inter-device variability as well as variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be measured only as a qualitative measure. For DSC, the observed temperature change will depend on the rate of temperature change as well as the sample preparation technique and the specific instrument used. Therefore, the endothermic / melting point values ​​reported herein for DSC / TGA thermograms may vary by ±5°C (and still be considered as features of the specific crystalline forms described herein). When used in the context of other features such as weight percentage (% by weight), reaction temperature, the term "about" indicates a change of ±5%.

[0056] The terms "crystalline form(s)" or "crystalline modification(s)" or "polymorph(s)" or "polymorph(s)" will be used interchangeably herein. "Polymorph(s)" as used herein refers to crystalline forms having the same chemical composition but differing in the spatial arrangement of the molecules, atoms, and / or ions forming the crystal. Each polymorph differs in thermodynamic stability, physical parameters, x-ray structure, and method of preparation.

[0057] As used herein, "amorphous" refers to a solid form of molecules, atoms, and / or ions that are not crystallized. Amorphous solids do not show a well-defined X-ray diffraction pattern.

[0058] As used herein, "substantially pure" when used with respect to a form means a compound having greater than 90% by weight, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, based on the weight of the compound, and also including a purity of the compound of formula (I) equal to about 100% by weight. The remaining material comprises one or more other forms of the compound, and / or reaction impurities and / or processing impurities resulting from its preparation. For example, a crystalline form of a compound of formula (I) may be considered substantially pure because it has a purity of greater than 90% by weight as measured by means known and generally accepted in the art at this time, wherein the remaining less than 10% by weight of the material comprises one or more other forms of the compound of formula (I) and / or reaction impurities and / or processing impurities.

[0059] As used herein, "substantially phase pure" when used with respect to any crystalline form of a compound of formula (I) means a compound having a phase purity of greater than about 90%, including greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and about 99%, and also including equal to about 100% by weight of a compound of formula (I) based on the weight of the compound (on anhydrous basis). The terms "phase pure" or "phase purity" herein refer to the phase homogeneity with respect to a particular solid state form of a compound of formula (I) and do not necessarily imply a high degree of chemical purity in the absence of an explicit statement thereof. Phase purity can be determined according to methods known in the art, for example, quantitative phase analysis using XRPD using one or more approaches known in the art, for example, by external standard methods, direct comparison of line (peak) features (which are attributed to different phases in a particular spectrum), or by internal standard methods. However, the presence of amorphous material may complicate XRPD quantification of phase purity. Therefore, other methods that can be used to determine phase purity include, for example, solid-state NMR spectroscopy, Raman and / or infrared spectroscopy. Those skilled in the art will readily understand these methods, and how to employ these additional (or alternative) methods to determine phase purity.

[0060] As used herein, "substantially chemically pure" when used with respect to any crystalline form of a compound of Formula (I) means a compound having a chemical purity of greater than about 90%, including greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and about 99%, by weight, based on the weight of the compound (on anhydrous basis), and also including a chemical purity of the compound of Formula (I) equal to about 100% by weight. The remaining material typically comprises other compounds (such as, for example, other stereoisomers of the compound of Formula (I)), reaction impurities, starting materials, reagents, by-products, and / or other processing impurities resulting from the preparation and / or isolation and / or purification of a particular crystalline form. For example, if it has been determined that a crystalline form of a compound of formula (I) has a chemical purity greater than about 90% by weight as measured by standard and generally accepted methods known in the art, it can be considered to be substantially chemically pure, with the remaining less than about 10% by weight constituting other materials, such as other stereoisomers of the compound of formula (I), reaction impurities, starting materials, reagents, by-products, and / or processing impurities. Chemical purity can be determined according to methods known in the art, for example, high performance liquid chromatography (HPLC), LC-MS (liquid chromatography-mass spectrometry), nuclear magnetic resonance (NMR) spectroscopy, or infrared spectroscopy. Those skilled in the art will readily understand these methods, as well as how to employ these additional (or alternative) methods to determine chemical purity.

[0061] As used herein, the term "seed" can be used as a noun to describe one or more crystals of a crystalline compound of formula (I). The term "seed" can also be used as a verb to describe the following behavior: introducing one or more crystals of the crystalline compound of formula (I) into an environment (including but not limited to, for example, a solution, a mixture, a suspension, or a dispersion), thereby resulting in the formation of more crystals of the crystalline compound of formula (I) or the growth of the introduced crystals of the crystalline compound of formula (I).

[0062] The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a subject, is effective to: (1) at least partially alleviate, inhibit, prevent and / or improve a condition or disorder or disease that (i) is mediated by KARS, or (ii) is a disease that is sensitive to KARS inhibition, or (iii) is characterized by the activity (normal or abnormal) of KARS; or (2) alleviate or inhibit a disease that is sensitive to KARS inhibition. The present invention further provides methods for treating or preventing diseases and / or disorders associated with high expression of AKR1C3 or that are sensitive to KARS inhibition, comprising administering to a subject in need thereof an effective amount of an AKR1C3-dependent KARS inhibitor.

[0063] As used herein, the term "subject" refers to primates (e.g., humans (male or female)), monkeys, dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0064] As used herein, a subject is "in need of" or "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0065] As used herein, the terms "a / an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0066] All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradictory to the context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention, without limiting the scope of the present invention otherwise claimed.

[0067] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the basal activity of a biological activity or process.

[0068] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refer to relieving or ameliorating the disease or disorder (i.e., slowing or preventing the development of the disease or at least one of its clinical symptoms); or relieving or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible by the patient. In one embodiment, "treat" or "treating" refers to delaying the progression of a disease or disorder.

[0069] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of; or delaying the onset of; a disease or disorder.

[0070] The term "comprising" encompasses "including" as well as "consisting of;" for example, a composition comprising X may consist solely of X, or may include additional components, such as X and Y.

[0071] As used herein, the term "combination" refers to a fixed combination in a dosage unit form, or a combined administration, wherein the crystalline form of the compound of formula (I) and the combination partner can be administered independently at the same time or separately at time intervals, particularly when these time intervals allow the combination partner to show cooperation, such as a synergistic effect. The individual components can be packaged in a kit or packaged separately. One or both components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration.

[0072] The terms "co-administration" or "combined administration" and the like as used herein are intended to encompass administration of the selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or administered at the same time.

[0073] The terms "drug combination" and "combination product" are used interchangeably and refer to a fixed combination in a dosage unit form or a non-fixed combination or kit for combined administration, wherein two or more therapeutic agents can be administered independently at the same time or separately at time intervals, particularly when these time intervals allow the combination partners to show cooperation, such as synergistic effects. The term "fixed combination" means a crystalline form of a compound of formula (I) and a combination partner (i.e., an immunotherapeutic agent) that are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means a crystalline form of a compound of formula (I) and a combination partner (i.e., an immunotherapeutic agent) that are administered to a patient simultaneously, in parallel or sequentially as separate entities (without a specific time limit), wherein such administration provides therapeutically effective levels of two compounds in the patient's body. The latter is also applicable to cocktail therapy, such as the administration of three or more therapeutic agents. In a preferred embodiment, the drug combination is a non-fixed combination.

[0074] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a KARS-related disease as described in the present disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple containers or in separate containers for each active ingredient (e.g., tablets, capsules, powders, and liquids). The powder and / or liquid may be reconstituted or diluted to the desired dose prior to administration. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner at approximately the same time or at different times. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0075] Crystal form:

[0076] The present disclosure relates to crystalline forms of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (compound of formula (I)) described and characterized herein.

[0077] In one embodiment, the present disclosure provides an anhydrous crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0078] In one embodiment, the present disclosure provides a crystalline form (Form A) of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide having an X-ray powder diffraction (XRPD) pattern comprising a representative peak at 9.6±0.2°2θ, measured at a temperature of about 25°C, in terms of °2θ. In another embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 17.1±0.2°2θ, 19.2±0.2°2θ, and 21.0±0.2°2θ. In a further embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 10.5±0.2°2θ and 30.4±0.2°2θ, measured at a temperature of about 25°C. In additional embodiments, the XRPD pattern further comprises one or more additional representative peaks selected from 13.4±0.2°2θ and 15.7±0.2°2θ, measured at a temperature of about 25°C. In yet further embodiments, the XRPD pattern further comprises one or more additional representative peaks selected from 22.4±0.2°2θ, 27.3±0.2°2θ, and 31.7±0.2°2θ, measured at a temperature of about 25°C. Thus, the XRPD pattern of Form A of the compound having Formula (I) may comprise one or more representative peaks selected from the group consisting of 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ and 31.7±0.2°2θ, measured at a temperature of about 25°C.

[0079] The XRPD pattern of Form A may comprise one or more (eg, two, three, four, five, six or seven) representative peaks selected from the peaks disclosed in Table 1 and measured at a temperature of about 25°C.

[0080] In another aspect of the above embodiment, Form A of the compound of Formula (I) is characterized by an x-ray powder diffraction pattern comprising two or more 2θ values ​​selected from the group consisting of: 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ, and 31.7±0.2°2θ measured at a temperature of about 25°C. In another aspect of the above embodiment, Form A of the compound of Formula (I) is characterized by comprising three or more 2θ values ​​selected from the group consisting of: The x-ray powder diffraction pattern of is: 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ and 31.7±0.2°2θ. In another aspect of the above embodiment, Form A of the compound having Formula (I) is characterized by an x-ray powder diffraction pattern comprising four or more 2θ values ​​selected from the group consisting of 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ and 31.7±0.2°2θ measured at a temperature of about 25°C. In another aspect of the above embodiment, Form A of the compound having Formula (I) is characterized by an x-ray powder diffraction pattern comprising five or more 2θ values ​​selected from the group consisting of 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ and 31.7±0.2°2θ measured at a temperature of about 25°C.

[0081] In yet another aspect of the above embodiment, Form A of the compound of formula (I) has substantially Figure 1 XRPD pattern shown.

[0082] The crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide can be thermally characterized. In one embodiment, the crystalline form A of the compound of formula (I) has a thermal profile as measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min, which comprises a single endothermic peak starting at about 208°C (corresponding to melting).

[0083] In another embodiment, Form A of the compound of Formula (I) has substantially Figure 2 DSC thermogram shown. It will be appreciated that hydrated forms may produce different thermograms (in terms of peak shape and profile) depending on instrument parameters and therefore the same material may have thermograms that appear substantially different from one another when data is generated on two different instruments.

[0084] In another embodiment, Form A of the compound of formula (I) has Figure 3 Thermogravimetric analysis (TGA) graphs are shown that are substantially the same. The TGA weight loss is about 0.3% in the range of about 24°C to 200°C. Thermal decomposition occurs at 240°C.

[0085] In yet another embodiment, Form A is substantially pure.

[0086] In yet another embodiment, Form A is substantially chemically pure.

[0087] In yet another embodiment, Form A is substantially phase pure.

[0088] In one aspect, the present invention also provides a method for preparing Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, the method comprising the following steps:

[0089] a) reacting 6'-fluoro-1'H-spiro[piperidin-4,2'-quinolin]-4'(3'H)-one with 4-fluorobenzyl isocyanate in a chlorinated solvent, optionally in the presence of a base; and

[0090] b) isolating the solid formed.

[0091] In an embodiment of the method, the reaction is carried out in the presence of a base. In an embodiment, the base is an amine. In another embodiment, the base is a tertiary amine. In another embodiment, the base is N,N-diisopropylethylamine.

[0092] In an embodiment of the method, the chlorinated solvent is dichloromethane.

[0093] In embodiments of the methods, the reaction is carried out at a temperature of about 20° C. to about 50° C. In embodiments of the methods, the reaction is carried out at a temperature of about 20° C. to about 30° C. In embodiments of the methods, the reaction is carried out at a temperature of about 23° C. to about 28° C.

[0094] In another aspect, the present invention also provides a method for preparing crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, the method comprising the following steps:

[0095] a) dissolving a certain amount of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (especially D form) in a solvent;

[0096] b) adding seed crystals of Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide; and

[0097] c) isolating the solid formed.

[0098] In an embodiment of the additional method, the solvent comprises a non-chlorinated solvent.

[0099] In an embodiment of the method, the non-chlorinated solvent is selected from THF, acetone, water, acetonitrile, dioxane, ethanol, methanol, butanone or a mixture thereof. In another embodiment of the method, the solvent comprises a solvent mixture containing a non-chlorinated solvent. In an embodiment, the solvent mixture comprises acetone and water. In an embodiment, the solvent in step a) of the method is a mixture of acetone: water 85: 15 w / w. In an embodiment, step a) of the method is carried out at a temperature of about 50 ° C to about 60 ° C (preferably about 50 ° C).

[0100] In an embodiment of the method, the seeds in step b) are added as a dispersion in a mixture of acetone and water. In an embodiment of the method, the dispersion is in a mixture of 40:60 w / w acetone:water. In an embodiment of the method, step b) is performed at a temperature of about 40°C, optionally followed by cooling to 20°C, optionally followed by addition of water to bring the solvent mixture to 40:60 w / w acetone:water.

[0101] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide and at least one pharmaceutically acceptable carrier, diluent or excipient. In a specific embodiment of this aspect, the present invention relates to a pharmaceutical composition comprising Form A, and one or more pharmaceutically acceptable carriers, diluents or excipients. In another embodiment, the present invention relates to a pharmaceutical composition comprising Form A in substantially phase-pure form.

[0102] In yet another embodiment, the present invention is directed to a pharmaceutical composition comprising Form A and further comprising at least one other solid state form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0103] In another aspect, the present invention relates to combinations, in particular pharmaceutical combinations, comprising a therapeutically effective amount of a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, and one or more other therapeutic agents. In a specific embodiment of this aspect, the present invention relates to a pharmaceutical combination comprising Form A, and one or more other therapeutic agents. In another embodiment, the present invention relates to a pharmaceutical combination comprising Form A in substantially pure form, and one or more other therapeutic agents. In another embodiment, the present invention relates to a pharmaceutical combination comprising Form A in substantially pure form, and one or more other therapeutic agents.

[0104] In yet another embodiment, the present invention is directed to a pharmaceutical combination comprising Form A and further comprising at least one other solid state form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide in addition to one or more other therapeutic agents.

[0105] In another embodiment, the present invention provides a pharmaceutical combination as described herein, wherein the other therapeutic agent is independently selected from the group consisting of anticancer or chemotherapeutic agents, antiemetics (or antiemetics), chemotherapy, analgesics, cytoprotective agents, and combinations thereof.

[0106] In some embodiments, a compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more second agents (selected from PD-1 inhibitors, PD-L1 inhibitors, LAG-3 inhibitors, cytokines, A2A antagonists, GITR agonists, TIM-3 inhibitors, STING agonists, and TLR7 agonists) to treat a disease (e.g., cancer).

[0107] In another embodiment, one or more chemotherapeutic agents are used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof to treat a disease (e.g., cancer), wherein the chemotherapeutic agent includes but is not limited to anastrozole. Bicalutamide Bleomycin sulfate Busulfan Busulfan Injection Capecitabine N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin Carmustine Chlorambucil Cisplatin Cladribine Cyclophosphamide ( or ), cytosine arabinoside, cytosine arabinoside Cytarabine liposome injection Dacarbazine Dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride Daunorubicin citrate liposome injection Dexamethasone, docetaxel Doxorubicin Hydrochloride Etoposide Fludarabine phosphate 5-Fluorouracil Flutamide Tezacitabine, gemcitabine (difluorodeoxycitidine), hydroxyurea Idabi Ifosfamide Irinotecan L-Asparaginase Calcium folinate, melphalan 6-Mercaptopurine Methotrexate Mitoxantrone Mylotarg, paclitaxel Phoenix (yttrium 90 / MX-DTPA), pentostatin, polifeprosan 20, and carmustine implants Tamoxifen citrate Teniposide 6-thioguanine, thiotepa, tirapazamine Topotecan Hydrochloride for Injection Vinblastine Vincristine Vinorelbine Epirubicin Oxaliplatin Exemestane Letrozole Fulvestrant

[0108] In other embodiments, the compound of formula (I) disclosed herein or a pharmaceutically acceptable salt thereof is combined with one or more other anti-HER2 antibodies (e.g., trastuzumab, pertuzumab, margetuximab, or HT-19 described above) or with other anti-HER2 conjugates (e.g., ado-trastuzumab-emtansine conjugate (also known as or T-DM1)) in combination.

[0109] In other embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof disclosed herein are used in combination with one or more tyrosine kinase inhibitors (including but not limited to EGFR inhibitors, Her3 inhibitors, IGFR inhibitors, and Met inhibitors) to treat diseases (e.g., cancer).

[0110] For example, tyrosine kinase inhibitors include, but are not limited to, erlotinib hydrochloride Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate Bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606 and described in U.S. Pat. No. 6,780,996); Dasatinib Pazopanib Sorafenib Vandetanib (ZD6474); and imatinib or imatinib mesylate ( and ).

[0111] Epidermal growth factor receptor (EGFR) inhibitors include but are not limited to erlotinib hydrochloride Gefitinib N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, ); Vandetanib Lapatinib (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); Canertinib dihydrochloride (CI-1033); 6-[4-[(4-ethyl-1-piperazinyl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE788, CAS 497839-62-0); Mubritinib (TAK165); Peritinib (EKB569); Afatinib Neratinib (HKI-272); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester (BMS599626); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); and 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol (PKI166, CAS 187724-61-4).

[0112] EGFR antibodies include but are not limited to cetuximab Panitumumab Matuzumab (EMD-72000); Nimotuzumab (hR3); Zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1); and ch806 (mAb-806, CAS 946414-09-1).

[0113] Other HER2 inhibitors include, but are not limited to, Neratinib (HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described in PCT Publication No. WO 05 / 028443); Lapatinib or Lapatinib ditosylate (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide (BIBW-2992, CAS 850140-72-6); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester (BMS 599626, CAS 714971-09-2); canertinib dihydrochloride (PD183805 or CI-1033); and N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8).

[0114] HER3 inhibitors include, but are not limited to, LJM716, MM-121, AMG-888, RG7116, REGN-1400, AV-203, MP-RM-1, MM-111, and MEHD-7945A.

[0115] MET inhibitors include, but are not limited to, Cabozantinib (XL184, CAS 849217-68-1); Foretinib (GSK1363089, formerly known as XL880, CAS 849217-64-7); Tivantinib (ARQ197, CAS1000873-98-2); 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG458); Crizotinib ( PF-02341066); (3Z)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-1,3-dihydro-2H-indol-2-one (SU11271); (3Z)-N-(3-chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-N-methyl 2-oxoindoline-5-sulfonamide (SU11274); (3Z)-N-(3-chlorophenyl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-1H-pyrrol-2-yl]methylene}-N-methyl-2-oxoindoline-5-sulfonamide (SU11606); 6-[difluoro[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]methyl]-quinoline (JNJ38877605, CAS 943540-75-8); 2-[4-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]-1H-pyrazol-1-yl]ethanol (PF04217903, CAS 956905-27-4); N-((2R)-1,4-dioxane-2-ylmethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfonamide (MK2461, CAS 917879-39-1); 6-[[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]thio]-quinoline (SGX523, CAS 1022150-57-7); and (3Z)-5-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4-[[(2R)-2-(1-pyrrolidinylmethyl)-1-pyrrolidinyl]carbonyl]-1H-pyrrol-2-yl]methylene]-1,3-dihydro-2H-indol-2-one (PHA665752, CAS 477575-56-7).

[0116] IGFR inhibitors include, but are not limited to, BMS-754807, XL-228, OSI-906, GSK0904529A, A-928605, AXL1717, KW-2450, MK0646, AMG479, IMCA12, MEDI-573, and BI836845. See, e.g., the review by Yee, JNCI [Journal of the National Cancer Institute], 104; 975 (2012).

[0117] In another embodiment, the compounds of formula (I) of the present disclosure are used in combination with one or more proliferation signaling pathway inhibitors (including but not limited to MEK inhibitors, BRAF inhibitors, PI3K / Akt inhibitors, SHP2 inhibitors, and also mTOR inhibitors and CDK inhibitors) to treat diseases (e.g., cancer).

[0118] For example, mitogen-activated protein kinase (MEK) inhibitors include, but are not limited to, XL-518 (also known as GDC-0973, CAS No. 1029872-29-4, available from ACC Corp.); 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352, and described in PCT Publication No. WO2000035436); N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (also known as PD0325901, and described in PCT Publication No. WO 2002006213); 2,3-bis[amino[(2-aminophenyl)thio]methylene]-succinonitrile (also known as U0126 and described in U.S. Pat. No. 2,779,780); N-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]-cyclopropanesulfonamide (also known as RDEA119 or BAY869766 and described in PCT Publication No. WO 2007014011); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxetrazolyltetradecyne-1,7(8H)-dione] (also known as E6201 and described in PCT Publication No. WO 2003076424); 2'-amino-3'-methoxyflavone (also known as PD98059, available from Biaffin GmbH & Co., KG, Germany); Vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS1035555-63-5); Pimasertib (AS-703026, CAS 1204531-26-9); and dimethyl sulfoxide trametinib (GSK-1120212, CAS1204531-25-80).

[0119] BRAF inhibitors include but are not limited to vemurafenib (or ), GDC-0879, PLX-4720 (available from Symansis), dabrafenib (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF265, Regorafenib (BAY 73-4506), CCT239065, or sorafenib (or sorafenib tosylate or ) or ipilimumab (or MDX-010, MDX-101, or Yervoy).

[0120] Phosphoinositide 3-kinase (PI3K) inhibitors include, but are not limited to, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC0941, RG7321, GNE0941, Pictrelisib, or Pictilisib; and described in PCT Publication Nos. WO 09 / 036082 and WO 09 / 055730); Tozasertib (VX680 or MK-0457, CAS 639089-54-6); (5Z)-5-[[4-(4-pyridyl)-6-quinolyl]methylene]-2,4-thiazolidinedione (GSK1059615, CAS958852-01-2); (1E,4S,4aR,5R,6aS,9aR)-5-(acetyloxy)-1-[(di-2-propenylamino)methylene]-4,4a,5,6,6a,8,9,9a-octahydro-11-hydroxy-4-(methoxymethyl)-4a,6a-dimethylcyclopenta[5,6]naphtho[1,2-c]pyran-2,7,10(1H)-trione (PX866, CAS 502632-66-8); 8-phenyl-2-(morpholin-4-yl)-chromen-4-one (LY294002, CAS154447-36-6); (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide (also known as BYL71 9 or apellisib); 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (also known as GDC0032, RG7604, or Taselisib).

[0121] mTOR inhibitors include but are not limited to temsirolimus Ridaforolimus (formally known as deferolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15 ,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]triacontahedral-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03 / 064383); everolimus ( or RAD001); Rapamycin (AY22989, ); simapimod (CAS164301-51-3); (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (PF04691502, CAS1013101-36-4); and N 2 -[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartyl-L-serine-, inner salt (SF1126, CAS 936487-67-1).

[0122] CDK inhibitors include, but are not limited to, palbociclib (also known as PD-0332991, 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one).

[0123] In yet another embodiment, the compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is used in combination with one or more pro-apoptotics (including but not limited to IAP inhibitors, BCL2 inhibitors, MCL1 inhibitors, TRAIL agents, CHK inhibitors) to treat a disease (e.g., cancer).

[0124] For example, IAP inhibitors include, but are not limited to, LCL161, GDC-0917, AEG-35156, AT406, and TL32711. Other examples of IAP inhibitors include, but are not limited to, those disclosed in WO 04 / 005284, WO 04 / 007529, WO 05 / 097791, WO 05 / 069894, WO 05 / 069888, WO 05 / 094818, US2006 / 0014700, US2006 / 0025347, WO 06 / 069063, WO 06 / 010118, WO 06 / 017295, and WO 08 / 134679 (all of which are incorporated herein by reference).

[0125] BCL-2 inhibitors include, but are not limited to, 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09 / 155386); tetrastatin A; antimycin; gossypol ((-)BL-193); obatoclax; ethyl-2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromone-3-carboxylate (HA14-1); oblimersen (G3139, ); Bak BH3 peptide; (-)-gossypol acetic acid (AT-101); 4-[4-[(4'-chloro[1,1'-biphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]-benzamide (ABT-737, CAS 852808-04-9); and Navitoclax (ABT-263, CAS 923564-51-6).

[0126] Pro-apoptotic receptor agonists (PARA) include DR4 (TRAILR1) and DR5 (TRAILR2), including but not limited to Dulanermin (AMG-951, RhApo2L / TRAIL); Mapatumumab (HRS-ETR1, CAS 658052-09-6); Lexatumumab (HGS-ETR2, CAS 845816-02-6); Apomab Conatumumab (AMG655, CAS 896731-82-1); and Tigatuzumab (CS1008, CAS 946415-34-5, available from Daiichi Sankyo).

[0127] Checkpoint kinase (CHK) inhibitors include, but are not limited to, 7-hydroxystaurosporine (UCN-01); 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3-piperidinylpyrazolo[1,5-a]pyrimidin-7-amine (SCH900776, CAS891494-63-6); 5-(3-fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZD7762, CAS860352-01-8); 4-[((3S)-1-azabicyclo[2.2.2]octan-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-aminodactinomycin (7-AAD), isoglutamic acid imide (Isogranulatimide), debromohymenialdisine (debromohymenialdisine); N-[5-bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]-phenyl]-N'-(5-methyl-2-pyrazinyl) urea (LY2603618, CAS 911222-45-2); sulforaphane (CAS 4478-93-7, 4-methylsulfinylbutyl isothiocyanate); 9,10,11,12-tetrahydro-9,12-epoxy-1H-diindol[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H)-dione (SB-218078, CAS135897-06-2); and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL (SEQ ID NO:33)), and CBP501 ((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr).

[0128] In one embodiment, the present invention relates to a method for treating or preventing a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor in a subject in need thereof, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (preferably Form A), alone or in combination with one or more other therapeutic agents.

[0129] In another embodiment, the present invention relates to a method for treating or preventing a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor in a subject in need thereof, the method comprising: administering to the subject a pharmaceutical composition as described herein, alone or in combination with one or more other therapeutic agents.

[0130] In another embodiment, the invention relates to a method for treating or preventing a disease or disorder (eg, cancer) treatable by an AKR1C3-dependent KARS inhibitor in a subject in need thereof, the method comprising administering to the subject a pharmaceutical combination as described herein.

[0131] In one embodiment, the present invention relates to the use of a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (preferably Form A) alone or in combination with one or more other therapeutic agents for treating or preventing a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor.

[0132] In yet another embodiment, the present invention relates to a crystalline form (preferably Form A) of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide for use in the treatment or prevention of a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor.

[0133] In yet another embodiment, the present invention relates to a combination of a crystalline form (preferably Form A) of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide and one or more other therapeutic agents for use in the treatment or prevention of a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor.

[0134] In one embodiment, the present invention relates to a method of treatment, a use, a compound for use, or a combination for use as described herein, wherein the disease or disorder that can be treated by an AKR1C3-dependent KARS inhibitor is selected from non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS).

[0135] The characterization of Form A is described herein with reference to the accompanying figures.

[0136] Additional crystalline forms of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide have been observed, designated herein as Forms B, C, D, and E. A hydrate form has also been observed, designated herein as Form H A Characterization of these additional forms is described herein and with reference to the accompanying drawings.

[0137] In one aspect, the present invention also provides 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide selected from A, B, C, D, E and hydrate H A The use of a crystalline form of the present invention or a mixture thereof for preparing a drug.

[0138] In one aspect, the present invention also provides 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide selected from A, B, C, D, E and hydrate H A In one embodiment of this aspect, the present invention provides the use of Form A for preparing a spray-dried composition. The composition can be used in the preparation of a drug. The drug can contain the spray-dried composition.

[0139] The spray-dried composition can be prepared by mixing a mixture selected from A, B, C, D, E and hydrate H A In one embodiment, the crystalline form of the present invention is dissolved in a suitable solvent and the solution is spray dried. In one embodiment, the suitable solvent is an organic solvent, water or a combination thereof. In another embodiment, the suitable solvent includes, but is not limited to, acetone, ethanol, methanol and propanol. In another embodiment, the suitable solvent comprises a mixture of acetone and water.

[0140] Pharmaceutical compositions, dosages and administration

[0141] In one embodiment, the crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide described herein can be used alone, or can be formulated into a pharmaceutical composition, which also contains at least one pharmaceutically acceptable excipient, and generally contains at least two or more pharmaceutically acceptable excipients. Some suitable excipients are disclosed herein. Other excipients known in the art may be used without departing from the purpose and scope of the present application.

[0142] In some embodiments, the present invention utilizes a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0143] As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, carriers, diluents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents, antioxidants), isotonic agents, absorption delaying agents, salts, drug stabilizers, binders, additives, bulking agents, disintegrants, lubricants, sweeteners, flavoring agents, dyes and the like, and combinations thereof, as will be known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329). It should be understood that unless the conventional excipient is incompatible with the active ingredient, the present application contemplates the use of any conventional excipient in any therapeutic or pharmaceutical composition.

[0144] The pharmaceutical composition can be formulated for a specific route of administration, such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical composition of the present invention can be in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories), or in liquid form (including but not limited to solutions, suspensions or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical operations (such as sterilization) and / or can contain conventional inert diluents, lubricants, carriers or buffers and adjuvants (such as solvents, preservatives, stabilizers, wetting agents, emulsifiers and swelling agents, etc.).

[0145] Typically, pharmaceutical compositions are tablets or capsules comprising the active ingredient together with at least one excipient, such as:

[0146] a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0147] b) lubricants, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, also

[0148] c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired;

[0149] d) carriers, such as aqueous vehicles containing cosolvation materials, such as captisol, PEG, glycerol, cyclodextrin, etc.;

[0150] e) disintegrants, for example, starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or

[0151] f) Adsorbents, colorants, flavoring agents and sweeteners.

[0152] Tablets may be film-coated or enteric-coated according to methods known in the art.

[0153] Preferably, the compound or composition is prepared for oral administration, such as tablets or capsules, and optionally packaged in a multidose form suitable for storing and / or dispensing unit doses of a pharmaceutical product. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, unit dose containers (e.g., vials), blister packs, and strip packs.

[0154] Tablets may contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for making tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period of time. For example, time delay materials such as monostearate or distearate can be used. Preparations for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0155] The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water can facilitate the degradation of certain compounds.

[0156] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-water content ingredients and low moisture or low humidity conditions. The anhydrous pharmaceutical compositions can be prepared and stored so as to maintain their anhydrous properties. Therefore, it is preferred to package the anhydrous compositions using materials known to prevent exposure to water so that they can be included in a suitable formulation kit. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0157] The present invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate at which the compounds of the present invention as active ingredients decompose. Such agents (referred to herein as "stabilizers") include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers, etc.

[0158] For a subject of about 50-70kg, the pharmaceutical composition of the present invention or combination can be in a unit dose of about 1-1000mg one or more active ingredients, or about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg, or about 10-50mg active ingredients. Preferably, the pharmaceutical composition of the present invention or combination can be in a unit dose of about 10mg, about 25mg or about 50mg. The therapeutically effective dose or amount of compound, pharmaceutical composition or combination thereof depends on the species, body weight, age and individual condition, disorder or disease or its severity of the subject. A physician, clinician or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient necessary for prevention, treatment or inhibition of disorder or disease progression.

[0159] The above dosage characteristics are demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and preparations thereof. The compounds of the invention can be applied in vitro in the form of solutions (e.g., preferably aqueous solutions), and in vivo enterally, parenterally, advantageously intravenously, for example, as a suspension or in an aqueous solution. In vitro doses can be administered at about 10 -3 Molar concentration and 10 -9 In the range between molar concentration.Depending on the route of administration, the in vivo therapeutic effective amount can be between about 0.1-500mg / kg, or in the range between about 1-100mg / kg.Preferably, the in vivo therapeutic effective amount is about 10mg to about 200mg daily, for example, in the range of about 10mg, about 20mg, about 25mg, about 35mg, about 50mg, about 100mg or about 200mg daily.Preferably, the in vivo therapeutic effective amount is selected from about 10mg, about 35mg, about 50mg or about 100mg, once a day.Also preferably, the in vivo therapeutic effective amount is selected from about 10mg, about 25mg, about 50mg or about 100mg, twice a day.

[0160] In other embodiments, a pharmaceutical composition is provided, which comprises at least one crystalline form (e.g., type A, type E, type H) described in the above embodiments. A Type or a mixture thereof, preferably Type A); and at least one pharmaceutically acceptable carrier.

[0161] Thus, in the embodiments of the present disclosure, there is provided a crystalline form (Form A, Form E or Form H) of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide in substantially phase pure form. A This substantially phase-pure crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (Form A, Form E or Form H) A Type A, preferably Type A) can be used to prepare a pharmaceutical composition, which may further contain one or more pharmaceutically acceptable excipients.

[0162] combination:

[0163] The crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (preferably Form A) can be administered simultaneously with one or more other therapeutic agents or before or after them. The crystalline form of the present invention can be administered separately by the same or different administration routes as other agents, or administered together in the same pharmaceutical composition.

[0164] The crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (preferably Form A) can be administered as a single active ingredient, or, for example, as an adjuvant, in combination with other drugs (e.g., anticancer agents or chemotherapeutic agents, antiemetic agents (or antiemetic drugs), chemotherapy, analgesics, cytoprotective agents, and combinations thereof). For example, the crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide can be administered with anastrozole. Bicalutamide Bleomycin sulfate Busulfan Busulfan Injection Capecitabine N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin Carmustine Chlorambucil Cisplatin Cladribine Cyclophosphamide ( or ), cytosine arabinoside, cytosine arabinoside Cytarabine liposome injection Dacarbazine Dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride Daunorubicin citrate liposome injection Dexamethasone, docetaxel Doxorubicin Hydrochloride Etoposide Fludarabine phosphate 5-Fluorouracil Flutamide Tezalcitabine, gemcitabine (difluorodeoxycytidine), hydroxyurea Idabi Ifosfamide Irinotecan L-Asparaginase Calcium folinate, melphalan 6-Mercaptopurine Methotrexate Mitoxantrone Milostat, paclitaxel Albumin-bound paclitaxel Phoenix (yttrium 90 / MX-DTPA), pentostatin, polyphenylpropanone 20, and carmustine implants Tamoxifen citrate Teniposide 6-thioguanine, thiotepa, tirapazamine Topotecan Hydrochloride for Injection Vinblastine Vincristine Vinorelbine Use in combination.

[0165] Treatment kit

[0166] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a crystalline form (preferably Form A) of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide. In one embodiment, the kit comprises a device for separately retaining the compositions, such as a container, a separate bottle, or a separate foil bag. An example of such a kit is a blister pack, such as typically used to package tablets, capsules, etc.

[0167] The kits of the invention may be used for administering different dosage forms (eg, oral and parenteral), for administering the separate compositions at different dosage intervals, or for titrating the separate compositions relative to each other. To aid compliance, the kits of the invention typically comprise instructions for administration.

[0168] In the combination therapy of the present invention, the crystalline form (preferably Form A) of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. In addition, the crystalline form (preferably Form A) of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide and other therapeutic agents may be incorporated into the combination therapy: (i) before the combination product is released to the physician (e.g., in the case where the kit contains a crystalline form of the compound of Formula (I) and other therapeutic agents); (ii) shortly before administration, by the physician himself (or under the guidance of the physician); (iii) for example, during the sequential administration of the crystalline form of the compound of Formula (I) and other therapeutic agents in the patient himself.

[0169] Thus, the present invention provides the use of a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (preferably Form A) for treating a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor, wherein the medicament is prepared for administration with another therapeutic agent. The present invention also provides the use of a therapeutic agent for treating a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor, wherein the medicament is administered with a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0170] The present invention also provides a crystalline form (preferably Form A) of a compound of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide for use in a method for treating or preventing a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor, wherein the crystalline form of the compound of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide is prepared for administration together with another therapeutic agent. The present invention also provides another chemotherapeutic agent for use in a method of treating or preventing a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor, wherein the other therapeutic agent is prepared for administration together with a crystalline form of a compound of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide. The present invention also provides a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide for use in a method for treating a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor, wherein the crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide is administered together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor, wherein the other therapeutic agent is administered together with a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0171] The present invention also provides the use of a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide for treating a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor, wherein the patient has been previously treated (e.g., within 24 hours) with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor, wherein the patient has been previously treated (e.g., within 24 hours) with a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0172] Preparation of crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide:

[0173] Crystal forms can be prepared by a variety of methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spray. Techniques for crystallizing or recrystallizing a crystal form from a solvent or solvent mixture include, for example, evaporating the solvent, lowering the temperature of the solvent or solvent mixture, seeding the crystal with a supersaturated solvent mixture of the molecule and / or salt, freeze drying the solvent mixture, and adding an antisolvent (counter solvent) to the solvent mixture. Exemplary methods for preparing the crystal forms described herein are listed in detail below.

[0174] Crystals of drugs (including polymorphs), methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, SR Byrn, RRP Feiffer, and JG Stowell, 2nd ed., SSCI, West Lafayette, Indiana (1999).

[0175] For crystallization techniques using solvents, the selection of one or more solvents typically depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Combinations of solvents can be used, for example, the compound can be dissolved in a first solvent to provide a solution, and then an antisolvent is added to reduce the solubility of the compound in the solution and provide for the formation of crystals. An antisolvent is a solvent in which the compound has a low solubility.

[0176] In one method of preparing crystals, the compound is suspended and / or stirred in a suitable solvent to provide a slurry, which may be heated to promote dissolution. As used herein, the term "slurry" means a saturated solution of a compound, which may also contain additional amounts of the compound to provide a heterogeneous mixture of the compound and solvent at a given temperature. This may also be referred to as a suspension.

[0177] Seed can be added to any crystallization mixture to promote crystallization. Inoculation can be used to control the growth of a specific polymorph or to control the particle size distribution of the crystallized product. Therefore, the calculation of the required amount of seed depends on the size of the available seed and the desired size of the average product particles, as described in "Programmed Cooling of Batch Crystallizers", JW Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small-sized seeds are needed to effectively control the growth of crystals in a batch. Small-sized seeds can be produced by screening, grinding or micronizing large crystals, or by micronizing a solution. It should be noted that grinding or micronizing of crystals does not result in any change in the crystallinity of the desired crystalline form (i.e., becoming amorphous or another polymorph).

[0178] The cooled crystallization mixture can be filtered under vacuum, and the separated solid can be washed with a suitable solvent (such as a cold recrystallization solvent), and the separated solid can be dried under a nitrogen purge to provide the desired crystal form. The separated solid can be analyzed by a suitable spectrum or analytical technique, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, etc., to ensure that the preferred crystal form of the product is formed. The resulting crystal form is typically produced in an amount greater than about 70% by weight of the isolated yield, preferably greater than 90% by weight of the isolated yield based on the weight of the compound initially used in the crystallization procedure. If necessary, the product can be co-ground or passed through a mesh screen to debulk the product.

[0179] Alternatively, the crystalline form can be prepared directly from the reaction medium of the final process for preparing 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide. This can be achieved, for example, by using a solvent or a mixture of solvents in the final process step, from which 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide can be crystallized. In addition, the crystalline form can be obtained by distillation or solvent addition techniques.

[0180] In addition to the methods briefly discussed below, it will be appreciated that a variety of analytical methods can be used to characterize any of the materials described herein.

[0181] The following non-limiting examples illustrate the present disclosure.

[0182] Examples

[0183] Example 1: 6'-Fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidin-4,2'-quinoline]-1- Preparation of anhydrous form A of formamide

[0184] At 23 ± 5 ° C, dichloromethane (DCM) (10 volumes) and intermediate 2 (WO 2021 / 005586) (as TFA salt, 1.0 equivalents) were added to a clean round-bottom flask. The reaction mass was stirred for 10 minutes. Then at 23 ± 5 ° C, DIPEA was added to the reaction mass and finally 4-fluorobenzyl isocyanate was added to the reaction mass. The reaction was kept at this temperature for 16 hours. After the reaction was completed (as determined by HPLC), the reaction mass was filtered, the wet solid was washed with hexane (5 volumes), the solid was blotted for 30 minutes and then the solid was recovered in a round-bottom flask and isopropanol (IPA) (5 volumes) was added and stirred at 23 ± 5 ° C for 1 hour. The solid was then filtered, the wet solid was washed with hexane (5 volumes), and dried on a vacuum tray dryer (VTD) at 50 ° C for 10 hours. Traces of DCM were detected in the final compound by 1H-NMR and the material was re-purified with hexanes and dried for longer time.

[0185] The obtained product was characterized as Form A by XRPD, TGA and DSC.

[0186] In an alternative method, Form A can be prepared as follows:

[0187] At 50°C, with stirring, an amount of Form D corresponding to 15 wt.% of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide was dissolved in a mixture of acetone and water (85:15 w / w). The solution was filtered (clarification filtration) and then added to a crystallizer, and stirring was continued at 50°C for at least 15 min. The temperature was then lowered to 40°C and a seed suspension consisting of seed crystals of Form A dispersed in a mixture of acetone and water (40:60 w / w) was added to the system. After seeding, the mixture was stirred at 40°C for at least 30 min, and then the system was cooled to 20°C at a rate of 0.2°C / min and kept at this temperature for at least 60 min under stirring. Then, water was added continuously during 360 min to a solvent mixture composition of 40:60 w / w acetone:water. Finally, after the addition of water was complete, the system was stirred for at least 60 min, all at 20 ° C. The solid was separated from the mixture by filtration, and the filter cake was washed with a mixture of acetone and water (40:60 w / w). The wet filter cake was unloaded and dried in an oven under vacuum at 50 ° C. The material was then sieved using a manual sieve (1 mm mesh size) to provide a yellow solid 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide Type A.

[0188] Example 2: 6'-Fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidin-4,2'-quinoline]-1- Preparation of Form B of Formamide

[0189] Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide was dissolved in acetone and the clear solution was allowed to evaporate slowly at 25° C. This preparation was found not to be reproducible.

[0190] Example 3: Preparation of Form C

[0191] Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-l'H-spiro[piperidine-4,2'-quinoline]-l-carboxamide was dissolved in butanone and the clear solution was allowed to evaporate slowly at 25 °C.

[0192] This preparation was found to be difficult to reproduce.

[0193] Example 4: 6'-Fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidin-4,2'-quinoline]-1- Preparation of D-form of formamide

[0194] Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-l'H-spiro[piperidine-4,2'-quinoline]-l-carboxamide was dissolved in isopropanol and the clear solution was allowed to evaporate slowly at 25 °C.

[0195] In an alternative approach, Form D of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide can be prepared as follows:

[0196] At 20°C jacket temperature (JT), 4-methylbenzenesulfonate of 6'-fluoro-1'H-spiro[piperidin-4,2'-quinoline]-4'(3'H)-one (6.0 g, 14.8 mmol) and acetonitrile (30 mL) were added to the reactor. N,N-diisopropylethylamine (2.3 g, 17.7 mmol) was added dropwise while maintaining the internal temperature (IT) at 20°C. The resulting suspension was continued to be stirred while the internal temperature was lowered to 2°C. 4-Fluorobenzyl isocyanate (2.4 g, 15.9 mmol) was added dropwise in such a way that the exothermic reaction was maintained below 5°C IT. Stirring was continued at 0°C-5°C IT for 10 min. The resulting suspension was warmed to 20°C IT and stirring was continued for 3 h.

[0197] H2O (36 ml) was added in batches over 20 min to obtain a good stirrable suspension. The resulting mixture was slowly cooled to 2 ° C IT, and stirring was continued at this temperature for 1 h. The suspension was cold filtered, washed twice with H2O and once with acetonitrile. The obtained filter cake was dried under vacuum at 55 ° C JT to provide a yellow solid 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3', 4'-dihydro-1'H-spiro [piperidine-4,2'-quinoline] -1-formamide Form D (5.1 g, 13.2 mmol, 90% yield).

[0198] Example 5: 6'-Fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidin-4,2'-quinoline]-1- Preparation of Formamide E

[0199] The hydrate of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide was prepared by A Heating to about 70°C or exposure to 5% relative humidity for about 12 hours affords Form E of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0200] Example 6: 6'-Fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidin-4,2'-quinoline]-1- Formamide hydrate H A Preparation of type

[0201] The amorphous form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide was prepared by equilibrating the amorphous form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide in water at 25°C for 4 weeks or by equilibrating the amorphous form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide in water at 25°C for 4 weeks. w >0.95) for about 3 weeks and the solid was collected by centrifugation and dried under ambient conditions to obtain the hydrate of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide H A .

[0202] Example 6: 6'-Fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidin-4,2'-quinoline]-1- Preparation of the amorphous form of formamide

[0203] Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide was dissolved in 1,4-dioxane. The obtained clear solution was filtered with a 0.45um nylon membrane. The clear solution was pre-frozen using solid carbon dioxide ethanol solution and then freeze-dried under the following parameters: SHLF = -24°C, SAMP = -18°C, COL = -84°C, SEG = M, VAC = 0.014m.

[0204] Example 7: Physical / chemical properties and stability of Form A and amorphous form

[0205] It has been found that Form A described herein has advantageous properties.

[0206] Form A of the compound of formula (I) is the most stable form. Form A in bulk is physically stable. Form A is also chemically stable when exposed to high relative humidity (RH) percentage levels (e.g., 75%) at elevated temperatures (e.g., 80° C.) and after exposure to long-term stress conditions.

[0207] Type A is slightly hygroscopic. The maximum water absorption of Type A is 0.6% at 25°C and 95% relative humidity. w = 0.7 water activity, type A is stable.

[0208] Due to its slightly hygroscopic behavior, the physicochemical properties of Form A of the invention are preserved regardless of the relative humidity of the surrounding atmosphere, which makes its manufacturing process easier and more reliable, as well as the storage of pharmaceutical products containing Form A simpler.

[0209] Additionally, Form A retains its crystalline structure even when it is slurried (equilibrated) in various solvents for extended periods of time (equilibrium studies).

[0210] Form A showed an initial purity of 99.4%. In a pH stability study, 0.1% suspensions / solutions of the compound of formula (I) in buffer solutions of various pHs were exposed to 80°C for one week. After 1 week at 80°C, the compound of formula (I) degraded the most in pH 1 buffer (about 5%), while at high pH, ​​the degradation was less than 1%.

[0211] In bulk, Form A and the amorphous form of the compound of formula (I) are chemically stable when exposed to 80°C and 80°C and 75% RH for one week. The amorphous form crystallizes into crystalline modification A.

[0212] Both solid forms of the compound of formula (I) are also stable in admixture with excipients.

[0213] Upon light stress, a slight increase of 0.6% of the degradation products of the crystalline modification A was noted, but no degradation was observed for the amorphous form.

[0214] Table 1: Stability of Form A and Amorphous Form

[0215]

[0216]

[0217] Degradation products (DP) and color (CL)

[0218]

[0219] DP were analyzed by HPLC (method see Appendix 2). They were calculated as area-% product.

[0220] Composition of excipient mixture [mass-%)

[0221]

[0222]

[0223] Example 8: High Resolution Powder X-Ray Diffraction

[0224] A sample of the material of Example 1 was placed on a silicon sample holder for reflection measurement and the holder was placed in the diffractometer. XRPD patterns were collected in reflection mode on a Bruker D8 Advance system equipped with a LynxEye solid-state detector at room temperature (about 296K). The radiation used to collect the data was CuKα (λ=0.15418nm). Diffraction data were collected in the range of 2-40° 2θ and the peaks were evaluated. The spectrum obtained was Figure 1 The peaks are shown in Table 1. This procedure was repeated with the material obtained from Examples 2-6.

[0225] Table 1: X-ray powder diffraction data of anhydrous form A

[0226]

[0227]

[0228] Table 2: X-ray powder diffraction data of anhydrous form B

[0229]

[0230] Table 3: X-ray powder diffraction data of anhydrous form C

[0231]

[0232] Table 4: X-ray powder diffraction data of anhydrous form D

[0233]

[0234]

[0235] Table 5: X-ray powder diffraction data of anhydrous form E

[0236]

[0237] Table 6: Hydrate H A X-ray powder diffraction data of

[0238]

[0239] Example 8: Differential Scanning Calorimetry (DSC)

[0240] DSC thermograms were recorded with a TA Discovery DSC instrument using heat flux compensation (TA Instruments, USA). The TA Discovery instrument was calibrated for temperature and enthalpy using certified reference materials (such as indium) according to the manufacturer's instructions. About 2 mg of sample material was sealed in a standard pin-pierced aluminum pan and heated from 0°C to 300°C at a heating rate of 10°C / min in the DSC. During the measurement, the DSC apparatus was purged with dry nitrogen at a flow rate of 50 ml / min. The obtained graphs are shown in the accompanying drawings.

[0241] Example 9: Thermogravimetric analysis (TGA):

[0242] Thermogravimetric analysis was performed using a TA Discovery TGA instrument (TA Instruments, USA). About 2-10 mg of sample material was sealed in a standard aluminum pan with a perforated lid and heated from 30°C to 250°C at a heating rate of 10°C / min in the TGA. During the measurement, a dry N2 gas purge with a flow rate of 20 ml / min was used to purge the TGA equipment. The obtained graph is shown in the accompanying drawings.

[0243] In summary of the experimental investigations, 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide showed polymorphic behavior.

[0244] Form A is an anhydrous crystalline form with a melting onset of about 208°C and a melting enthalpy of about 111-119 J / g. The melting onset temperature is not significantly dependent on the heating rate, as demonstrated by DSC performed using different heating rates. Form A is only slightly hygroscopic, and the water absorption is maximum at 25°C and 95% relative humidity, at 0.6%.

[0245] In the range of about 24°C to 200°C, the TGA weight loss was about 0.3%.

[0246] In addition to Form A, several other designated solid forms were identified based on the distinct XRPD spectra each exhibited (as described in detail below).

[0247] Form B was obtained by evaporative crystallization in acetone. Form B showed a different XRPD pattern from Form A. DSC showed a melting onset of about 184°C, followed by recrystallization to Form A, which had a melting onset of about 206°C. TGA analysis of Form B showed a drying loss of 2.8% between about 28°C and 190°C. However, Form B could not be reproduced and further characterized.

[0248] Type C is obtained by slow evaporation in butanone. However, it is difficult to reproduce, and only Type A is obtained in crystallization trials. After heating at about 150°C, Type C is converted to Type A. The DSC of Type C shows an endothermic conversion to Type A at about 152°C to 159°C, after which Type A melts at 207°C to 208°C. This endothermic transition indicates the interconversion relationship between Type C and Type A. Based on competitive slurry experiments (which show that Type C is converted to Type A at 25°C), the transition temperature will be lower than 25°C.

[0249] Form D was obtained by slow evaporation in isopropanol. Form D shows a different XRPD pattern from the other forms, indicating that Form D is a pure crystalline phase. Form D begins to convert to Form A above about 190°C. The DSC of Form D shows a small endothermic event at about 70°C, followed by a melting onset of 204°C and a melting enthalpy of 106 J / g. The DSC data show a unidirectional transition relationship between Forms A and D. Competitive slurry experiments show that Form D will convert to Form A at 25°C.

[0250] Form E is obtained by hydrating H A Obtained by heating to about 70°C or exposure to 5% relative humidity for about 12 hours. Upon heating to 150°C, Form E converts to Form A. DSC of Form E shows a small exothermic event starting at about 115°C followed by melting at 207°C (melting point of Form A).

[0251] The data obtained indicate that forms B, C, D and E are metastable crystalline forms relative to form A.

[0252] The amorphous form was prepared by equilibrating the amorphous form in water at 25°C for 4 weeks or by equilibrating the A form in MeOH / water = 5 / 95 (a w >0.95) for about 3 weeks and the solid was collected by centrifugation and dried under ambient conditions to obtain the hydrate H A Hydrate H A It is a monohydrate with a calculated water content of 4.5%.

[0253] When the relative humidity drops from 40%RH to 5%RH at 25℃, the hydrate H A The hydrate H A After exposure to 5% RH for about 12 hours, the XRPD pattern changed to E-type.

[0254] At about 70 °C, hydrate H A It also converts to Form E, which then converts to Form A at 150°C.

[0255] The amorphous form is obtained by dissolving Form A in 1,4-dioxane and freeze-drying the resulting solution.

[0256] Form A and hydrate H A Slurry experiments in media with different water activities showed that at 25°C, type A w = 0.7 and lower water activity is stable, while hydrates are stable at a w = 0.9 and above. At 40°C, type A is stable at a w = 0.8 and lower water activity is stable, while hydrates are stable at a w >0.95 is stable.

Claims

1. A crystalline form of the compound 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

2. The crystalline form of the compound 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide according to claim 1, characterized in that An x-ray powder diffraction pattern comprising a representative peak at 9.6 ± 0.2 ° 2θ, in terms of ° 2θ, when measured at a temperature of about 25 °C.

3. A crystalline form of the compound 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, characterized in that An x-ray powder diffraction pattern comprising, with respect to 2θ, one or more representative peaks selected from the group consisting of 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ, and 31.7±0.2°2θ when measured at a temperature of about 25°C.

4. The crystalline form according to claim 1, which has an x-ray diffraction spectrum substantially the same as the x-ray powder diffraction spectrum shown in FIG1.

5. The crystal form according to claim 1, characterized in that A differential thermogravimetric curve measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min includes a single endothermic peak starting at about 208°C.

6. The crystalline form according to claim 1, which has a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG.

2.

7. The crystalline form of claim 1, having a decomposition point greater than 200°C and a loss on drying of about 0.3% in the range of 24°C-200°C as determined by thermogravimetric analysis.

8. The crystalline form according to claim 1, which has a thermogravimetric analysis (TGA) graph substantially the same as that shown in FIG3 .

9. A pharmaceutical composition, comprising the crystal form according to claim 1 and a pharmaceutically acceptable carrier.

10. Use of a substantially phase-pure crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide according to any one of claims 1 to 8 for the preparation of a medicament.

11. Use of a substantially phase pure crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide according to any one of claims 1 to 8 for the preparation of a medicament for treating a disorder ameliorated by an AKR1C3-dependent KARS inhibitor.

12. A method of treating a disorder ameliorated by an AKR1C3-dependent KARS inhibitor, the method comprising administering to a patient in need of such treatment an effective amount of a substantially phase-pure crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide according to any one of claims 1 to 8.

13. The use according to claim 10, or the method according to claim 11, wherein the disorder improved by the AKR1C3-dependent KARS inhibitor is selected from non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS).

14. The use or method of claim 12, wherein the disorder is non-small cell lung cancer (NSCLC).

15. A method for preparing crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, the method comprising the following steps: a) reacting 6'-fluoro-1'H-spiro[piperidin-4,2'-quinolin]-4'(3'H)-one with 4-fluorobenzyl isocyanate in a chlorinated solvent, optionally in the presence of a base; and b) isolating the solid formed.

16. A method for preparing crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, the method comprising the following steps: a) dissolving a certain amount of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide in a solvent; b) adding seed crystals of Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide; and c) isolating the solid formed.

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