Crystal Forms of an AKR1C3-Dependent KARS Inhibitor

Abstract

This application relates to a crystalline form of an inhibitor of AKR1C3-dependent KARS. [Chemical 1] TIFF2025524064000013.tif26170

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, and methods of obtaining such crystalline forms and methods of using such crystalline forms in the treatment of diseases and disorders typically ameliorated by inhibition of AKR1C3-dependent KARS. Such diseases and disorders can include solid tumors from cancers having genetic alterations in the NRF2 / KEAP1 pathway, such as 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 syndromes (MDS).

Background Art

[0003] Polymorphism indicates the existence of two or more crystalline forms 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 ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and bioavailability in vivo of that drug. Crystalline forms occur when substances of the same composition crystallize in different lattice arrangements, resulting in different thermodynamic properties and stabilities unique to a particular crystalline form. Crystalline forms can also include different hydrates or solvates of the same compound. When determining which form is preferred, numerous properties of the form are compared, and the preferred form is selected based on many physical property variables. In some situations where certain aspects such as ease of preparation and stability are emphasized, it may well be sufficient that one form is preferred. In other situations, different forms may be preferred for higher dissolution rates and / or better bioavailability.

[0005] Thus, this ability of a chemical substance to crystallize in two or more crystal forms can have a significant impact on the shelf life, solubility, formulation properties, and processing properties of a drug. In addition, the action of a drug can be affected by the polymorphs of the drug molecule. Different polymorphs can have different uptake rates in the body and can result in a lower or higher biological activity than desired. In extreme cases, an undesired polymorph may even exhibit toxicity. The occurrence of an unknown crystal form during manufacturing can have a major impact.

[0006] Whether a particular compound or salt of a compound forms polymorphs, whether any such polymorphs are suitable for commercial use in a therapeutic composition, or which polymorphs exhibit such desired properties still cannot be predicted. However, by understanding which crystal forms of a drug are possible in a particular case, researchers can maximize the desired properties of the compound, such as solubility, formulation properties, processing properties, and shelf life. Understanding these factors early in the development of a new drug can mean a more active, more stable, or less expensive to manufacture drug.

[0007] Therefore, there is a need to provide a solid form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide having physicochemical properties that enable the reliable manufacture of a safe and effective pharmaceutical product containing the same.

[0008] Example 40 of International Publication No. 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 formula (I): [Chemical formula] and has the structure of:

[0010] 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 (reduced form of nicotinamide adenine dinucleotide phosphate). (R)-6’-Fluoro-N-(4-fluorobenzyl)-4’-hydroxy-3’,4’-dihydro-1’H-spiro[piperidine-4,2’-quinoline]-1-carboxamide is disclosed in Example 152 of International Publication No. WO 2021 / 005586 Pamphlet and has the formula (II): [Chemical formula] and has the structure of:

[0011] Lysine t-RNA synthetase is an essential and ubiquitous enzyme in protein synthesis that is part of the multi-tRNA synthetase complex. AKR1C3 (also known as type 2 3α(17β)-hydroxysteroid dehydrogenase) is an NADP(H)-dependent ketosteroid reductase that is a member of the aldo-keto reductase (AKR) superfamily, which plays specific roles in steroid hormone metabolism and signaling as well as in xenobiotic detoxification.

[0012] However, International Publication No. WO 2021 / 005586 pamphlet 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.

[0013] The 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, which is generally useful for the treatment of diseases improved by the inhibition of AKR1C3-dependent KARS. Such diseases and conditions include cancer, 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

[0014] 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 the free form (i.e., non-salt form). In certain embodiments, the free form is the anhydrous form of the compound of formula (I). In one embodiment, the crystalline form comprises a form referred to herein as Form A.

[0015] Preferably, crystalline Form A is substantially pure. More preferably, crystalline Form A is substantially phase pure.

[0016] The designation "Form A" is a name used herein to identify a particular form and should not be considered limiting with respect to any other substance having similar or identical physical and chemical properties. Rather, these designations are to be understood as mere identifiers to be interpreted in accordance with the property evaluation information also presented herein.

[0017] 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.

[0018] In one aspect, the present invention also provides a process for producing crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, said process comprising a) reacting 6'-fluoro-1'H-spiro[piperidine-4,2'-quinoline]-4'(3'H)-one with 4-fluorobenzyl isocyanate in a chlorinated solvent, optionally in the presence of a base; b) isolating the solid formed; and

[0019] In yet another aspect, the present invention also provides a process for producing crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, said process comprising a) dissolving an amount of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, particularly in its form D, in a solvent; b) adding seed crystals of crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide; c) isolating the solid formed; and

[0020] In one aspect, the present invention provides a method of 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.

[0021] 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 the preparation of a medicament.

[0022] 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 the preparation of a medicament for the treatment of a disorder that can be treated by an AKR1C3-dependent KARS inhibitor.

[0023] In one aspect, the present invention also provides crystalline 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 of a disorder that can be treated by an AKR1C3-dependent KARS inhibitor.

[0024] Accordingly, crystalline Form A of the compound of formula (I) described herein is useful for the treatment of cancer, in particular, 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).

[0025] The crystalline form of the compound of formula (I) is particularly useful for the treatment of non-small cell lung cancer (NSCLC).

[0026] This specification also describes crystalline forms B, C, D, E and hydrate form H A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, which are also referred to as such. These crystalline forms can be used directly or indirectly in the preparation of pharmaceuticals.

[0027] In yet another aspect, the present invention provides the use of crystalline forms A, B, C, D, E and hydrate form H of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide A selected therefrom or mixtures thereof for the preparation of spray-dried compositions. BRIEF DESCRIPTION OF THE DRAWINGS

[0028]

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DETAILED DESCRIPTION OF THE INVENTION

[0029] A more detailed list of the XRPD peaks for each form is provided in Tables 1-5 of this specification, and these tables also provide the % relative intensity (I / I0×100). In an X-ray powder diffraction spectrum or pattern, it should be understood that there are inherent variations in the values measured at the angle 2θ (°2θ) as a result of, for example, instrument variability (including differences between instruments). Therefore, there are variations of up to ±0.2°2θ in the XRPD peak measurements, but it should be understood that such peak values are still considered to be representative of the specific solid-state forms of the crystalline substances described herein. Other measured values from the XRPD experiments and DSC / TGA experiments, such as relative intensity and water content, may vary as a result of, for example, sample preparation and / or storage and / or environmental conditions, but it should also be understood that these measured values are still considered to be representative of the specific solid-state forms of the crystalline substances described herein.

[0030] Definition As used herein, the terms "about" and "substantially" indicate that the values of the features, such as heat absorption amount, heat absorption peak, heat generation amount, baseline shift, etc., can vary. With respect to the X-ray diffraction peak position, "about" or "substantially" means that typical peak position and intensity variations are considered. For example, one of ordinary skill in the art would understand that the peak position (2θ) exhibits some variation between apparatuses, typically on the order of about 0.2°. In some cases, this variation can be higher than 0.2° depending on the calibration difference of the apparatus. Further, one of ordinary skill in the art would understand that the relative peak intensity exhibits variations due to variations between apparatuses as well as crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to one of ordinary skill in the art, and should be interpreted only as a qualitative measure. In the case of DSC, the observed temperature variations will depend on the rate of temperature change as well as the sample preparation technique and the particular equipment employed. Accordingly, the heat absorption / melting point values reported herein for DSC / TGA thermograms can vary by ±5°C (and still be considered characteristic of the particular crystalline form described herein). When used in connection with other features, such as weight percent (wt%), reaction temperature), the term "about" indicates a variation of ±5%.

[0031] The terms "crystalline form", or "crystalline modification", or "polymorphic form", or "polymorph" are used interchangeably herein. As used herein, "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions that form the crystal. Each polymorph has different thermodynamic stability, physical parameters, X-ray structure, and preparation methods.

[0032] As used herein, "amorphous" refers to a non-crystalline solid form of molecules, atoms, and / or ions. Amorphous solids do not exhibit a distinct X-ray diffraction pattern.

[0033] As used herein, "substantially pure", when used with respect to a form, means a compound having a purity greater than 90% by weight of the compound of formula (I), based on the weight of the compound, including purities greater than 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99% by weight and also including a purity equal to about 100% by weight. The remaining material includes other forms of the compound and / or reaction impurities and / or processing impurities resulting from its preparation. For example, a crystalline form of the compound of formula (I) may be considered to be substantially pure in that it has a purity greater than 90% by weight when measured by means known at present and generally accepted in the art, and the remaining material less than 10% by weight includes other forms of the compound of formula (I) and / or reaction impurities and / or processing impurities.

[0034] As used herein, "substantially phase pure", when used with respect to any crystalline form of the compound of formula (I), means a compound having a phase purity greater than 90% by weight of the compound of formula (I), based on the weight of the compound on an anhydrous basis, including purities greater than 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99% by weight and also including a purity equal to about 100% by weight. The terms "phase pure" or "phase purity" refer herein to the phase homogeneity with respect to a particular solid form of the compound of formula (I) and do not necessarily imply a high degree of chemical purity unless so stated explicitly. For example, X-ray powder diffraction (XRPD) can be used to determine phase purity according to methods known in the art in order to perform quantitative phase analysis using one or more approaches known in the art, such as external or internal standard methods which are direct comparisons of line (peak) characteristics due to different phases in a particular spectrum. However, XRPD quantification of phase purity can be complicated by the presence of amorphous materials. Accordingly, other methods which may be useful for determining phase purity include, for example, solid state NMR spectroscopy, Raman spectroscopy and / or infrared spectroscopy. Those skilled in the art will readily understand how to employ these methods and these additional (or alternative) methods for determining phase purity.

[0035] 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 phase purity of greater than 90 weight % of the compound of formula (I) based on the weight of the compound on an anhydrous basis, including purities greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and including a purity equal to about 100 weight %. The remaining material generally includes other compounds, such as 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, a crystalline form of a compound of formula (I) is considered to be substantially chemically pure when determined to have a chemical purity of greater than about 90 weight % as measured by standard and generally accepted methods known in the art, and the remaining less than about 10 weight % comprises other substances, 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, such as 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 how to employ these and additional (or alternative) methods to determine these methods and chemical purity.

[0036] 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 act of introducing the one or more crystals of the crystalline compound of formula (I) into an environment (e.g., but not limited to, a solution, mixture, suspension, or dispersion), thereby resulting in the formation of more crystals or the growth of the introduced crystals of the crystalline compound of formula (I).

[0037] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that can elicit a biological or medical response in a subject, such as, for example, a decrease or inhibition of enzyme or protein activity, or an improvement of symptoms, a remission of a condition, a slowing or delaying of the progression of a disease, or a prevention of a disease. In one non-limiting embodiment, the term "therapeutically effective amount" means that when administered to a subject, it is effective to (1) at least partially alleviate, inhibit, prevent, and / or improve (i) a disease mediated by KARS, or (ii) a disease sensitive to KARS inhibition, or (iii) a condition, disorder, or disease characterized by (normal or abnormal) activity of KARS, or (2) reduce or inhibit a disease sensitive to KARS inhibition. The present invention further provides a method of treating or preventing a disease and / or disorder associated with high AKR1C3 expression or sensitivity to KARS inhibition, the method comprising administering to a subject in need thereof an effective amount of an AKR1C3-dependent KARS inhibitor.

[0038] 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 another embodiment, the subject is a human.

[0039] As used herein, a subject "in need of" or "in need thereof" treatment is a subject who would benefit biologically, medically, or in terms of quality of life from such treatment.

[0040] As used herein, the terms "a", "an", "the", and similar terms used in connection with the present invention (especially in connection with the claims) should be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by the context.

[0041] Unless otherwise indicated herein or unless clearly inconsistent with the context, all methods described herein can be performed in any suitable order. The use of any examples or exemplary language (e.g., "such as") provided herein is merely intended to clarify the invention and is not otherwise intended to limit the scope of the claimed invention.

[0042] As used herein, the terms "inhibit", "inhibiting", or "inhibition" refer to the reduction or suppression of a given symptom, sign, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0043] As used herein, the terms "treat", "treating", or "treatment" of any disease or disorder refer to alleviating or ameliorating the disease or disorder (i.e., delaying or preventing the onset of at least one manifestation of the disease or its clinical symptoms), or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be recognizable to the patient. In one embodiment, "treat" or "treating" refers to delaying the progression of a disease or disorder.

[0044] As used herein, the terms "prevent", "preventing", or "prevention" of any disease or disorder refer to prophylactic treatment of the disease or disorder or delaying the onset of the disease or disorder.

[0045] The term "comprising" also includes "including" and "consisting of", for example, a composition comprising X can consist of only X or can include additional components, such as X and Y.

[0046] As used herein, the term "combination" refers to a fixed combination or combination administration as a single dosage form, and in the latter case, the crystalline form of the compound of formula (I) and the combination partner can be administered simultaneously independently or separately within a time interval, in particular, these time intervals enable the combination partners to exhibit a synergistic effect, such as a multiplicative effect. The single components can be packaged in a kit or individually packaged. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration.

[0047] Terms such as "co-administration" or "combination administration" as used herein are meant to encompass the administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens where the agents are not necessarily administered by the same route of administration or simultaneously.

[0048] The terms "pharmaceutical combination" and "combination formulation" are used interchangeably and refer to a fixed combination or non-fixed combination or a kit of parts for combination administration as a single dosage form, and in the latter case, two or more therapeutic agents can be administered simultaneously or separately independently within a time interval, in particular, the above time intervals enable the combination partners to exhibit a synergistic effect, such as a multiplicative effect. The term "fixed combination" means that both a crystalline form of the compound of formula (I) and a combination partner (i.e., an immunotherapy agent) are administered to a patient simultaneously in the form of a single entity or dosage form. The term "non-fixed combination" means that the crystalline form of the compound of formula (I) and the combination partner (i.e., an immunotherapy agent) are administered to a patient as separate entities simultaneously, in parallel or sequentially without a specific time limit, and such administration provides two compounds at therapeutically effective levels in the patient's body. The latter also applies to cocktail therapies, e.g., the administration of three or more therapeutic agents. In a preferred embodiment, the pharmaceutical combination is a non-fixed combination.

[0049] The term "combination therapy" refers to the administration of two or more therapeutic agents for treating KARS-related diseases as described in the present disclosure. Such administration includes co-administration of the above therapeutic agents in a substantially simultaneous manner, for example, in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration includes co-administration of the individual active ingredients in multiple or separate containers (e.g., tablets, capsules, powders, and liquids). The powders and / or liquids can be reconstituted or diluted to the desired dosage prior to administration. Further, such administration also includes the sequential use of each type of therapeutic agent either almost simultaneously or at different times. In any case, the treatment regimen provides a beneficial effect of the drug combination for treating the conditions or disorders described herein.

[0050] Crystal form: The present disclosure relates to a crystal form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (the compound of formula (I)) as described and characterized herein.

[0051] In one embodiment, the present disclosure provides an anhydrous crystal form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0052] In one embodiment, the present disclosure provides a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (Form A) having an X-ray powder diffraction (XRPD) pattern that includes a representative peak at 9.6 ± 0.2° 2θ, measured at a temperature of about 25°C, with respect to 2θ. In another embodiment, the XRPD pattern further includes 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 another embodiment, the XRPD pattern further includes 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 yet another embodiment, the XRPD pattern further includes 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 still another embodiment, the XRPD pattern further includes one or more additional representative peaks selected from 22.4 ± 0.2° 2θ, 27.3 ± 0.2° 2θ, and 31.7 ± 0.2° 2θ. Accordingly, the XRPD pattern of crystalline Form A of the compound of formula (I) includes 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.

[0053] The XRPD pattern of crystalline Form A can include one or more (e.g., 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.

[0054] In another aspect of the above embodiment, crystalline 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, crystalline form A of the compound of formula (I) is characterized by an X-ray powder diffraction pattern comprising three or more 2θ values (CuKαλ=1.54184 Å) 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, crystalline form A of the compound of 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, crystalline form A of the compound of 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.

[0055] In yet another aspect of the above embodiment, crystalline form A of the compound of formula (I) has an XRPD pattern substantially shown in Figure 1.

[0056] 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 thermally characterized. In one embodiment, crystalline Form A of the compound of formula (I) has a thermal profile that includes a single endothermic peak (corresponding to melting) starting at about 208 °C as measured by differential scanning calorimetry (DSC) at a heating rate of 10 °C / min.

[0057] In another embodiment, crystalline Form A of the compound of formula (I) has a DSC thermogram substantially shown in Figure 3. The hydrated form can give rise to different thermograms depending on the instrument parameters (with respect to peak shape and profile), and thus it should be understood that the same substance can have thermograms that appear substantially different from each other if the data is generated on two different instruments.

[0058] In another embodiment, crystalline Form A of the compound of formula (I) has a thermogravimetric analysis (TGA) plot substantially the same as that shown in Figure 3. The weight loss by TGA is about 0.3% in the range of about 24 to 200 °C. Thermal decomposition occurred at 240 °C.

[0059] In yet another embodiment, crystalline Form A is substantially pure.

[0060] In still another embodiment, crystalline Form A is substantially chemically pure.

[0061] In yet still another embodiment, crystalline Form A is substantially phase pure.

[0062] In one aspect, the present invention provides a process for producing crystalline Form A of 6’-fluoro-N-(4-fluorobenzyl)-4’-oxo-3’,4’-dihydro-1’H-spiro[piperidine-4,2’-quinoline]-1-carboxamide, said process comprising a) Reacting 6'-fluoro-1'H-spiro[piperidine-4,2'-quinolin]-4'(3'H)-one with 4-fluorobenzyl isocyanate in a chlorinated solvent, optionally in the presence of a base; b) Isolating the formed solid; and comprising.

[0063] In one embodiment of the process, the reaction is carried out in the presence of a base. In one embodiment, the base is an amine. In another embodiment, the base is a tertiary amine. In another embodiment, the base is N,N-diisopropylethylamine.

[0064] In one embodiment of the process, the chlorinated solvent is dichloromethane.

[0065] In one embodiment of the process, the reaction is carried out at a temperature of about 20°C to about 50°C. In one embodiment of the process, the reaction is carried out at a temperature of about 20°C to about 30°C. In one embodiment of the process, the reaction is carried out at a temperature of about 23°C to about 28°C.

[0066] In another aspect, the present invention also provides a process for producing crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, said process comprising: a) Dissolving an amount of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide (especially its form D) 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; c) Isolating the formed solid; and comprising.

[0067] In one embodiment of the process, the solvent comprises a non-chlorinated solvent.

[0068] In one embodiment of the process, the non-chlorinated solvent is selected from THF, acetone, water, acetonitrile, dioxane, ethanol, methanol, butanone or mixtures thereof. In another embodiment of the process, the solvent comprises a mixture of solvents comprising a non-chlorinated solvent. In one embodiment, the mixture of solvents comprises acetone and water. In one embodiment, the solvent in step a) of the process is a mixture of acetone:water 85:15 w / w. In one embodiment, step a) of the process is carried out at a temperature of about 50 °C to about 60 °C (preferably about 50 °C).

[0069] In one embodiment of the process, the seed crystal of step b) is added as a dispersion in a mixture of acetone and water. In one embodiment of the process, the dispersion is in a mixture of acetone:water 40:60 w / w. In one embodiment of the process, step b) is carried out at a temperature of about 40 °C, subsequently optionally cooled to 20 °C and then optionally water is added to make the solvent mixture 40:60 w / w acetone:water.

[0070] 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 particular embodiment of this aspect, the present invention relates to a pharmaceutical composition comprising crystalline form A and one or more pharmaceutically acceptable carriers, diluents or excipients. In another embodiment, the present invention relates to a pharmaceutical composition comprising crystalline form A in a substantially phase-pure form.

[0071] In yet another embodiment, the present invention relates to a pharmaceutical composition comprising crystalline 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.

[0072] In another aspect, the present invention relates to a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of the 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 certain embodiments of this aspect, the present invention relates to a pharmaceutical combination comprising crystalline form A and one or more other therapeutic agents. In another embodiment, the present invention relates to a pharmaceutical combination comprising crystalline form A in a substantially phase-pure form and one or more other therapeutic agents. In another embodiment, the present invention relates to a pharmaceutical combination comprising crystalline form A in a substantially phase-pure form and one or more other therapeutic agents.

[0073] In yet another embodiment, the present invention relates to a pharmaceutical combination comprising crystalline form A and further comprising at least one other solid 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.

[0074] 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 anti-cancer agents or chemotherapeutic agents, anti-emetic agents (or anti-nausea agents), chemotherapeutic agents, analgesics, cytoprotective agents, and combinations thereof.

[0075] In some embodiments, the 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 for treating a disease, such as cancer.

[0076] In another embodiment, for treating a disease, such as cancer, one or more chemotherapeutic agents are used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, and examples of the chemotherapeutic agents include, but are not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (ActinomycinD, Cosmegan), daunorubicin hydrochloride (Cerubidine (registered trademark)), daunorubicin citrate liposome injection (DaunoXome (registered trademark)), dexamethasone, docetaxel (Taxotere (registered trademark)), doxorubicin hydrochloride (Adriamycin (registered trademark), Rubex (registered trademark)), etoposide (Vepesid (registered trademark)), fludarabine phosphate (Fludara (registered trademark)), 5-fluorouracil (Adrucil (registered trademark), Efudex (registered trademark)), flutamide (Eulexin (registered trademark)), tiazofurin, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea (registered trademark)), idarubicin (Idamycin (registered trademark)), ifosfamide (IFEX (registered trademark)), irinotecan (Camptosar (registered trademark)), L-asparaginase (ELSPAR (registered trademark)), leucovorin calcium, melphalan (Alkeran (registered trademark)), 6-mercaptopurine (Purinethol (registered trademark)), methotrexate (Folex (registered trademark)), mitoxantrone (Novantrone (registered trademark)), Myotarg, paclitaxel (Taxol (registered trademark)), Phoenix (yttrium 90 / MX-DTPA), pentostatin, polifeprosan 20·carmustine implant (Gliadel (registered trademark)), tamoxifen citrate (Nolvadex (registered trademark)), teniposide (Vumon (registered trademark)), 6-thioguanine, thiotepa, tirapazamine (Tirazone (registered trademark)), topotecan hydrochloride for injection (Hycamptin (registered trademark)), vinblastine (Velban (registered trademark)), vincristine (Oncovin (registered trademark)), vinorelbine (Navelbine (registered trademark)), epirubicin (Ellence (registered trademark)), oxaliplatin (Eloxatin (registered trademark)), exemestane (Aromasin (registered trademark)), letrozole (Femara (registered trademark)) and fulvestrant (Faslodex (registered trademark)) are mentioned.

[0077] In other embodiments, the compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof is used in combination with one or more other anti-HER2 antibodies, such as trastuzumab, pertuzumab, margetuximab or HT-19 described above, or other anti-HER2 conjugates, such as ado-trastuzumab emtansine (also known as Kadcyla® or T-DM1).

[0078] In other embodiments, the compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof is used in combination with one or more tyrosine kinase inhibitors including, but not limited to, EGFR inhibitors, Her3 inhibitors, IGFR inhibitors and Met inhibitors, for treating diseases such as cancer.

[0079] For example, tyrosine kinase inhibitors include, but are not limited to, erlotinib hydrochloride (Tarceva®); linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT869, available from Genentech); sunitinib malate (Sutent®); 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, described in U.S. Patent No. 6,780,996); dasatinib (Sprycel®); pazopanib (Votrient®); sorafenib (Nexavar®); Zactima (ZD6474) and imatinib or imatinib mesylate (Gilvec® and Gleevec®).

[0080] Examples of epidermal growth factor receptor (EGFR) inhibitors include, but are not limited to, erlotinib hydrochloride (Tarceva (registered trademark)), gefitinib (Iressa (registered trademark)); N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3’’S’’)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, Tovok (registered trademark)); vandetanib (Caprelsa (registered trademark)); lapatinib (Tykerb (registered trademark)); (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); mobitinib (TAK165); pelitinib (EKB569); afatinib (Gilotrif (registered trademark)); 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, CAS187724-61-4).

[0081] Examples of EGFR antibodies include, but are not limited to, cetuximab (Erbitux®); panitumumab (Vectibix®); matuzumab (EMD-72000); nimotuzumab (hR3); zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1) and ch806 (mAb-806, CAS 946414-09-1).

[0082] Examples of 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 as described in PCT Publication No. WO 05 / 028443 pamphlet); lapatinib or lapatinib ditosylate (Tykerb®); (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, CAS850140-72-6); 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, CAS714971-09-2); 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).

[0083] Examples of 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.

[0084] Examples of MET inhibitors include, but are not limited to, cabozantinib (XL184, CAS 849217-68-1); foretinib (GSK1363089, former name: XL880, CAS 849217-64-7); cibantinib (ARQ197, CAS 1000873-98-2); 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 (AMG 458); crizotinib (Xalkori (registered trademark), PF-02341066); (3Z)-5-(2,3-dihydro-1H-indole-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-1Hpyrazol-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-dioxan-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]sulfamide (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) are included.;

[0085] Examples of 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. For example, see Yee, JNCI, 104;975 (2012) for consideration.

[0086] In another embodiment, the compound of formula (I) of the present disclosure is used in combination with one or more growth signaling pathway inhibitors for treating a disease, such as cancer, and such inhibitors include, but are not limited to, MEK inhibitors, BRAF inhibitors, PI3K / Akt inhibitors, SHP2 inhibitors, and also mTOR inhibitors and CDK inhibitors.

[0087] For example, mitogen-activated protein kinase (MEK) inhibitors include, but are not limited to, XL-518 (also known as GDC-0973, CAS number 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, described in PCT Publication No. WO 2000 / 035436 pamphlet); N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (also known as PD0325901, described in PCT Publication No. WO 2002 / 006213 pamphlet); 2,3-bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126, described in U.S. Patent 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, described in PCT Publication No. WO 2007 / 014011 pamphlet); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecin-1,7(8H)-dione (also known as E6201, described in PCT Publication No. WO 2003 / 076424 pamphlet); 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, CAS 1035555-63-5); pimasertib (AS-703026, CAS 1204531-26-9) and trametinib dimethyl sulfoxide (GSK-1120212, CAS 1204531-25-80).

[0088] BRAF inhibitors include, but are not limited to, vemurafenib (or Zelboraf®), GDC-0879, PLX-4720 (available from Symansis), dabrafenib (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, regorafenib (BAY 73-4506), CCT239065, or sorafenib (or sorafenib tosylate or Nexavar®) or ipilimumab (or MDX-010, MDX-101 or Yervoy).

[0089] Examples of 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, picrelisib or piktolisib; 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-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione (GSK1059615, CAS 958852-01-2); (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, CAS 154447-36-6); (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 BYL719 or alpelisib); 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).

[0090] Examples of mTOR inhibitors include, but are not limited to, temsirolimus (Torisel®); ridafolimus (official name: deforolimus, (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]hexatriaconta-16,24,26,28-tetraene-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669, described in PCT Publication No. WO 03 / 064383 pamphlet); everolimus (Afinitor® or RAD001); rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3); (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, CAS 1013101-36-4) 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).

[0091] Examples of CDK inhibitors include, but are not limited to, palbociclib (also known as PD-0332991, Ibrance®, 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one).

[0092] In yet another embodiment, for treating a disease, such as cancer, a 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 apoptosis promoters, and such apoptosis promoters include, but are not limited to, IAP inhibitors, BCL2 inhibitors, MCL1 inhibitors, TRAIL agents, CHK inhibitors.

[0093] 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 brochures, US Patent Application Publication Nos. 2006 / 0014700, 2006 / 0025347, WO 06 / 069063, WO 06 / 010118, WO 06 / 017295 and WO 08 / 134679 brochures, which are all incorporated herein by reference.

[0094] Examples of 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, described in the pamphlet of PCT Publication No. WO 09 / 155386); tetrocarcin A; antimycin; gossypol ((-)BL-193); obatoclax; ethyl-2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1); oblimersen (G3139, Genasense (registered trademark)); 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).

[0095] Examples of apoptosis-promoting receptor agonists (PARAs) that include DR4 (TRAILR1) and DR5 (TRAILR2) include, but are not limited to, dulalermin (AMG-951, RhApo2L / TRAIL); mapatumumab (HRS-ETR1, CAS 658052-09-6); lexatumumab (HGS-ETR2, CAS 845816-02-6); apomab (Apomab (registered trademark)); conatumumab (AMG655, CAS 896731-82-1) and tigatuzumab (CS1008, CAS 946415-34-5, available from Daiichi Sankyo).

[0096] 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, CAS 891494-63-6); 5-(3-fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-aminodaunomycin (7-AAD), isogranulatimide, dehydrobromohymenialdisine; 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-dii ndolo[1,2,3-FG:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1,3(2H)-dione (SB-218078, CAS 135897-06-2) and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL (SEQ ID NO: 33)) and CBP501 ((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr).

[0097] In one embodiment, the present invention relates to a method of 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 in need thereof a therapeutically effective amount 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, alone or in combination with one or more other therapeutic agents.

[0098] In another embodiment, the present invention relates to a method of 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 said subject a pharmaceutical composition as described herein, alone or in combination with one or more other therapeutic agents.

[0099] In another embodiment, the present invention relates to a method of 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 said subject a pharmaceutical combination as described herein.

[0100] In one embodiment, the present invention relates to the use 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, alone or in combination with one or more other therapeutic agents, for the treatment or prevention of a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor.

[0101] 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 with an AKR1C3-dependent KARS inhibitor.

[0102] 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 with an AKR1C3-dependent KARS inhibitor.

[0103] In one embodiment, the present invention relates to a method of treatment, use, compound for use, or combination for use as described herein, and the diseases or disorders that can be treated with an AKR1C3-dependent KARS inhibitor are 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).

[0104] The characteristics of Form A are described herein and with reference to the figures.

[0105] 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 and are referred to herein as Forms B, C, D, and E. A hydrate form referred to herein as H A has also been observed. The properties of these additional forms are described herein and with reference to the figures.

[0106] In one aspect, the present invention relates to the use of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide in the form of crystal forms A, B, C, D, E and hydrate form H for the preparation of a pharmaceutical product. A The present invention also provides the use of a crystal form selected from or a mixture thereof.

[0107] In one aspect, the present invention relates to the use of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide in the form of crystal forms A, B, C, D, E and hydrate form H for the preparation of a spray-dried composition. A The present invention provides the use of a crystal form selected from or a mixture thereof. In an embodiment of this aspect, the present invention provides the use of crystal form A for the preparation of a spray-dried composition. The composition can be used for the preparation of a pharmaceutical product. The pharmaceutical product can comprise the spray-dried composition.

[0108] The spray-dried composition can be prepared by dissolving a crystal form selected from or a mixture thereof in a suitable solvent and subjecting the solution to spray drying. In one embodiment, the suitable solvent is an organic solvent, water or a combination thereof. In another embodiment, suitable organic solvents include, but are not limited to, acetone, ethanol, methanol and propanol. In yet another embodiment, the preferred solvent comprises a mixture of acetone and water. A

[0109] Pharmaceutical Compositions, Dosages and Administration ​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 formulated into a pharmaceutical composition further containing at least one pharmaceutically acceptable excipient, and often contains at least two or more pharmaceutically acceptable excipients. Some suitable excipients are disclosed herein. Without departing from the spirit and scope of the present application, other excipients known in the art can be used.

[0110] In some embodiments, the present invention uses a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0111] As used herein, the term "pharmaceutically acceptable excipient" includes any solvent, carrier, diluent, dispersion medium, coating agent, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent, antioxidant), isotonic agent, absorption delaying agent, salts, drug stabilizer, binder, additive, filler, disintegrant, lubricant, sweetening agent, flavoring agent, pigment and the like and combinations thereof known to those skilled in the art (see, e.g., Remington’s Pharmaceutical Sciences, 18th EdMack Printing Company, 1990, pp. 1289-1329). It should be understood that the use of any conventional excipient in any therapeutic or pharmaceutical composition is contemplated by this application, except where the conventional excipient is incompatible with the active ingredient.

[0112] The pharmaceutical composition can be formulated for specific routes of administration such as oral administration, parenteral administration, and rectal administration. In addition, the pharmaceutical composition of the present invention can be formulated in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or 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 buffering agents and adjuvants (for example, solvents, preservatives, stabilizers, wetting agents, emulsifying agents, and fillers, etc.).

[0113] Typically, the pharmaceutical composition contains the active ingredient with, for example, a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine, b) lubricants such as silica, talcum, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol, and in the case of tablets, additionally, c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, if necessary, d) carriers such as aqueous vehicles containing cosolvating substances such as captisol, PEG, glycerin, cyclodextrin, etc., e) disintegrants such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or f) absorbents, colorants, flavorants, and sweeteners and is a tablet or capsule containing at least one excipient such as these.

[0114] Tablets can be film-coated or enteric-coated according to methods known in the art.

[0115] Preferably, the compound or composition is prepared for oral administration, for example, as tablets or capsules, and is optionally packaged in a multi-dose format suitable for storing and / or dispensing pharmaceutical dosage units. Examples of suitable packaging include, but are not limited to, sealed foil, dosage unit containers (e.g., vials), blister packs, and strip packs.

[0116] Tablets may contain the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, delaying agents such as glyceryl monostearate or glyceryl distearate can be used. Oral formulations may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, for example arachis oil, liquid paraffin or olive oil.

[0117] The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising a compound of the present invention as an active ingredient, since water can promote the decomposition of certain compounds.

[0118] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous components or components with low water content and low moisture conditions or low humidity conditions. The anhydrous pharmaceutical compositions can be prepared and stored so as to maintain their anhydrous nature. Thus, the anhydrous compositions are preferably packaged using substances known to prevent exposure to water so that the compositions can be included in suitable prescription kits. Examples of suitable packaging include, but are not limited to, sealed foil, plastic, unit dose containers (e.g., vials), blister packs, and strip packs.

[0119] 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, would decompose. Such agents, herein referred to as "stabilizers", include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers.

[0120] The pharmaceutical compositions or combinations of the present invention can be in unit doses of from about 1 to 1000 mg of active ingredient, or from about 1 to 500 mg, or from about 1 to 250 mg, or from about 1 to 150 mg, or from 0.5 mg to 100 mg, or from about 10 to 50 mg of active ingredient, for a subject of about 50 - 70 kg. Preferably, the pharmaceutical compositions or combinations of the present invention can be in unit doses of about 10 mg, about 25 mg or about 50 mg. The therapeutically effective dosage or amount of the compound, pharmaceutical composition or combination thereof depends on the species, body weight, age and individual condition of the subject, the disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient necessary to prevent, treat or inhibit the progression of the disorder or disease.

[0121] The dosage characteristics listed above can advantageously be demonstrated in in vitro and in vivo tests using mammals such as mice, rats, dogs, monkeys or isolated organs, tissues and their preparations. The compounds of the present invention can be applied in vitro in the form of a solution, for example preferably in an aqueous solution, and in vivo either enterally or parenterally, preferably intravenously, for example as a suspension or in an aqueous solution. The dosage in vitro can be in the range of about 10 -3 mol to 10 -9 mol concentration. The therapeutically effective amount in vivo can be in the range of about 0.1 to 500 mg / kg or about 1 to 100 mg / kg depending on the route of administration. Preferably, the therapeutically effective amount in vivo is in the range of about 10 mg to about 200 mg per day, for example about 10 mg, about 20 mg, about 25 mg, about 35 mg, about 50 mg, about 100 mg or about 200 mg per day. Preferably, the therapeutically effective amount in vivo is selected from about 10 mg, about 35 mg, about 50 mg or about 100 mg once a day. Preferably, the therapeutically effective amount in vivo is also selected from about 10 mg, about 25 mg, about 50 mg or about 100 mg twice a day.

[0122] In other embodiments, a pharmaceutical composition is provided that includes at least one crystalline form (e.g., Form A, Form E, Form H A or a mixture thereof, preferably Form A) according to the embodiments described above herein, and at least one pharmaceutically acceptable carrier.

[0123] Accordingly, in one embodiment of the present disclosure, a crystalline form (Form A, Form E or Form H A or preferably Form A) of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide is provided in a substantially phase-pure form. This crystalline form (Form A, Form E or Form H AAlternatively, or preferably using Form A), a pharmaceutical composition can be prepared which may further comprise one or more pharmaceutically acceptable excipients.

[0124] Combination: 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 can be administered simultaneously with, before or after one or more other therapeutic agents. The crystalline forms of the present invention can be administered together, individually, by the same or different routes of administration as the other agents or in the same pharmaceutical composition.

[0125] 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 can be administered as the sole active ingredient or together with other agents, such as anti-cancer agents or chemotherapeutic agents, anti-emetic agents (or anti-nausea agents), chemotherapeutic agents, analgesics, cytoprotective agents, and combinations thereof (e.g., as adjuvants thereto). 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 used in combination with the following: anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (ActinomycinD, Cosmegan), daunorubicin hydrochloride (Cerubidine (registered trademark)), daunorubicin citrate liposome injection (DaunoXome (registered trademark)), dexamethasone, docetaxel (Taxotere (registered trademark)), doxorubicin hydrochloride (Adriamycin (registered trademark), Rubex (registered trademark)), etoposide (Vepesid (registered trademark)), fludarabine phosphate (Fludara (registered trademark)), 5-fluorouracil (Adrucil (registered trademark), Efudex (registered trademark)), flutamide (Eulexin (registered trademark)), tiazofurin, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea (registered trademark)), idarubicin (Idamycin (registered trademark)), ifosfamide (IFEX (registered trademark)), irinotecan (Camptosar (registered trademark)), L-asparaginase (ELSPAR (registered trademark)), leucovorin calcium, melphalan (Alkeran (registered trademark)), 6-mercaptopurine (Purinethol (registered trademark)), methotrexate (Folex (registered trademark)), mitoxantrone (Novantrone (registered trademark)), Myotarg, paclitaxel (Taxol (registered trademark)), nab-paclitaxel (Abraxane (registered trademark)), Phoenix (yttrium 90 / MX-DTPA), pentostatin, polifeprosan 20·carmustine implant (Gliadel (registered trademark)), tamoxifen citrate (Nolvadex (registered trademark)), teniposide (Vumon (registered trademark)), 6-thioguanine, thiotepa, tirapazamine (Tirazone (registered trademark)), topotecan hydrochloride for injection (Hycamptin (registered trademark)), vinblastine (Velban (registered trademark)), vincristine (Oncovin (registered trademark)) and vinorelbine (Navelbine (registered trademark)).

[0126] Therapeutic kit In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises 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 means for separately holding said compositions, such as a container, a divided bottle or a divided foil packet. An example of such a kit is a blister pack as commonly used for packaging tablets, capsules and the like.

[0127] The kits of the present invention can be used to administer different dosage forms, e.g., orally and parenterally, to administer separate compositions at different dosing intervals or to titrate separate compositions against each other. To assist with compliance, the kits of the present invention typically include instructions for administration.

[0128] 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 can be manufactured and / or formulated by the same or different manufacturers. Further, (i) before marketing a combination formulation to physicians (e.g., in the case of a kit comprising a crystalline form of the compound of formula (I) and other therapeutic agents), (ii) immediately prior to administration by the physician himself (or under the guidance of the physician), (iii) in the patient himself, e.g., when sequentially administering a crystalline form of the compound of formula (I) and other therapeutic agents, 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 can be combined into a combination therapy.

[0129] Accordingly, the present invention provides the use 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 for treating a disease or condition (e.g., cancer) that can be treated by an AKR1C3-dependent KARS inhibitor, and the pharmaceutical is prepared for administration together 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 pharmaceutical 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.

[0130] The present invention provides a crystalline form (preferably Form A) of the compound 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide for use in a method of treating or preventing a disease or condition (e.g., cancer) treatable by an AKR1C3-dependent KARS inhibitor, and 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 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) treatable by an AKR1C3-dependent KARS inhibitor, and the other therapeutic agent is prepared for administration together with 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. 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 of treating a disease or condition (e.g., cancer) treatable by an AKR1C3-dependent KARS inhibitor, and 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) treatable by an AKR1C3-dependent KARS inhibitor, and the other therapeutic agent is administered together with the crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0131] 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 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 (e.g., within 24 hours) treated 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 (e.g., within 24 hours) treated with a crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.

[0132] Preparation of the crystalline form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide: The crystalline form can be prepared by various methods such as crystallization or recrystallization from a suitable solvent, sublimation, growth from the melt, solid-state transformation from another phase, crystallization from supercritical fluids, and jet spraying. Techniques for crystallization or recrystallization of the crystalline form from a solvent or solvent mixture include, for example, evaporation of the solvent, lowering the temperature of the solvent or solvent mixture, seeding the supersaturated solvent mixture with the molecule and / or salt, lyophilization of the solvent mixture, and addition of an anti-solvent (counter solvent) to the solvent mixture. Exemplary methods for preparing the crystalline forms described herein are detailed below.

[0133] The crystallization of drugs (including polymorphs), methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2 nd Edition, SSCI, West Lafayette, Indiana (1999).

[0134] In the case of crystallization techniques using solvents, the choice of solvent 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 obtain a solution, and then an anti-solvent can be added to reduce the solubility of the compound in the solution and form crystals. An anti-solvent is a solvent in which the compound has low solubility.

[0135] In one method of preparing crystals, the compound can be suspended and / or agitated in a suitable solvent to obtain a slurry, which can be heated to promote dissolution. The term "slurry" as used herein means a saturated solution of the compound, which may also include an additional amount of the compound to obtain a heterogeneous mixture of the compound and the solvent at a given temperature. This can also be referred to as a suspension.

[0136] Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a particular polymorph or to control the particle size distribution of the crystalline product. Therefore, the calculation of the amount of seed required depends on, for example, the size of the available seed and the desired size of the average product particles, as described in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, smaller seeds are required to efficiently control the growth of crystals in a batch. Smaller seeds can be produced by sieving, grinding, or micronizing larger crystals, or by microcrystallization of the solution. Care should be taken to ensure that the crystallization degree of the desired crystal form does not change (i.e., change to an amorphous or another polymorph) during the grinding or micronizing of the crystals.

[0137] The cooled crystallization mixture can be filtered under vacuum, and the isolated solid can be washed with a suitable solvent such as a cold recrystallization solvent and dried under a nitrogen purge to obtain the desired crystalline form. The isolated solid can be analyzed by suitable spectroscopic or analytical techniques, such as solid nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction or the like, to ensure the formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an isolated yield amount of greater than about 70% by weight, preferably greater than 90% by weight, based on the weight of the compound initially used in the crystallization procedure. Optionally, this product can be co-ground or passed through a mesh screen to remove chunks of the product.

[0138] Alternatively, the crystalline form can be prepared directly from the reaction medium of the final step 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 which 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide can be crystallized in the final manufacturing step. In addition, the crystalline form can also be obtained by distillation or solvent addition techniques.

[0139] It should be understood that in addition to the methods briefly described below, various analytical methods can be used for the characterization of any of the materials described herein.

[0140] The following non-limiting examples illustrate the present disclosure.

Example

[0141] Example 1: Preparation of the anhydrous crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide Dichloromethane (DCM) (10 vol.) and Intermediate 2 as the TFA salt (International Publication No. WO 2021 / 005586 pamphlet) (1.0 eq.) were charged into a clean round-bottom flask at 23 ± 5 °C. The reaction mass was stirred for 10 minutes. Next, DIPEA was added to the reaction mass at 23 ± 5 °C, and finally 4-fluorobenzyl isocyanate was added to the reaction mass. The reaction was maintained at this temperature for 16 hours. After completion of the reaction (determined by HPLC), the reaction mass was filtered, the wet solid was washed with hexane (5 vol.), the solid was suction dried over 30 minutes, then the solid was returned to the round-bottom flask, isopropyl alcohol (IPA) (5 vol.) was added, and the mixture was stirred at 23 ± 5 °C for 1 hour. Next, the solid was filtered, the wet solid was washed with hexane (5 vol.), and dried at 50 °C for 10 hours on a vacuum tray dryer (VTD). Since a trace amount of DCM was detected in the final compound by 1H-NMR, the mass was repurified with hexane and dried for a longer time.

[0142] The obtained product was characterized as crystalline form A by XRPD, TGA and DSC.

[0143] Alternatively, Form A can be prepared as follows: An amount corresponding to 15% by weight of Form D of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide is dissolved in a mixture of acetone and water (85:15 w / w) while stirring at 50 °C. After filtering the solution (clarifying filtration), the crystallization apparatus is filled and stirring is continued at 50 °C for at least 15 minutes. Next, the temperature is lowered to 40 °C, and a seed suspension consisting of seed crystals (micronized) of Form A dispersed in a mixture of acetone and water (40:60 w / w) is added to the system. After seeding, the mixture is stirred at 40 °C for at least 30 minutes, then the system is cooled to 20 °C at a rate of 0.2 °C / min and held there with stirring for at least 60 minutes. Next, water is continuously added over 360 minutes such that the composition of the solvent mixture becomes acetone:water of 40:60 w / w. Finally, after the addition of water is complete, the above system is stirred for at least 60 minutes, all at 20 °C. The solid is isolated from the mixture by filtration, and the filter cake is washed with a mixture of acetone and water (40:60 w / w). The wet cake is taken out and dried in an oven at 50 °C under vacuum. Then, the material is sieved using a hand sieve with a mesh size of 1 mm to obtain Form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide as a yellow solid.

[0144] Example 2: Preparation of Crystal Form B of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide 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 slowly evaporated at 25 °C. This preparation was found to be non-reproducible.

[0145] Example 3: Preparation of Form C 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 butanone, and the clear solution was slowly evaporated at 25 °C.

[0146] This preparation was found to be difficult to repeat.

[0147] Example 4: Preparation of Form D of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide 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 isopropanol, and the clear solution was slowly evaporated at 25 °C.

[0148] Alternatively, 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: Charge a reactor with a jacket temperature (JT) of 20 °C with 4-methylbenzenesulfonate of 6'-fluoro-1'H-spiro[piperidine-4,2'-quinoline]-4'(3'H)-one (6.0 g, 14.8 mmol) and acetonitrile (30 mL). Dropwise add N,N-diisopropylethylamine (2.3 g, 17.7 mmol) while maintaining the internal temperature (IT) at 20 °C. Continue stirring the resulting suspension while lowering the internal temperature (IT) to 2 °C. Dropwise add 4-fluorobenzyl isocyanate (2.4 g, 15.9 mmol) so that the exothermic reaction is maintained at an IT of less than 5 °C. Continue stirring at an IT of 0 - 5 °C for 10 minutes. Warm the resulting suspension to an IT of 20 °C and continue stirring for 3 hours.

[0149] Add H2O (36 ml) in small portions over 20 minutes to obtain a well-stirrable suspension. Cool the resulting mixture slowly to IT at 2 °C and continue stirring at that temperature for 1 hour. Filter the suspension at low temperature and wash it twice with H2O and once with acetonitrile. Vacuum dry the resulting filter cake at JT of 55 °C to obtain crystalline form D of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide as a yellow solid (5.1 g, 13.2 mmol, 90% yield).

[0150] Example 5: Preparation of Form E of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide Hydrate H of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide A Form E of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide was obtained by heating to about 70 °C or exposing to about 5% relative humidity for about 12 hours.

[0151] Example 6: Hydrate Form H of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide A Preparation Equilibrate 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 form A in MeOH / water = 5 / 95 at 25 °C (a wIt was equilibrated for about 3 weeks in (acetonitrile / water = 1 / 1, v / v, >0.95), and after recovering the solid by centrifugation and drying it under ambient conditions, the hydrate H of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide was obtained. A was obtained.

[0152] Example 6: Preparation of an amorphous form of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide 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 resulting clear solution was filtered through a 0.45 μm nylon membrane. This clear solution was pre-frozen using a solid carbon dioxide ethanol solution and then lyophilized under the following parameters: SHLF=-24 °C, SAMP=-18 °C, COL=-84 SEG = M, VAC = 0.014 m.

[0153] Example 7: Physical / Chemical Properties and Stability of Form A and the Amorphous Form The crystalline Form A described herein has been found to have advantageous properties.

[0154] Form A of the compound of formula (I) is the most stable form. Form A is physically stable in bulk. Form A is also chemically stable when exposed to high temperatures (e.g., 80 °C), high percentage levels of relative humidity (RH) (e.g., 75%), and long-term stress conditions.

[0155] Form A is slightly hygroscopic. The maximum water absorption rate of Form A is 0.6% at 95% relative humidity at 25 °C. Form A is stable at a water activity aw w = 0.7 at 25 °C.

[0156] Due to the slightly hygroscopic behavior, the physicochemical properties of Form A of the present invention are preserved regardless of the relative humidity of the ambient atmosphere, which promotes a more facile and reliable manufacturing process and facilitates the storage of pharmaceutical formulations containing said Form A.

[0157] Furthermore, crystalline Form A preserves its crystal structure even when slurried (equilibrated) in various solvents for extended periods (equilibration tests).

[0158] The initial purity of Form A was 99.4%. In the pH stability test, 0.1% suspensions / solutions of the compound of formula (I) in buffer solutions of various pHs were exposed to 80 °C for 1 week. The compound of formula (I) showed the highest decomposition in the buffer solution at pH 1, which was approximately 5%, while the decomposition at high pH was less than 1% after standing at 80 °C for 1 week.

[0159] In bulk, the crystalline Form A and the amorphous form of the compound of formula (I) are chemically stable when exposed to 80 °C and to 80 °C and 75% RH for 1 week. The amorphous form crystallized to crystalline Form A.

[0160] Both solid forms of the compound of formula (I) are stable even in mixtures with excipients.

[0161] Under light stress, a slight increase in the decomposition product of 0.6% was observed for crystalline Form A, while no decomposition was observed for the amorphous form.

[0162] [Table 1]

[0163] [Table 2]

[0164] [Table 3]

[0165] Example 8: High-Resolution Powder X-Ray Diffraction The material sample of Example 1 was filled into a silicon test piece holder for reflection measurement, and the holder was installed on a diffractometer. The XRPD pattern was collected at room temperature (about 296K) using a Bruker D8 Advance system equipped with a LynxEye solid-state detector in reflection mode. The radiation used for data collection was CuKα (λ = 0.15418 nm). The diffraction data was collected in the 2 - 40° 2θ range, and the peaks were evaluated. The obtained spectrum is shown in Figure 1, and the peaks are listed in Table 1. This procedure was repeated with the materials obtained in Examples 2 - 6.

[0166] [Table 4]

[0167] [Table 5]

[0168] [Table 6]

[0169] [Table 7]

[0170] [Table 8]

[0171] [Table 9]

[0172] Example 8: Differential Scanning Calorimetry (DSC) The DSC thermogram was recorded using a TA Discovery DSC instrument (TA Instruments, USA) with heat flux correction. The TA Discovery instrument was calibrated for temperature and enthalpy using a certified reference material such as indium, following the manufacturer's instructions. Approximately 2 mg of the sample material was sealed in a standard aluminum pan with a pinhole and heated from 0 °C to 300 °C at a heating rate of 10 °C / min in the DSC. The DSC instrument was purged with dry nitrogen gas at a flow rate of 50 ml / min during the measurement. The resulting graph is shown in the figure.

[0173] Example 9: Thermogravimetric analysis (TGA): Thermogravimetric analysis was performed using a TA Discovery TGA instrument (TA Instruments, USA). Approximately 2 - 10 mg of the 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 during the TGA. The TGA instrument was purged with dry N2 gas at a flow rate of 20 ml / min during the measurement. The resulting graph is shown in the figure.

[0174] From the experimental verification, it is concluded that 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide exhibits polymorphic behavior.

[0175] Form A is an anhydrous crystalline form with a melting onset temperature of approximately 208 °C and a melting enthalpy of approximately 111 - 119 J / g. The melting onset temperature does not significantly depend on the heating rate, as demonstrated by DSC performed using different heating rates. Form A is slightly hygroscopic and absorbs up to 0.6% water at 95% relative humidity at 25 °C.

[0176] The weight loss by TGA is approximately 0.3% in the range of about 24 - 200 °C.

[0177] In addition to crystalline form A, several other assigned solid forms were identified based on those each showing a distinct XRPD spectrum, as detailed below.

[0178] Form B was obtained by evaporative crystallization in acetone. Form B shows an XRPD pattern different from that of form A. DSC shows recrystallization to form A with a melting onset at about 206 °C after a melting onset of about 184 °C. In the TGA analysis of form B, a weight loss on drying of 2.8% was observed at about 28 °C to 190 °C. However, form B could not be reproduced and further characterized.

[0179] Form C was obtained by slow evaporation in butanone. However, reproduction was difficult and only form A was obtained in the crystallization test. Form C changes to form A when heated at about 150 °C. The DSC of form C shows melting of form A at 207 °C to 208 °C after an endothermic transition to form A at about 152 °C to 159 °C. The endothermic transition suggests an enantiotropic relationship between form C and form A. According to a competitive slurry experiment showing the conversion from form C to form A at 25 °C, the transition temperature would be below 25 °C.

[0180] Form D was obtained by slow evaporation in isopropanol. Form D shows an XRPD pattern different from the other forms, suggesting that form D is a pure crystalline phase. Form D started to convert to form A at above about 190 °C. The DSC of form D shows a small endothermic event at about 70 °C, followed by a melting onset at 204 °C and an enthalpy of 106 J / g. The DSC data suggest a univariant relationship between form A and form D. The competitive slurry experiment shows that form D converts to form A at 25 °C.

[0181] Form E is the hydrate H A obtained by heating to about 70 °C or exposing to 5% relative humidity for about 12 hours. Form E changes to form A when heated up to 150 °C. The DSC of form E shows melting at 207 °C, which is the melting point of form A, after a small exothermic event starting at about 115 °C.

[0182] The obtained data suggests that polymorphs B, C, D, and E are metastable crystal forms with respect to polymorph A.

[0183] Hydrate H A was obtained by equilibrating the amorphous form in water at 25 °C for 4 weeks or by equilibrating polymorph A in MeOH / water = 5 / 95 (a w > 0.95) at 25 °C for about 3 weeks, then recovering the solid by centrifuge and drying it under ambient conditions. Hydrate H A is a monohydrate with a calculated water content of 4.5%.

[0184] Hydrate H A maintains its stability by humidity-controlled XRPD when the relative humidity is decreased from 40% RH to 5% RH at 25 °C. Hydrate H A When exposed to 5% RH for about 12 hours, the XRPD pattern changed to polymorph E.

[0185] Hydrate H A also changes to polymorph E at about 70 °C and then to polymorph A at about 150 °C.

[0186] The amorphous form was obtained by dissolving polymorph A in 1,4-dioxane and lyophilizing the resulting solution.

[0187] Polymorph A and hydrate H in media with different water activities A From slurry experiments of, at 25 °C, polymorph A is stable at a water activity of a w = 0.7 or less, while the hydrate is stable at a w = 0.9 or more. At 40 °C, polymorph A is stable at a water activity of a w = 0.8 or less, while the hydrate is stable at a w > 0.95.

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 by an X-ray powder diffraction pattern comprising a representative peak at 9.6 ± 0.2° 2θ when measured at a temperature of about 25°C.

3. 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, characterized by an X-ray powder diffraction pattern comprising one or more representative peaks at 2θ 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, having an X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG.

1.

5. The crystalline form according to claim 1, characterized by a differential thermogravimetric profile comprising a single endothermic peak starting at about 208°C as measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min.

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

2.

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

8. The crystalline form according to claim 1, having a thermogravimetric analysis (TGA) diagram substantially the same as that shown in FIG.

3.

9. A pharmaceutical composition comprising the crystalline 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 preparing 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 preparing a medicament for the treatment of 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 thereof 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 ameliorated 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).

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

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

16. A process for producing crystalline form A of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, a) dissolving an 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; c) isolating the formed solid and a process comprising the same.

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