Cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its salts

Abstract

The present invention relates to co-crystals and pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, as well as pharmaceutical compositions containing them, and also to their use as medicaments, more particularly for use in the prevention and / or treatment of inflammatory diseases, diseases caused by viruses and / or cancer or dysplasia. The present invention also relates to methods for preparing said co-crystals and said pharmaceutically acceptable salts.

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, more particularly to novel co-crystals and novel pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine (also designated as ABX464), their preparation methods, and their use as pharmaceuticals, in particular for the prevention and / or treatment of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH (non-alcoholic steatohepatitis), and multiple sclerosis, diseases caused by viruses, and / or cancer or dysplasia. The present invention also relates to pharmaceutical compositions comprising said co-crystals and / or pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine. [Background technology]

[0002] International Publication No. WO 2010 / 143169 describes the preparation and use of compounds, particularly quinoline derivatives, including certain pharmaceutically acceptable salts thereof, useful in the treatment of HIV infection. The publication specifically discloses 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine (also referred to as (8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)amine), which is in clinical development. The inventors have noted that ABX464 is highly crystalline in nature and therefore exists naturally in a specific, unique, stable, and crystalline form designated "Crystalline Form I."

[0003] International Publication No. WO2017 / 158201 deals with certain mineral or sulfonate salts of ABX464.

[0004] ABX464 has low solubility in aqueous solutions. The main drawback of low solubility is that if the drug remains undissolved in the gastrointestinal system, the active ingredients cannot fully reach their targets in the body.

[0005] Therefore, there is a need to provide new means to improve the solubility of ABX464. Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have surprisingly discovered that the implementation of novel co-crystals and pharmaceutically acceptable salts of ABX4644 offers new opportunities for improving the performance of pharmaceuticals, for example, with respect to solubility and dissolution rate control. The present inventors have now developed novel pharmaceutically acceptable salts and novel co-crystals of ABX464.

[0007] As noted above, there is always a need to improve the performance of pharmaceuticals, for example, in terms of solubility, especially when the free base is not water-soluble, as in the case of ABX464. It has been observed that when salts and cocrystals according to the present disclosure are suspended in water, the corresponding free base (i.e., 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine itself) is so weak that it dissociates and the free base tends to precipitate. Consequently, to avoid precipitate formation and such instability during solubility measurements, these salts and cocrystals are classically formulated in the presence of at least one precipitation inhibitor, as described in more detail later in this specification. As shown in the experimental section (Example 10), salts and cocrystals according to the present disclosure surprisingly have significantly higher solubility than ABX464 crystalline Form I (i.e., the free base). In addition, Example 11 of the present disclosure demonstrates that salts according to the present disclosure surprisingly have significantly higher solubility than ABX464 crystalline Form I (i.e., the free base) in an intestinal compartment model.

[0008] Accordingly, the present invention is intended to provide a cocrystal and a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, as well as a pharmaceutically acceptable salt of the cocrystal and / or ABX464 (including solvates and / or hydrates thereof). The cocrystal, the pharmaceutically acceptable salt of ABX464, and pharmaceutical compositions containing them can be used as pharmaceuticals, more particularly for the treatment and / or prevention of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH (non-alcoholic steatohepatitis), and multiple sclerosis, diseases caused by viruses, and / or cancer or dysplasia. [Means for solving the problem]

[0009] Accordingly, the present invention provides a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine selected from: 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline The following peaks were observed: 16.5; 20.6; 21.4 and 22.1 (each time ±0.2) 2-theta angle in degrees having a powder X-ray diffraction pattern showing and / or 、 A single endotherm with an onset temperature of 172.0°C (±2°C) 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as above: L-proline; 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine: gentisic acid, The following peaks were observed: 7.9; 14.0; 15.2 and 25.2 (each time ±0.2) 2-theta angle in degrees having a powder X-ray diffraction pattern showing and / or 、 A single endotherm with an onset temperature of 133.0°C (±2°C) 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as above: gentisic acid; 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid The following peaks were observed (±0.2 each time): 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; and 25.6. 2-theta angle in degrees having a powder X-ray diffraction pattern showing and / or 、 A single endotherm with an onset temperature of 109.0°C (±2°C) 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid as above; and 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine: 4,4′-bipyridine, The following peaks were observed: 12.0; 19.2; 21.2 and 24.3 (each time ±0.2) 2-theta angle in degrees having a powder X-ray diffraction pattern showing and / or 、 A single endotherm with an onset temperature of 127.0°C (±2°C) 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as described above: 4,4'-bipyridine.

[0010] Accordingly, the present invention also provides pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine (including solvates and / or hydrates thereof), including lactate, oleate, oxalate, palmitate, stearate, valerate, pantothenate, picrate, butyrate, malonate, succinate, bitartrate, malate, mandelate, benzoate, edetate, gluceptate, gluconate, lactobionate, salicylate, disalicylate, mucate, pamoate, adipate, alginate, methyl ... The acid salt is selected from the group consisting of phosphate, aspartate, camphorate, cyclopentanepropionate, digluconate, glucoheptonate, heptanoate, hexanoate, laurate, nicotinate, pamoate, pivalate, propionate, undecanoate, etc., phosphate, etc., camphorsulfonate, 2-hydroxyethanesulfonate, estolate, napsylate, esylate, napadisylate, dodecyl sulfate, etc., perchloric acid, boric acid, glycerophosphate, nitric acid, persulfate, etc.

[0011] Also provided herein are the following: A method for preparing a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention; A process for preparing pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, including solvates and / or hydrates thereof; a pharmaceutical composition comprising the cocrystal as defined in the present invention and / or a pharmaceutically acceptable salt of ABX464 as defined in the present invention (including solvates and / or hydrates thereof), and at least one pharmaceutically acceptable excipient; a pharmaceutically acceptable salt of ABX464 as defined in the present invention (including a solvate and / or hydrate thereof), a co-crystal as defined in the present invention, or a pharmaceutical composition as defined in the present invention, for use as a medicament; and A pharmaceutically acceptable salt of ABX464 as defined in the present invention (including solvates and / or hydrates thereof), a co-crystal as defined in the present invention, or a pharmaceutical composition as defined in the present invention for use in the prevention or treatment of cancer, AIDS, HIV infection, and / or inflammatory diseases.

[0012] A cocrystal is a crystalline complex composed of at least two neutral molecules bound to each other in a crystal lattice by non-covalent interactions. The main difference between a solvate and a cocrystal is related to the physical state of the pure components. If one of the components is liquid at ambient temperature, the molecular complex is a solvate. If all components are solid at ambient temperature, the complex is designated by the term "cocrystal." The main difference between a solvate and a cocrystal is that a cocrystal is much more stable than a solvate. A cocrystal is characterized by the method by which it is obtained and by the regular three-dimensional structure shown, for example, by an X-ray diffraction pattern. It is not possible to know a priori whether two given components can form a cocrystal with a specific three-dimensional structure or simply result in the juxtaposition of two powders.

[0013] As used herein, the term "pharmaceutically acceptable" refers to a compound, ingredient, excipient, carrier, adjuvant, vehicle, composition or dosage form that is suitable, within the scope of sound medical judgment, for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem complications, commensurate with a reasonable benefit / risk ratio.

[0014] In the context of the present invention, the term "treat" or "treatment" as used herein means to reverse, alleviate, inhibit progression of or prevent inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, diseases caused by viruses, and / or cancer or dysplasia.

[0015] The term "prevent" as used herein means reducing the risk of developing or slowing the rate of onset of a given phenomenon, i.e., in the present invention, inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, viral diseases and / or cancer or dysplasia. As used herein, "prevent" also encompasses "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence."

[0016] "Subjects" (including patients) include mammals, such as humans, companion animals (e.g., dogs, cats, birds, etc.), farm animals (e.g., cows, sheep, pigs, horses, chickens, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, birds, etc.).

[0017] As used herein, the term "ambient temperature" or "room temperature" refers to a temperature in the range of 15°C to 30°C, more particularly 18°C ​​to 25°C. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 is an X-ray powder diagram of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal (see Example 1 below). [Figure 2] FIG. 2 is an X-ray powder diagram of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal (see Example 2 below). [Figure 3] FIG. 3 is an X-ray powder diagram of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal (see Example 3 below). [Figure 4] FIG. 4 is an X-ray powder diagram of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4′-bipyridine co-crystal (see Example 4 below). [Figure 5]FIG. 5 is an X-ray powder diagram of the anhydrous crystalline ABX464 hemina padisylate co-crystal (see Example 5 below). [Figure 6] FIG. 6 is an X-ray powder diagram of the anhydrous crystalline ABX464 esylate salt (see Example 6 below). [Figure 7] FIG. 7 is an X-ray powder diagram of the crystalline hemi-THF (tetrahydrofuran) solvate of ABX464 hemina padisylate (see Example 7 below). [Figure 8] FIG. 8 depicts three X-ray powder diagrams: one recorded for ABX464 crystalline form I (see top line), a second recorded for the solid residue collected at time point G at 30 minutes in the gastric compartment (see middle line), and a third recorded for the solid residue collected at time point I at 120 minutes in the intestinal compartment of a fasted dissolution / precipitation study performed on ABX464 crystalline form I (see bottom line) (see Example 11 below). [Figure 9] FIG. 9 depicts four powder X-ray diagrams: one recorded for ABX464 crystalline Form I (see top line), a second recorded for anhydrous ABX464 hemina padisylate (see second line from the top), a third recorded for the solid residue collected at time point G in the gastric compartment (see third line from the top), and a fourth recorded for the solid residue collected at time point I in the intestinal compartment of a fasted dissolution / precipitation study performed on anhydrous ABX464 hemina padisylate (see bottom line, i.e., fourth line from the top) (see Example 11 below).

[0019] As explained above, the inventors have demonstrated that the salts and co-crystals according to the present disclosure exhibit improved solubility compared to the solubility of ABX464 crystalline Form I.

[0020] As will be demonstrated in Example 10 below, the improved solubility was investigated in two typical media: FaSSIF (Fasted State Simulated Intestinal Fluid) (i.e., fasted state simulated intestinal fluid) and FeSSIF (Fed State Simulated Intestinal Fluid) (i.e., fed state simulated intestinal fluid).

[0021] As is clear from the above example, a precipitation inhibitor or precipitate, i.e., (polyvinylpyrrolidone-vinyl acetate) PVP-VA, is also present in the vehicle. The use of such a precipitation inhibitor is classically used in the well-known "spring and parachute" approach. In fact, the concept of gastrointestinal supersaturation can be used as a strategy to enhance the intestinal absorption of poorly water-soluble drugs. To utilize supersaturation, two key steps must be considered: the creation and maintenance of a metastable supersaturated state, also known as the "spring and parachute" approach (see Guzman et al.: A "spring and parachute" approach to designing solid celecoxib formulations having enhanced oral absorption. AAPS J 6, 2004, Abstract T2189). Once supersaturation (called "spring") is induced, drug molecules tend to precipitate through a process that may be kinetically or thermodynamically controlled. To benefit from the supersaturated state, the increased concentration must be maintained for a sufficient time for absorption. This may require temporary inhibition of precipitation through the use of pharmaceutical excipients or by other components that interfere with nucleation and / or crystal growth, i.e., "parachutes," or precipitation inhibitors.

[0022] Among the precipitation inhibitors that may be mentioned are polymers such as PVP-VA (polyvinylpyrrolidone-vinyl acetate), HPMC (hydroxypropyl methylcellulose), HPMC-AS, HPMC-P, surfactants such as TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) or Pluronic® F127 (also known as P407: poloxamer 407), hydroxypropyl cellulose (HPC), PVP (polyvinylpyrrolidone), such as PVP-K15, PVP-K30 or PVP-K90, Carbopol® 974P (a highly carboxylated polymer composed of lightly crosslinked polyacrylic acid), polyvinyl alcohol (PVA) and mixtures thereof, or sodium dodecyl sulfate (SDS).

[0023] As demonstrated in Example 10, significantly higher solubility of all solid forms was observed in FeSSIF pH 5.0 + 1% PVPVA medium, which mimics fed intestinal medium. In other words, the presence of precipitation inhibitors in the medium not only prevents the precipitation of ABX464 free base, but also paves the way for its implementation in novel galenic forms.

[0024] Example 11, examination of the dissolution behavior of salts of ABX464 in a two-step dissolution-precipitation fasted human in vitro model (see, e.g., Dressman et al., "Estimating drug solubility in the gastrointestinal tract," Advanced Drug Delivery Reviews, 2007, volume 59, issue 7, pp. 591-602), further verifies that salts of ABX464 according to the present disclosure exhibit improved solubility compared to ABX464 crystalline Form I. Indeed, significantly higher solubility of ABX464 hemina padisylate in the intestinal compartment of this model (-430 μg / ml) was clearly observed compared to the solubility of ABX464 crystalline Form I in the intestinal compartment (-80 μg / ml).

[0025] Therefore, the inventors have discovered a novel means to increase the solubility of ABX464 and to allow the preparation of a wider variety of galenic formulations, ensuring that ABX464 reaches its biological target with the best bioavailability, as detailed in the paragraph "Pharmaceutical Compositions" herein.

[0026] The salts and co-crystals of ABX464 that are the subject of the present invention are described in more detail herein below.

[0027] ABX464 Salt As stated above, an object of the present invention is the pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, including solvates and / or hydrates thereof, such as lactate, oleate, oxalate, palmitate, stearate, valerate, pantothenate, picrate, butyrate, malonate, succinate, bitartrate, malate, mandelate, benzoate, edetate, gluceptate, gluconate, lactobionate, salicylate, disalicylate, mucate, pamoate, adipate, alginate, aspartate, camphorate, cyclopentanepropionate, digluconate, glucoheptonate, cyclopentanepropion ... the salt is selected from anhydrous crystalline ABX464 heminapadisylate, anhydrous crystalline ABX464 esylate, and a crystalline hemi-THF solvate of ABX464 heminapadisylate;

[0028] Thus, according to one embodiment, the pharmaceutically acceptable salt is anhydrous and is selected from anhydrous crystalline ABX464 heminapadisylate and anhydrous crystalline ABX464 esylate salt.

[0029] Thus, according to another embodiment, the pharmaceutically acceptable salt is in the form of a solvate or hydrate, more particularly a solvate, even more particularly a crystalline hemi-THF (tetrahydrofuran) solvate of hemina padisylate.

[0030] Therefore, in certain embodiments, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention is selected from anhydrous crystalline ABX464 heminapadisylate, anhydrous crystalline ABX464 esylate salt, and a crystalline hemi-THF solvate of ABX464 heminapadisylate, as demonstrated in Examples 5, 6, and 7 herein (and Figures 5, 6, and 7, respectively).

[0031] In a particularly preferred embodiment, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention is anhydrous crystalline ABX464 heminapadisylate.

[0032] Pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine can be characterized, for example, by X-Ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC).

[0033] More particularly, the anhydrous crystalline ABX464 hemina padisylate of Example 5 has the following structure: As shown in Figure 5 (powder X-ray diffraction), the following peaks were observed: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5 and 26.3 (each time ±0.2). 2-theta angle in degrees wherein said powder X-ray diffractogram optionally contains the following additional peaks: 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2 and 25.9 (each ±0.2 times). 2-theta angle in degrees and optionally the following additional peaks: 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees may further be shown: and / or 、 There is a single endotherm with an onset temperature of 269.0°C (±2°C).

[0034] A characteristic X-ray powder diffraction pattern of anhydrous crystalline ABX464 hemina padisylate can be seen in Figure 5, and its characteristic signals are summarized in Table 1 below.

[0035] [Table 1]

[0036] According to one embodiment, the anhydrous crystalline ABX464 hemina padisylate of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least one peak selected from

[0037] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least two peaks selected from

[0038] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least three peaks selected from

[0039] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least four peaks selected from

[0040] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least five peaks selected from

[0041] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least six peaks selected from

[0042] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees1 shows a powder X-ray diffraction pattern showing at least seven peaks selected from

[0043] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least eight peaks selected from

[0044] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least nine peaks selected from

[0045] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 10 peaks selected from

[0046] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 11 peaks selected from:

[0047] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 12 peaks selected from

[0048] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 13 peaks selected from

[0049] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 14 peaks selected from

[0050] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate salt of the present invention has the following peaks: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5; 26.3; 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2; 25.9; 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 15 peaks selected from:

[0051] According to another embodiment, the anhydrous crystalline ABX464 hemina padisylate of the present invention has an XRPD substantially similar to the XRPD depicted in FIG.

[0052] More particularly, the anhydrous crystalline ABX464 esylate salt of Example 6 has the following structure: As shown in Figure 6 (powder X-ray diffraction), the following peaks 12.2 and 22.2 (each time ±0.2) 2-theta angle in degrees wherein said powder X-ray diffractogram optionally exhibits the following additional peaks: 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0 and 20.7 (each ±0.2). 2-theta angle in degrees and optionally further showing the following additional peaks: 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each ±0.2 times). 2-theta angle in degrees may further be shown: and / or 、 It has a single endotherm with an onset temperature of 108.0°C (±2°C).

[0053] A characteristic X-ray powder diffraction pattern of the anhydrous crystalline ABX464 esylate salt can be given in Figure 6, and its characteristic signals are summarized in Table 2 below.

[0054] [Table 2]

[0055] According to one embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least one peak selected from

[0056] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least two peaks selected from

[0057] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least three peaks selected from

[0058] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least four peaks selected from

[0059] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least five peaks selected from

[0060] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least six peaks selected from

[0061] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least seven peaks selected from

[0062] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least eight peaks selected from

[0063] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least nine peaks selected from

[0064] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 10 peaks selected from

[0065] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 11 peaks selected from:

[0066] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 12 peaks selected from

[0067] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 13 peaks selected from

[0068] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 14 peaks selected from

[0069] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has the following peaks: 12.2; 22.2; 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; 20.7; 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 15 peaks selected from:

[0070] According to another embodiment, the anhydrous crystalline ABX464 esylate salt of the present invention has an XRPD substantially similar to the XRPD depicted in FIG.

[0071] More particularly, the crystalline hemi-THF solvate of ABX464 hemina padisylate of Example 7 is As shown in Figure 7 (powder X-ray diffraction), the following peaks were observed: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6 and 24.6 (each time ±0.2). 2-theta angle in degreeswherein said powder X-ray diffractogram optionally contains the following additional peaks, expressed as 2-theta angles: 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9 and 25.2 (each ±0.2). 2-theta angle in degrees and optionally further showing the following additional peaks: 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each ±0.2 times). 2-theta angle in degrees may further be shown: and / or 、 There is a single endotherm with an onset temperature of 172.0°C (±2°C).

[0072] A characteristic X-ray powder diffraction pattern of the crystalline hemi-THF solvate of ABX464 hemina padisylate can be seen in Figure 7, and its characteristic signals are summarized in Table 3 below.

[0073] [Table 3]

[0074] According to one embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least one peak selected from

[0075] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees1 shows a powder X-ray diffraction pattern showing at least two peaks selected from

[0076] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least three peaks selected from

[0077] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least four peaks selected from

[0078] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least five peaks selected from

[0079] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least six peaks selected from

[0080] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least seven peaks selected from

[0081] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least eight peaks selected from

[0082] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least nine peaks selected from

[0083] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 10 peaks selected from

[0084] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 11 peaks selected from:

[0085] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 12 peaks selected from

[0086] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees1 shows a powder X-ray diffraction pattern showing at least 13 peaks selected from

[0087] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has the following peaks: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 14 peaks selected from

[0088] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention teeth, The following peaks were observed (±0.2 each time): 8.4; 12.3; 14.0; 19.2; 21.3; 22.6; 24.6; 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9; 25.2; 16.7; 18.1; 18.8; 19.5; 20.9, and 22.3. 2-theta angle in degrees 1 represents a powder X-ray diffraction pattern showing at least 15 peaks selected from

[0089] According to another embodiment, the crystalline hemi-THF solvate of ABX464 hemina padisylate of the present invention has an XRPD substantially similar to the XRPD depicted in FIG.

[0090] Methods for preparing pharmaceutically acceptable salts of ABX464 Further provided herein is a method for preparing a pharmaceutically acceptable salt of ABX464 (including a solvate or hydrate thereof), the method comprising: a) dissolving ABX464 in one or more solvents; b) adding counterions in the form of an acid to the mixture of step a) thus obtained to obtain a molar ratio of ABX464:counterions of 3:1 to 1:2, preferably 5:2 to 1:2, more particularly preferably 2:1 to 1:2, even more particularly 2:1 or 1:1, wherein the counterions themselves may already be dissolved in a solvent or in a mixture of solvents; c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of the selected solvent(s) or mixture of solvents of step a) and step b), in particular between room temperature and 60°C, more in particular between room temperature and 50°C; d) Optionally, Adding a solvent or a mixture of solvents; e) Applying a temperature program; f) optionally filtering; and g) Optionally, drying at a temperature between room temperature and 60°C to obtain the desired salt of ABX464. The process includes the steps of:

[0091] According to one embodiment, the one or more solvents used in steps a), b) and d) are any solvents conventionally used in crystallization processes, in particular organic solvents, more particularly selected from C1-C6 aliphatic alcohols, methyl ethyl ketone (butanone, also called MEK), cyclohexane, alkanes such as heptane, methylene chloride, chloroform, formic acid, DMSO, 1-methyl-2-pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), diethyl ether, dioxane, toluene, ethyl acetate, and mixtures thereof, optionally in mixtures with water, even more particularly selected from C1-C6 aliphatic alcohols, mixtures of HO / C1-C6 aliphatic alcohols, and mixtures thereof, and even more particularly selected from methanol, ethanol, isopropanol, HO / methanol, HO / ethanol, and mixtures thereof.

[0092] A person skilled in the art would know how to determine the more suitable solvent or solvents in each step a), b) and d) to obtain the desired pharmaceutically acceptable salt.

[0093] According to one embodiment, the one or more solvents used in step a), step b) and / or step d) are the same.

[0094] According to another embodiment, the one or more solvents used in step a), step b) and / or step d) are the same.

[0095] Advantageously, the counterion in the acid form of step b) is tansulfonic acid or naphthalene 1,5-disulfonic acid.

[0096] Thus, in some embodiments, the solvent in step a), step b) and / or step d) is any solvent, particularly an organic solvent, conventionally used in crystallization processes, more particularly C1-C6 aliphatic alcohols, methyl ethyl ketone (also called butanone, i.e. MEK), cyclohexane, alkanes such as heptane, methylene chloride, chloroform, formic acid, DMSO, 1-methyl-2-pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), diethyl ether, dioxane, toluene, ethyl acetate, and mixtures thereof, optionally in a mixture with water, more particularly selected from C1-C66 aliphatic alcohols, mixtures of HO / C1-C6 aliphatic alcohols, and mixtures thereof, and even more particularly selected from methanol, ethanol, isopropanol, HO / methanol, HO / ethanol, and mixtures thereof; and / or the counterion in the acid form of step b) is ethanesulfonic acid or naphthalene 1,5-disulfonic acid,

[0097] According to one embodiment, the evaporation step c) is carried out under an inert gas, such as N2.

[0098] According to one embodiment, said step e) of temperature programming comprises heating to reflux at a temperature between room temperature and the boiling point of one or more solvents, in particular between room temperature and 60°C.

[0099] According to one embodiment, said step e) of temperature programming comprises reflux cooling to a temperature of 0°C to 60°C, in particular 5°C to 40°C, more in particular room temperature to 40°C, at a rate of 30°C / min to 0.05°C / min, in particular 10°C / min to 0.05°C / min, more in particular 5°C / min to 0.05°C / min.

[0100] According to one embodiment, said step e) relating to the temperature program comprises i) heating under reflux to a temperature between room temperature and the boiling point of one or more solvents, in particular between room temperature and 60°C, and / or ii) reflux cooling to a temperature between 0°C and 60°C, in particular between 5°C and 40°C, more in particular between room temperature and 40°C, at a rate between 30°C / min and 0.05°C / min, in particular between 10°C / min and 0.05°C / min, more in particular between 5°C / min and 0.05°C / min.

[0101] According to a particular embodiment, said step e) relating to the temperature program comprises i) heating under reflux to a temperature between room temperature and the boiling point of one or more solvents, in particular between room temperature and 60°C, and ii) reflux cooling to a temperature between 0°C and 60°C, in particular between 5°C and 40°C, more in particular between room temperature and 40°C, at a rate between 30°C / min and 0.05°C / min, in particular between 10°C / min and 0.05°C / min, more in particular between 5°C / min and 0.05°C / min.

[0102] According to one embodiment, step f) of filtration is carried out using conventional glass fiber, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride), in particular cellulose filter paper with a filtration mesh of 0.45 μm or 0.2 μm.

[0103] According to one embodiment, said step g) of drying is carried out under vacuum at a temperature between 30°C and 60°C, in particular 40°C.

[0104] According to one embodiment, said step g) of drying is carried out under atmosphere at a temperature between 30°C and 60°C, in particular 40°C.

[0105] For the preparation of the pharmaceutically acceptable salts of ABX464 as defined in the present invention, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine can be previously obtained either from the method described in WO 2010 / 143169 or from any other suitable method.

[0106] According to some embodiments, a method for preparing a pharmaceutically acceptable salt of ABX464 (including a solvate or hydrate thereof) comprises: a) dissolving ABX464 in one or more solvents; b) adding counterions in the form of an acid to the mixture of step a) thus obtained to obtain a molar ratio of ABX464:counterions of 3:1 to 1:2, preferably 5:2 to 1:2, more particularly preferably 2:1 to 1:2, even more particularly 2:1 or 1:1, wherein the counterions themselves may already be dissolved in a solvent or in a mixture of solvents; c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of the selected solvent(s) or mixture of solvents of step a) and step b), in particular between room temperature and 60°C, more in particular between room temperature and 50°C; d) Optionally, Adding a solvent or a mixture of solvents; e) applying a temperature program, wherein the temperature program comprises: i) a temperature between room temperature and the boiling point of one or more solvents, in particular between room temperature and 60°C; Reflux heating and / or ii) reflux cooling at a rate of 30°C / min to 0.05°C / min, particularly 10°C / min to 0.05°C / min, more particularly 5°C / min to 0.05°C / min, to a temperature of 0°C to 60°C, particularly 5°C to 40°C, more particularly room temperature to 40°C, f) optionally filtering by using conventional glass fiber, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride), in particular cellulose filter paper with a filtering mesh of 0.45 μm or 0.2 μm; and g) then, optionally, drying under vacuum at a temperature of 30°C to 60°C, in particular 40°C, or under atmosphere at a temperature of 30°C to 60°C, in particular 40°C, to obtain the desired salt of ABX464. The process includes the steps of:

[0107] According to some embodiments, a method for preparing a pharmaceutically acceptable salt of ABX464 comprises: a) dissolving ABX464 in methanol; b) adding a counterion which is ethanesulfonic acid or naphthalenesulfonic acid to the mixture of step a) thus obtained, to obtain a molar ratio of ABX464:counterion of 3:1 to 1:2, preferably 5:2 to 1:2, more particularly preferably 2:1 to 1:2, even more particularly 2:1 or 1:1, wherein the counterion itself is already dissolved in water / ethanol or in ethanol; c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of the selected solvent(s) or mixture of solvents of step a) and step b), in particular between room temperature and 60°C, more in particular between room temperature and 50°C; d) optionally adding a solvent selected from ethyl acetate, THF, acetone and mixtures thereof; e) applying a temperature program, wherein the temperature program comprises i) heating under reflux to a temperature between room temperature and the boiling point of one or more solvents, in particular between room temperature and 60°C, and / or (ii) reflux cooling to a temperature between 0°C and 60°C, in particular between 5°C and 40°C, more in particular between room temperature and 40°C, at a rate between 30°C / min and 0.05°C / min, in particular between 10°C / min and 0.05°C / min, more in particular between 5°C / min and 0.05°C / min; f) optionally filtering; and g) Optionally, drying at a temperature between room temperature and 60°C to obtain the desired salt of ABX464. The process includes the steps of:

[0108] According to some embodiments, a method for preparing a pharmaceutically acceptable salt of ABX464 comprises: a) dissolving ABX464 in methanol; b) adding a counterion which is ethanesulfonic acid or naphthalenesulfonic acid to the mixture of step a) thus obtained, to obtain a molar ratio of ABX464:counterion of 3:1 to 1:2, preferably 5:2 to 1:2, more particularly preferably 2:1 to 1:2, even more particularly 2:1 or 1:1, wherein the counterion itself is already dissolved in water / ethanol or in ethanol; c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of the selected solvent(s) or mixture of solvents of step a) and step b), in particular between room temperature and 60°C, more in particular between room temperature and 50°C; d) optionally adding a solvent selected from ethyl acetate, THF, acetone and mixtures thereof; e) applying a temperature program, wherein the temperature program comprises: i) a heating step to reflux to a temperature of 60°C and / or a cooling step to reflux from 5°C to 40°C, more particularly from room temperature to 40°C, at a rate of 1°C / min; f) optionally filtering; and g) Then, optionally, drying at 40°C to obtain the desired salt of ABX464. The process includes the steps of:

[0109] According to one particular embodiment, ABX464 is dissolved in a C1-C6 aliphatic alcohol, particularly methanol, and then naphthalene 1,5-disulfonic acid is added to this mixture to obtain a molar ratio of ABX464:counterion of 3:1 to 1:2, preferably 5:2 to 1:2, more particularly preferably 2:1 to 1:2, even more particularly 2:1 or 1:1, where the naphthalene 1,5-disulfonic acid itself is already dissolved in the C1-C6 aliphatic alcohol, particularly ethanol. This is followed by evaporation under N2 at room temperature (25°C), followed by the addition of acetone, followed by a temperature program before filtration through a 0.2 μm filter, and vacuum drying at 40°C to obtain anhydrous crystalline ABX464 hemina padisylate.

[0110] According to another particular embodiment, ABX464 is dissolved in a C1-C6 aliphatic alcohol, in particular methanol, and then ethanesulfonic acid is added to this mixture to obtain ABX464:counterion in a molar ratio of 3:1 to 1:2, preferably 5:2 to 1:2, more particularly preferably 2:1 to 1:2, even more particularly 2:1 or 1:1, where the ethanesulfonic acid itself is already dissolved in the HO / C1-C6 aliphatic alcohol mixture, in particular a water / ethanol mixture. Evaporation under N2 at room temperature (25°C) is then performed, followed by addition of ethyl acetate and applying a temperature program before evaporation, which is carried out under N2 at room temperature (25°C), to obtain the anhydrous crystalline ABX464 esylate salt.

[0111] According to another embodiment, ABX464 is dissolved in a C1-C6 aliphatic alcohol, particularly methanol, and then naphthalene 1,5-disulfonic acid is added to this mixture to obtain a molar ratio of ABX464:counterion of 3:1 to 1:2, particularly 5:2 to 1:2, more particularly 2:1 to 1:2, and even more particularly 2:1, where the naphthalene 1,5-disulfonic acid itself is already dissolved in the C1-C6 aliphatic alcohol, particularly ethanol. This is then evaporated under N2 at 40°C, followed by the addition of THF, followed by a temperature program before 0.2 μm filtration and vacuum drying at 40°C to obtain a crystalline hemi-THF solvate of ABX464 hemina padisylate.

[0112] Cocrystals of ABX464 As noted above, in another aspect, the present invention relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine selected from the following: 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline The following peaks were observed: 16.5; 20.6; 21.4 and 22.1 (each time ±0.2) 2-theta angle in degrees wherein said powder X-ray diffractogram optionally exhibits the following additional peaks: 11.0; 15.9; 18.3 and 19.4 (each ±0.2 times). 2-theta angle in degrees and optionally further showing the following additional peaks: 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees and optionally may be further characterized by powder X-ray diffraction as shown in FIG. and / or 、 A single endotherm with an onset temperature of 172.0°C (±2°C) 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as above: L-proline; 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine: gentisic acid, The following peaks were observed: 7.9; 14.0; 15.2 and 25.2 (each time ±0.2) 2-theta angle in degrees wherein said powder X-ray diffractogram optionally exhibits the following additional peaks: 15.8; 16.9; 18.5; 19.9; 20.3; 23.0 and 24.7 (each ±0.2 times). 2-theta angle in degrees and still optionally the following additional peaks: 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees and optionally may be further characterized by powder X-ray diffraction as shown in FIG. and / or 、 A single endotherm with an onset temperature of 133.0°C (±2°C) 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as above: gentisic acid; 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid The following peaks were observed (±0.2 each time): 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; and 25.6. 2-theta angle in degrees wherein said powder X-ray diffractogram optionally exhibits the following additional peaks: 19.0; 21.4; 24.6; 26.8; 27.6 and 29.9 (each ±0.2 sec). 2-theta angle in degrees and optionally further showing the following additional peaks: 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees and optionally may be further characterized by powder X-ray diffraction as shown in FIG. and / or 、 a single endotherm with an onset temperature of 109.0°C (±2°C); and 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine: 4,4′-bipyridine, The following peaks were observed: 12.0; 19.2; 21.2 and 24.3 (each time ±0.2) 2-theta angle in degrees wherein said powder X-ray diffractogram optionally exhibits the following additional peaks: 16.0; 17.0; 17.8; 20.3; 22.5 and 22.7 (each ±0.2 sec). 2-theta angle in degrees and optionally further showing the following additional peaks: 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees and optionally may be further characterized by powder X-ray diffraction as shown in FIG. and / or 、 There is a single endotherm with an onset temperature of 127.0°C (±2°C).

[0113] In a particularly preferred embodiment, the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine is 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline, The following peaks were observed: 16.5; 20.6; 21.4 and 22.1 (each time ±0.2) 2-theta angle in degrees wherein said powder X-ray diffractogram optionally exhibits the following additional peaks: 11.0; 15.9; 18.3 and 19.4 (each ±0.2 times). 2-theta angle in degrees and optionally further showing the following additional peaks: 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees and optionally may be further characterized by powder X-ray diffraction as shown in FIG. and / or 、 There is a single endotherm with an onset temperature of 172.0°C (±2°C).

[0114] The four co-crystals are shown herein in Example 1 (and Figure 1), Example 2 (and Figure 2), Example 3 (and Figure 3), and Example 4 (and Figure 4), respectively.

[0115] A characteristic X-ray powder diffraction pattern of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline cocrystal can be seen in Figure 1, and its characteristic signals are summarized in Table 4 below.

[0116] [Table 4]

[0117] According to one embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least one peak selected from

[0118] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least two peaks selected from

[0119] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least three peaks selected from

[0120] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least four peaks selected from

[0121] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least five peaks selected from

[0122] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least six peaks selected from

[0123] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least seven peaks selected from

[0124] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least eight peaks selected from

[0125] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least nine peaks selected from

[0126] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 10 peaks selected from

[0127] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 11 peaks selected from:

[0128] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 12 peaks selected from

[0129] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 13 peaks selected from

[0130] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 14 peaks selected from

[0131] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention exhibits the following peaks: 16.5; 20.6; 21.4; 22.1; 11.0; 15.9; 18.3; 19.4; 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 15 peaks selected from:

[0132] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal of the present invention has an XRPD substantially similar to the XRPD depicted in FIG. 1.

[0133] A characteristic X-ray powder diffraction pattern of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal can be seen in Figure 2, and its characteristic signals are summarized in Table 5 below.

[0134] [Table 5]

[0135] According to one embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least one peak selected from

[0136] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least two peaks selected from

[0137] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least three peaks selected from

[0138] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least four peaks selected from

[0139] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least five peaks selected from

[0140] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees1 shows a powder X-ray diffraction pattern showing at least six peaks selected from

[0141] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least seven peaks selected from

[0142] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least eight peaks selected from

[0143] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least nine peaks selected from

[0144] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 10 peaks selected from

[0145] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 11 peaks selected from:

[0146] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 12 peaks selected from

[0147] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees1 shows a powder X-ray diffraction pattern showing at least 13 peaks selected from

[0148] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 14 peaks selected from

[0149] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention exhibits the following peaks: 7.9; 14.0; 15.2; 25.2; 15.8; 16.9; 18.5; 19.9; 20.3; 23.0; 24.7; 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7 and 24.0 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 15 peaks selected from:

[0150] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal of the present invention has an XRPD substantially similar to the XRPD depicted in FIG. 2.

[0151] A characteristic X-ray powder diffraction pattern of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal can be seen in Figure 3, and its characteristic signals are summarized in Table 6 below.

[0152] [Table 6]

[0153] According to one embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least one peak selected from

[0154] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least two peaks selected from

[0155] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least three peaks selected from

[0156] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees1 shows a powder X-ray diffraction pattern showing at least four peaks selected from

[0157] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least five peaks selected from

[0158] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least six peaks selected from

[0159] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least seven peaks selected from

[0160] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least eight peaks selected from

[0161] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least nine peaks selected from

[0162] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 10 peaks selected from

[0163] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees1 shows a powder X-ray diffraction pattern showing at least 11 peaks selected from:

[0164] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 12 peaks selected from

[0165] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 13 peaks selected from

[0166] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 14 peaks selected from

[0167] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention exhibits the following peaks: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; 25.6; 19.0; 21.4; 24.6; 26.8; 27.6; 29.9; 16.8; 17.8; 20.9; 23.8; 28.0 and 29.6 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 15 peaks selected from:

[0168] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal of the present invention has an XRPD substantially similar to the XRPD depicted in FIG. 3.

[0169] A characteristic X-ray powder diffraction pattern of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4′-bipyridine cocrystal can be seen in FIG. 4, and its characteristic signals are summarized in Table 7 below.

[0170] [Table 7]

[0171] According to one embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4′-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least one peak selected from

[0172] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least two peaks selected from

[0173] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least three peaks selected from

[0174] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least four peaks selected from

[0175] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees1 shows a powder X-ray diffraction pattern showing at least five peaks selected from

[0176] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least six peaks selected from

[0177] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least seven peaks selected from

[0178] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least eight peaks selected from

[0179] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least nine peaks selected from

[0180] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 10 peaks selected from

[0181] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 11 peaks selected from:

[0182] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees1 shows a powder X-ray diffraction pattern showing at least 12 peaks selected from

[0183] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 13 peaks selected from

[0184] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 14 peaks selected from

[0185] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal of the present invention exhibits the following peaks: 12.0; 19.2; 21.2; 24.3; 16.0; 17.0; 17.8; 20.3; 22.5; 22.7; 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees 1 shows a powder X-ray diffraction pattern showing at least 15 peaks selected from:

[0186] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4′-bipyridine co-crystal of the present invention has an XRPD substantially similar to the XRPD depicted in FIG. 4.

[0187] Methods for preparing cocrystals of ABX464 According to another aspect, the present invention further provides a method for preparing a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, comprising the steps of: a) dissolving ABX464 in one or more solvents; b) adding to the mixture of step a) thus obtained a coformer selected from L-proline, gentisic acid, malonic acid and 4,4'-bipyridine to obtain an ABX464:coformer molar ratio of 3:1 to 1:2, in particular 5:2 to 1:2, more in particular 2:1 to 1:2, even more in particular 2:1 or 1:1, wherein the coformer itself may already be dissolved in a solvent or a mixture of solvents; c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of the selected solvent(s) or mixture of solvents of step a) and step b), in particular between room temperature and 60°C, more in particular between room temperature and 50°C; d) Optionally, Adding a solvent or a mixture of solvents; e) Applying a temperature program; f) optionally filtering; and g) Then, optionally, drying at a temperature between room temperature and 60°C to obtain the desired co-crystal of ABX464. The present invention relates to the above method, which comprises the steps of:

[0188] According to one embodiment, the one or more solvents used in steps a), b) and d) are any solvents conventionally used in crystallization processes, in particular organic solvents, more particularly selected from C1-C6 aliphatic alcohols, methyl ethyl ketone (butanone, also called MEK), cyclohexane, alkanes such as heptane, methylene chloride, chloroform, formic acid, DMSO, 1-methyl-2-pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), diethyl ether, dioxane, toluene, ethyl acetate, and mixtures thereof, optionally in mixtures with water, even more preferably selected from C1-C6 aliphatic alcohols, mixtures of HO / C1-C6 aliphatic alcohols, acetonitrile, and mixtures thereof, and even more particularly selected from methanol, ethanol, isopropanol, HO / methanol, HO / ethanol, acetonitrile, and mixtures thereof.

[0189] A person skilled in the art would know how to determine which solvent or solvents are more suitable in each step a), b) and d) to obtain the desired co-crystal.

[0190] According to one embodiment, the one or more solvents used in step a), step b) and / or step d) are the same.

[0191] According to another embodiment, the one or more solvents used in step a), step b) and / or step d) are the same.

[0192] According to one embodiment, the evaporation step c) is carried out under an inert gas, such as N2.

[0193] According to one embodiment, said step e) of the temperature program comprises a heating stage at reflux to a temperature between room temperature and the boiling point of one or more solvents, in particular between room temperature and 60°C.

[0194] According to one embodiment, said step e) of the temperature program comprises a reflux cooling step at a rate of 30°C / min to 0.05°C / min, in particular 10°C / min to 0.05°C / min, more in particular 5°C / min to 0.05°C / min, to a temperature of 0°C to 60°C, in particular 5°C to 40°C, more in particular room temperature to 40°C.

[0195] According to one embodiment, said step e) relating to the temperature program comprises i) heating under reflux to a temperature between room temperature and the boiling point of one or more solvents, in particular between room temperature and 60°C, and / or ii) reflux cooling to a temperature between 0°C and 60°C, in particular between 5°C and 40°C, more in particular between room temperature and 40°C, at a rate between 30°C / min and 0.05°C / min, in particular between 10°C / min and 0.05°C / min, more in particular between 5°C / min and 0.05°C / min.

[0196] According to a particular embodiment, said step e) relating to the temperature program comprises i) heating under reflux to a temperature between room temperature and 60°C, and ii) reflux cooling to a temperature between 5°C and 40°C at a rate between 30°C / min and 0.05°C / min, in particular between 10°C / min and 0.05°C / min, more in particular between 5°C / min and 0.05°C / min.

[0197] According to one embodiment, step f) of filtration is carried out using conventional glass fibre, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride), in particular cellulose filter paper with a filtration mesh of 0.45 μm or 0.2 μm.

[0198] According to one embodiment, said step g) of drying is carried out under vacuum at a temperature between 30°C and 60°C, in particular 40°C.

[0199] According to one embodiment, said step g) of drying is carried out under atmosphere at a temperature between 30°C and 60°C, in particular 40°C.

[0200] According to a particular embodiment, the method for preparing the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention comprises: a) dissolving ABX464 in one or more solvents; b) adding to the mixture of step a) thus obtained a coformer selected from L-proline, gentisic acid, malonic acid and 4,4'-bipyridine to obtain an ABX464:coformer molar ratio of 3:1 to 1:2, in particular 5:2 to 1:2, more in particular 2:1 to 1:2, even more in particular 2:1 or 1:1, wherein the coformer itself may already be dissolved in a solvent or a mixture of solvents; c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of the selected solvent(s) or mixture of solvents of step a) and step b), in particular between room temperature and 60°C, more in particular between room temperature and 50°C; d) Optionally, Adding a solvent or a mixture of solvents; e) applying a temperature program, wherein the temperature program is: i) at a temperature of room temperature to 60°C; Reflux heating and / or ii) reflux cooling to a temperature of 5°C to 40°C at a rate of 30°C / min to 0.05°C / min, particularly 10°C / min to 0.05°C / min, more particularly 5°C / min to 0.05°C / min, f) optionally filtering by using conventional glass fiber, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride), in particular cellulose filter paper with a filtering mesh of 0.45 μm or 0.2 μm; and g) then optionally drying under vacuum at a temperature of 30°C to 60°C, in particular 40°C, or under atmosphere at a temperature of 30°C to 60°C, in particular 40°C, to obtain the desired co-crystal of ABX464. The process includes the steps of:

[0201] According to another particular embodiment, the method for preparing the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention comprises: a) dissolving ABX464 in methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile or mixtures thereof; b) adding to the mixture of step a) thus obtained a coformer selected from L-proline, gentisic acid, malonic acid and 4,4'-bipyridine to obtain ABX464:coformer in a molar ratio of 3:1 to 1:2, in particular 5:2 to 1:2, more in particular 2:1 to 1:2, even more in particular 2:1 or 1:1, wherein the coformer itself may already be dissolved in methanol, ethanol, isopropanol, HO / methanol, HO / ethanol, acetonitrile, or a mixture thereof; c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of the selected solvent(s) or mixture of solvents of step a) and step b), in particular between room temperature and 60°C, more in particular between room temperature and 50°C; d) optionally adding a solvent selected from methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile, and mixtures thereof; e) Applying a temperature program; f) optionally filtering; and g) Optionally, the mixture is then dried at a temperature between room temperature and 60°C to obtain the desired co-crystal of ABX464. The process includes the steps of:

[0202] According to another particular embodiment, the method for preparing the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention comprises: a) dissolving ABX464 in methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile or mixtures thereof; b) adding to the mixture of step a) thus obtained a coformer selected from L-proline, gentisic acid, malonic acid and 4,4'-bipyridine to obtain ABX464:coformer in a molar ratio of 3:1 to 1:2, in particular 5:2 to 1:2, more in particular 2:1 to 1:2, even more in particular 2:1 or 1:1, wherein the coformer itself may already be dissolved in methanol, ethanol, isopropanol, HO / methanol, HO / ethanol, acetonitrile or a mixture thereof; c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of the selected solvent(s) or mixture of solvents of step a) and step b), in particular between room temperature and 60°C, more in particular between room temperature and 50°C; d) optionally adding a solvent selected from methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile, and mixtures thereof; e) applying a temperature program, wherein the temperature program comprises i) heating under reflux to a temperature between room temperature and 60°C, and / or ii) reflux cooling to a temperature between 5°C and 40°C, more particularly between room temperature and 40°C, at a rate between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, more particularly between 5°C / min and 0.05°C / min; f) optionally filtering by using conventional glass fiber, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride), in particular cellulose filter paper with a filtering mesh of 0.45 μm or 0.2 μm; and g) then optionally drying under vacuum at a temperature of 30°C to 60°C, in particular 40°C, or under atmosphere at a temperature of 30°C to 60°C, in particular 40°C, to obtain the desired co-crystal of ABX464. The process includes the steps of:

[0203] According to another aspect, the present invention further provides a method for preparing a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, comprising the steps of: a') physically mixing 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine with a coformer selected from L-proline, gentisic acid, malonic acid and 4,4'-bipyridine in a molar ratio of 2:1 to 1:2, in particular in a molar ratio of 1:1, in a suitable solvent or in a mixture of suitable solvents; and b') grinding the physical mixture of step a') thus obtained in the presence of one drop of a solvent or one drop of a mixed solvent of several solvents to obtain said co-crystals; The present invention relates to the above method, which comprises the steps of:

[0204] A person skilled in the art would know how to determine which solvent or solvents are more suitable in each step a') and b') to obtain the desired co-crystal.

[0205] According to one embodiment, the one or more solvents used in step a') and / or step b') are any solvents customarily used in crystallization processes, in particular organic solvents, more particularly selected from C1-C6 aliphatic alcohols, methyl ethyl ketone (butanone, also called MEK), cyclohexane, alkanes such as heptane, methylene chloride, chloroform, formic acid, DMSO, 1-methyl-2-pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), diethyl ether, dioxane, toluene, ethyl acetate, and mixtures thereof, optionally in mixtures with water, even more particularly selected from C1-C6 aliphatic alcohols, mixtures of HO / C1-C6 aliphatic alcohols, acetonitrile, and mixtures thereof, and even more particularly selected from methanol, ethanol, isopropanol, HO / methanol, HO / ethanol, acetonitrile, and mixtures thereof.

[0206] In some embodiments, the milling is carried out by milling at 20 Hz for 45 minutes using a Retsch MM200 instrument.

[0207] According to one embodiment, the grinding is carried out by using non-oxidizable balls.

[0208] According to one embodiment, the grinding is carried out using a horizontal movement, in particular a horizontal movement with a frequency in the range 20-30 Hz.

[0209] Advantageously, the horizontal movement is applied for a period of time which may be, for example, between 15 minutes and 3 hours, in particular 45 minutes.

[0210] According to a particular embodiment, the present invention further provides a method for preparing a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, comprising the steps of: a') physically mixing 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine with a coformer selected from L-proline, gentisic acid, malonic acid and 4,4'-bipyridine in a molar ratio of 2:1 to 1:2, in particular a molar ratio of 1:1, in a suitable solvent selected from methanol, ethanol, isopropanol, HO / methanol, HO / ethanol, acetonitrile, and mixtures thereof; and b') grinding the physical mixture of step a') thus obtained in the presence of one drop of a solvent selected from methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile, and mixtures thereof, to obtain said co-crystal. The present invention relates to the above method, which comprises the steps of:

[0211] For the preparation of the co-crystal of ABX464, i.e., 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, it is understood that it can be previously obtained either from the method described in WO 2010 / 143169 or from any other suitable method.

[0212] Cocrystals of ABX464, pharmaceutically acceptable salts of ABX464, and pharmaceutical compositions according to the present invention for use as pharmaceuticals According to another aspect, the present invention further relates to a pharmaceutical composition comprising, as one or more active ingredients, at least one co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or at least one pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), and at least one pharmaceutically acceptable excipient.

[0213] According to another aspect, the present invention further relates to pharmaceutical compositions comprising, as the sole pharmaceutically active ingredient, at least one co-crystal as defined in the present invention and / or at least one pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, including solvates and / or hydrates thereof.

[0214] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powders, ointments, or drops), buccally as a mouth spray or nasal spray, etc. Depending on the severity of the infection being treated, the term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, nasal, and intracranial injection or infusion techniques. In certain embodiments, the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof) can be administered orally or parenterally, once or more times a day, at a dosage level of the active ingredient ABX464 contained in the cocrystal or salt, of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, in order to achieve the desired therapeutic effect.

[0215] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, eg, aqueous solutions, suspensions, eg, aqueous suspensions, syrups and elixirs. In addition to the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), the liquid dosage form may include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsions, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral composition may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, and fragrances. When an aqueous suspension is required for oral use, the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention and / or the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention (including solvates and / or hydrates thereof) may be combined with emulsifying and suspending agents.

[0216] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectable preparations.

[0217] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter before use, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium.

[0218] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof) with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active ABX464.

[0219] Solid dosage forms for oral administration include capsules, tablets, pills, powders, lozenges, chewing gum, and granules. In such solid dosage forms, the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein and / or the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein (including solvates and / or hydrates thereof) can be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) a filler or extender, such as starch, e.g., corn starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) a binder, such as carboxymethylcellulose; The following may be mixed with the following ingredients: sugar, alginate, gelatin, polyvinylpyrrolidinone, sucrose, acacia, etc.; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) humectants, such as cetyl alcohol and glyceryl monostearate; h) adsorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffering agent. If desired, certain sweeteners, flavorings, or colorings may also be added.

[0220] Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release one or more active ingredients only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight octavalent polyethylene glycols.

[0221] The co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof) can also be in microencapsulated form with one or more excipients, as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof) may be admixed with at least one inert diluent, such as sucrose, lactose or starch.

[0222] Such dosage forms may also contain, as is normal practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, for example, magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release one or more of the active ingredients only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0223] Pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0224] Topical application for the lower intestinal tract can be effected in the form of a rectal suppository (see above) or a suitable enema. Topical transdermal patches may also be used.

[0225] For topical administration, the provided pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention and / or the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention (including solvates and / or hydrates thereof) include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.

[0226] Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0227] In addition, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispensing the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention (including its solvates and / or hydrates) in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein, including solvates and / or hydrates thereof, in a polymer matrix or gel.

[0228] Dosage forms for topical or transdermal administration of the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or the pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof) include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.

[0229] The co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof) is admixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives or buffers which may be required.

[0230] Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.

[0231] Indeed, for ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or, preferably, as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment, such as petrolatum.

[0232] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions may be prepared by techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food.

[0233] Thus, according to a particular embodiment, the pharmaceutical composition comprising a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, including solvates and / or hydrates thereof, and at least one pharmaceutically acceptable excipient, is in particular in the form of a tablet, capsule, pill, lozenge, chewing gum, powder, granules, suppository, emulsion, microemulsion, solution, e.g. an aqueous solution, suspension, e.g. an aqueous suspension, syrup, elixir, ointment, drops, paste, cream, lotion, gel, spray, inhalant or patch.

[0234] In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0235] The amount of co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof) that may be combined with the excipient or carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.

[0236] Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, granules, sublingual tablets, capsules, troches, suppositories, creams, ointments, dermal gels, injections, drinkable suspensions, and chewing gum.

[0237] According to a particular embodiment, the pharmaceutical composition according to the invention is an oral pharmaceutical composition.

[0238] Oral pharmaceutical compositions of the invention can be in the form of capsules, tablets, or sachets containing a powdered composition. Therapeutically effective oral doses for the formulations of the invention are determined by standard clinical techniques according to the judgment of a healthcare professional.

[0239] Thus, according to one embodiment, when the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof) are formulated into capsules, tablets, suspensions, solutions, or syrups using conventional methods, they are protected in blisters. Another advantage conferred by the use of blisters is that the capsules or tablets are also protected from oxygen and other contaminants.

[0240] The capsules may be soft gel or hard gel capsules. When the capsules are soft gel or hard gel capsules, they may advantageously contain liquid excipients, in particular a lipophilic liquid vehicle, Viscosity modifier for semi-solid lipophilic vehicles / lipophilic liquid vehicles, Solubilizers, surfactants, emulsifiers and adsorption promoters may include:

[0241] Among these excipients, mention may be made of the following: Refined specialty oils, such as: Peanut oil Castor oil cottonseed oil Corn (maize) oil olive oil Sesame oil soybean oil sunflower oil Medium chain triglycerides and their related esters, such as: Caprylic / capric triglyceride (Akomed E, Akomed R, Miglyol 810, and Captex 355) Medium-chain triglycerides (Labrafac CC) Propylene glycol diester of caprylic / capric acid (Labrafac PG) Propylene glycol monolaurate (Lauroglycol FCC) Fractionated coconut oil (Miglyol 812) Caprylic / Capric / Diglyceryl Succinate (Miglyol 829) Medium-chain diester of propylene glycol (Miglyol 840) Partial ester of diglycerides with natural fatty acids (Softisan 645). Solubilizers, surfactants, emulsifiers, and adsorption promoters, e.g. Propylene glycol monocaprylate (Capryol 90) Polyglycolic acid glycerides (Gelucire 44 / 14 and 50 / 13) Polyoxyl-40 hydrogenated castor oil (Cremophor RH 40) Glycerol Monostearate / Ditriglyceride + Glycerin (Imwitor 191) Glyceryl monocaprylate (Imwitor 308*) Glyceryl Cocoate / Citrate / Lactate (Imwitor 380) Glyceryl Mono-Di-Caprylate / Caprate (Imwitor 742) Isosteryl diglyceryl succinate (Imwitor 780K) Glyceryl Cocoate (Imwitor 928) Glyceryl Caprylate (Imwitor 988) Oleoyl macrogol-8 glycerides (Labrafil M 1944 CS) Linoleoyl macrogolglycerides (Labrafil M 2125 CS) PEG-8 Caprylic / Capric Glyceride (Labrasol) lauric acid Propylene glycol laurate (Lauroglycol 90) oleic acid Polyethylene glycol Propylene glycol Polyglycerol dioleate (Plurol Oleique CC 497) Polyoxyethylene-polyoxypropylene copolymers (Poloxamer 124 and 188) Partial glycerides of hydroxylated unsaturated fatty acids (Softigen 701) PEG-6 Caprylic / Capric Glycerides (Softigen 767) Polyoxyethylene glyceryl trioleate (Tagat TO) Polyoxyethylene (20) sorbitan monooleate (Tween 80).

[0242] In some embodiments, the present invention provides a tablet or capsule comprising a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein (including solvates and / or hydrates thereof), and at least one pharmaceutically acceptable excipient.

[0243] In some specific embodiments, the present invention provides a capsule comprising a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein (including solvates and / or hydrates thereof) and at least one pharmaceutically acceptable excipient; or provides a tablet comprising granules formed by a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein (including solvates and / or hydrates thereof) and at least one intragranular excipient, wherein the granules are compressed together with at least one extragranular excipient.

[0244] When the pharmaceutical composition according to the present invention is a tablet, the tablet may be coated or uncoated. Preferably, the tablet is coated by using any suitable film coating agent well known in the art.

[0245] In particular, there is provided herein an oral galenic form comprising at least one co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or at least one pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined above, including solvates and / or hydrates thereof, and at least one precipitation inhibitor as defined above.

[0246] Further provided herein is a coated oral dosage form, in particular a coated oral dosage form dedicated to delayed release dosage forms, comprising at least one pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined above (including solvates and / or hydrates thereof), and / or at least one pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined above (including solvates and / or hydrates thereof).

[0247] Said delayed release dosage forms are specific modified dosage forms that allow the release of the active ingredient from the dosage form at a specific time after administration, for example after the active ingredient has reached the intestinal tract.

[0248] The term "modified release dosage form" means that the dosage form allows for the release of a specific amount of an active ingredient into the body over a specific period of time, i.e., a specific pharmacokinetic profile. The term "modified release" encompasses all types of release that are modified compared to immediate release. In other words, the term "controlled release" is equivalent to "modified release" and includes extended release, as well as delayed and pulsed release.

[0249] The oral dosage form may take the form of a multiparticulate drug delivery system or a multi-layer compression coated tablet, the coating of which may be selected from polymers that allow the dosage form to reach its biological target, more particularly the intestinal tract, and allow the salt or co-crystal to rapidly solubilize once the polymer is solubilized.

[0250] Therefore, the present invention further provides the use of at least one co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined above and / or at least one pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined above (including solvates and / or hydrates thereof) for the manufacture of a delayed release oral dosage form.

[0251] The useful dosage may vary depending on the nature and severity of the disorder, the route of administration, and the age and weight of the patient.

[0252] According to one embodiment, the pharmaceutical composition according to the invention is administered to a subject in need thereof at a dose of 1 mg to 1 g per day, in particular 10 mg to 150 mg per day, of the active ingredient ABX464, one or more times per day.

[0253] The excipient can be any conventionally used excipient, such as those excipients described above, including intragranular and / or extragranular excipients.

[0254] The excipients may be selected from fillers, flow agents, binders, antioxidants, disintegrants, lubricants, surfactants, precipitation retardants, film coating agents, and mixtures thereof.

[0255] Fillers that can be used in accordance with the present invention include, but are not limited to, lactose (anhydrous), lactose monohydrate, spray-dried lactose; compressible sugars, dextrose, dextrates; starch (from any source, e.g., corn, potato, rice, wheat, which can be fully pregelatinized and partially gelatinized); cellulose; microcrystalline cellulose; inorganic salts, such as calcium phosphate, calcium tribasic, and calcium sulfate; and polyols, such as mannitol, sorbitol, and xylitol.

[0256] In some embodiments, the filler can be in an amount of 10% to 85% by weight, based on the total weight of the composition.

[0257] Lubricants that can be used according to the present invention include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, mineral oil, polyethylene glycol, talc, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, leucine, and magnesium lauryl sulfate.

[0258] In some embodiments, the lubricant can be in an amount of 0.3% to 2% by weight, based on the total weight of the composition.

[0259] Disintegrants that can be used in accordance with the present invention include, but are not limited to, croscarmellose sodium, sodium starch glycolate, starch (including starch from any source, e.g., corn, potato, rice, wheat, which can be fully pregelatinized and partially gelatinized), crospovidone, alginates such as calcium alginate and sodium alginate, alginic acid, and magnesium aluminum silicate.

[0260] In some embodiments, the disintegrant can be in an amount of 30% to 60% by weight, based on the total weight of the composition.

[0261] Surfactants that can be used as additives in the present invention include, but are not limited to, sodium lauryl sulfate, tocopherol, lecithin, lauryl sulfate, vitamin E, egg yolk phospholipids, docusate sodium, capryol, labrafil, labrasol, lauroglycol, solutol (macrogol-15 hydroxystearate), and mixtures thereof.

[0262] In some embodiments, the surfactant can be in an amount of 1% to 3% by weight, based on the total weight of the composition.

[0263] Glidants that can be used in accordance with the present invention include, but are not limited to, colloidal silicon dioxide.

[0264] In some embodiments, the fluidizing agent can be in an amount of 0.3% to 2% by weight, based on the total weight of the composition.

[0265] In some embodiments, the binder can be in an amount of 5% to 20% by weight, based on the total weight of the composition.

[0266] Pharmaceutical compositions according to the present invention may be in modified, sustained, controlled, delayed, or immediate release form.

[0267] According to another aspect, the present invention also relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention, for use as a medicament.

[0268] According to another aspect, the present invention also relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention for use in the prevention and / or treatment of inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia.

[0269] According to another aspect, the present invention also relates to a method of using a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a method of using a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a method of using a pharmaceutical composition as defined in the present invention for the manufacture of a medicament.

[0270] According to another aspect, the present invention also relates to a method of using a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a method of using a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine (including solvates and / or hydrates thereof) as defined in the present invention, or a method of using a pharmaceutical composition as defined in the present invention for the manufacture of a medicament for the prevention and / or treatment of inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia.

[0271] According to another aspect, the present invention also relates to a therapeutic method for treating and / or preventing inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia, comprising administering to a patient in need thereof a composition comprising a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, including solvates and / or hydrates thereof.

[0272] According to another aspect, the present invention also relates to a therapeutic method for treating and / or preventing inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia, which method comprises administering to a patient in need thereof a therapeutically effective amount of a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, including solvates and / or hydrates thereof.

[0273] A method of administering a cocrystal of ABX464 to a subject in need thereof is provided, the method comprising: providing an oral pharmaceutical composition comprising a co-crystal of ABX464 and / or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein (including solvates and / or hydrates thereof), and at least one pharmaceutically acceptable excipient; and orally administering said pharmaceutical composition in a therapeutically effective amount to a subject in need thereof. Includes:

[0274] The co-crystals of ABX464 defined in the present invention can be administered alone or in combination with other therapeutic agents that can act synergistically with the co-crystals of ABX464 defined in the present invention. For example, the other therapeutic agent can be a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention (including solvates and / or hydrates thereof).

[0275] Similarly, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof) can be administered alone or in combination with another therapeutic agent that can act synergistically with a pharmaceutically acceptable salt of ABX464 as defined in the present invention (including solvates and / or hydrates thereof). For example, the other therapeutic agent can be a co-crystal of ABX464 as defined in the present invention.

[0276] inflammatory diseases Accordingly, the present invention also relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention for use in the treatment and / or prevention of an infectious disease.

[0277] According to the present invention, "inflammation" is a defensive response by the immune system to tissue injury and infection. However, the inflammatory response can be damaging to the body in some circumstances. In the acute phase, inflammation is characterized by pain, heat, redness, swelling, and loss of function. Inflammation can result from infection, irritation, or injury.

[0278] Thus, "inflammatory disease" refers to a group of diseases and / or disorders caused by excessive or uncontrolled inflammation.

[0279] Inflammatory diseases include, but are not limited to, inflammatory diseases associated with autoimmune diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the skin and other inflammatory diseases involving epithelial cells such as bronchitis, inflammation associated with cancer such as colon cancer, inflammation associated with irritants, and inflammation associated with injury.

[0280] According to the present invention, the inflammatory disease, disorder or condition is selected from: (a) an inflammatory disease, disorder, or condition of the pancreas selected from type 1 diabetes, type 2 diabetes, acute and chronic pancreatitis; (b) an inflammatory disease, disorder, or condition of the kidney selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, Goodpasture's syndrome, Wegener's granulomatosis, and acute or chronic rejection of a kidney transplant; (c) an inflammatory disease, disorder, or condition of the liver selected from nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), biliary liver disease, sclerosing cholangitis, and acute or chronic rejection of a liver transplant; (d) an inflammatory disease, disorder, or condition in the lung or heart selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary arterial hypertension, sarcoidosis, myocarditis, pericarditis, and acute or chronic rejection of a lung or heart transplant; (e) an inflammatory disease, disorder, or condition of the skin selected from contact dermatitis, atopic dermatitis, urticaria, chronic dermatitis, psoriasis, eczema, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne, keloids, and other inflammatory or allergic diseases of the skin; (f) an inflammatory disease, disorder, or condition in the blood vessels / blood selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, arteriosclerosis, proliferative vascular disease, and restenosis; (g) an inflammatory disease, disorder, or condition of the eye selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optic neuritis; (h) an inflammatory disease, disorder, or condition in the central or peripheral nervous system selected from non-viral and viral encephalitis and meningitis, depression, neuropathic pain, chronic pain, traumatic brain injury including stroke, Alzheimer's disease, Parkinson's disease, myelitis, Charcot-Marie-Tooth disease type 1 (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, demyelinating polyneuropathy, and peripheral neuropathy; (i) an autoimmune disease, disorder, or condition selected from lupus, including the skin and kidney, Guillain-Barré syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis; (j) an inflammatory disease, disorder, or condition of the intestine selected from intestinal disorders, ulcerative colitis (UC), and Crohn's disease; (k) an inflammatory disease, disorder, or condition of the reproductive system selected from endometriosis, uterine fibroids, prostate dysplasia or hyperplasia, and cervical dysplasia; and (l) An inflammatory disease, disorder, or condition of the bones and / or joints selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and / or demineralization of the hand, foot, ankle, knee, hip, shoulder, elbow, or spine.

[0281] In certain embodiments, the inflammatory disease can be selected from the list consisting of inflammatory diseases associated with autoimmune diseases, central nervous system (CNS) inflammatory diseases, joint inflammatory diseases, inflammatory gastrointestinal diseases, inflammatory skin and other inflammatory diseases involving epithelial cells, inflammation associated with cancer, inflammation associated with irritation, and inflammation associated with injury.

[0282] In particular, the inflammatory disease is selected from the list consisting of inflammation associated with inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Alzheimer's disease, Parkinson's, osteoarthritis, arteriosclerosis, ankylosing spondylitis, psoriasis, dermatitis, Sjogren's syndrome, bronchitis, asthma, pulmonary arterial hypertension, NASH and colon cancer.

[0283] More particularly, the inflammatory disease is selected from the list consisting of inflammation associated with inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, osteoarthritis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, bronchitis, pulmonary arterial hypertension, NASH and colon cancer.

[0284] More particularly, the inflammatory disease is selected in the list consisting of inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, osteoarthritis, ankylosing spondylitis, pulmonary arterial hypertension, NASH and psoriasis.

[0285] Preferably, inflammatory diseases according to the present invention include inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis.

[0286] Even more preferably, inflammatory diseases according to the present invention include inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis.

[0287] Inflammatory diseases can also include Alzheimer's disease, Parkinson's disease, asthma, arteriosclerosis and dermatitis.

[0288] Dermatitis may include eczema.

[0289] In view of the above, the present invention relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention, for use in the treatment and / or prevention of an inflammatory disease, for example, including inflammation itself and inflammation associated with an inflammatory disease.

[0290] Accordingly, the present invention also relates to a method of using a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention for treating and / or preventing inflammatory diseases, such as inflammation itself and inflammation associated with inflammatory diseases.

[0291] The present invention also relates to a method of using a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), for treating and / or preventing inflammation, for example, including inflammation itself and inflammation associated with inflammatory diseases.

[0292] The present invention also relates to a method for treating and / or preventing an inflammatory disease, for example, including inflammation itself and inflammation associated with said inflammatory disease, the method comprising the step of administering to a patient in need thereof a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof).

[0293] In some embodiments, the method of the present invention or the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention (including solvates and / or hydrates thereof) defined in the present invention, or the pharmaceutical composition defined in the present invention for the use defined above for treating an inflammatory disease, disorder or condition further comprises measuring and / or monitoring the presence and / or level of a biomarker in a patient, for example, a blood, plasma, tissue, saliva, and / or serum sample. In some embodiments, the biomarker measured and / or monitored in the method of the present invention is miR-124.

[0294] In some embodiments, the method of the present invention or the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention (including solvates and / or hydrates thereof) defined in the present invention, or the pharmaceutical composition defined in the present invention for treating an inflammatory disease, disorder or condition further comprises measuring and / or monitoring the presence and / or expression level of miR-124 in the patient, for example in blood, plasma, tissue, saliva, and / or serum samples, before administering the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine defined in the present invention (including solvates and / or hydrates thereof) defined in the present invention, or the pharmaceutical composition defined in the present invention as described herein.

[0295] In some embodiments, the method of the present invention or the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention or the use as defined above for treating an inflammatory disease, disorder or condition further comprises measuring and / or monitoring the presence and / or expression level of miR-124 in the patient during the course of treatment with the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention as described herein.

[0296] In some embodiments, the method of the present invention for treating an inflammatory disease, disorder or condition, or the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention for the use as defined above, further comprises selecting a patient for treatment with the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention, by measuring and / or monitoring the presence and / or expression level of miR-124 in the patient as described herein.

[0297] The provided cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention or the provided pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof) can be administered alone or in combination with one or more other therapeutic compounds, where possible combination therapy takes the form of a fixed combination, or staggered or independent administration of the compound of the present invention and one or more other therapeutic compounds, or a fixed combination and one or more other therapeutic compounds. The compound of the present invention can alternatively or additionally be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor therapy. Long-term therapy can be equivalent to adjuvant therapy in the context of other treatment strategies, as described above. Other possible therapies are therapy to maintain the patient's condition after tumor regression, or chemopreventive therapy, for example in at-risk patients.

[0298] The additional agents may be administered separately from the co-crystals of the provided 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amines as defined herein, or separately from the pharmaceutically acceptable salts of the provided 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amines as defined herein, including solvates and / or hydrates thereof, as part of a multiple dose regimen. Alternatively, the agents may be part of a single dosage form, mixed together with the co-crystals of the provided 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amines as defined herein, or the pharmaceutically acceptable salts of the provided 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amines as defined herein, including solvates and / or hydrates thereof, in a single composition. When administered as part of a multiple dose regimen, the two active agents may be administered simultaneously, sequentially, or within a period typically less than 5 hours of each other.

[0299] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine provided herein or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine provided herein (including solvates and / or hydrates thereof) can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a co-crystal of a provided 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention or a pharmaceutically acceptable salt of a provided 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0300] In some embodiments, a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein, or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein (including solvates and / or hydrates thereof) may be administered with one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, for example, nonsteroidal anti-inflammatory drugs (NSAIDS) such as acetaminophen, aspirin, ibuprofen, naproxen, etc.; corticosteroids such as etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.; antimalarials such as probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), hydroxychloroquine (Plaquenil®), and chloroquine (Aralen®); methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridau®). ra®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®, Neoral®), tacrolimus, sirolimus, mycophenolate, leflunomide (Arava®), and "Anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®); "anti-IL-1" agents such as anakinra (Kineret®), rilonacept (Arcalyst®); thymoglobulin, IV immune globulin (IVIg);Anti-T cell antibodies such as canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), "anti-IL-6" agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®). antidiarrheals such as steroids, difenoxate (Lomotil®) and loperamide (Imodium®); bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®); laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®; anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®; albuterol (Ventolin® HFA, Proventil®); beta-2 agonists such as HFA, levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), (registered trademark)), anticholinergics such as beclomethasone dipropionate (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®,Inhaled corticosteroids such as cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine Nucleoside reverse transcriptase inhibitors such as zidovudine (Trizivir®), didanosine (Videx®), emcitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etorafenib (Ethiram®). Non-nucleoside reverse transcriptase inhibitors such as virin (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), amprenavir (Agenerase®), atazanavir (Reyataz), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (N orvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®),and lenalidomide (Revlimid®), in combination with dexamethasone (Decadron®), anti-IL36 agents such as BI655130, dihydroorotate dehydrogenase inhibitors such as IMU-838, anti-OX40 agents such as KHK-4083, microbiome agents such as RBX2660 and SER-287, narrow-spectrum kinase inhibitors such as TOP-1288, anti-CD40 agents such as BI-655064 and FFP-104, guanylate synthase inhibitors such as dolucatide, cyclase agonists, sphingosine kinase inhibitors such as opaganib, anti-IL-12 / IL-23 agents such as AK-101, ubiquitin protein ligase complex inhibitors such as BBT-401, sphingosine receptor modulators such as BMS-986166, P38MAPK / PDE4 inhibitors such as CBS-3595, CCR9 antagonists such as CCX-507, FimH antagonists such as EB-8018, HIF-PH inhibitors such as FG-6874, HIF-1α stabilizers such as GB-004, GS-4 MAP3K8 protein inhibitors such as 875, LAG-3 antibodies such as GSK-283171, RIP2 kinase inhibitors such as GSK-2983559, farnesoid X receptor agonists such as MET-409, CCK2 antagonists such as PNB-001, IL-23 receptor antagonists such as PTG-200, purinergic P2X7 receptor antagonists such as SGM-1019, PDE4 inhibitors such as apremilast, ICAM-1 inhibitors such as alicaforsen sodium, guselkumab, brazikumab, and anti-IL23 drugs such as mirquizumab, anti-IL15 drugs such as AMG-714, TYK2 inhibitors such as BMS-986165, NK cell activators such as CNDO-201, RIP-1 kinase inhibitors such as GSK-2982772, anti-NKGD2 agents such as JNJ-4500, CXCL-10 antibodies such as JT-02, IL-22 receptor agonists such as RG-7880, GATA-3 antagonists such as SB-012, and colony-stimulating factor 1 receptor inhibitors such as edicotinib, or a combination of one or more thereof.

[0301] Diseases caused by viruses The co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention may be useful in the treatment and / or prevention of various diseases caused by viruses, in particular retroviruses, and more in particular HIV, more in particular for use in reducing viral load in patients infected by viruses, in particular HIV, or conditions associated with the virus, with long-term efficacy and without resistance.

[0302] Examples of viruses contemplated by the present invention include enveloped and naked viruses, which include DNA viruses, RNA viruses, and retroviruses, which include dsDNA viruses, ssDNA viruses, dsRNA viruses, (+)ssRNA viruses, (-)ssRNA viruses, ssRNA-RT viruses, and dsDNA-RT viruses.

[0303] More particularly considered viruses are RNA viruses and retroviruses, such as the above-mentioned RNA viruses and retroviruses, including lentiviruses, and preferably HIV. Thus, more particularly considered virus-associated conditions are associated with RNA viruses or retroviruses, preferably HIV. HIV can include HIV-I, HIV-2, and all subtypes thereof, including HIV-I strains belonging to HIV-I subtype B, HIV-I subtype C, and HIV-I recombinant types. Examples include HIV-I strains selected from Ad8, AdAm, Isolate B, Isolate C, CRF01, CRF02, and CRF06. According to a preferred embodiment, the virus-associated condition is AIDS.

[0304] Three subfamilies can be distinguished within the retrovirus family: the oncoviruses, the lentiviruses and the spumaviruses. HIV belongs to the lentiviruses.

[0305] According to a particular embodiment, the retrovirus is selected from the group consisting of HIV viruses (HIV1 and HIV2), visna / maedi viruses, i.e., MVV (MVV / visna), equine infectious anemia virus, i.e., EIAV (equine infectious anemia virus), caprine arthritis encephalitis virus, i.e., CAEV (caprine arthritis encephalitis virus), simian immunodeficiency virus, i.e., SIV (simian immunodeficiency virus), avian leukemia virus, i.e., ALV (avian leukemia virus), Moloney virus, i.e., murine leukemia virus, also called MULV (Moloney virus), Abelson leukemia virus, mouse mammary tumor virus, Mason-Pfizer monkey virus, i.e., MPMV (Mason-Pfizer monkey virus), feline leukemia virus, i.e., FELV (feline leukemia virus), human leukemia virus HTLV-I, human leukemia virus HTLV-II, simian leukemia virus, i.e., STLV (simian leukemia virus), leukemia virus), bovine leukemia virus (BLV), primate type D tumor virus, type B tumor virus, Rous sarcoma virus (RSV), simian foamy virus (SFV) or chimpanzee simian virus, human foamy virus, and feline immunodeficiency virus, the human foamy virus (HFV), bovine syncytial virus (BSV), feline syncytial virus (FSV), the feline immunodeficiency virus, avian leukosis virus, walleye cutaneous sarcoma virus, T-cell lymphoma, acute ATL, lymphomatous ATL, chronic ATL, smoldering ATL, neurological diseases, tropical spastic paraplegia (HTLV),paraparesis-related myelopathy, inflammatory and autoimmune diseases such as uveitis, dermatitis, pneumonia, rheumatoid arthritis, and polymyositis, blood and skin diseases, lung diseases, brain diseases, and / or immunodeficiencies.

[0306] As used herein, the term oncovirus can include alpharetroviruses (e.g., avian leukosis virus and Rous sarcoma virus); betaretroviruses (e.g., mouse mammary tumor virus); gammaretroviruses (e.g., murine leukemia virus and feline leukemia virus); deltaretroviruses (e.g., bovine leukemia virus and human T lymphotropic virus); and epsilonretroviruses (e.g., walleye cutaneous sarcoma virus).

[0307] More generally, the retroviruses described herein include, for example, Visna / Medivirus or MVV / Visna, Equine Infectious Anemia Virus, or EIAV, Caprine Arthritis Encephalitis Virus, or CAEV, Simian Immunodeficiency Virus, or SIV, Avian Leukosis Virus, or ALV, Murine Leukemia Virus, also called Moloney Virus, or MULV, Abelson Leukemia Virus, Mouse Mammary Tumor Virus, Mason-Pfizer Monkey Virus, or MPMV, Feline Leukemia Virus, or FELV, Human Leukemia Virus, or HTLV- The virus may be human leukemia virus I, human leukemia virus HTLV-II, simian leukemia virus, i.e., STLV, bovine leukemia virus, i.e., BLV, primate oncovirus D, oncovirus B, Rous sarcoma virus, i.e., RSV, and / or simian foamy virus, i.e., SFV or chimpanzee simian virus, human foamy virus, and feline immunodeficiency virus, the human foamy virus (i.e., HFV), bovine syncytial virus (i.e., BSV), feline syncytial virus (FSV), and the feline immunodeficiency virus.

[0308] More particularly, HTLV-I is responsible for T-cell lymphoma (e.g., ATL, for adult T-cell leukemia / lymphoma, including different forms of ATL, e.g., ATL for adult T-cell leukemia / lymphoma, such as acute ATL, lymphomatous ATL, chronic ATL, and smoldering ATL), neurological disorders, tropical spastic paraparesis (TSP) (also known as HTLV-associated myelopathy (HAM) or chronic progressive myelopathy), and various inflammatory and autoimmune diseases such as uveitis, dermatitis, pneumonia, and rheumatoid arthritis; HTLV-II can be responsible for certain neurological, hematological, and skin disorders; HIV (HIV1 and HIV2) causes AIDS; the Visna virus causes lung and brain disease in sheep, and the feline immunodeficiency virus causes immunodeficiency in cats; and the Rous sarcoma virus and mouse mammary tumor virus cause tumor growth and cancer.

[0309] The present invention also relates to a method for treating and / or preventing a disease caused by a virus, in particular a retrovirus and more in particular HIV, which method comprises the step of administering to a patient in need thereof a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention.

[0310] Additionally, the present invention has the object of reducing the viral load in patients infected by a virus, in particular HIV, or a condition associated with the virus, with long-lasting effectiveness and without resistance, by using a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention.

[0311] In one embodiment, the present invention relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention for use in treating or preventing a retroviral infection or a retroviral-related condition, in particular an HIV infection or an HIV-related disease, in a patient in whom ineffective or reduced efficacy of prior art antiretroviral treatments has been demonstrated.

[0312] In another embodiment, the present invention relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention, for use for treating or preventing a retroviral infection or a retroviral-related condition, in particular an HIV infection or an HIV-related disease, in a patient, wherein the patient is infected with a drug-resistant viral strain, more in particular a drug-resistant HIV strain.

[0313] Furthermore, the present invention further relates to new doses and regimens of co-crystals of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, or pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), and their use in the treatment or prevention of viral infections, and in particular HIV, or virus-related conditions, more particularly where said use results in maintaining a low viral load after completion of treatment. Thus, according to one embodiment, the present invention relates to an ASD as defined in the present invention, or a pharmaceutical composition as defined in the present invention, for use for the treatment or prevention of a viral infection or a virus-related condition, in particular an HIV infection or an HIV-related disease, in a patient, where, after completion of treatment; a low or undetectable viral load is maintained; and / or the CD4+ cell count is stabilized or increased.

[0314] According to another embodiment, the present invention relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention, for use in the treatment or prevention of viral infections or virus-related conditions in patients, in particular HIV infections or HIV-related diseases for which inefficacy of prior art antiretroviral treatments or a reduced therapeutic efficacy of prior art antivirals or antiretrovirals has been demonstrated.

[0315] According to yet another embodiment, the present invention relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention, for use in the treatment or prevention of a viral infection or a virus-related condition, in particular an HIV infection or an HIV-related disease, in a patient, wherein the patient is infected with a drug-resistant strain.

[0316] Within the framework of the present invention, the co-crystals of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention or the pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, including their solvates and / or hydrates, may be administered in combination with other antiretroviral agents. According to one embodiment, ART (antiretroviral therapy) or HAART (highly active antiretroviral therapy) may be carried out using one or more of the following antiretroviral compounds: (i) Nucleoside / nucleotide reverse transcriptase inhibitors, also known as nucleoside analogues, such as abacavir, emtricitabine, and tenofovir; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as efavirenz, etravirine, and nevirapine; (iii) protease inhibitors (PIs), such as atazanavir, darunavir, and ritonavir; (iv) entry inhibitors, such as enfuvirtide and maraviroc; (v) Integrase inhibitors, such as dolutegravir and raltegravir.

[0317] Other examples of antiretroviral agents include, in a non-limiting manner: Zidovudine, Lamivudine, Emtricitabine, Didanosine, Stavudine, Abacavir, Zalcitabine, Racivir, Amdoxovir, Apricitabine, Elvucitabine, Efavirenz, Nevirapine, Etravirine, Delavirdine, Rilpvirine, Tenofovir, Fosal These include Fosalvudine, Amprenavir, Tipranavir, Indinavir, Saquinavir, Fosamprenavir, Ritonavir, Darunavir, Atazanavir, Nelfinavir, Lopinavir, Raltegravir, Elvitegravir, Dolutegravir, Enfuvirtide, Maraviroc, Vicriviroc, and combinations thereof.

[0318] In some embodiments, a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein, or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein (including solvates and / or hydrates thereof) is co-crystallized with zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom ... Nucleoside reverse transcriptase inhibitors such as zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), )) and etravirine (Intelence®), non-nucleoside reverse transcriptase inhibitors such as tenofovir (Viread®), nucleotide reverse transcriptase inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Presista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viravir®), It may be administered in combination with one or more additional therapeutic agents selected from protease inhibitors such as acetaminophen (Cycloheximide), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentres®), and combinations thereof.

[0319] The co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention may also be useful for the treatment and / or prevention of diseases caused by viruses belonging to the Coronaviridae family or Coronaviridae infections and conditions associated therewith, and in particular Severe Acute Respiratory Syndrome caused by infection with SARS-CoV or SARS-CoV-2, including the causative strain of COVID-19 (also referred to herein as Coronavirus Disease 2019) and its mutant strains.

[0320] More particularly, SARS-CoV-2, formerly known as 2019-nCoV, belongs to the Coronaviridae family and is part of group 4 of the Baltimore classification.

[0321] For reference, the content of the "Baltimore Classification" reported herein further references the virus taxonomy set forth in the International Committee on Taxonomy of Viruses (ICTV) database, available online at https: / / talk.ictvonline.org / taxonomy / on March 20, 2020 (Email ratification February 2019 & MSL #34), which is incorporated herein in its entirety.

[0322] This classification therefore clusters viruses into families (or "groups") according to their genome type. As of 2018, the virus classification includes seven different groups: Group 1: double-stranded DNA viruses (dsDNA); Group 2: single-stranded DNA viruses (ssDNA); Group 3: double-stranded RNA viruses (dsRNA); Group 4: (+)strand or sense RNA viruses ((+)ssRNA); Group 5: (-)strand or antisense RNA viruses ((-)ssRNA); Group 6: single-stranded RNA viruses with DNA intermediates (ssRNA-RT); Group 7: double-stranded DNA viruses with an RNA intermediate (dsDNA-RT).

[0323] Furthermore, the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention are further particularly useful for the treatment and / or prevention of severe forms of SARS-CoV-2 infection: anti-inflammatory effect to counter the cytokine storm, mucosal effect, promotion of tissue repair to avoid prolonged post-ventilation sequelae.

[0324] According to a particular embodiment, the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention may be used in the early stages of COVID-19.

[0325] Clinically, SARS-CoV-2 infection can lead to cytokine storm syndrome, acute respiratory distress syndrome (ARDS), and multiple organ failure. Notably, cytokine storm (i.e., hyperinflammatory syndrome) is associated with the severity of COVID-19 (including increased MCP1, IL-1β, TNFα, IL-17, G-CSF, and IL-6). Early treatment and actions on viral replication and various cytokine pathways can successfully reduce the cytokine storm syndrome and "hyperinflammation," preventing ARDS and multiple organ failure.

[0326] Thus, in one embodiment, the present invention relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention, for use in a method for treating a group of patients, who may or may not be hospitalized, prior to the onset of respiratory distress syndrome associated with a coronavirus infection.

[0327] Accordingly, in one embodiment, the present invention relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention, for use in a method for treating or preventing the occurrence of respiratory distress syndrome associated with a coronavirus infection.

[0328] In certain embodiments, a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined herein (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined herein is for use in a method for treating or preventing a coronavirus infection, or for treating or preventing the occurrence of vascular, cardiovascular, neurological, or gastrointestinal diseases associated with a coronavirus infection.

[0329] Advantageously, a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, including solvates and / or hydrates thereof, may be considered for use in the prophylactic treatment of Coronaviridae infections, alone or in combination with any other active agent, in particular any dynamin inhibitor, in particular any dynamin-2 inhibitor.

[0330] As used herein, a "condition associated with a Coronaviridae infection", particularly a condition associated with a severe acute respiratory syndrome-associated coronavirus such as SARS-CoV2, may be selected from the list including or consisting of severe respiratory distress syndrome, a cardiovascular condition, a vascular condition, a gastrointestinal condition or a neurological condition.

[0331] Advantageously, such patients who have or are at risk for a condition associated with a coronavirus family infection may also be considered.

[0332] In exemplary embodiments, the conditions associated with coronavirus infection that are particularly contemplated include pulmonary fibrosis, vasculitis, Kawasaki disease, and tissue damage or destruction, particularly lung tissue damage and destruction.

[0333] Unless otherwise indicated, the co-crystals of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), and the pharmaceutical compositions as defined in the present invention are specifically contemplated herein for the treatment or prevention of coronaviruses, and therefore, although they may trivially refer to any member of the coronaviruses family within the meaning of the Baltimore Protocol, a particular selection of viruses will be considered hereinafter as preferred embodiments.

[0334] As used herein, the term "coronavirus family" refers to the corresponding family of RNA viruses belonging to Group 4 of the Baltimore classification, which itself is part of the suborder Coronidovirnae and order Nidovirales. The coronavirus family encompasses both the subfamily Letovirinae and the subfamily Orthocoronavirus.

[0335] As used herein, the term "Retoviridae" refers to the corresponding family of the Baltimore classification, which includes the genus Alpharetovirus, subgenus Myrchovirus, which includes (non-exhaustively) one species, Microhilaretoviridae.

[0336] As used herein, the term "Orthocoronavirus family" refers to the corresponding family of the Baltimore classification, which includes the genera Alphacoronavirus, Betacoronavirus, Deltacoronavirus, and Gammacoronavirus.

[0337] As used herein, the term "alphacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the subgenera Coracovirus, Decacovirus, Dubinacovirus, Ruchacovirus, Minacovirus, Minunacovirus, Myotakovirus, Mictakovirus, Pedakovirus, Rhynacovirus, Setracovirus, and Tegacovirus. In a non-exhaustive manner, this includes the following species: bat coronavirus CDPHE15, bat coronavirus HKU10, horseshoe bat alphacoronavirus HuB-2013, human coronavirus 229E, Lushen Rn rat coronavirus, ferret coronavirus, mink coronavirus 1, miniopterus bat coronavirus 1, miniopterus bat coronavirus HKU8, Myotis rickettii alphacoronavirus Sax-2011, gecko shark alphacoronavirus SC-2013, porcine epidemic diarrhea virus, Scotophilum bat coronavirus 512, horseshoe bat coronavirus HKU2, human coronavirus NL63, NL63-related bat coronavirus strain BtKYNL63-9b, and alphacoronavirus 1.

[0338] As used herein, the term "betacoronavirus" refers to the corresponding family of the Baltimore classification, including the subgenera Enbecovirus, Hibecovirus, Marbecovirus, Novecovirus, and Cerbecovirus. In a non-exhaustive manner, this encompasses the following species: Betacoronavirus 1, Chinese rat coronavirus HKU24, Human coronavirus HKU1, Murine coronavirus, Bat Hp-betacoronavirus Zhejiang2013, Hedgehog coronavirus 1, Middle East respiratory syndrome-associated coronavirus, Pipistrelle's bat coronavirus HKU5, Lesser long-eared bat coronavirus HKU4, Hedgehog coronavirus 1, Middle East respiratory syndrome-associated coronavirus, Pipistrelle's bat coronavirus HKU5, Lesser long-eared bat coronavirus HKU4, Rouset's bat coronavirus GCCDC1, Rouset's bat coronavirus HKU9, and Severe acute respiratory syndrome-associated coronavirus.

[0339] As used herein, the term "severe acute respiratory syndrome-associated coronavirus", i.e., SARS virus, includes, in a non-exhaustive manner, the SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, and SARS-CoV-2; including the strain that causes COVID-19 and their variants.

[0340] As used herein, the term "deltacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the subgenera Andechovirus, Buldechovirus, Herdechovirus, and Mualdecovirus. In a non-exhaustive manner, this includes the following species: Wigeon coronavirus HKU20, Bulbul coronavirus HKU11, coronavirus HKU15, Munia coronavirus HKU13, White-eye coronavirus HKU16, Night heron coronavirus HKU19, and Common moorhen coronavirus HKU21.

[0341] As used herein, the term "gammacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the subgenera Segakovirus and Igakovirus. In a non-exhaustive manner, this includes the following species: Beluga coronavirus SW1 and avian coronaviruses.

[0342] In certain embodiments, the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention for use in a method for treating or preventing a coronavirus infection is for reducing inflammation associated with a coronavirus infection.

[0343] In certain embodiments, the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention for use in a method for treating or preventing a coronavirus infection is for reducing the viral load of the Coronaviridae family.

[0344] In certain embodiments, the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention for use in a method for treating or preventing a Coronaviridae infection is in combination with: Dynamin inhibitors, such as dynasore; and / or Antibiotics, for example, one selected from the group consisting of β-lactams, fluoroquinolones, and macrolides, such as azithromycin; Remdesivir; Ribavirin; ritonavir; Lopanibil; chloroquine or hydroxychloroquine; beta-interferon; an anti-inflammatory compound, such as one selected from the group consisting of anti-TNF, Jak inhibitors, anti-IL6 antibodies, and IL6 receptor antagonists; and / or Calcium inhibitors, such as diltiazem.

[0345] According to some particular embodiments, the coronavirus family is selected from the families Retroviridae and Orthocoronavirus.

[0346] According to some particular embodiments, the coronavirus is an alphacoronavirus or a betacoronavirus or a deltacoronavirus or a gammacoronavirus.

[0347] According to some particular embodiments, the coronavirus is an Enbecovirus or a Hibecovirus or a Marbecovivirus or a Novecovirus or a Sarbecovirus.

[0348] According to some particular embodiments, the coronavirus is a sarbecovirus selected from severe acute respiratory syndrome-associated coronaviruses.

[0349] According to some specific embodiments, the Severe Acute Respiratory Syndrome (SARS) associated coronavirus is selected from the group consisting of: SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, SARS-CoV-2.

[0350] According to some preferred embodiments, the severe acute respiratory syndrome (SARS)-associated coronavirus is selected from SARS-CoV and SARS-CoV-2, e.g., SARS-CoV and SARS-CoV-2, including the causative strain of COVID-19 and variants thereof.

[0351] According to some embodiments, a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention is used in a method for treating or preventing a Coronaviridae infection, wherein the level of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine free base equivalent in a patient's blood, plasma, tissue, saliva, pharynx, trachea, bronchoalveolar, and / or serum sample is measured during said use.

[0352] cancer A co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention may be useful in the treatment and / or prevention of various cancers.

[0353] As used herein, the term "cancer," unless otherwise stated, may relate to any disorder associated with abnormal cell proliferation, and thus includes malignant and benign tumors, metastatic and non-metastatic tumors, solid and non-solid tumors, such as blood-related cancers, which may include leukemia, lymphoma, and myeloma; it may relate to central nervous system (CNS) and non-CNS cancers. Unless otherwise stated, the term "cancer" also includes juvenile cancers, non-juvenile cancers, recurrent and non-recurrent cancers, and recurrent cancers.

[0354] Among the cancers, the following may be mentioned: blood-related cancer, pancreatic cancer, urinary tract cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, thyroid cancer, gallbladder cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumor (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, ascites, malignant pleural effusion, mesothelioma, Wilms' tumor, trophoblastic neoplasm, hemangiopericytoma, Kaposi's sarcoma, mucinous carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, carcinoma of the adrenal cortex, or ACTH-producing tumors.

[0355] According to one embodiment, the following cancers may be mentioned: head and neck cancer, stomach cancer, breast cancer, basal and squamous cell carcinoma, liver cancer, kidney cancer, brain cancer, lung cancer, pancreatic cancer, eye cancer, digestive cancer, colorectal cancer, esophageal cancer, colon cancer, bladder cancer, gallbladder cancer, thyroid cancer, melanoma, uterine / cervical cancer, ovarian cancer, bone cancer and kidney cancer.

[0356] According to another embodiment, the cancer is head and neck cancer, head and neck squamous cell carcinoma, cervical squamous cell carcinoma, adult or pediatric acute lymphocytic leukemia (ALL), adult or pediatric acute myeloid leukemia (AML), Leukemia), acute lymphocytic leukemia, adrenal cancer, anal cancer, astrocytic glioma, astrocytoma (grade 1, 2, 3 or 4), B- or NK / T-cell lymphoma, basal and squamous cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, adult brain and spinal cord tumor, pediatric brain and spinal cord tumor, anaplastic astrocytoma, breast cancer, gastrointestinal cancer, female breast cancer, young female breast cancer, male breast cancer, recurrent breast cancer, hereditary breast cancer, HER2-positive breast cancer, breast cancer with lymph node metastasis, ERα-positive breast cancer, adolescent cancer, childhood cancer, young adult cancer, cancer of unknown primary, Castleman's disease, cervical cancer, cervical intraepithelial neoplasia, bile duct cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML) Myelomonocytic leukemia, colorectal cancer, colorectal adenoma, cutaneous squamous cell carcinoma, endometrial cancer, epithelial ovarian cancer, epithelial ovarian cancer with metastasis, esophageal cancer, esophageal squamous cell carcinoma, Ewing's sarcoma, Ewing's family of tumors, lymphocytic leukemia (ALL), eye cancer such as ocular melanoma and lymphoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioblastoma, glioblastoma multiforme (GBM)multiforme), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive ductal carcinoma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leiomyosarcoma, leukemia, childhood leukemia, liver cancer, lung cancer, pulmonary carcinoid tumor, lymphoma, cutaneous lymphoma, malignant mesothelioma, mantle cell lymphoma, medulloblastoma, melanoma skin cancer, malignant melanoma, meningioma, Merkel cell skin cancer, multiple myeloma, multiple myeloma with osteonecrosis of the jaw, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, recurrent and metastatic nasopharyngeal cancer, neuroblastoma, glioma, non- The cancer may be selected from Hodgkin's lymphoma, childhood non-Hodgkin's lymphoma, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, oral cavity cancer, oral cavity and oropharyngeal cancer, osteosarcoma, pulmonary metastatic osteosarcoma, ovarian cancer, pancreatic cancer, thyroid cancer, papillary thyroid cancer, childhood spinal ependymoma, penile cancer, pituitary tumor, pituitary adenoma, proneural tumor, prostate tumor, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, tongue squamous cell carcinoma, gastric cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, kidney cancer, retinoblastoma, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0357] According to another embodiment, the cancer is head and neck squamous cell carcinoma, cervical squamous cell carcinoma, adult or pediatric acute lymphoblastic leukemia (ALL), adult or pediatric acute myeloid leukemia (AML), acute lymphoblastic leukemia, adrenal gland cancer, anal cancer, astrocytic glioma, astrocytoma (grade 1, 2, 3, 4), B- or NK / T-cell lymphoma, basement membrane and squamous cell carcinoma, bile duct cancer, bone cancer, brain tumor, adult brain and spinal cord tumor, pediatric brain and spinal cord tumor, anaplastic astrocytoma, gastrointestinal cancer, female breast cancer, young female breast cancer, male breast cancer, recurrent breast cancer, hereditary breast cancer, HER2 positive Breast cancer, breast cancer with lymph node metastasis, ERα-positive breast cancer, adolescent cancer, childhood cancer, young adult cancer, cancer of unknown primary site, Castleman's disease, cervical intraepithelial neoplasia, cholangiocarcinoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal adenoma, cutaneous squamous cell carcinoma, endometrial cancer, epithelial ovarian cancer, epithelial ovarian cancer with metastasis, esophageal squamous cell carcinoma, Ewing's sarcoma, Ewing's family of tumors, lymphocytic leukemia (ALL), eye cancers such as ocular melanoma and lymphoma, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor GIST, gestational trophoblastic disease, glioblastoma, glioblastoma multiforme (GBM), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive ductal carcinoma of the breast, Hodgkin's lymphoma, Kaposi's sarcoma, laryngeal and hypopharyngeal cancer, leiomyosarcoma, leukemia, childhood leukemia, pulmonary carcinoid tumor, lymphoma, cutaneous lymphoma, malignant mesothelioma, mantle cell lymphoma, medulloblastoma, malignant melanoma, meningioma, Merkel cell skin cancer, multiple myeloma, multiple myeloma with osteonecrosis of the jaw, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, recurrent and metastatic nasal The cancer may be selected from oropharyngeal carcinoma, neuroblastoma, glioma, non-Hodgkin's lymphoma, childhood non-Hodgkin's lymphoma, gefitinib-resistant non-small cell lung cancer, oral cavity cancer, oral cavity and oropharyngeal cancer, osteosarcoma, pulmonary metastatic osteosarcoma, thyroid cancer, papillary thyroid cancer, childhood spinal cord ependymoma, penile cancer, pituitary tumor, pituitary adenoma, proneural tumor, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, tongue squamous cell carcinoma, testicular cancer, thymic carcinoma, uterine sarcoma, vaginal cancer, vulvar cancer, renal cancer, retinoblastoma, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0358] According to a further embodiment, the cancer is head and neck cancer, head and neck squamous cell carcinoma, cervical squamous cell carcinoma, malignant melanoma, gastric cancer, breast cancer, female breast cancer, young female breast cancer, basal and squamous cell carcinoma, liver cancer, brain tumor, anaplastic astrocytoma, lung cancer, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, oral cancer, eye cancer, gastric cancer, gastrointestinal cancer, astrocytic glioma, astrocytoma (grade 1, 2, 3, or 4), Colorectal cancer, colorectal adenoma, cutaneous squamous cell carcinoma, bladder cancer, bone cancer, recurrent breast cancer, hereditary breast cancer, HER2-positive breast cancer, breast cancer with lymph node metastasis, ERα-positive breast cancer, renal cancer, cervical intraepithelial neoplasia, bile duct cancer, leiomyosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), adult or pediatric acute myeloid leukemia (AML), acute lymphocytic leukemia Hematologic malignancies, B- or NK / T-cell lymphoma, cervical cancer, glioblastoma, glioblastoma multiforme (GBM), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive ductal carcinoma, renal carcinoma, endometrial carcinoma, ovarian cancer, epithelial ovarian cancer, epithelial ovarian cancer with metastasis, esophageal cancer, esophageal squamous cell carcinoma, Ewing's sarcoma, lymphoblastic leukemia (ALL), mantle cell lymphoma, medulloblastoma The cancer may be selected from lymphoma, myelodysplastic syndrome, meningioma, multiple myeloma (MM), multiple myeloma with osteonecrosis of the jaw, nasopharyngeal carcinoma, recurrent and metastatic nasopharyngeal carcinoma, neuroblastoma, glioma, papillary thyroid carcinoma, pediatric spinal ependymoma, osteosarcoma, pulmonary metastatic osteosarcoma, pancreatic cancer, thyroid cancer, sarcoma, pituitary tumor, pituitary adenoma, proneural tumor, tongue squamous cell carcinoma, mesothelioma, retinoblastoma, and prostate cancer.

[0359] According to further embodiments, the cancer may be selected from head and neck cancer, head and neck squamous cell carcinoma, cervical squamous cell carcinoma, malignant melanoma, astroglioma, glioma, gastric cancer, breast cancer, cholangiocarcinoma, recurrent or metastatic nasopharyngeal carcinoma, basal and squamous skin cell carcinoma, liver cancer, brain tumor, anaplastic astrocytoma, lung cancer, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, oral cancer, glioblastoma, osteosarcoma, pulmonary metastatic osteosarcoma, pancreatic cancer, eye cancer, gastrointestinal cancer, colorectal cancer, colorectal adenoma, cutaneous squamous cell carcinoma, endometrial cancer, epithelial ovarian cancer, esophageal cancer, Ewing's sarcoma, gastric cancer, hepatocellular carcinoma, HER2-positive breast cancer, bladder cancer, bone cancer, prostate cancer, retinoblastoma, and kidney cancer.

[0360] According to further embodiments, the cancer may be selected from anaplastic astrocytoma, astrocytic glioma, bladder cancer, breast cancer, cholangiocarcinoma, colorectal cancer, colorectal adenoma, cutaneous squamous cell carcinoma, endometrial cancer, epithelial ovarian cancer, esophageal cancer, Ewing's sarcoma, gastric cancer, gefitinib-resistant non-small cell lung cancer, glioblastoma, glioma, hepatocellular carcinoma, HER2-positive breast cancer, head and neck squamous cell carcinoma, malignant melanoma, nasopharyngeal carcinoma (recurrent or metastatic), neck squamous cell carcinoma, non-small cell lung cancer, oral cancer, osteosarcoma, osteosarcoma (lung metastasis), prostate cancer, and retinoblastoma.

[0361] According to further embodiments, the cancer may be selected from anal cancer, bile duct cancer, gastrointestinal cancer, cholangiocarcinoma, colorectal cancer, colorectal adenoma, esophageal cancer, esophageal squamous cell carcinoma, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver cancer, lung cancer, pulmonary carcinoid tumor, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, pulmonary metastatic osteosarcoma, gastric cancer, pancreatic cancer, small cell lung cancer, and small intestine cancer.

[0362] According to one embodiment, the patient does not present with clinically detectable metastases, in particular the patient has a precancerous condition, early stage cancer or non-metastatic cancer, or the patient presents with clinically detectable metastases and the co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, or the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, including solvates and / or hydrates thereof, does not directly target the invasion of metastases.

[0363] In view of the above, the present invention relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention for use in the treatment and / or prevention of cancer, such as the cancers mentioned above, and of dysplasia.

[0364] Therefore, the present invention also relates to the use of a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention for treating and / or preventing cancer, such as the cancers mentioned herein above, and dysplasia.

[0365] The present invention also relates to the use of a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), for the preparation of a composition, e.g., a medicament, for the treatment and / or prevention of cancer, such as the cancers mentioned herein above, and dysplasia, etc.

[0366] The present invention also relates to a method for preventing, inhibiting or treating cancer or dysplasia, which method comprises at least one step consisting of administering to a patient suffering therefrom an effective amount of a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention.

[0367] In some embodiments, the present invention relates to a method of the present invention or a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention for the use as defined above for treating and / or preventing cancer or dysplasia, wherein the presence and / or expression level of miR-124 in blood and / or tissue samples of the patient is measured before and / or during said use.

[0368] In some embodiments, the present invention relates to the method of the present invention or a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention, for the use as defined above for treating and / or preventing cancer or dysplasia, wherein the presence and / or expression levels of miR-124 in blood and / or tissue samples are measured to guide dosage or monitor response to the treatment.

[0369] In some embodiments, the present invention relates to a method of the present invention or a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention for the use as defined above for treating and / or preventing cancer or dysplasia, wherein levels of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine in blood, plasma, tissue, saliva, and / or serum samples of the patient are measured during said use.

[0370] In some embodiments, the present invention relates to the method of the present invention or a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention, for the use as defined above for treating and / or preventing cancer or dysplasia, wherein they are used in combination with another anti-tumor agent.

[0371] In some embodiments, the present invention relates to the method of the present invention or the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or the pharmaceutical composition as defined in the present invention, for the use as defined above for treating and / or preventing cancer or dysplasia, wherein it is used in combination with another therapy selected from chemotherapy, immunotherapy, radiation therapy, surgery, ultrasound, monoclonal antibodies, and cancer vaccines.

[0372] Among other anticancer drugs, mention may be made of: androgen receptor inhibitors, such as enzalutamide (Xtandi®, Astellas / Medivation), abiraterone (Zytiga®, Centocor / Ortho), antagonists of the gonadotropin-releasing hormone (GnRH) receptor, such as degalarix, Firmagon®, Fering Pharmaceuticals; anti-apoptotic agents, such as venetoclax (Venclexta®, AbbVie / Genentech), blinatumomab (Blincyto®, Amgen), navitoclax (ABT-263, Abbott); Antiproliferative and anti-inflammatory agents such as vinca alkaloids (which include vinblastine, vincristine); Antibiotics such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), and mitomycin; L-asparaginase; antiplatelet agents; Antiproliferative / antibacterial alkylating agents, such as the nitrogen mustard cyclophosphamide and analogs (which include melphalan, chlorambucil, hexamethylmelamine, and thiotepa), alkylnitrosoureas (which include carmustine) and analogs, streptozocin, and triazenes (which include dacarbazine); Antiproliferative / antimitotic antimetabolites, such as folic acid analogues (which include methotrexate), aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platin compounds; compounds that target / decrease protein or lipid kinase activity, as well as anti-angiogenic compounds; compounds that target, decrease or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine amine peptide enzyme inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of Flt-3; Conforma Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZd6 244 from AstraZeneca, PD181461 and leucovorin from Pfizer; Anti-fatigue agent; angiogenesis inhibitors, such as TNP-470; Aromatase inhibitors such as letrozole and anastrozole, exemestane; angiotensin; antisense oligonucleotides, e.g., antisense nucleic acids directed against miR124; anticoagulants, such as heparin, synthetic heparin salts, and other thrombin inhibitors; arginine inhibitors, such as AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics) and CB-1158 (Calithera Biosciences); Bone resorption inhibitors, such as Denosumab (Xgeva®, Amgen), bisphosphonates, such as Zoledronic acid (Zometa®, Novartis); CC chemokine receptor 4 (CCR4) inhibitors, such as mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan); CDK inhibitors, such as palbociclib (Ibrance®, Pfizer); ribociclib (Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and CDK4 / CDK6 inhibitors such as trilaciclib (G1T28, G1 Therapeutics); Cell cycle inhibitors and differentiation inducers, such as tretinoin; Corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, and prednisolone; DNA damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, mercuroretamine, mitomycin, mitoxantrone, nitrosoureas, procarbazine, taxol, taxotere, teniposide, etoposide, and triethylenethiophene phosphamide; Fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel; folate antagonists; FLT3 receptor inhibitors, such as enzalutamide, abiraterone, apalutamide, erlotinib, crizotinib, niraparib, olaparib, osimertinib, regorafenib, sunitinib, lestaurtinib, midostaurin, gilteritinib, semaxinib, linifanib, fostamatinib, pexidartinib, sorafenib, cabozantinib, ponatinib, irolasteltib, pacritinib, famitinib, pexidartinib, and quizartinib; glutaminase inhibitors, such as CD-839 (Calithera Biosciences); growth factor signaling kinase inhibitors; Growth factor inhibitors, such as vascular endothelial growth factor inhibitors and fibroblast growth factor inhibitors, such as olaratumab (Lartruvo®; Eli Lilly), cetuximab (Erbitux®, Eli Lilly), necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); hedgehog pathway inhibitors, such as sonidegib (Odomzo®, Sun Pharmaceuticals), and vismodegib (Erivedge®, Genentech); Histone deacetylase (HDAC) inhibitors, such as vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); velinostat (Beleodaq®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China); Hormones and their analogues, such as estrogen, tamoxifen, goserelin, bicalutamide, nilutamide; Isocitrate dehydrogenase (IDH) inhibitors, such as AG120 (Celgene, NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010); Isoflavones such as genistein; immunosuppressants, such as tacrolimus, sirolimus, azathioprine, and mycophenolate; inhibitors of p53 suppressor proteins, such as ALRN-6924 (Aileron); inhibitors of transforming growth factor β (TGF-β or TGFβ), such as NIS793 (Novartis), fresolimumab (GC1008; Sanofi-Genzyme), M7824 (Merck KgaA—formerly MSB0011459X); iNKT cell agonists, e.g., ABX196 (Abivax) mTOR inhibitors, such as everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer); Microtubule inhibitors, such as taxanes (which include paclitaxel, docetaxel), vinblastine, nocodazole, epothilones, vinorelbine (NAVELBINE®), and epipodophyllotoxins (etoposide, teniposide); Nitric oxide donor; Nucleoside inhibitors, such as trabectedin (a guanidine alkylating agent, Yondelis®, Janssen Oncology); mechlorethamine (an alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (a prodrug of the alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, an antimetabolite cytidine analog, Pfizer); lomustine (an alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource) Biotechnology); azacitidine (a pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesacinate (cephalotaxine ester) (a protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (an enzyme for asparagine depletion, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based anti-atherogenic agent, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based anti-atherogenic agent, Jevtana®, Sanofi-Aventis); capacetrin (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, thought to form interstrand DNA crosslinks, Treanda®, Cephalon / Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based agent, Ixempra®, Bristol-Myers Squibb);Nelarabine (prodrug of a deoxyguanosine analog, a nucleoside metabolism inhibitor, Arranon®, Novartis); chlorafavine (prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleic acid analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Pharmaceutical); PI3K inhibitors, such as idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pitilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics); Platinum coordination complexes (e.g., cisplatin, oxiloplatin, carboplatin, nedaplatin, picoplatin, procarbazine, mitotane, satraplatin, and aminoglutethimide); Poly(ADB) ribose polymerase (PARP) inhibitors, such as those selected from olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800 / BMN673 / LT00673, Medivation / Pfizer / Biomarin); velivalib (ABT-888, AbbVie); and BGB-290 (BeyGene, Inc); Proteasome inhibitors, such as everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer), bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda); Pyrimidine and purine analogues such as floxuridine, capecitabine, and cytarabine; Receptor antagonists, secretion inhibitors, such as breviridin; Selective estrogen receptor modulators (SERMs), such as raloxifene (Evista®, Eli Lilly); Therapeutic antibodies, for example selected from: anti-TNF antibodies, anti-VEGF antibodies, anti-EGFR antibodies, anti-PD-1 antibodies, anti-HER2 antibodies, anti-CD20 antibodies, anti-IL17 antibodies, and anti-CTLA4 antibodies, anti-PDL1, anti-CD25, anti-α4 integrin, anti-IL6R, anti-C5, anti-IL 1. Anti-TPO, anti-IL12 / 23, anti-EPCAM / CD3, anti-CD30, anti-CD80 / 86, anti-anthrax, anti-CCR4, anti-CD6, anti-CD19, anti-α4β7, anti-IL6, anti-VEGFR-2, anti-SLAMF7, anti-GD2, anti-IL17A, anti-PCSK9, anti-IL5, anti-CD 22, anti-IL4, anti-PDGFRα, anti-IL17RA and anti-TcdB, and for example those selected from the following: abagovomab, abatacept, abciximab, abituzumab, abrilumab, actoxumab, adalimumab, adecatumab, aducanumab, aflibercept, afutuji Afutuzymab, Alacizumab, Alefacept, Alemtuzumab, Alirocumab, Altumomab, Amatixumab, Anatumomab, Anetumab, Anifromumab, Anrukinzumab, Apolizumab, Arcitumomab ab), Ascrinvacumab, Aselizumab, Atezolizumab, Atinumab, Altizumab, Atorolimumab, Bapineuzumab, Basiliximab, Bavituximab, Bectumomab, Begelomab, Belatacept,Belimumab, Benralizumab, Bertilimumab, Besilesomab, Bevacizumab, Bezlotoxumab, Biciromab, Bimagrumab, Bimekizumab, Bivatuzumab, Blinatumomab, Blosozumab, Bococizumab Bococizumab, Brentuximab, Briakimumab, Brodalumab, Brolucizumab, Bronticizumab, Canakinumab, Cantuzumab, Caplacizumab, Capromab, Carlumab, Catumaxomab, Cedelizumab zumab, certolizumab, cetixumab, sitatuzumab, cixutumumab, clazakizumab, clenoliximab, clivatuzumab, codrituzumab, coltuximab, conatumumab, concizumab, crenezumab zumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab, daratumumab, dectrekumab, demcizumab, denintuzumab, denosumab, derlotixumab, detumomab, dinutuximab,Diridavumab, Dorlinomab, Drozitumab, Dupilumab, Durvalumab, Dusigitumab, Ecromeximab, Eculizumab, Edobacomab, Edrecolomab, Efalizumab, Efungumab, Eldelu mab, Elgemtumab, Elotuzumab, Elsilimomab, Emactuzumab, Emibetuzumab, Enavatuzumab, Enfortumab, Enlimomab, Enoblituzumab, Enokizumab, Enoticumab, Ensituximab mab, epitumomab, epratuzumab, erlizumab, ertumaxomab, etanercept, etaracizumab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab b), Farletuzumab, Fasinumab, Felvizumab, Fezkimumab, Ficlatuzumab, Figitumumab, Filivumab, Flanvotumab, Fletikumab, Fontolizumab, Foralumab, Foravirumab,Fresolimumab, Fulramumab, Futuximab, Galiximab, Ganitumab, Gantenerumab, Gavilimomab, Gemtuzumab, Gevokizumab, Girentuximab, Glembatumumab, Golim ... Omiliximab, Guselkumab, Ibalizumab, Ibritumomab, Icrucumab, Idarucizumab, Igovomab, Imalumab, Imciromab, Imgatuzumab, Inclacumab, Indatuximab, Indusatumab, Infu Infliximab, Intetumumab, Inolimomab, Inotuzumab, Ipilimumab, Iratumumab, Isatuximab, Itolizumab, Ixekizumab, Keliximab, Labetuzumab, Lambrolizumab, Lampalizumab izumab, lebrikizumab, lemaresomab, lenzilumab, lerdelimumab, lexatumumab, ribivirumab, rifastuzumab, ligelizumab, rilotomab, lintuzumab, lirilumab, rodelizumab,Lokivetmab, Lorvotuzumab, Lucatumumab, Lulizumab, Lumiliximab, Lumretuzumab, Mapatumumab, Margetuximab, Maslimomab, Mavrilimumab, Matuzumab, Mepolizumab, Metelim Metelimumab, Milatuzumab, Minetumomab, Mirvetuximab, Mitumomab, Mogamulizumab, Morolimumab, Motavizumab, Moxetumomab, Muromonab-CD3, Nacolomab, Namilumab, Naptumomab Naptumomab, Narnatumab, Natalizumab, Nebacumab, Necitumumab, Nemolizumab, Nerelimomab, Nesvacumab, Nimotuzumab, Nivolumab, Nofetumomab, Obiltoxaximab, Obinutuzumab umab), Ocaratuzumab, Ocrelizumab, Odulimomab, Ofatumumab, Olaratumab, Olokizumab, Omalizumab, Onartuzumab, Ontuxizumab, Opicinumab, Oportuzumab, Oregovomab,Orticumab, Otelixizumab, Oltertuzumab, Oxelumab, Ozanezumab, Ozoralizumab, Pagibaximab, Palivizumab, Panitumumab, Pancomab, Panobacumab, Parsatuzumab, Pascoli Pascolizumab, Pasotuxizumab, Pateclizumab, Patritumab, Pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab, Pexelizumab, Pidilizumab, Pinatuzumab, Pintumomab, Po Polatuzumab, Ponezumab, Priliximab, Pritumumab, Quilizumab, Racotumomab, Radretumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranibizumab, Raxibacumab, Refanezumab Refanezumab, Regavirumab, Reslizumab, Rilonacept, Rilotumumab, Linucumab, Rituximab, Robatumumab, Roledumab, Romosozumab, Rontalizumab, Rovelizumab, Ruplizumab,Sacituzumab, Samalizumab, Sarilumab, Satumomab, Secukimumab, Seribantumab, Setoxaximab, Sevirumab, Sibrotuzumab, Sifalimumab, Siltuximab, Siplizumab, Sirukumab, Sofituzumab, Solanezumab ab), solitomab, sonepcizumab, sontuzumab, stamulumab, sulesomab, suvizumab, tabalumab, tacatuzumab, tadocizumab, talizumab, tanezumab, taplitumomab, tarextumab, tefibazumab, telimomab aritox, tenatumomab, teneliximab, teplizumab, tesidolumab, TGN 1412, Ticlimumab, Tildrakizumab, Tigatuzumab, TNX-650, Tocilizumab, Toralizumab, Tosatoxumab, Tositumomab, Tovetumab, Tralokinumab, Trastuzumab, TRBS07, Tregalizumab, Tremelimumab, Trevogrumab, Tucotuzumab,Tuvirumab, Ublituximab, Ulocuplumab, Urelumab, Urtoxazumab, Ustekimumab, Vandortuzumab, Vantictumab, Vanucizumab, Vapaliximab, Varlilumab, Vulvoxamic acid globulin (VVU) Vatelizumab, Vedolizumab, Veltuzumab, Vepalimomab, Vesencumab, Visilizumab, Volocixumab, Vorsetuzumab, Votumumab, Zalutumimab, Zanolimumab, Zatuximab, Zatuximab, Ziralimumab, Ziv-Aflibercept, and Zolimomab; Topoisomerase inhibitors such as doxorubicin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, topotecan, and irinotecan; Toxins such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators; Kinase or VEGF inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx; dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors such as cobimetanib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, Bristol-Myers Squibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals; Her2 and EGFR inhibitors such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); and brigutinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors such as cabozantinib (Cometriq®, Exelexis); and multikinase inhibitors such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors such as crizotinib (Xalkori®, Pfizer);Ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis), tivozanib (Aveo Pharmaceuticals); vatalanib (Bayer / Novartis); lusitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang) Pharmaceuticals, Republic of Korea; ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda);

[0373] In a non-limiting manner, the co-crystals of the present invention or salts thereof may be combined, alone or in the form of a kit of parts, with one or more of the following anti-cancer drugs or compounds: ABVD, AC, ACE, Abiraterone (Zytiga®), Abraxane, Abstral, Actinomycin D D), Actiq, Adriamycin, Afatinib (Giotrif®), Afinitor, Aflibercept (Zaltrap®), Aldara, Aldesleukin (IL-2, Proleukin or Interleukin 2), Alemtuzumab (MabCampath), Alkeran, Amsacrine (Amsidine, m-AMSA), Amsidine, Anastrozole (Arimidex®), Ara C, Aredia, Arimidex, Aromasin, arsenic trioxide (Trisenox®, ATO), asparaginase (Crisantaspase®, Erwinase®), axitinib (Inlyta®), azacitidine (Vidaza®), BEACOPP, BEAM, bendamustine (Levact®), bevacizumab Bevacizumab (Avastin), Bexarotene (Targretin®), Bicalutamide (Casodex®), Bleomycin, Etoposide and Platinum (BEP), Bortezomib (Velcade®), Bosulif, Bosutinib (Bosulif),Brentuximab (Adcetris®), Brufen, Buserelin (Suprefact®), Busilvex, Busulfan (Myleran, Busilvex), CAPE-OX, CAPOX, CAV, CAVE, CCNU, CHOP, CMF, CMV, CVP, Cabazitaxel (Jevtana®), Cabozantinib (Cometriq®), Caelyx, Calpol, Campto, Capecitabine (Xeloda®), Caprelsa, CarboMV MV), CarboTaxol, Carboplatin, Carboplatin and etoposide, Carboplatin and paclitaxel paclitaxel, Carmustine (BCNU, Gliadel®), Casodex, Ceritinib (Zykadia®), Cerubidin, Cetuximab (Erbitux®), ChlVPP, Chlorambucil (Leukeran®), Cisplatin, Cisplatin and Teysuno, Cisplatin and capecitabine (CX), Cisplatin, etoposide and ifosfamide ifosfamide (PEI), cisplatin, fluorouracil (5-FU) and trastuzumab, cladribine (Leustat®, LITAK), Clasteon,Clofarabine (Evoltra®), Co-codamol (Kapake®, Solpadol®, Tylex®), Cometriq, Cosmegen, Crisantaspase, Crizotinib (Xalkori®), Cyclophosphamide, Thalidomide and Dexamethasone (CTD), Cyprostat, Cyproterone acetate (Cyprostat®), Cytarabine (Ara C, cytosine arabinoside), Cytarabine in the cerebrospinal fluid, Cytosine arabinoside arabinoside, DHAP, DTIC, Dabrafenib (Tafinlar®), Dacarbazine (DTIC), Dacogen, Dactinomycin (actinomycin D, Cosmegen®), Dasatinib (Sprycel), Daunorubicin, De Gramont, Decapeptyl SR SR), Decitabine (Dacogen®), Degarelix (Firmagon®), Denosumab (Prolia®, Xgeva®), Depocyte, Dexamethasone, Diamorphine, Disodium pamidronate, Disprol, Docetaxel (Taxotere®), Docetaxel, Cisplatin and Fluorouracil (TPF), Doxifos, Doxil,Doxorubicin (Adriamycin), Doxorubicin and Ifosfamide, Doxifos, Drogenil, Durogesic, EC, ECF, EOF, EOX, EP, ESHAP, Effentora, Efudix, Eldisine, Eloxatin, Enzalutamide mide), Epirubicin (Pharmorubicin®), Epirubicin, cisplatin and capecitabine (ECX), Epirubicin, carboplatin and capecitabine (ECarboX), Eposin, Erbitux, Eribulin (Halaven®), Erlotinib (Tarceva®), Erwinase, Est Estracyt, Etopophos, Etoposide (Eposin®, Etopophos®, Vepesid®), Everolimus (Afinitor®), Evoltra, Exemestane (Aromasin®), FAD, FEC, FEC-T chemotherapy, FMD, FOLFIRINOX, FOLFOX, Fenix Faslodex, Femara, Fentanyl, Firmagon, Fludara, Fludarabine (Fludara®), Fludarabine, cyclophosphamide and rituximab (FCR), Fluorouracil (5FU), Flutamide, Folinic acid,Fluorouracil and irinotecan (FOLFIRI), Fulvestrant (faslodex®), G-CSF, gefitinib (Iressa), GemCarbo (gemcitabine and carboplatin), GemTaxol, gemcitabine (Gemzar), gemcitabine and capecitabine (GemCap), gemcitabine (Gemcita bine and cisplatin (GC), gemcitabine and paclitaxel (GemTaxol®), Gemzar, Giotrif, Gliadel, Glivec, Gonapeptyl, Depot, goserelin (Zoladex®), goserelin (Zoladex®, Novgos®), granulocyte colony-stimulating factor (GNF) colony stimulating factor (G-CSF), Halaven, Herceptin, Hycamtin, Hydrea, Hydroxycarbamide (Hydrea®), Hydroxyurea, I-DEX, ICE, IL-2, IPE, Ibandronic acid, Ibritumomab (Zevalin®), Ibrutinib (Imbruvica®), Ibuprofen (Brufen®, Nurofen®), Iclusig, Idarubicin (Zavedos®),Idarubicin and dexamethasone, Idelalisib (Zydelig®), Ifosfamide (Mitoxana®), Imatinib (Glivec®), Imiquimod cream (Aldara®), Imnovid, Instanyl, Interferon (Intron A), Interleukin (Intron A), A), ipilimumab (Yervoy®), Iressa, irinotecan (Campto®), irinotecan and capecitabine (Xeliri®), irinotecan de Gramont, irinotecan modified degramont Gramont, Javlor, Jevtana, Kadcyla, Kapake, Keytruda, Lanreotide (Somatuline®), Lanvis, Lapatinib (Tyverb®), Lenalidomide (Revlimid®), Letrozole (Femara®), Leukeran, Leuprorelin (Prostap®, Lutrate®), Leustat, Levact, Liposomal doxorubicin doxorubicin, Litak, Lomustine (CCNU), Lynparza, Lysodren, MIC, MMM, MPT, MST Continus, MVAC, MVP, MabCampath,Mabthera, Maxtrex, Medroxyprogesterone acetate (Provera), Megace, Megestrol acetate (Megace®), Melphalan (Alkeran®), Mepact, Mercaptopurine (Xaluprine®), Methotrexate (Maxtrex), Methyl prednisolone, Mifamurtide (Mepact®), Mitomycin C C), Mitotane, Mitoxana, Mitoxantrone (Mitozantrone®), Morphgesic SR, Morphine, Myleran, Myocet, Nab-paclitaxel, Nab-paclitaxel (Abraxane®), Navelbine, Nelarabine (Atriance®), Nexavar, Nilotinib (Tasigna®), Nintedanib (Vargatef®), Nipent ( Nipent, Nivolumab (Opdivo®), Novgos, Nurofen, Obinutuzumab (Gazyvaro®), Octreotide, Ofatumumab (Arzerra®), Olaparib (Lynparza®), Oncovin, Onkotrone, Opdivo, Oramorph,Oxaliplatin (Eloxatin), Oxaliplatin and capecitabine (Xelox®), PAD, PC (paclitaxel and carboplatin, CarboTaxol), PCV, PE, PMitCEBO, POMB / ACE, Paclitaxel (Taxol®), Paclitaxel and CarboTaxol Carboplatin, Pamidronate, Panadol, Panitumumab (Vectibix®), Paracetamol, Pazopanib (Votrient®), Pembrolizumab (Keytruda), Pemetrexed (Alimta®), Pemetrexed and carboplatin, Pemetrexed and cisplatin, Pentostatin (Nipent®), Perjeta, Pertuzumab (Perjeta®), Pixantro, ne) (Pixuvri®), Pixuvri, Pomalidomide (Imnovid®), Ponatinib, Potactasol, Prednisolone, Procarbazine, Proleukin, Prolia, Prostap, Provera, Purinesol thol), R-CHOP, R-CVP, R-DHAP, R-ESHAP, R-GCVP, RICE, Raloxifene, Raltitrexed (Tomudex®), Regorafenib (Stivarga®), Revlimid, Rituximab (Mabthera®), Sevredol, Sodium Clodronate clodronate (Bonefos®, Clasteon®, Loron®), Solpadol, sorafenib (Nexavar®), steroids (dexamethasone, prednisolone, methylprednisolone), streptozocin zocin (Zanosar®), Sunitinib (Sutent®), Sutent, TAC, TIP, Tafinlar, Tamoxifen, Tarceva, Targretin, Tasigna, Taxol, Taxotere, Taxotere and cyclophosphamidecyclophosphamide (TC), Temodal, Temozolomide (Temodal®), Temsirolimus (Torisel®), Tepadina, Teysuno, Thalidomide, Thiotepa (Tepadina®), Thioguanine (R), 6-TG, 6-thioguanine, Tomudex, Topotecan (Hycamtin, Potactasol), Torisel, Trabectedin (Yondelis), Trastuzumab (Herceptin®), Trastuzumab emtansine (Kadcyla®), Treosulfan, Tretinoin (Vesanoid®, ATRA), Triptorelin (Decapeptyl SR®, Gonapeptyl Depot®), Trisenox, Tylex, Tyverb, VIDE, vandetanib (Caprelsa®), Vargatef, VeIP, Vectibix, Velbe, Velcade, vemurafenib (Zelboraf®), Vepesid, Vesanoid, Vidaza, vinblastine (Velbe®), vincristine, actinomycin DD) (dactinomycin®) and cyclophosphamide (VAC), vincristine, actinomycin and ifosfamide (VAI), vincristine, doxorubicin and dexamethasone (VAD), vindesine (Eldisine®), vinflunine (Javlor®), vinorelbine (Navelbine®), vismodegib (Erivedge®), Votrient, XELOX, Xalkori, Zero Xeloda, Xgeva, Xtandi, Yervoy, Yondelis, Z-DEX, Zaltrap, Zanosar, Zavedos, Zelboraf, Zevalin, Zoladex (breast cancer), Zoladex (prostate cancer), zoledronic acid (Zometa®), Zometa, Zomorph, Zydelig, Zytiga.

[0374] According to certain embodiments, a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), can be combined with various chemotherapies, immunotherapies (e.g., checkpoint inhibitors, monoclonal antibodies), anti-tumor vaccines, RNA vaccines, magnetic particles, intravascular microrobots, radiation therapy, surgery, ultrasound or other anti-tumor treatments, as described herein.

[0375] Therefore, the present invention further provides a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in the present invention (including solvates and / or hydrates thereof), or a pharmaceutical composition as defined in the present invention, for use as an anti-tumor agent intended for patients who are also being treated with any of immunotherapy, anti-tumor vaccines, RNA vaccines, radiation therapy, surgery, ultrasound therapy or other anti-tumor therapies.

[0376] According to one embodiment, the present invention relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine for the use defined above, or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine for the use defined above, or said pharmaceutical composition for the use defined above, wherein the level of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine in blood, plasma, tissue, saliva and / or serum samples of the patient is measured during said use.

[0377] According to another embodiment, the present invention also relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine for the use defined above, or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine for the use defined above, or said pharmaceutical composition for the use defined above, wherein said use is intended for a patient in which the level of the free base equivalent of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine is measured in a blood, plasma, tissue, saliva and / or serum sample of said patient during said use.

[0378] According to yet another embodiment, the present invention also relates to a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine for the use defined above, or a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine for the use defined above, or said pharmaceutical composition for the use defined above, wherein the presence and / or expression level of miR-124 in blood and / or tissue samples of the patient is measured before and / or during said use, in particular to monitor the effectiveness of and / or response to said use.

[0379] The present invention will now be described in more detail with reference to the following examples, which are provided to illustrate the present invention and should not be construed as limiting the scope and spirit of the present invention.

[0380] Example

[0381] Materials and Methods

[0382] I. Differential Scanning Calorimetry (DSC) TA INSTRUMENTS Q200 Aluminum sealed sample pan (non-sealed) Atmosphere: Nitrogen Heating rate: 10K / min Data processing: UNIVERSAL ANALYSIS 2000 v4.3 The samples were analyzed by DSC from 0 to 300 °C.

[0383] II. X-ray Powder Diffraction (XRPD) Diffractometer Bruker D8 Advance; Copper anticathode, tension 35KV, strength 40mA Bragg-Brentano configuration, fixed sample Analysis range: 2 to 40 Step increment: 0.04 Measurement time per step: 1 second Experimental processing of data with EVA software (v 11.0) X-ray peak positions and intensities are extracted from the analyzed sample.

[0384] III .HPLC-UV method The samples were analyzed by HPLC-UV according to the following method: Instrument: Agilent 1200 and 1100 with PDA detector Column: Waters XTerra MS C18 3.5μm 4.6x50mm Flow rate: 1.5ml / min UV detection: 220nm, 270nm, 290nm Column temperature: 40℃ Injection volume: 1μl Mobile phase: gradient with solution A and solution B prepared according to: Eluent A: Ultrapure water adjusted to pH 2 with 85% orthophosphoric acid Eluent B: Acetonitrile

[0385] Table 7a below shows the HPLC gradient method used for kinetic solubility measurements and dissolution / precipitation in vitro models.

[0386] [Table 7a]

[0387] Example 1: Preparation of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal 6.6 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine was mixed with 1.6 mg of L-proline as a coformer and 2 μl of acetonitrile, and then the resulting mixture was milled using a Retsch MM200 apparatus at 20 Hz for 45 minutes to obtain 7 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline cocrystal.

[0388] The 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline co-crystal was characterized by X-ray powder diffraction (XRPD) to confirm co-crystal formation and by differential scanning calorimetry (DSC) to determine the thermal behavior of the novel solid form.

[0389] More particularly, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline cocrystal is The following peaks were observed: 16.5; 20.6; 21.4; and 22.1 (±0.2 each time) 2-theta angle in degrees wherein said powder X-ray diffractogram optionally exhibits the following additional peaks: 11.0; 15.9; 18.3; and 19.4 (each ±0.2 times). 2-theta angle in degrees and optionally further showing the following additional peaks: 6.1; 12.2; 12.6; 13.3; 13.7; 15.4; 17.3 and 22.4 (each time ±0.2). 2-theta angle in degrees and optionally may be further characterized by powder X-ray diffraction as shown in FIG. and / or 、 There is a single endotherm with an onset temperature of 172.0°C (±2°C).

[0390] The same experiment was carried out except that acetonitrile was replaced with methanol as the polar organic solvent, resulting in a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline.

[0391] Example 2: Preparation of a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid 8.9 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine was mixed with 2.3 mg of gentisic acid as a coformer and 2 μl of acetonitrile, and then the resulting mixture was milled using a Retsch MM200 apparatus at 20 Hz for 45 minutes to obtain 7 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid cocrystal.

[0392] The 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal was characterized by X-ray powder diffraction (XRPD) to confirm co-crystal formation and by differential scanning calorimetry (DSC) to determine the thermal behavior of the novel solid form.

[0393] More particularly, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid co-crystal is The following peaks were observed: 7.9; 14.0; 15.2; and 25.2 (each time ±0.2). 2-theta angle in degrees wherein said powder X-ray diffractogram optionally exhibits the following additional peaks: 15.8; 16.9; 18.5; 19.9; 20.3; 23.0 and 24.7 (each ±0.2 times). 2-theta angle in degrees and optionally, the following additional peaks: 7.6; 14.7; 16.1; 19.7; 21.6; 22.0; 22.3; 23.7; and 24.0 (each time ±0.2). 2-theta angle in degrees and optionally may be further characterized by powder X-ray diffraction as shown in FIG. and / or 、 There is a single endotherm with an onset temperature of 133.0°C (±2°C).

[0394] The same experiment was carried out except that acetonitrile was replaced with methanol as the polar organic solvent, resulting in a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid.

[0395] Example 3: Preparation of a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid 5.8 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine was mixed with 1.5 mg of malonic acid as a coformer and 2 μl of acetonitrile, and then the resulting mixture was milled using a Retsch MM200 apparatus at 20 Hz for 45 minutes to obtain 7 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal.

[0396] The 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal was characterized by X-ray powder diffraction (XRPD) to confirm co-crystal formation and by differential scanning calorimetry (DSC) to determine the thermal behavior of the novel solid form.

[0397] More particularly, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid co-crystal is The following peaks were observed (±0.2 each time): 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8; and 25.6. 2-theta angle in degrees wherein said powder X-ray diffractogram optionally exhibits the following additional peaks: 19.0; 21.4; 24.6; 26.8; 27.6; and 29.9 (each ±0.2 times). 2-theta angle in degrees and optionally, the following additional peaks: 16.8; 17.8; 20.9; 23.8; 28.0; and 29.6 (each ±0.2 times). 2-theta angle in degrees and optionally may be further characterized by powder X-ray diffraction as shown in FIG. and / or 、 It has a single endotherm with an onset temperature of 109.0°C (±2°C).

[0398] The same experiment was carried out except that acetonitrile was replaced with methanol as the polar organic solvent, resulting in a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid.

[0399] Example 4: Preparation of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal 8.6 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine was mixed with 2.4 mg of 4,4'-bipyridine as a coformer and 2 μl of acetonitrile, and then the resulting mixture was milled using a Retsch MM200 apparatus at 20 Hz for 45 minutes to obtain 7 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine cocrystal.

[0400] The 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4′-bipyridine co-crystal was characterized by X-ray powder diffraction (XRPD) to confirm co-crystal formation and by differential scanning calorimetry (DSC) to determine the thermal behavior of the novel solid form.

[0401] More particularly, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine co-crystal is The following peaks were observed: 12.0; 19.2; 21.2; and 24.3 (±0.2 each time). 2-theta angle in degrees wherein said powder X-ray diffractogram optionally exhibits the following additional peaks: 16.0; 17.0; 17.8; 20.3; 22.5 and 22.7 (each ±0.2 sec). 2-theta angle in degrees and optionally further showing the following additional peaks: 8.5; 13.0; 15.7; 16.7; 20.9; 22.0; 23.1; 23.6 and 24.7 (each time ±0.2). 2-theta angle in degrees and optionally may be further characterized by powder X-ray diffraction as shown in FIG. and / or 、 There is a single endotherm with an onset temperature of 127.0°C (±2°C).

[0402] The same experiment was carried out except that acetonitrile was replaced with methanol as the polar organic solvent, resulting in a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4′-bipyridine.

[0403] Example 5: Preparation of anhydrous crystalline ABX464 heminapadisylate 11.9 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine was dissolved in 500 μl of methanol. To this mixture was added 175 μl of 0.1 M naphthalene-1,5-disulfonic acid (counterion) in ethanol to give a molar ratio of ABX464:counterion of 2:1.

[0404] The mixed preparation was magnetically stirred for 1 / 2 hour at room temperature (25°C). The solvent was evaporated at room temperature (25°C) under a stream of N2 gas. Next, acetone was added to the tube as a crystallization solvent (1180 μl of acetone). The tube was then sealed to prevent evaporation of the crystallization solvent and heated at 60°C for 1 hour, while the solution was stirred by a magnetic bare. To induce crystallization of the product, the tube was cooled to 5°C at a rate of 0.1°C / min, while the solution was stirred by a magnetic bare. The resulting suspension was then filtered through a 0.2 μm mesh and then dried under vacuum at 40°C.

[0405] In this way, 8 mg of anhydrous crystalline ABX464 hemina padisylate was obtained.

[0406] As already mentioned herein, this salt is As shown in Figure 5 (powder X-ray diffraction), the following peaks were observed: 9.8; 16.4; 18.2; 20.1; 21.2; 21.6; 23.5 and 26.3 (each time ±0.2). 2-theta angle in degrees wherein said powder X-ray diffractogram optionally contains the following additional peaks: 12.4; 13.1; 17.8; 20.9; 22.6; 24.5; 24.7; 25.2 and 25.9 (each ±0.2 times). 2-theta angle in degreesand optionally further showing the following additional peaks: 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2). 2-theta angle in degrees may further be shown: and / or 、 There is a single endotherm with an onset temperature of 269.0°C (±2°C).

[0407] Accordingly, a characteristic X-ray powder diffraction pattern of anhydrous crystalline ABX464 hemina padisylate is provided in FIG.

[0408] Example 6: Preparation of anhydrous crystalline ABX464 esylate salt 11.4 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine was dissolved in 500 μl of methanol. To this mixture was added 337 μl of 0.1 M ethanesulfonic acid (counterion) in water / ethanol (1 / 10) to give a molar ratio of ABX464:counterion of 1:1.

[0409] The mixed preparation was magnetically stirred for 1 / 2 hour at room temperature (25°C). The solvent was evaporated at room temperature (25°C) under a stream of N2 gas. Ethyl acetate was then added to the tube as a crystallization solvent (480 μl of ethyl acetate). The tube was then sealed to prevent evaporation of the crystallization solvent and heated at 60°C for 1 hour, while the solution was stirred by a magnetic bare. To induce crystallization of the product, the tube was cooled to 5°C at a rate of 0.1°C / min, while the solution was stirred by a magnetic bare. The resulting suspension was then evaporated at room temperature under a stream of N2 gas.

[0410] In this way, 12 mg of anhydrous crystalline ABX464 esylate salt was obtained.

[0411] As already mentioned herein, this salt is As shown in Figure 6 (powder X-ray diffraction), the following peaks 12.2 and 22.2 (each time ±0.2) 2-theta angle in degreeswherein said powder X-ray diffractogram optionally contains the following additional peaks: 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.6; 19.5; 20.0; and 20.7 (each ±0.2). 2-theta angle in degrees and optionally further showing the following additional peaks: 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each ±0.2 times). 2-theta angle in degrees may further be shown: and / or 、 It has a single endotherm with an onset temperature of 108.0°C (±2°C).

[0412] Accordingly, a characteristic X-ray powder diffraction pattern of the anhydrous crystalline ABX464 esylate salt is given in FIG.

[0413] Example 7: Preparation of crystalline hemi-THF (tetrahydrofuran) solvate of hemina padisylate 10.6 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine was dissolved in 500 μl of methanol. To this mixture was added 313 μl of 0.1 M naphthalene-1,5-disulfonic acid (counterion) in ethanol to give a molar ratio of ABX464:counterion of 2:1.

[0414] The mixture was magnetically stirred for 1 / 2 hour at room temperature (25°C). It was evaporated under a stream of N2 gas at room temperature (25°C). Then, THF was added to the tube as a crystallization solvent (1030 μl of THF). The tube was then sealed to prevent evaporation of the crystallization solvent and heated to 60°C for 1 hour, while the solution was stirred by a magnetic bare. To induce crystallization of the product, the tube was cooled to 5°C at a rate of 0.1°C / min, while the solution was stirred by a magnetic bare. The resulting suspension was then filtered through a 0.2 μm mesh and then dried under vacuum at 40°C.

[0415] In this way, 8 mg of crystalline hemi-THF (tetrahydrofuran) solvate of ABX464 heminapadisylate was obtained.

[0416] As already mentioned herein, this salt is As shown in Figure 7 (powder X-ray diffraction), the following peaks were observed: 8.4; 12.3; 14.0; 19.2; 21.3; 22.6 and 24.6 (each time ±0.2). 2-theta angle in degrees wherein said powder X-ray diffractogram optionally exhibits the following additional peaks: 9.6; 13.0; 13.5; 14.8; 17.2; 17.8; 23.4; 24.1; 24.9 and 25.2 (each ±0.2 times). 2-theta angle in degrees and optionally further showing the following additional peaks: 16.7; 18.1; 18.8; 19.5; 20.9 and 22.3 (each ±0.2 times). 2-theta angle in degrees may further be shown: and / or 、 There is a single endotherm with an onset temperature of 172.0°C (±2°C).

[0417] Accordingly, a characteristic X-ray powder diffraction pattern of the crystalline hemi-THF solvate of ABX464 hemina padisylate is given in FIG.

[0418] Example 8: Pharmaceutical composition in the form of a capsule according to the invention, comprising a cocrystal of ABX464 as defined in the present invention The following capsules were prepared with the ingredients in the respective amounts specified in Table 8 below.

[0419] [Table 8]

[0420] The pharmaceutical compositions according to the present invention are useful for the prevention and / or treatment of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia.

[0421] Example 9: Pharmaceutical composition in the form of a capsule according to the invention, comprising a pharmaceutically acceptable salt of ABX464 as defined in the present invention The following capsules were prepared with the ingredients in the respective amounts specified in Table 9 below.

[0422] [Table 9]

[0423] The pharmaceutical compositions according to the present invention are useful in the treatment and / or prevention of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary arterial hypertension, NASH and multiple sclerosis, diseases caused by viruses and / or cancer or dysplasia.

[0424] Example 10: Preparation and dissolution kinetics measurements of anhydrous ABX464 hemina padisylate and ABX464:L-proline co-crystal according to the present disclosure in two different specific aqueous media at selected sampling times compared to ABX464 crystalline Form I. In accordance with the present disclosure, anhydrous ABX464 hemina padisylate and the ABX464:L-proline cocrystal, which have been tested, were prepared according to the following two protocols (see Example 10a and Example 10b, respectively).

[0425] Example 10a: Preparation of anhydrous ABX464 hemina padisylate The synthesis of anhydrous ABX464 hemina padisylate was carried out according to the following protocol: 200 mg of ABX464 crystalline form I was weighed into a 20 mL glass vial; 10 ml of methanol was added into the glass vial to solubilize ABX464 crystalline form I using magnetic stirring at room temperature for 15 minutes; The ABX464 methanol solution was then filtered through a 0.45 μm PTFE filter. 5.9 mL of naphthalene 1,5 disulfonic acid in 0.05 M ethanol solution was added dropwise at room temperature; The solution was magnetically stirred at room temperature for 60 minutes (a clear yellow solution was observed); The solvent was then evaporated under a stream of N2 gas at room temperature (a slightly yellow solid was obtained); 10 mL of acetone was added into a glass vial at room temperature, and ABX464 hemina padisylate was crystallized overnight by adding 10 mL of acetone, while the suspension was magnetically stirred; The suspension was filtered through a 0.2 μm cellulose mesh filter (yielding a slightly yellow solid); The resulting solid was finally dried under vacuum at room temperature to give anhydrous ABX464 hemina padisylate.

[0426] X-ray powder diffraction analysis was performed to characterize this salt, and the corresponding XRPD pattern was characteristic of a crystalline solid and was identical to that shown in FIG.

[0427] Example 10b: Preparation of ABX464:L-proline cocrystal The synthesis of ABX464:L-proline cocrystal was carried out according to the following protocol: A powder physical mixture was prepared by mixing 200 mg of ABX464 crystalline form I with 68 mg of L-proline (1 / 1 molar stoichiometry) in a 10 ml stainless steel milling jar; Two stainless steel milling balls with a diameter of 5 mm were placed in the milling jar; 130 μl of methanol was added; Immediately after adding the solvent drop, the jar was sealed; The jar was then placed on a milling apparatus (Retsch MM200) and milled at 20 Hz for 45 minutes; Thus, an ABX464:L-proline cocrystal was obtained.

[0428] X-ray powder diffraction analysis was performed to characterize this co-crystal, and the corresponding XRPD pattern was characteristic of a crystalline solid and was identical to that shown in Figure 1.

[0429] Example 10c: Kinetic solubility in two aqueous media Kinetic solubility measurements for ABX464 crystalline Form I, anhydrous ABX464 hemina padisylate, and ABX464:L-proline cocrystal were each performed using the following protocols.

[0430] Kinetic Solubility Protocol Sample preparation for kinetic solubility measurements at room temperature protected from light at a target concentration of 2 mg / ml (ABX464 equivalent): In a 4 mL glass vial, 2 mg equivalent of test substance ABX464 was weighed; At room temperature, 1 ml of selection medium (see below for details) was added; Orbital stirring was performed at room temperature protected from light (see below); The soluble fraction was separated from the insoluble fraction by filtration on a PTFE 0.45 μm membrane at selected sampling times (5 min, 30 min, 2 h, 4 h, and 24 h); Immediately after filtration, an external single point calibration of the HPLC-UV dose of the resulting filtrate was performed. The HPLC-UV method selected for these measurements was as described above (see also Table 7a above).

[0431] Preparation of 1 mg / ml ABX464 reference solution: 1 mg of ABX464 crystalline form I was weighed; It was solubilized in DMSO until a clear DMSO solution of 1 mg / ml was obtained.

[0432] These two particular aqueous media are more particularly as follows: FaSSIF (Fasted State Simulated Intestinal Fluid) pH=6.5 + 1% by weight PVPVA (Polyvinylpyrrolidone-Vinyl Acetate: suspending agent); and FeSSIF (Fed State Simulated Intestinal Fluid) (i.e., fed state simulated intestinal fluid) pH=5.0+1 wt% PVPVA (precipitation inhibitor).

[0433] The steps to make 5 mL of FaSSIF are as follows: Weigh out 11.2 mg of SIF powder, add 175 μl of FaSSIF Buffer Concentrate, and then add ultrapure water to make 5.0 mL; leave for 2 hours; add 1% w / w PVPVA.

[0434] The steps to make 5 mL of FeSSIF are as follows: Weigh out 56.0 mg of SIF powder and add 350 μl of FeSSIF Buffer Concentrate, then bring to 5.0 mL with ultrapure water; add 1% w / w PVPVA.

[0435] Kinetic solubility results The kinetic solubility results of ABX464 crystalline Form I, the kinetic solubility results of anhydrous ABX464 hemina padisylate, and the kinetic solubility results of ABX464:L-proline cocrystal in FassiF and FessiF media at different sample times are reported in Table 10 below.

[0436] [Table 10]

[0437] In conclusion of these solubility measurements, the following general observations can be highlighted: In both media and at each time point, the solubility of anhydrous ABX464 hemina padisylate and the solubility of the ABX464:L-proline cocrystal are increased compared to ABX464 crystalline Form I. In FeSSIF pH 5.0 + 1% PVPVA medium, the solubility of all solid forms is significantly increased.

[0438] Finally, the following solubilities were noted: Anhydrous ABX464 heminapadisylate in FeSSIF+1% PVPVA medium rapidly plateaus at approximately 1.05 mg / ml at 2 hours and continues to increase to a maximum of approximately 1.52 mg / ml at 24 hours. The ABX464:L-proline cocrystal in FeSSIF+1% PVPVA medium rapidly plateaus at about 1.16 mg / ml at 2 hours and continues to increase to a maximum of about 1.28 mg / ml at 24 hours. ABX464 crystalline Form I in FeSSIF+1% PVPVA medium rapidly plateaus at about 0.30 mg / mL at 2 hours and continues to increase to a maximum of about 0.42 mg / mL at 24 hours.

[0439] Example 11: Solubility Measurements in the Intestinal Compartment of a Fasted Human In Vitro Model of Two-Step Dissolution-Precipitation of Anhydrous ABX464 Hemina Padisylate Compared to ABX464 Crystalline Form I ABX464 crystalline Form I and anhydrous ABX464 hemina padisylate were evaluated in a two-stage dissolution / precipitation in vitro human model.

[0440] The anhydrous ABX464 hemina padisylate salt used in this study was prepared according to the protocol detailed in Example 10a above.

[0441] The ABX464 crystalline Form I used in this study was the same as that used in Example 10 above.

[0442] The model consists of the following steps: Selected substances were dispensed into fasted simulated gastric fluid containing 1% by weight PVPVA (a precipitation retardant), and then, after 30 minutes, The resulting suspension is diluted with simulated fasted intestinal medium.

[0443] This model is used to assess the dissolution of selected substances (ABX464 crystalline form I, or anhydrous ABX464 hemina padisylate) in gastric fluid and the risk of API (Active Pharmaceutical Ingredient) precipitation in the intestinal compartment.

[0444] The crystallinity of the solid residue collected at the end of each step (stomach and intestine) has been determined by XRPD after centrifugation (18000 rpm for 15 min).

[0445] Protocol for the Dissolution / Precipitation Model in Human Fasting In six different vials, 4.0 mg equivalent of ABX464 of the selected substance is weighed out. Solubility measurements in the gastric compartment (also named G) after 15 minutes (G15min) and 30 minutes (G30min). The solubility measurements comprise the following steps: Add 1 mL of FaSSGF pH 1.2 medium containing 1 wt% PVPVA (target ABX464 concentration = mg / ml) to 6 vials. Mix by vortexing at 37°C. Considering one vial (labeled G15 min and G30 min, respectively) and each vial, at the 15 min and 30 min time points, Focusing on the aspect of suspension, Centrifuge at 18000 rpm for 5 minutes and filter through a 0.45 μm filter (filter Millex LCR Ref. SLCR0,13NK). Measure the pH of the supernatant, administering ABX464 soluble fraction by HPLC; The XPRD pattern is recorded for the final time point sample. The solubility measurements in the intestinal compartment (also designated I) after 15 minutes (Vial I 15 min), 30 minutes (Vial I 30 min), 60 minutes (Vial I 60 min) and 120 minutes (Vial I 120 min) comprised the following steps: Add 1 mL of FaSSIF x 2 (pH 6.5 medium / sodium bicarbonate 90 / 10) to the remaining four vials (ABX464 target concentration = 2 mg / ml). Mix by vortexing at 37°C. Consider one vial at 15 min, 30 min, 60 min, and 120 min (the vials labeled I 15 min, I 30 min, I 60 min, and I 120 min, respectively). For each vial, Focusing on the aspects of suspensions, Centrifuge at 18000 rpm for 5 minutes and filter through a 0.45 μm filter (filter Millex LCR Ref. SLCR0,13NK). Measure the pH of the supernatant, administering ABX464 soluble fraction by HPLC; For the final time point sample, the XPRD pattern is recorded.

[0446] Composition and preparation of biorelevant media in fasting conditions (see Tables 11 and 12 below):

[0447] Fasted gastric medium = FaSSGF pH=1.2 / 1% VPVA w / v

[0448] [Table 11]

[0449] Fasted intestinal medium (FaSSIF X 2 pH=6.5 / sodium bicarbonate, 80g / l 90 / 10v / v) Composition / preparation of FaSSIF X 2 (2x concentrated medium to account for dilution in fasted models):

[0450] [Table 12]

[0451] A FaSSIF X 2 / sodium bicarbonate 80 g / l (90 / 10; v / v) mixture was prepared to maintain the pH in the intestinal compartment after dilution at a pH equal to 6.5.

[0452] Results of a human fasting model of two-phase dissolution / precipitation As reported in Tables 13-16 below, solubility values ​​were obtained for ABX464 crystalline Form I and anhydrous ABX464 hemina padisylate in a two-stage dissolution / precipitation human fasting model.

[0453] XRPD patterns recorded on solid residues collected at the end of the gastric (G 30 min) and intestinal (I 120 min) compartments of fasted dissolution / precipitation studies for ABX464 crystalline Form I and anhydrous ABX464 hemina padisylate were performed and reported in Figure 8 (lower trace) and Figure 9 (lower trace), respectively.

[0454] In Figure 8, an X-ray powder diagram showing ABX464 crystalline Form I (top trace) is also included for comparison.

[0455] In Figure 9, two powder X-ray diagrams showing ABX464 crystalline Form I (top line) and anhydrous ABX464 hemina padisylate (second line from the top) are also included for comparison.

[0456] The data and results for ABX464 crystalline Form I (solubility measured in a fasted model containing 1% PVPVA in FaSSGF pH 1.2) are summarized in Tables 13 and 14 below.

[0457] [Table 13]

[0458] [Table 14]

[0459] The data and results for anhydrous ABX464 hemina padisylate (solubility measured in a fasted model using 1% PVPVA in FaSSGF pH 1.2) are summarized in Tables 15 and 16 below.

[0460] [Table 15]

[0461] [Table 16]

[0462] From these results, the following points can be emphasized: Intestinal compartment at pH 6.5: There was no significant evolution of the ABX464 soluble fraction starting from ABX464 crystalline Form I in the intestinal compartment (~80 μg / ml) and no crystalline phase transformation, as detected by XRPD. Starting with anhydrous ABX464 heminapadisylate, there was a significant increase in the soluble fraction of ABX464 in the intestinal compartment (~43080 μg / ml) without crystalline phase transformation as detected by XRPD.

[0463] As shown above in Examples 10 and 11, the main conclusions of these solubility studies are as follows: ABX464 heminapadisylate and ABX464:L-proline cocrystal have significantly higher solubility in Fassif and Fessif media compared to ABX464 crystalline Form I. The solubility of ABX464 hemina padisylate (~430 μg / ml) in the intestinal compartment of a fasted in vitro human model of two-step dissolution / precipitation is significantly higher than that of ABX464 crystalline Form I (~80 μg / ml). The present invention may be configured as follows. [Section 1] A co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline, having an X-ray powder diffractogram showing the following peaks, expressed as order 2-theta angles: 16.5; 20.6; 21.4; and 22.1 (each ±0.2 hours), wherein said X-ray powder diffractogram may optionally further show the following additional peaks, expressed as order 2-theta angles: 11.0; 15.9; 18.3; and 19.4 (each ±0.2 hours); and still optionally 17.3 and 22.4 (each time ±0.2°C), expressed as order 2-theta angles, and may optionally be further characterized by powder X-ray diffraction as shown in Figure 1, and / or the above 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:L-proline; 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid, having an X-ray powder diffractogram showing the following peaks, expressed as order 2-theta angles: 7.9; 14.0; 15.2, and 25.2 (each ±0.2 hours), wherein the X-ray powder diffractogram may optionally further show the following additional peaks, expressed as order 2-theta angles: 15.8; 16.9; 18.5; 19.9; 20.3; 23.0, and 24.7 (each ±0.2 hours); and 22.3; 23.7, and 24.0 (each ±0.2°C), expressed as order 2-theta angles, and may optionally be further characterized by powder X-ray diffraction as shown in FIG. 2; and / or 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:gentisic acid as above, having a single endotherm with an onset temperature of 133.0°C (±2°C). 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid, having an X-ray powder diffractogram showing the following peaks, expressed as order 2-theta angles: 9.5; 12.2; 15.8; 17.3; 19.7; 22.8; 24.8, and 25.6 (each time ±0.2), wherein said X-ray powder diffractogram optionally shows the following additional peaks, expressed as order 2-theta angles: 19.0; 21.4; 24.6; 26.8; 27.6, and 29.9 (each time ±0.2). 2); and optionally further exhibit the following additional peaks expressed as order 2-theta angles: 16.8; 17.8; 20.9; 23.8; 28.0, and 29.6 (each time ±0.2), and may optionally be further characterized by powder X-ray diffraction as shown in FIG. 3; and / or the above 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:malonic acid, having a single endotherm with an onset temperature of 109.0° C. (±2° C.). 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4′-bipyridine having an X-ray powder diffractogram showing the following peaks, expressed as order 2-theta angles: 12.0; 19.2; 21.2, and 24.3 (each ±0.2 times), wherein the X-ray powder diffractogram may optionally further show the following additional peaks, expressed as order 2-theta angles: 16.0; 17.0; 17.8; 20.3; 22.5, and 22.7 (each ±0.2 times); and 23.1; 23.6, and 24.7 (each time ±0.2°C), expressed as order 2-theta angles, and may optionally be further characterized by powder X-ray diffraction as shown in Figure 4, and / or the above 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine:4,4'-bipyridine having a single endotherm with an onset temperature of 127.0°C (±2°C). The co-crystal is selected from: [Section 2] Item 1. A method for preparing a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in item 1, comprising: a) dissolving ABX464 in one or more solvents; b) adding to the mixture of step a) thus obtained a coformer selected from L-proline, malonic acid, gentisic acid and 4,4'-bipyridine to obtain an ABX464:coformer molar ratio of 3:1 to 1:2, in particular 5:2 to 1:2, more in particular 2:1 to 1:2, even more in particular 2:1 or 1:1, wherein the coformer itself may already be dissolved in a solvent or a mixture of solvents, c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of the selected solvent(s) or mixture of solvents of step a) and step b), in particular between room temperature and 60°C, more in particular between room temperature and 50°C; d) optionally adding a solvent or a mixture of solvents; e) Applying a temperature program; f) optionally filtering; and g) Optionally, the mixture is then dried at a temperature between room temperature and 60°C to obtain the desired co-crystal of ABX464. The process includes the steps of: Or, a') physically mixing 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine with a coformer selected from L-proline, gentisic acid, malonic acid and 4,4'-bipyridine in a molar ratio of 2:1 to 1:2, in particular in a molar ratio of 1:1, in a suitable solvent or in a mixture of suitable solvents; and b') grinding the physical mixture of step a') thus obtained in the presence of one drop of a solvent or one drop of a mixed solvent of several solvents to obtain said co-crystals; The method, comprising the steps of: [Section 3] The solvent(s) of step a), step b) and / or step d) or the solvent(s) of step a') and / or step b') may be any solvent conventionally used in crystallization processes, in particular an organic solvent, more particularly C 1 ~C 6 Preferably, the solvent is selected from aliphatic alcohols, methyl ethyl ketone (butanone, also called MEK), cyclohexane, alkanes such as heptane, methylene chloride, chloroform, formic acid, DMSO, 1-methyl-2-pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), diethyl ether, dioxane, toluene, ethyl acetate, and mixtures thereof, optionally in a mixture with water, and even more preferably, C 1 ~C 6 Fatty alcohols, H 2 O / C 1 ~C 6 A mixture of aliphatic alcohols, acetonitrile, and mixtures thereof, and more particularly methanol, ethanol, isopropanol, H 2 O / methanol, H 2 Item 3. The method according to item 2, wherein the solvent is selected from the group consisting of ethanol, acetonitrile, and mixtures thereof. [Section 4] Pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, including solvates and / or hydrates thereof, including lactate, oleate, oxalate, palmitate, stearate, valerate, pantothenate, picrate, butyrate, malonate, succinate, bitartrate, malate, mandelate, benzoate, edetate, gluceptate, gluconate, lactobionate, salicylate, disalicylate, mucate, pamoate, adipate, alginate, aspartate, camphorate, cyclopentanepropionate, digluconate, glucoheptonate, heptanoate, hexanoate, laurate, nicotinate , pamoate, pivalate, propionate, undecanoate, etc., phosphate, etc., camphorsulfonate, 2-hydroxyethanesulfonate, estolate, napsylate, esylate, napadisylate, dodecylsulfate, etc., perchloric acid, boric acid, glycerophosphate, nitric acid, persulfate, etc., particularly selected from esylate and napadisylate, and more particularly selected from anhydrous crystalline ABX464 heminapadisylate, anhydrous crystalline ABX464 esylate salt, and crystalline hemi-THF solvate of ABX464 heminapadisylate. [Section 5] Item 5. A pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to item 4, wherein the salt includes a solvate and / or a hydrate thereof, 21.6; 23.5; and 26.3 (each ±0.2 times), expressed as order 2-theta angles, as illustrated in FIG. 5 (Powder X-ray Diffraction), wherein the powder X-ray diffractogram optionally includes the following additional peaks, expressed as order 2-theta angles: 12.4; 13.1; 17.8; 20.1; 21.2; 21.6; 23.5; and 26.3 (each ±0.2 times), 24.7; 25.2 and 25.9 (each time ±0.2°C); and optionally further exhibiting the following additional peaks expressed as order 2-theta angles: 8.8; 13.3; 15.1; 17.2; 17.5; 19.4; 19.5 and 19.8 (each time ±0.2°C), and / or having a single endotherm with an onset temperature of 269.0°C (±2°C); 1. An anhydrous crystalline ABX464 esylate salt, having a powder X-ray diffractogram showing the following peaks, expressed as order 2-theta angles: 12.2 and 22.2 (each ±0.2 times), as illustrated in FIG. 6 (Powder X-ray Diffraction), wherein said powder X-ray diffractogram optionally shows the following additional peaks, expressed as order 2-theta angles: 6.2; 12.9; 13.1; 15.3; 16.3; 18.2; 18.3; 0.6; 19.5; 20.0 and 20.7 (each time ±0.2°C); and optionally still further exhibiting the following additional peaks, expressed as order 2-theta angles: 10.1; 15.8; 17.7; 17.9; 20.3 and 21.4 (each time ±0.2°C): and / or the anhydrous crystalline ABX464 esylate salt as above, having a single endotherm with an onset temperature of 108.0°C (±2°C); and 19.2; 21.3; 22.6; and 24.6 (each ±0.2 times), expressed as order 2-theta angles, wherein the powder X-ray diffractogram optionally includes the following additional peaks, expressed as order 2-theta angles: 9.6; 13.0; 13.5; 14.6; 15.0; 16.0; 17.0; 18.0; 19.2; 21.3; 22.6; and 24.6 (each ±0.2 times), as illustrated in FIG. 7 (Powder X-ray Diffraction). 20.9 and 22.3 (each time ±0.2), expressed as order 2-theta angles; and / or a single endotherm with an onset temperature of 172.0°C (±2°C). The salt is selected from the group consisting of: [Section 6] Item 6. A method for preparing a pharmaceutically acceptable salt of ABX464 according to Item 4 or 5, wherein the salt includes a solvate and / or hydrate thereof, comprising: a) dissolving ABX464 in one or more solvents; b) adding counterions in the form of an acid to the mixture of step a) thus obtained to obtain a molar ratio of ABX464:counterions of 3:1 to 1:2, preferably 5:2 to 1:2, more particularly preferably 2:1 to 1:2, even more particularly 2:1 or 1:1, wherein the counterions themselves may already be dissolved in a solvent or in a mixture of solvents, c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of the selected solvent(s) or mixture of solvents of step a) and step b), in particular between room temperature and 60°C, more in particular between room temperature and 50°C; d) Adding a solvent or a mixture of solvents; e) Applying a temperature program; f) optionally filtering; and g) Optionally, drying at a temperature between room temperature and 60°C to obtain the desired salt of ABX464. The method, comprising the steps of: [Section 7] The solvent of step a), step b) and / or step d) is any solvent conventionally used in crystallization processes, in particular an organic solvent, more particularly C 1~C 6 The solvents are selected from aliphatic alcohols, methyl ethyl ketone (butanone, also called MEK), cyclohexane, alkanes such as heptane, methylene chloride, chloroform, formic acid, DMSO, 1-methyl-2-pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), diethyl ether, dioxane, toluene, ethyl acetate, and mixtures thereof, optionally in admixture with water, and even more particularly C 1 ~C 6 Fatty alcohols, H 2 O / C 1 ~C 6 and mixtures thereof, and more particularly methanol, ethanol, isopropanol, H 2 O / methanol, H 2 and / or The counterion in the acid form of step b) is ethanesulfonic acid or naphthalene 1,5-disulfonic acid; The method according to item 6. [Section 8] The temperature program step e) may comprise: i) reflux heating to a temperature between room temperature and the boiling point of one or more solvents, particularly between room temperature and 60°C; and / or ii) reflux cooling to a temperature between 0°C and 60°C, particularly between 5°C and 40°C, more particularly between room temperature and 40°C, at a rate between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, more particularly between 5°C / min and 0.05°C / min. Item 8. The method according to any one of items 2, 3, 6 and 7, comprising: [Section 9] Item 2, 3, 6, 7 and 8, wherein step f) of filtering is carried out using conventional glass fiber, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride), in particular cellulose filter paper with a filtering mesh of 0.45 μm or 0.2 μm. [Section 10] 11. The method according to any one of items 2, 3, 6, 7, 8, 9 and 10, wherein step g) of drying is carried out under vacuum at a temperature of 30°C to 60°C, in particular 40°C, or under atmosphere at a temperature of 30°C to 60°C, in particular 40°C. [Section 11] Item 1. A pharmaceutical composition comprising at least one of the cocrystals according to Item 1 and / or at least one pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in Item 4 or 5, wherein the salt includes a solvate and / or a hydrate thereof, and at least one pharmaceutically acceptable excipient, in particular in the form of a tablet, capsule, pill, lozenge, chewing gum, powder, granule, suppository, emulsion, microemulsion, solution, e.g., aqueous solution, suspension, e.g., aqueous suspension, syrup, elixir, ointment, drop, paste, cream, lotion, gel, spray, inhalant or patch. [Section 12] Item 12. A cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to Item 1, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to Item 4 or 5, or a pharmaceutical composition according to Item 11, for use as a pharmaceutical. [Section 13] Item 12. The cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to Item 1, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to Item 4 or 5, or the pharmaceutical composition according to Item 11, for use in the prevention and / or treatment of an inflammatory disease. [Section 14] Item 12. The cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to Item 1, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to Item 4 or 5, or the pharmaceutical composition according to Item 11, for use in the treatment and / or prevention of cancer. [Section 15] 15. A cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or the pharmaceutical composition thereof for use according to any one of Items 12 to 14, wherein the presence and / or expression level of miR-124 in a patient's blood and / or tissue samples is measured before and / or during use, particularly to monitor the effectiveness of and / or response to the use. [Section 16] Item 12. The cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to Item 1, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to Item 4 or 5, or the pharmaceutical composition according to Item 11, for use in the treatment and / or prevention of a disease caused by a virus, particularly a retrovirus, more particularly HIV, more particularly for use in reducing the viral load in a patient infected with a virus, particularly HIV, or a virus-related condition, with long-lasting effect and without resistance. [Section 17] Item 12. The cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to Item 1, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to Item 4 or 5, or the pharmaceutical composition according to Item 11, for use in the treatment and / or prevention of diseases caused by viruses belonging to the Coronaviridae family or Coronaviridae infections and conditions associated therewith, and in particular severe acute respiratory syndrome caused by infection with SARS-CoV or SARS-CoV-2, including the COVID-19 causative strain and its mutant strains. [Section 18] Item 18. A co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or a pharmaceutical composition for use according to any one of Items 12 to 17, wherein the level of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine free base equivalent in a patient's blood, plasma, tissue, saliva, and / or serum sample is measured during the use of the co-crystal, salt, or pharmaceutical composition.

Claims

1. A co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine: L-proline and a 2-theta angle of 22.1±0.2 degrees, wherein the powder X-ray diffractogram may optionally further exhibit the following additional peaks: 11.0±0.2; 15.9±0.2; 18.3±0.2; and a 2-theta angle of 19.4±0.2 degrees; and still optionally further exhibit the following additional peaks: 6.1±0.2; 12.2±0.2; 12.6±0.2; 13.3±0.2; 13.7±0.2; 15.4±0.2; 17.3±0.2; and a 2-theta angle of 22.4±0.2 degrees. and, A single endotherm with an onset temperature of 172.0°C (±2°C) 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as above: L-proline; 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine: gentisic acid, and a 2-theta angle of 25.2±0.2 degrees, wherein said powder X-ray diffractogram may optionally further exhibit the following additional peaks: 15.8±0.2; 16.9±0.2; 18.5±0.2; 19.9±0.2; 20.3±0.2; 23.0±0.2; and a 2-theta angle of 24.7±0.2 degrees; and still optionally further exhibit the following additional peaks: 7.6±0.2; 14.7±0.2; 16.1±0.2; 19.7±0.2; 21.6±0.2; 22.0±0.2; 22.3±0.2; 23.7±0.2; and a 2-theta angle of 24.0±0.2 degrees. and, A single endotherm with an onset temperature of 133.0°C (±2°C) 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as above: gentisic acid; 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine: malonic acid and a 2-theta angle of 25.6±0.2 degrees, wherein the X-ray powder diffractogram optionally further exhibits the following additional peaks: 19.0±0.2; 21.4±0.2; 24.6±0.2; 26.8±0.2; 27.6±0.2; and a 2-theta angle of 29.9±0.2 degrees; and still optionally further exhibits the following additional peaks: 16.8±0.2; 17.8±0.2; 20.9±0.2; 23.8±0.2; 28.0±0.2; and a 2-theta angle of 29.6±0.2 degrees. and, A single endotherm with an onset temperature of 109.0°C (±2°C) 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as above:malonic acid; and 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine: 4,4′-bipyridine, and a 2-theta angle of 24.3±0.2 degrees, wherein said powder X-ray diffractogram may optionally further exhibit the following additional peaks: 16.0±0.2; 17.0±0.2; 17.8±0.2; 20.3±0.2; 22.5±0.2; and a 2-theta angle of 22.7±0.2 degrees; and still optionally further exhibit the following additional peaks: 8.5±0.2; 13.0±0.2; 15.7±0.2; 16.7±0.2; 20.9±0.2; 22.0±0.2; 23.1±0.2; 23.6±0.2; and a 2-theta angle of 24.7±0.2 degrees. and, A single endotherm with an onset temperature of 127.0°C (±2°C) 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as above: 4,4'-bipyridine The co-crystal is selected from:

2. 10. A method for preparing a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in claim 1, comprising: a) dissolving ABX464 in one solvent; b) adding to the mixture of step a) thus obtained a coformer selected from L-proline, malonic acid, gentisic acid and 4,4'-bipyridine to obtain a molar ratio of ABX464:coformer of 3:1 to 1:2, wherein the coformer itself may already be dissolved in a solvent; c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of said selected one or more solvents of steps a) and b); d) optionally adding a solvent; e) Applying a temperature program; f) optionally filtering; and g) Optionally, the mixture is then dried at a temperature between room temperature and 60°C to obtain the desired co-crystal of ABX464. The process includes the steps of: Or, a') physically mixing 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine with a coformer selected from L-proline, gentisic acid, malonic acid and 4,4'-bipyridine in a molar ratio of 2:1 to 1:2 in a suitable solvent or in a mixture of suitable solvents; and b') grinding the physical mixture of step a') thus obtained in the presence of one drop of a solvent or one drop of a mixed solvent of several solvents to obtain said co-crystals; The process includes the steps of: wherein one or more solvents in step a), step b) and / or step d), or one or more solvents in step a') and / or step b') are C 1 ~C 6 selected from aliphatic alcohols, acetonitrile, and mixtures thereof; wherein step e) of the temperature program comprises: i) reflux heating to a temperature of between room temperature and 60°C; and / or ii) reflux cooling to a temperature of between 0°C and 60°C at a rate of between 30°C / min and 0.05°C / min; and wherein step g) of drying is carried out under vacuum at a temperature between 30°C and 60°C or under atmosphere at a temperature between 30°C and 60°C; The method.

3. A pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, Anhydrous crystalline ABX464 hemina padisylate, and a powder X-ray diffractogram showing the following peaks: 9.8±0.2; 16.4±0.2; 18.2±0.2; 20.1±0.2; 21.2±0.2; 21.6±0.2; 23.5±0.2 and a 2-theta angle of 26.3±0.2 degrees, wherein said powder X-ray diffractogram optionally shows the following additional peaks: 12.4±0.2; 13.1±0.2; 17.8±0.2; 20.9±0.2; 2 and 25.9±0.2 degrees; and optionally may further exhibit the following additional peaks of 2-theta angle: 8.8±0.2; 13.3±0.2; 15.1±0.2; 17.2±0.2; 17.5±0.2; 19.4±0.2; 19.5±0.2 and 19.8±0.2 degrees. and, A single endotherm with an onset temperature of 269.0°C (±2°C) the anhydrous crystalline ABX464 heminapadisylate salt described above; An anhydrous crystalline ABX464 esylate salt, 19.5±0.2; 20.0±0.2; and a 2-theta angle of 20.7±0.2 degrees; and optionally, the following additional peaks may further be present: 10.1±0.2; 15.8±0.2; 17.7±0.2; 17.9±0.2; 20.3±0.2; and a 2-theta angle of 21.4±0.2 degrees. and, It has a single endotherm with an onset temperature of 108.0°C (±2°C). the anhydrous crystalline ABX464 esylate salt as above; and A crystalline hemi-THF solvate of ABX464 hemina padisylate, and a powder X-ray diffractogram showing the following peaks: 8.4±0.2; 12.3±0.2; 14.0±0.2; 19.2±0.2; 21.3±0.2; 22.6±0.2 and a 2-theta angle of 24.6±0.2 degrees, wherein said powder X-ray diffractogram optionally shows the following additional peaks: 9.6±0.2; 13.0±0.2; 13.5±0.2; 14.8±0.2; 17.6±0.2; and 25.2±0.2 degrees 2-theta angles; and optionally still further exhibit the following additional peaks: 16.7±0.2; 18.1±0.2; 18.8±0.2; 19.5±0.2; 20.9±0.2 and 22.3±0.2 degrees 2-theta angles. and, A single endotherm with an onset temperature of 172.0°C (±2°C) Crystalline hemi-THF solvate of the above ABX464 hemina padisylate salt The salt is selected from the group consisting of:

4. 4. A method for preparing a pharmaceutically acceptable salt of ABX464 according to claim 3, comprising: a) dissolving ABX464 in one solvent; b) adding a counterion in the form of an acid to the mixture of step a) thus obtained to obtain a molar ratio of ABX464:counterion of 3:1 to 1:2, wherein the counterion itself may already be dissolved in a solvent; c) optionally evaporating one or more solvents at a temperature between 0°C and the boiling point of said selected one or more solvents of steps a) and b); d) optionally adding a solvent; e) Applying a temperature program; f) optionally filtering; and g) Optionally, drying is then performed at a temperature between room temperature and 60°C to obtain the desired salt of ABX464. The process includes the steps of: wherein the solvent in step a), step b) and / or step d) is C 1 ~C 6 selected from aliphatic alcohols, acetone, ethyl acetate, tetrahydrofuran (THF), optionally in a mixture with water, and mixtures thereof; wherein step e) of the temperature program comprises: i) reflux heating to a temperature of between room temperature and 60°C; and / or ii) reflux cooling to a temperature of between 0°C and 60°C at a rate of between 30°C / min and 0.05°C / min; and wherein step g) of drying is carried out under vacuum at a temperature between 30°C and 60°C or under atmosphere at a temperature between 30°C and 60°C; The method.

5. 5. The method of claim 2, wherein said step e) of temperature programming comprises ii) reflux cooling to a temperature of from 5°C to 40°C at a rate of from 30°C / min to 0.05°C / min.

6. 6. The method of any one of claims 2, 4, and 5, wherein step f) of filtration is carried out using conventional glass fiber, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride).

7. 10. A pharmaceutical composition comprising at least one co-crystal according to claim 1 and / or at least one pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined in claim 3, and at least one pharmaceutically acceptable excipient.

8. 2. The co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to claim 1 for use as a pharmaceutical.

9. 4. A pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to claim 3 for use as a medicine.

10. 8. A pharmaceutical composition according to claim 7 for use as a medicament.

11. 10. The co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to claim 1 for use in the prevention and / or treatment of inflammatory diseases.

12. 4. The pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine according to claim 3 for use in the prevention and / or treatment of inflammatory diseases.

13. 8. The pharmaceutical composition according to claim 7 for use in the prevention and / or treatment of inflammatory diseases.

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