TW202506653A - Microcrystalline forms of (r)-2-(n-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide and processes for their preparation - Google Patents

Abstract

The present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, and processes for their preparation, and pharmaceutical compositions comprising them.

Description

Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide and preparation method thereof

The present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, a method for preparing the same and a pharmaceutical composition containing the same.

Among the characteristics of crystalline active pharmaceutical ingredients (APIs), their polymorphic form and particle size are the two most often mentioned. The latter directly determines the dissolution rate (and hence the in vivo bioavailability) according to the Noyes–Whitney equation (Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897; 19(12):930–934). To improve the dissolution rate, APIs are often pulverized during their manufacture. One of the widely used methods is jet milling (M. Djokić et al., Chemical Engineering Research and Design 2014, 92 (3), 500-508; see also http://dx.doi.org/10.1016/j.cherd.2013.09.011) . Unfortunately, surface amorphization of otherwise fully crystalline input materials can occur due to mechanical stresses induced by collisions between particles and the walls of the chamber (M. Djokić et al., Chemical Engineering Research and Design 2014, 92 (3), 500-508; see also http://dx.doi.org/10.1016/j.cherd.2013.09.011) . The degree of amorphization produced during processing is often unpredictable and varies between the scales of equipment used. Quantifying the degree of amorphization is crucial, as even the smallest amount of amorphous material can alter the processing behavior and properties of the API (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; see also https://doi.org/10.1002/jps.24160) . Parameters affected by amorphization: dissolution rate, apparent solubility, solid-state instability (recrystallization), and changes in solubility properties over time (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; see also https://doi.org/10.1002/jps.24160) . Quantification of the degree of amorphization remains a major analytical challenge (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; see also https://doi.org/10.1002/jps.24160) and partial amorphization should generally be avoided.

The suitability of a given particle size distribution range for pharmaceutical development of a given API depends on a variety of parameters, including (but not limited to) the intended route of administration and the solubility properties of the respective API (see, e.g., B. Y. Shekunov et al., Pharmaceutical Research 2007, 24 (2), 203. (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide requires pulverization of particles to provide, e.g., good bioavailability after oral administration through adequate solubility and dissolution rate, which is related to the particle surface and therefore also to the particle size. Taking into account the project details, x10 / x50 / x90 is selected as: >0.3 / 1 to 8 / <20 μm particle size distribution (PSD) as the target size distribution of micronized (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

In studies aimed at identifying the pharmaceutically acceptable form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide starting from coarse crystalline material, it was found that mechanical stress during jet milling micronization leads to the formation of a solid material which, in addition to crystalline particles, also contains significant and varying proportions of amorphous material. Since partial amorphization poses a threat to the chemical and physical stability of the drug substance, thus leading to variability in solubility, dissolution rate and bioavailability, and since quantification of the degree of amorphization remains a major analytical challenge (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; see also https://doi.org/10.1002/jps.24160) , efforts have been made to provide sufficiently small particles with complete crystallinity. Despite significant efforts in optimizing the jet milling process, it is impossible to eliminate the loss of crystallinity when performing the jet milling process to give the desired particle size.

The present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide of the present invention, a preparation method thereof and a pharmaceutical composition containing the same. Prior Art

(R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoroanilino)propionamide is a chemical compound known to inhibit diacylglycerol kinase ζ isoform (DGKζ) and is disclosed in international patent application PCT/EP2021/060167, published as WO 2021/214019, as Example 62.2. (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide

However, the state of the art at the time of patent application did not describe a method for crystallizing the compound (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide to produce crystalline particles of a size that is advantageous for preparing solid pharmaceutical compositions that can then be used as drugs, nor did it disclose the resulting microcrystalline form of the compound or a pharmaceutical composition containing the same.

It has now been discovered, and this forms the basis of the present invention, that the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the method for its preparation and the pharmaceutical compositions containing it have surprising and advantageous properties.

The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide of the present invention is free of amorphous material within the accuracy of the analytical method used, has a characteristic particle size distribution within the desired range, and exhibits substantially improved solubility properties compared to coarse crystalline material of the same compound.

The preparation process is robust, efficient, and delivers materials of excellent chemical and enantiomeric purity. In addition, the processes address the risk of racemization during the alkylation of the intermediate [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone with (S)-2-bromopropionamide. The risk of racemization in such alkylations involving a stereocenter at the alpha position to the carbonyl group as the site of alkylation is known to those skilled in the art. (See, e.g., P. S. Dragovich et al., J. Med. Chem. 2003, 46, 4572; L. Chen et al., Organic Process Research & Development 2006, 10 (4), 838). The synthesis of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as disclosed in WO 2021/214019 is carried out via the synthesis of rac-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide followed by enantiomeric separation by preparative chiral HPLC. For drug development purposes, such enantiomeric separation is disadvantageous as it incurs costs and substantially prolongs the process time.

According to a first aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide wherein the presence of amorphous form is less than 15% and the particle size distribution is as follows: x10 is <5 µm, x50 is <10 µm, and x90 is <35 µm. Definition

Enantiomeric excess is frequently abbreviated ee and expressed as a percentage (%) and is derived from the ratio of the (R)- and (S)-enantiomers in a given mixture of two enantiomers and is calculated as ee = [(R)-(S) / (R)+(S)] x 100, such that a racemic mixture is 0% ee and a pure enantiomer is 100% ee .

As used herein, the term "leaving group" means an atom or group of atoms that is displaced in a chemical reaction as a stable species that carries bonding electrons. In particular, such a leaving group is selected from the group comprising: a halogen atom, in particular a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, displaced as a halide, in particular a fluoride, a chloride, a bromide or an iodide; a (methylsulfonyl)oxy group, a [(trifluoromethyl)sulfonyl]oxy group, a [(nonafluorobutyl)sulfonyl]oxy group, a (phenylsulfonyl)oxy group, a [(4-methylphenyl)sulfonyl]oxy group, a [(4- The following examples include: [(4-(2-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

As used herein, "microcrystals" refers to fully crystalline solid forms characterized by a particle size distribution within the range of x10 / x50 / x90: <5 / <10 / <35 μm, or <3 / 10 to 15 / <35 μm, or smaller, such as x10 / x50 / x90: <5 / <10 / <20 μm, particularly within the range of x10 / x50 / x90: 0.3 to 4 / 4 to 10 / 10 to 20 μm, 0.5 to 2.5 / 3 to 7 / 8-20 μm, 1 to 4 / 4 to 8 / 12 to 18 μm, 1 to 2 / 4 to 5.5 / 10 to 18 μm, or >0.3 / 1 to 8 / <20 μm.

As used herein, "coarse-grained" refers to a fully crystalline solid form characterized by a particle size distribution in the range of x10/x50/x90: 3/10 to 15/35 μm, or larger.

The term "C ₁ -C ₃ -alkyl" means a straight-chain or branched, saturated, monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms, such as methyl, ethyl, propyl or isopropyl.

According to the second embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide wherein the presence of an amorphous form is less than 15% and its particle size distribution is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to the third embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 15%, and the particle size distribution thereof is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to the fourth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 15%, and the particle size distribution thereof is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm.

According to the fifth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 10%, and the particle size distribution thereof is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm.

According to the sixth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 10%, and the particle size distribution thereof is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to the seventh embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 10%, and the particle size distribution thereof is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to the eighth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm.

According to the ninth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to the tenth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to the eleventh embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 5%, and the particle size distribution thereof is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm.

According to the twelfth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 5%, and the particle size distribution thereof is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to the thirteenth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 5%, and the particle size distribution thereof is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to the fourteenth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm.

According to the fifteenth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to the sixteenth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to the seventeenth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 99%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm.

According to the eighteenth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 99%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to the nineteenth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 2.5%, and the particle size distribution thereof is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm.

According to the twentieth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 2.5%, and the particle size distribution thereof is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to the twenty-first embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 2.5%, and the particle size distribution thereof is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to the twenty-second embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of differential scanning calorimetry, and the particle size distribution is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm.

According to the twenty-third embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of differential scanning calorimetry, and the particle size distribution is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to the twenty-fourth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of XRPD, and the particle size distribution thereof is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm.

According to the twenty-fifth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of XRPD, and the particle size distribution is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to the twenty-sixth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of differential scanning calorimetry according to method DSC1, and its particle size distribution determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm.

According to the twenty-seventh embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of differential scanning calorimetry according to method DSC1, and its particle size distribution measured according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to the twenty-eighth embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of XRPD according to method XRPD1, and its particle size distribution determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm.

According to the twenty-ninth embodiment of the first aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of XRPD according to method XRPD1, and its particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm. Other embodiments of the first aspect of the present invention:

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of amorphous form is less than 5%, and its particle size distribution determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of amorphous form is less than 5%, and its particle size distribution measured according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of amorphous form is less than 5%, and its particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 99%, the presence of amorphous form is less than 5%, and the particle size distribution determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 99%, the presence of amorphous form is less than 5%, and the particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of amorphous form is less than 2.5%, and its particle size distribution determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of amorphous form is less than 2.5%, and its particle size distribution measured according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of amorphous form is less than 2.5%, and its particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined according to method PSD2a is as follows: x50 is in the range of 4 to 5.5 µm.

According to another embodiment of the first aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein

Its particle size distribution determined according to method PSD4 is as follows: x50 in the range of 4 to 8 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined according to method PSD2a is as follows: x90 is in the range of 10 to 18 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof measured according to method PSD4 is as follows: x90 is in the range of 12 to 18 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 15%.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 10%.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 5%.

According to another embodiment of the first aspect, the present invention covers a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 2.5%.

According to another embodiment of the first aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of an amorphous form is below the detection limit of differential scanning calorimetry.

According to another embodiment of the first aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of XRPD.

According to another embodiment of the first aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of differential scanning calorimetry according to method DSC1.

According to another embodiment of the first aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of XRPD according to method XRPD1.

According to another embodiment of the first aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide has an enantiomeric excess of at least 99%.

According to another embodiment of the first aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide has an enantiomeric excess of at least 98%.

According to another embodiment of the first aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein

The (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide has an enantiomeric excess of at least 95%.

According to another embodiment of the first aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide has an enantiomeric excess of at least 90%.

In a specific further embodiment of the first aspect, the present invention encompasses a combination of two or more of the above-mentioned embodiments under the heading "Other embodiments of the first aspect of the present invention".

The present invention encompasses any sub-combination of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in any embodiment or aspect of the present invention, the preparation method thereof, and the pharmaceutical composition comprising the same.

As described in the experimental section herein, the present invention encompasses microcrystalline forms of the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide of the present invention.

According to a second aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: i. allowing an intermediate compound of formula (II) to (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, ii. dissolving the crude product produced in step i. in a solvent or a solvent mixture, iii. mixing the solution produced in step ii. with an anti-solvent, and iv. separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the second embodiment of the second aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: i. allowing an intermediate compound of formula (II) to (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, ii. dissolving the crude product produced from step i. in acetone containing water in the range of 0% to 30% (v/v), iii. combining the solution produced from step ii. with water, and iv. separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the third embodiment of the second aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: i. allowing an intermediate compound of formula (II) to (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, ii. dissolving the crude product produced in step i. in a dipolar aprotic solvent and/or a protic solvent and then optionally filtering, iii. adding the solution or filtrate produced in step ii. to an antisolvent, and iv. separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the fourth embodiment of the second aspect, the present invention covers methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps iii.    adding a solution of ((R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in a dipolar aprotic solvent and/or a protic solvent, which may be filtered, to an antisolvent, and iv.    separating and drying the resulting precipitate, To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the fifth embodiment of the second aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps i. allowing an intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates at a temperature in the range of 20 to 80° C. in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone and isopropanol for a period of time in the range of 30 minutes to 24 hours, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, ii. dissolving the crude product from step (i) in a mixture of acetone and water and then filtering, the ratio of acetone to water being in the range of 8:1 (v/v) to 12:1 (v/v) in favor of acetone, iii. adding the filtrate to water at a temperature in the range of 0°C to 20°C for a time in the range of 20 minutes to 1.5 hours; and iv. separating and drying the resulting precipitate, To obtain (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in microcrystalline form.

According to the sixth embodiment of the second aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: i. allowing an intermediate compound of formula (II) to (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70° C. for a period of time in the range of 1 to 2 hours in acetonitrile, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, ii. dissolving the crude product produced from step (i) in a mixture of acetone and water and then filtering, the ratio of acetone to water being in the range of 8:1 (v/v) to 12:1 (v/v) in favor of acetone, iii. adding the filtrate to water at a temperature in the range of 4°C to 10°C for a time in the range of 30 minutes to 1 hour; and iv. separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide.

According to the seventh embodiment of the second aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: i. allowing an intermediate compound of formula (II) to (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C in acetonitrile for a time in the range of 1 to 2 hours, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, ii. dissolving the crude product produced from step (i) in a mixture of acetone and water and then filtering, the ratio of acetone to water being in the range of 8:1 (v/v) to 12:1 (v/v) in favor of acetone, iii. adding the filtrate to water at a temperature in the range of 4°C to 10°C for a time in the range of 30 minutes to 1 hour; and iv. separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide.

According to the eighth embodiment of the second aspect, the present invention covers methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps: iii. adding a filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in a mixture of acetone and water at a temperature in the range of 4°C to 10°C for a period of time in the range of 30 minutes to 1 hour, wherein the ratio of acetone to water is in the range of 8:1 (v/v) to 12:1 (v/v) in favor of acetone to water, and iv. separating and drying the resulting precipitate, To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide. Other embodiments of the second aspect of the present invention:

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x10 is in the range of 1 to 2 µm.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x50 is in the range of 4 to 5.5 µm.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x50 is in the range of 4 to 8 µm.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x90 is in the range of 10 to 18 µm.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 µm.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined by method PSD2a is as follows: x50 is in the range of 4 to 5.5 µm.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined by method PSD4 is as follows: x50 is in the range of 4 to 8 µm.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined according to method PSD2a is as follows: x90 is in the range of 10 to 18 µm.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined by method PSD4 is as follows: x90 is in the range of 12 to 18 µm.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined by method PSD4 is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of an amorphous form is less than 15%.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 10%.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 5%.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 2.5%.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of differential scanning calorimetry.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of XRPD.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of differential scanning calorimetry according to method DSC1.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of XRPD according to method XRPD1.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide has an enantiomeric excess of at least 99%.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide has an enantiomeric excess of at least 98%.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide has an enantiomeric excess of at least 95%.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide has an enantiomeric excess of at least 90%.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step i. is a chlorine atom, a bromine atom or an iodine atom; or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step i. is a chlorine atom, a bromine atom or an iodine atom; or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy and [(4-methylphenyl)sulfonyl]oxy.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step i. is a chlorine atom.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step i. is [(4-methylphenyl)sulfonyl]oxy.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step i. is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step i. is a bromine atom.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein step i. is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein step i. is carried out in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein step i. is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in the presence of 1.5 to 6 equivalents of a base selected from the following: an alkali metal carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate, potassium bicarbonate and cesium bicarbonate; and an alkali metal phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate and potassium phosphate.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate and potassium phosphate.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is performed in the presence of 1.5 to 3 equivalents of potassium phosphate. According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is performed in the presence of 2 to 6 equivalents of potassium carbonate.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out at a temperature in the range of 0°C to 100°C.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out at a temperature in the range of 20°C to 90°C.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out at a temperature in the range of 40°C to 80°C.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out at a temperature in the range of 50°C to 70°C.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out at a temperature in the range of 40°C to 80°C, and optionally followed by lowering the temperature to 20°C over a period of time in the range of up to one hour.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out at a temperature in the range of 50°C to 70°C, and optionally followed by lowering the temperature to 20°C over a period of time in the range of up to one hour.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out at a temperature in the range of 40°C to 80°C, followed by lowering the temperature to 20°C over a period of time in the range of up to one hour.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out at a temperature in the range of 50°C to 70°C, followed by lowering the temperature to 20°C over a period of time in the range of up to one hour.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, and isopropanol, or a mixture of acetone and isopropanol.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, acetone, and isopropanol, or a mixture of acetone and isopropanol in a range of 5:1 (v/v) to 1:5 (v/v).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in N,N-dimethylformamide as a solvent.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is carried out in acetonitrile as a solvent.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is performed over a period of time ranging from 30 minutes to 24 hours.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is performed over a period of time ranging from 30 minutes to 6 hours.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is performed over a period of time ranging from 30 minutes to 2 hours.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step i. is performed over a period of time ranging from 1 to 2 hours.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in one or more dipolar aprotic solvents and/or polar solvents optionally mixed with water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in one or more solvents selected from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in one or more solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in one or more solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in one or more solvents selected from acetonitrile, diethyl ketone, methyl ethyl ketone, acetone and 1,4-dioxane, optionally mixed with water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in one or more solvents selected from acetonitrile, acetone and 1,4-dioxane, optionally mixed with water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in a mixture of acetone and water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in a mixture of acetone and water, the ratio of acetone to water being in the range of 5:1 (v/v) to 20:1 (v/v) in favor of acetone.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in a mixture of acetone and water, the ratio of acetone to water being in the range of 6:1 (v/v) to 15:1 (v/v) in favor of acetone.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in a mixture of acetone and water, the ratio of acetone to water being in the range of 6:1 (v/v) to 12:1 (v/v) in favor of acetone.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in a mixture of acetone and water, the ratio of acetone to water being in the range of 8:1 (v/v) to 12:1 (v/v) in favor of acetone.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step ii. is carried out in a mixture of acetone and water, the ratio of acetone to water being in the range of 8:1 (v/v) to 10:1 (v/v) in favor of acetone.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in step ii. to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide is in the range of 6:1 to 20:1 (w/w; solvent: compound).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in step ii. to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide is in the range of 8:1 to 15:1 (w/w; solvent: compound).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide used in step ii. is in the range of 10:1 (w/w) to 14:1 (w/w) in favor of the solvent.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide used in step ii. is in the range of 11:1 (w/w) to 12:1 (w/w) in favor of the solvent.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the mixture of acetone and water to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide used in step ii. is in the range of 8:1 (w/w) to 15:1 (w/w) in favor of the mixture of acetone and water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the mixture of acetone and water to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide used in step ii. is in the range of 10:1 (w/w) to 14:1 (w/w) in favor of the mixture of acetone and water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the mixture of acetone and water to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide used in step ii. is in the range of 11:1 (w/w) to 12:1 (w/w) in favor of the mixture of acetone and water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is one or more dipolar aprotic solvents and/or polar solvents mixed with water as appropriate.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is one or more solvents selected from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, which are mixed with water as appropriate.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is one or more solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is one or more solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is one or more solvents selected from acetonitrile, diethyl ketone, methyl ethyl ketone, acetone and 1,4-dioxane mixed with water as appropriate.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is one or more solvents selected from acetonitrile, acetone and 1,4-dioxane mixed with water as appropriate.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is a mixture of acetone and water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is a mixture of acetone and water, and the ratio of acetone to water is in the range of 5:1 (v/v) to 20:1 (v/v) in favor of acetone.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is a mixture of acetone and water, and the ratio of acetone to water is in the range of 6:1 (v/v) to 15:1 (v/v) in favor of acetone.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is a mixture of acetone and water, and the ratio of acetone to water is in the range of 6:1 (v/v) to 12:1 (v/v) in favor of acetone.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is a mixture of acetone and water, and the ratio of acetone to water is in the range of 8:1 (v/v) to 12:1 (v/v) in favor of acetone.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the solvent in step iii. is a mixture of acetone and water, and the ratio of acetone to water is in the range of 8:1 (v/v) to 10:1 (v/v) in favor of acetone.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in the solution used in step iii. is in the range of 6:1 to 20:1 (w/w; solvent: compound).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in the solution used in step iii. is in the range of 8:1 to 15:1 (w/w; solvent: compound).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in the solution used in step iii. is in the range of 10:1 (w/w) to 14:1 (w/w) in favor of the solvent.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in the solution used in step iii. is in the range of 11:1 (w/w) to 12:1 (w/w) in favor of the solvent.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the mixture of acetone and water to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in the solution used in step iii. is in the range of 8:1 (w/w) to 15:1 (w/w) in favor of the mixture of acetone and water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the mixture of acetone and water to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in the solution used in step iii. is in the range of 10:1 (w/w) to 14:1 (w/w) in favor of the mixture of acetone and water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the mixture of acetone and water to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in the solution used in step iii. is in the range of 11:1 (w/w) to 12:1 (w/w) in favor of the mixture of acetone and water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the antisolvent in step iii. is water, or a mixture of water and one or more organic solvents selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, 1,4-dioxane or 2-methyltetrahydrofuran.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the anti-solvent in step iii. is hexane, cyclohexane, n-heptane, ethyl acetate, or a mixture thereof with one or more solvents selected from the group consisting of ethyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether or methyl tert-butyl ether.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the antisolvent in step iii. is water, or a mixture of water and one or more organic solvents selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran and acetonitrile.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the anti-solvent in step iii. is hexane, cyclohexane, n-heptane, ethyl acetate, or a mixture thereof with one or more solvents selected from the group consisting of isopropyl acetate, diethyl ether, diisopropyl ether or methyl tert-butyl ether.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the antisolvent in step iii. is water, or a mixture of water and one or more organic solvents selected from the group consisting of methanol, ethanol and isopropanol.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the anti-solvent in step iii. is hexane, cyclohexane, n-heptane or ethyl acetate.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the anti-solvent in step iii. is water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the anti-solvent in step iii. is water without other anti-solvents.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide to the anti-solvent in step iii. is in the range of 1:1 to 1:100 (w/w) in favor of the anti-solvent.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide to the anti-solvent in step iii. is in the range of 1:2 to 1:50 (w/w) in favor of the anti-solvent.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide to the anti-solvent in step iii. is in the range of 1:4 to 1:40 (w/w) in favor of the anti-solvent.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide to the anti-solvent in step iii. is in the range of 1:6 to 1:40 (w/w) in favor of the anti-solvent.

According to another embodiment of the second aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide to the anti-solvent in step iii. is in the range of 1:10 to 1:30 (w/w) in favor of the anti-solvent.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide to the water used as the anti-solvent in step iii. is in the range of 1:4 to 1:40 (w/w) in favor of the water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide to the water used as the anti-solvent in step iii. is in the range of 1:6 to 1:40 (w/w) in favor of the water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide to the water used as the anti-solvent in step iii. is in the range of 1:10 to 1:30 (w/w) in favor of the water.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in step ii. to the anti-solvent in step iii. is in the range of 1:10 to 10:1 (v/v; solvent: anti-solvent).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in step ii. to the anti-solvent in step iii. is in the range of 1:6 to 6:1 (v/v; solvent: anti-solvent).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in step ii. to the anti-solvent in step iii. is in the range of 1:4 to 4:1 (v/v; solvent: anti-solvent).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in step ii. to the anti-solvent in step iii. is in the range of 1:3 to 2:1 (v/v; solvent: anti-solvent).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in step ii. to the anti-solvent in step iii. is in the range of 1:2 to 1:1 (v/v; solvent: anti-solvent).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in the solution to the anti-solvent in step iii. is in the range of 1:10 to 10:1 (v/v; solvent: anti-solvent).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in the solution to the anti-solvent in step iii. is in the range of 1:6 to 6:1 (v/v; solvent: anti-solvent).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in the solution to the anti-solvent in step iii. is in the range of 1:4 to 4:1 (v/v; solvent: anti-solvent).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in the solution to the anti-solvent in step iii. is in the range of 1:3 to 2:1 (v/v; solvent: anti-solvent).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in the solution to the anti-solvent in step iii. is in the range of 1:2 to 1:1 (v/v; solvent: anti-solvent).

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step iii. is performed at a temperature in the range of 0°C to 20°C for a period of time in the range of 20 minutes to 2 hours.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step iii. is performed at a temperature in the range of 0°C to 20°C for a period of time in the range of 20 minutes to 1.5 hours.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step iii. is performed at a temperature in the range of 2°C to 15°C for a period of time in the range of 30 minutes to 1 hour.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step iii. is performed at a temperature in the range of 4°C to 10°C for a period of time in the range of 30 minutes to 1 hour.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step iii. is performed at a temperature in the range of 2°C to 15°C for a period of time in the range of 30 to 45 minutes.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step iii. is performed at a temperature in the range of 4°C to 10°C for a period of time in the range of 35 to 40 minutes.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the addition of the optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in step iii. is carried out at a temperature in the range of 0°C to 20°C for a period of time in the range of 20 minutes to 2 hours.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the addition of the optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in step iii. is carried out at a temperature in the range of 0°C to 20°C for a period of time in the range of 20 minutes to 1.5 hours.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the addition of the optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in step iii. is carried out at a temperature in the range of 2°C to 15°C for a period of time in the range of 30 minutes to 1 hour.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the addition of the filtered (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide solution in step iii. is performed at a temperature in the range of 2°C to 15°C for a period of time in the range of 30 minutes to 1 hour.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the addition of the optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in step iii. is carried out at a temperature in the range of 4°C to 10°C for a period of time in the range of 30 minutes to 1 hour.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the addition of the filtered (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide solution in step iii. is performed at a temperature in the range of 4°C to 10°C for a period of time in the range of 30 minutes to 1 hour.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the addition of the filtered (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide solution in step iii. is performed at a temperature in the range of 2°C to 15°C for a period of time in the range of 30 to 45 minutes.

According to another embodiment of the second aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the addition of the filtered (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide solution in step iii. is performed at a temperature in the range of 4°C to 10°C for a period of time in the range of 35 to 40 minutes.

In a specific further embodiment of the second aspect, the present invention encompasses a combination of two or more of the above-mentioned embodiments under the heading "Other embodiments of the second aspect of the present invention".

The present invention encompasses any sub-combination of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in any embodiment or aspect of the present invention, the preparation method thereof, and the pharmaceutical composition comprising the same.

The present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide of the present invention, said methods comprising the steps as described in the experimental section herein.

According to a third aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps allowing the intermediate compound of formula (II) (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the obtained crude product is dissolved in a solvent or a solvent mixture, and then the obtained solution is mixed with an anti-solvent, and then the obtained precipitate is separated and dried to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the second embodiment of the third aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps to allow the intermediate compound of formula (II) (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, the obtained crude product is dissolved in acetone containing water in the range of 0% to 30% (v/v), and then the obtained solution is mixed with water, and then the obtained precipitate is separated and dried to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide.

According to the third embodiment of the third aspect, the present invention covers methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps: Dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in a solvent or a solvent mixture, Then The resulting solution is mixed with an anti-solvent, Then Separating and drying the resulting precipitate, To obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the fourth embodiment of the third aspect, the present invention covers methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps: dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in acetone containing water in the range of 0% to 30% (v/v), mixing the resulting solution with water, separating and drying the resulting precipitate, To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the fifth embodiment of the third aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: 1) allowing an intermediate compound of formula (II) (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, 2) dissolving the crude product produced by step 1) in a solvent, 3) creating supersaturation, 4) adding a nanosuspension comprising other (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, an anti-solvent, at least one surfactant and at least one polymer, 5) followed by one or more of the following sub-steps: a. cooling, b. adding an anti-solvent, and c. evaporating the solvent , 6) separating and drying the resulting precipitate, To obtain (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in microcrystalline form.

According to a sixth embodiment of the third aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the steps of 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in a solvent, 3) creating supersaturation, 4) adding a nanosuspension comprising other (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, an antisolvent, at least one surfactant and at least one polymer, 5) followed by one or more of the following sub-steps: a. cooling, b. adding an anti-solvent, and c. evaporating the solvent , 6) isolating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the seventh embodiment of the third aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: 1) allowing an intermediate compound of formula (II) (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, 2) dissolving the crude product from step 1) in a dipolar aprotic solvent and/or a protic solvent and optionally filtering, 3) creating a supersaturated suspension by one or more of the following sub-steps: a. cooling, b. adding an anti-solvent, and c. evaporating the solvent , 4) adding a nanosuspension comprising further (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, an anti-solvent, at least one surfactant and at least one polymer, 5) Then one or more of the following sub-steps are selected: a. cooling; b. adding an anti-solvent; and c. evaporating the solvent . 6) separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the eighth embodiment of the third aspect, the present invention covers methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps: 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in a dipolar aprotic solvent and/or a protic solvent and optionally filtering, 3) creating a supersaturated solution by one or more of the following sub-steps: a. cooling, b. adding an anti-solvent, and c. evaporating the solvent , 4) Adding a nanosuspension comprising other (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, an antisolvent, at least one surfactant and at least one polymer, 5) followed by one or more sub-steps selected from the following: a. cooling, b. adding an antisolvent, and c. evaporating the solvent , 6) separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the ninth embodiment of the third aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: 1) allowing an intermediate compound of formula (II) to be (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, 2) dissolving the crude product from step 1) in a dipolar aprotic solvent and/or a protic solvent and optionally filtering, 3) creating supersaturation by cooling, 4) adding a nanosuspension comprising other (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, an antisolvent, at least one surfactant and at least one polymer, 5) followed by a. cooling, followed by b. adding an antisolvent, 6) The resulting precipitate was separated and dried to obtain microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide.

According to the tenth embodiment of the third aspect, the present invention covers methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps: 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in a dipolar aprotic solvent and/or a protic solvent and optionally filtering, 3) creating supersaturation by cooling, 4) Adding a nanosuspension containing other (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, an antisolvent, at least one surfactant and at least one polymer, 5) followed by a. cooling, followed by b. adding an antisolvent, 6) separating and drying the resulting precipitate, to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the eleventh embodiment of the third aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: 1) allowing an intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates at a temperature in the range of 20 to 80° C. in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone and isopropanol for a period of time in the range of 30 minutes to 24 hours, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, 2) dissolving the crude product from step 1) in acetone containing water in the range of 10 to 30% v/v and optionally filtering, 3) creating supersaturation by cooling, the temperature reduction being in the range of 5°C to 30°C, 4) adding a nanosuspension comprising further (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, water, at least one surfactant and at least two polymers, 5) followed by a. cooling, followed by b. adding water, 6) The resulting precipitate was separated and dried to obtain microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide.

According to the twelfth embodiment of the third aspect, the present invention covers methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps: 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in acetone containing water in the range of 10 to 30% v/v, and optionally filtering, 3) creating supersaturation by cooling, the temperature reduction being in the range of 5°C to 30°C, 4) Adding a nanosuspension containing other (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, water, at least one surfactant and at least two polymers, 5) followed by a. cooling, followed by b. adding water, 6) separating and drying the resulting precipitate, to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the thirteenth embodiment of the third aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: 1) allowing an intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70° C. for a period of time in the range of 1 to 2 hours in acetonitrile, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, 2) dissolving the crude product from step 1) in acetone containing water in the range of 10 to 30% v/v at a temperature in the range of 40°C to 70°C and optionally filtering, 3) creating supersaturation by cooling, the temperature reduction being in the range of 15°C to 25°C, 4) adding a saturated mixture comprising further (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide (5 to 20% w/w), water (60 to 90% w/w), at least one surfactant (0.05 to 1% w/w) and at least two polymers (0.5 to 15% w/w each), wherein the amount of the nanosuspension is in the range of 0.1 to 20% w/w of the supersaturated solution produced by step 3), 5) followed by a. cooling, the temperature reduction being in the range of 5° C. to 25° C., and then b. adding water, 6) separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the fourteenth embodiment of the third aspect, the present invention covers methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps: 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in acetone containing water in the range of 10 to 30% v/v at a temperature in the range of 40°C to 70°C, and optionally filtering, 3) creating supersaturation by cooling, the temperature reduction being in the range of 15°C to 25°C, 4) adding a nanosuspension comprising other (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide (5 to 20% w/w), water (60 to 90% w/w), at least one surfactant (0.05 to 1% w/w) and at least two polymers (0.5 to 15% w/w each), wherein the amount of the nanosuspension is in the range of 0.1 to 20% w/w of the supersaturated solution produced by step 3), 5) followed by a. cooling, the temperature reduction being in the range of 5°C to 25°C, followed by b. adding water, 6) separating and drying the resulting precipitate, To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the fifteenth embodiment of the third aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: 1) allowing an intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C in acetonitrile for a time in the range of 1 to 2 hours, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, 2) dissolving the crude product from step 1) in acetone containing water in the range of 10 to 30% v/v at a temperature in the range of 40°C to 70°C and optionally filtering, 3) creating supersaturation by cooling, the temperature reduction being in the range of 15°C to 25°C, 4) adding a saturated mixture comprising further (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide (5 to 20% w/w), water (60 to 90% w/w), at least one surfactant (0.05 to 1% w/w) and at least two polymers (each independently 0.5 to 15% w/w), wherein the at least one surfactant comprises an alkali metal salt of _C8 - _C20 -alkyl sulfate, and the at least two polymers comprise hydroxypropyl cellulose and polyvinyl pyrrolidone, and wherein the amount of the nanosuspension is in the range of 1 to 6% w/w of the supersaturated solution produced by step 3), 5) followed by a. cooling, the temperature reduction being in the range of 5°C to 25°C, and then b. adding water, 6) separating and drying the resulting precipitate, To obtain (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in microcrystalline form.

According to the sixteenth embodiment of the third aspect, the present invention covers methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the methods comprising the following steps: 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in acetone containing water in a range of 10 to 30% v/v at a temperature in the range of 40°C to 70°C, and optionally filtering, 3) creating supersaturation by cooling, the temperature reduction being in the range of 15°C to 25°C, 4) adding a nanosuspension comprising other (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide (5 to 20% w/w), water (60 to 90% w/w), at least one surfactant (0.05 to 1% w/w) and at least two polymers (0.5 to 15% w/w each independently), wherein the at least one surfactant comprises an alkali metal salt of a _C8 - _C20 -alkyl sulfate, and the at least two polymers comprise hydroxypropyl cellulose and polyvinylpyrrolidone, and wherein the amount of the nanosuspension is in the range of 1 to 6% w/w of the supersaturated solution produced in step 3), 5) followed by a. Cooling, the temperature reduction is in the range of 5°C to 25°C, and then b. adding water, 6) separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide. Other embodiments of the third aspect of the present invention:

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x10 is in the range of 1 to 2 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x50 is in the range of 4 to 5.5 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x50 is in the range of 4 to 8 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x90 is in the range of 10 to 18 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined by method PSD2a is as follows: x10 is in the range of 1 to 2 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined according to method PSD2a is as follows: x50 is in the range of 4 to 5.5 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined by method PSD4 is as follows: x50 is in the range of 4 to 8 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined according to method PSD2a is as follows: x90 is in the range of 10 to 18 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined by method PSD4 is as follows: x90 is in the range of 12 to 18 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined by method PSD2a is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution measured according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the particle size distribution thereof as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of an amorphous form is less than 15%.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 10%.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of an amorphous form is less than 5%.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 2.5%.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of differential scanning calorimetry.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of XRPD.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of differential scanning calorimetry according to method DSC1.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is below the detection limit of XRPD according to method XRPD1.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide has an enantiomeric excess of at least 99%.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide has an enantiomeric excess of at least 98%.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide has an enantiomeric excess of at least 95%.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide has an enantiomeric excess of at least 90%.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step 1) is a chlorine atom, a bromine atom or an iodine atom; or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step 1) is a chlorine atom, a bromine atom or an iodine atom; or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy and [(4-methylphenyl)sulfonyl]oxy.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step 1) is a chlorine atom.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step 1) is [(4-methylphenyl)sulfonyl]oxy.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step 1) is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in step 1) is a bromine atom.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein step 1) is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein step 1) is carried out in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from the following: an alkali metal carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate, potassium bicarbonate and cesium bicarbonate; and an alkali metal phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate and potassium phosphate.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate and potassium phosphate.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in the presence of 2 to 6 equivalents of potassium carbonate.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out at a temperature in the range of 0°C to 100°C.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out at a temperature in the range of 20°C to 90°C.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is performed at a temperature in the range of 40°C to 80°C.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out at a temperature in the range of 50°C to 70°C.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out at a temperature in the range of 40°C to 80°C, and then the temperature is reduced to 20°C for a period of time in the range of up to one hour, as appropriate.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out at a temperature in the range of 50°C to 70°C, and then the temperature is reduced to 20°C for a period of time in the range of up to one hour, as appropriate.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out at a temperature in the range of 40°C to 80°C, followed by lowering the temperature to 20°C over a period of time in the range of up to one hour.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is performed at a temperature in the range of 50°C to 70°C, followed by lowering the temperature to 20°C over a period of time in the range of up to one hour.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, and isopropanol, or a mixture of acetone and isopropanol.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is performed in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, acetone, and isopropanol, or a mixture of acetone and isopropanol in a range of 5:1 (v/v) to 1:5 (v/v).

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in N,N-dimethylformamide as a solvent.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is carried out in acetonitrile as a solvent.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is performed over a period of time ranging from 30 minutes to 24 hours.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is performed over a period of time ranging from 30 minutes to 6 hours.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is performed over a period of time ranging from 30 minutes to 2 hours.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 1) is performed over a period of time ranging from 1 to 2 hours.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 2) is carried out in one or more dipolar aprotic solvents and/or polar solvents optionally mixed with water.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 2) is carried out in one or more solvents selected from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 2) is carried out in one or more solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 2) is carried out in one or more solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 2) is carried out in one or more solvents selected from acetonitrile, diethyl ketone, methyl ethyl ketone, acetone and 1,4-dioxane, optionally mixed with water.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 2) is carried out in one or more solvents selected from acetonitrile, acetone and 1,4-dioxane, optionally mixed with water.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 2) is carried out in a mixture of acetone and water.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 2) is carried out in a mixture of acetone and water, the acetone containing water in the range of 0 to 50% v/v.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 2) is carried out in a mixture of acetone and water, the acetone containing water in the range of 10 to 30% v/v.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 2) is carried out at a temperature in the range of 40°C to 70°C in a mixture of acetone and water, the acetone containing water in the range of 10 to 30% v/v.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide is in the range of 4:1 to 10:1 (w/w; solvent: compound).

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide is in the range of 4:1 to 8:1 (w/w; solvent: compound).

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide is in the range of 5:1 (w/w) to 7:1 (w/w) in favor of the solvent.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the solvent used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide is in the range of 5.5:1 (w/w) to 6:1 (w/w) in favor of the solvent.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the mixture of acetone and water to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide used in step 2) is in the range of 4:1 (w/w) to 8:1 (w/w) in favor of the mixture of acetone and water.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the mixture of acetone and water to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide used in step 2) is in the range of 5:1 (w/w) to 7:1 (w/w) in favor of the mixture of acetone and water.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the ratio of the mixture of acetone and water to (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide used in step 2) is in the range of 5.5:1 (w/w) to 6:1 (w/w) in favor of the mixture of acetone and water.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by cooling.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by adding an antisolvent.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by evaporating the solvent.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the creation of supersaturation in step 3) is achieved by cooling, and the temperature reduction is in the range of 5°C to 30°C.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by cooling, the temperature reduction being in the range of 15°C to 25°C.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by cooling, the temperature reduction is in the range of 5°C to 30°C, and wherein the solvent is acetone containing water in the range of 10 to 30% v/v.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by cooling, the temperature reduction is in the range of 15°C to 25°C, and wherein the solvent is acetone containing water in the range of 10 to 30% v/v.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by cooling, the temperature reduction is in the range of 15°C to 25°C, and wherein the solvent is acetone containing water in the range of 10 to 30% v/v.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the nanosuspension used in step 4) contains (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in an amount ranging from 5 to 20% w/w.

According to another embodiment of the third aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the anti-solvent in the nanosuspension used in step 4) is water.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the nanosuspension used in step 4) contains water in a range of 60 to 90% w/w.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the nanosuspension used in step 4) contains at least one surfactant in the range of 0.05 to 1% w/w.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the nanosuspension used in step 4) contains a surfactant in the range of 0.05 to 1% w/w.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the nanosuspension used in step 4) contains a surfactant in the range of 0.05 to 1% w/w, and wherein the surfactant is an alkali metal salt of a _C8 - _C20 -alkyl sulfate.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the nanosuspension used in step 4) contains a surfactant in the range of 0.05 to 1% w/w, and wherein the surfactant is a sodium or potassium salt of a _C10 - _C16 -alkyl sulfate.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the nanosuspension used in step 4) contains a surfactant in the range of 0.05 to 1% w/w, and wherein the surfactant is sodium dodecyl sulfate.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the nanosuspension used in step 4) comprises at least two polymers, which are independently in the range of 0.5 to 15% w/w.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the nanosuspension used in step 4) comprises at least two polymers, which are independently in the range of 0.5 to 15% w/w, one of which is hydroxypropyl cellulose and one is polyvinyl pyrrolidone.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the nanosuspension used in step 4) contains two polymers, which are independently in the range of 0.5 to 15% w/w, one of which is hydroxypropyl cellulose and the other is polyvinyl pyrrolidone.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the amount of the nanosuspension used in step 4) is in the range of 0.1 to 20% w/w of the supersaturated solution produced in step 3).

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the amount of the nanosuspension used in step 4) is in the range of 0.25 to 10% w/w of the supersaturated solution produced in step 3).

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the amount of the nanosuspension used in step 4) is in the range of 1 to 6% w/w of the supersaturated solution produced in step 3).

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the amount of the nanosuspension used in step 4) is in the range of 2 to 4% w/w of the supersaturated solution produced in step 3).

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the amount of the nanosuspension used in step 4) is in the range of 2.5 to 3.0% w/w of the supersaturated solution produced in step 3).

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 5) is achieved by cooling followed by adding an anti-solvent.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein step 5) is achieved by cooling followed by the addition of water.

According to another embodiment of the third aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein step 5) is achieved by cooling, the temperature reduction being in the range of 5°C to 25°C, followed by the addition of water.

The present invention encompasses any sub-combination of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in any embodiment or aspect of the present invention, the preparation method thereof, and the pharmaceutical composition comprising the same.

The present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide of the present invention, which methods comprise the steps as described in the experimental section herein.

According to a fourth aspect, the present invention encompasses methods for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps to allow the intermediate compound of formula (II) (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide.

According to the second embodiment of the fourth aspect, the present invention covers methods for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 80%, the methods comprising the following steps: allowing an intermediate compound of formula (II) (II) reacts with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 80%.

According to the third embodiment of the fourth aspect, the present invention encompasses methods for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 90%, the methods comprising the following steps allowing the intermediate compound of formula (II) (II) reacts with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 90%.

According to a fourth embodiment of the fourth aspect, the present invention encompasses methods for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 90%, the methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates at a temperature in the range of 20 to 80° C. in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone and isopropanol for a period of time in the range of 30 minutes to 24 hours, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 90%.

According to a fifth embodiment of the fourth aspect, the present invention encompasses methods for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 90%, the methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and sodium phosphate, at a temperature in the range of 40 to 80° C. in a solvent selected from N,N-dimethylformamide and acetonitrile for a period of time in the range of 30 minutes to 6 hours, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in an enantiomeric excess of at least 90%.

According to the sixth embodiment of the fourth aspect, the present invention encompasses methods for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 90%, the methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate at a temperature in the range of 40 to 80°C in a solvent selected from N,N-dimethylformamide and acetonitrile for a period of time in the range of 30 minutes to 6 hours, and then optionally lowering the temperature to 20°C over a period of time in the range of up to one hour, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 90%.

According to the seventh embodiment of the fourth aspect, the present invention encompasses methods for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 95%, the methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70° C. for a period of time in the range of 1 to 2 hours in acetonitrile, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 95%.

According to the eighth embodiment of the fourth aspect, the present invention encompasses methods for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 95%, the methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C in acetonitrile for a time in the range of 1 to 2 hours, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 95%. Other embodiments of the fourth aspect of the present invention:

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in the step is a chlorine atom, a bromine atom or an iodine atom; or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy and [(4-methylphenyl)sulfonyl]oxy.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in the step is a chlorine atom.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in the step is [(4-methylphenyl)sulfonyl]oxy.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in the step is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in the step is a bromine atom.

According to another embodiment of the fourth aspect, the present invention encompasses a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the step is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates.

According to another embodiment of the fourth aspect, the present invention encompasses a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the step is performed in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the fourth aspect, the present invention encompasses a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the step is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 1.5 to 6 equivalents of a base selected from the following: an alkali metal carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate, potassium bicarbonate and cesium bicarbonate; and an alkali metal phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate and potassium phosphate.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate and potassium phosphate.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 2 to 6 equivalents of potassium carbonate.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 0°C to 100°C.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 20°C to 90°C.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 40°C to 80°C.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 50°C to 70°C.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 40°C to 80°C, and then the temperature is reduced to 20°C for a period of time in the range of up to one hour.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 50°C to 70°C, and then the temperature is reduced to 20°C for a period of time in the range of up to one hour.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is performed at a temperature in the range of 40°C to 80°C, followed by lowering the temperature to 20°C over a period of time in the range of up to one hour.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is performed at a temperature in the range of 50°C to 70°C, followed by lowering the temperature to 20°C over a period of time in the range of up to one hour.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, and isopropanol, or a mixture of acetone and isopropanol.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, acetone, and isopropanol in a range of 5:1 to 1:5, or a mixture of acetone and isopropanol.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step included therein is carried out in N,N-dimethylformamide as a solvent.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step included therein is carried out in acetonitrile as a solvent.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step included therein is carried out over a period of time ranging from 30 minutes to 24 hours.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is performed over a period of time ranging from 30 minutes to 6 hours.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is performed over a period of time ranging from 30 minutes to 2 hours.

According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step included therein is performed over a period of time ranging from 1 to 2 hours.

According to a fifth aspect, the present invention encompasses methods for preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, which methods include the following steps to allow the intermediate compound of formula (II) (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propylamine.

According to the second embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 80%, said methods comprising the following steps allowing the intermediate compound of formula (II) (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide having an enantiomeric excess of at least 80%.

According to the third embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 90%, said methods comprising the following steps allowing the intermediate compound of formula (II) (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide having an enantiomeric excess of at least 90%.

According to the fourth embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 90%, said methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates at a temperature in the range of 20 to 80° C. in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone and isopropanol for a period of time in the range of 30 minutes to 24 hours, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide having an enantiomeric excess of at least 90%.

According to a fifth embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide having an enantiomeric excess of at least 90%, said methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate, at a temperature in the range of 40 to 80° C. in a solvent selected from N,N-dimethylformamide and acetonitrile for a period of time in the range of 30 minutes to 6 hours, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide having an enantiomeric excess of at least 90%.

According to the sixth embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 90%, the methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate at a temperature in the range of 40 to 80°C in a solvent selected from N,N-dimethylformamide and acetonitrile for a period of time in the range of 30 minutes to 6 hours, and then optionally lowering the temperature to 20°C over a period of time in the range of up to one hour, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide having an enantiomeric excess of at least 90%.

According to the seventh embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 95%, said methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70° C. for a period of time in the range of 1 to 2 hours in acetonitrile, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide having an enantiomeric excess of at least 95%.

According to an eighth embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide having an enantiomeric excess of at least 95%, said methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C in acetonitrile for a time in the range of 1 to 2 hours, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide having an enantiomeric excess of at least 95%.

According to the ninth embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide having an enantiomeric excess of at least 98%, the methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70° C. for a period of time in the range of 1 to 2 hours in acetonitrile, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide having an enantiomeric excess of at least 98%.

According to the tenth embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide having an enantiomeric excess of at least 98%, said methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70° C. for a period of time in the range of 1 to 2 hours in acetonitrile, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 98%, wherein the presence of an amorphous form is less than 5%, and whose particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

According to the eleventh embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide having an enantiomeric excess of at least 98%, said methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70° C. for a period of time in the range of 1 to 2 hours in acetonitrile, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 98%, wherein the presence of an amorphous form is less than 5%, and whose particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

According to the twelfth embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide having an enantiomeric excess of at least 99%, said methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70° C. for a period of time in the range of 1 to 2 hours in acetonitrile, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 99%, wherein the presence of an amorphous form is below the detection limit of differential scanning calorimetry and has a particle size distribution as follows: x10 in the range of 0.5 to 2.5 µm, x50 in the range of 3 to 7 µm, and x90 in the range of 8 to 20 µm.

According to the thirteenth embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide having an enantiomeric excess of at least 99%, said methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70° C. for a period of time in the range of 1 to 2 hours in acetonitrile, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 99%, wherein the presence of an amorphous form is below the detection limit of differential scanning calorimetry and has a particle size distribution as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm.

According to the fourteenth embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide having an enantiomeric excess of at least 99%, the methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70° C. for a period of time in the range of 1 to 2 hours in acetonitrile, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 99%, wherein the presence of an amorphous form is below the detection limit of XRPD, and whose particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

According to the fifteenth embodiment of the fifth aspect, the present invention encompasses methods for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide having an enantiomeric excess of at least 99%, said methods comprising the following steps allowing the intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70° C. for a period of time in the range of 1 to 2 hours in acetonitrile, thereby obtaining A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide with an enantiomeric excess of at least 99%, wherein the presence of an amorphous form is below the detection limit of XRPD, and its particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm. Other embodiments of the fifth aspect of the present invention:

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in the step is a chlorine atom, a bromine atom or an iodine atom; or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy and [(4-methylphenyl)sulfonyl]oxy.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in the step is a chlorine atom.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in the step is [(4-methylphenyl)sulfonyl]oxy.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in the step is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the leaving group LG in the step is a bromine atom.

According to another embodiment of the fifth aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the step included is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates.

According to another embodiment of the fifth aspect, the present invention encompasses a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the step included is carried out in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the fifth aspect, the present invention encompasses a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, wherein the step is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetra(C ₁ -C ₃ -alkyl)guanidine.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 1.5 to 6 equivalents of an alkali selected from the following: an alkali metal carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate, an alkali metal bicarbonate selected from sodium bicarbonate, potassium bicarbonate and cesium bicarbonate, and an alkali metal phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate and potassium phosphate.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate and potassium phosphate.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in the presence of 2 to 6 equivalents of potassium carbonate.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 0°C to 100°C.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 20°C to 90°C.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 40°C to 80°C.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 50°C to 70°C.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 40°C to 80°C, and then the temperature is reduced to 20°C for a period of time in the range of up to one hour.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out at a temperature in the range of 50°C to 70°C, and then the temperature is reduced to 20°C for a period of time in the range of up to one hour.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is performed at a temperature in the range of 40°C to 80°C, followed by lowering the temperature to 20°C over a period of time in the range of up to one hour.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is performed at a temperature in the range of 50°C to 70°C, followed by lowering the temperature to 20°C over a period of time in the range of up to one hour.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, and isopropanol, or a mixture of acetone and isopropanol.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, acetone, and isopropanol, or a mixture of acetone and isopropanol in a range of 5:1 (v/v) to 1:5 (v/v).

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step included therein is carried out in N,N-dimethylformamide as a solvent.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step included therein is carried out in acetonitrile as a solvent.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step included therein is carried out over a period of time ranging from 30 minutes to 24 hours.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out over a period of time ranging from 30 minutes to 6 hours.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is carried out over a period of time ranging from 30 minutes to 2 hours.

According to another embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the step is performed over a period of time ranging from 1 to 2 hours.

According to a sixth aspect, the present invention encompasses a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide and one or more pharmaceutically acceptable excipients.

According to the second embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 15%, and the particle size distribution is as follows: x10 is <5 µm, x50 is <10 µm, and x90 is <35 µm. And one or more pharmaceutically acceptable excipients.

According to the third embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 15%, and the particle size distribution thereof is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to the fourth embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 15%, and the particle size distribution thereof is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to the fifth embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of the amorphous form is less than 15%, and the particle size distribution thereof is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm, and one or more pharmaceutically acceptable excipients.

According to the sixth embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to the seventh embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to the eighth embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm, and one or more pharmaceutically acceptable excipients.

According to the ninth embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of an amorphous form is less than 5%, and the particle size distribution thereof is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to the tenth embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of an amorphous form is less than 5%, and the particle size distribution thereof is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to the eleventh embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the presence of an amorphous form is less than 5%, and the particle size distribution thereof is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm, and one or more pharmaceutically acceptable excipients.

According to the twelfth embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to the thirteenth embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to the fourteenth embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm, and one or more pharmaceutically acceptable excipients.

According to the fifteenth embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 99%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm, and one or more pharmaceutically acceptable excipients.

According to the sixteenth embodiment of the sixth aspect, the present invention encompasses a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 99%, the presence of an amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm, and one or more pharmaceutically acceptable excipients. Other embodiments of the sixth aspect of the present invention:

According to another embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to another embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to another embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 95%, the presence of amorphous form is less than 10%, and the particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm, and one or more pharmaceutically acceptable excipients.

According to another embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to another embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm, and one or more pharmaceutically acceptable excipients.

According to another embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm, and one or more pharmaceutically acceptable excipients.

According to another embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 99%, the presence of amorphous form is less than 5%, and the particle size distribution determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm, and one or more pharmaceutically acceptable excipients.

According to another embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, wherein the enantiomeric excess is at least 99%, the presence of amorphous form is less than 5%, and the particle size distribution determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm, and one or more pharmaceutically acceptable excipients.

The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide of the present invention can be used to inhibit, block, reduce or decrease DGKζ activity, thereby resulting in the regulation of dysregulated immune responses in the context of cancer and cancer immunotherapy, for example, to block immunosuppression and increase immune response activation and infiltration, which will ultimately lead to a reduction in tumor growth.

The method comprises administering to a mammal (including a human) in need thereof an amount of a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide effective to treat the disorder.

The present invention also provides methods of treating various other disorders in which DGKξ is implicated, such as, but not limited to, disorders with dysregulated immune responses, inflammation, vaccination against infection and cancer, viral infections, lymphoproliferative disorders, asthma, eye diseases, and type 2 diabetes/insulin resistance.

These disorders are well characterized in humans, but also exist in other mammals with similar etiologies and can be treated by administering the pharmaceutical compositions of the present invention.

According to another aspect, the present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as described above, which is used to treat or prevent a disease, particularly a cancer or condition with a disordered immune response or other disorders associated with abnormal DGKξ signaling.

The pharmaceutical activity of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide according to the present invention can be explained by the activity of the base compound (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as a DGKξ inhibitor.

According to another aspect, the present invention encompasses the use of microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as described above for treating or preventing diseases, particularly cancers or conditions with a dysregulated immune response or other conditions associated with abnormal DGKζ signaling (particularly liquid and solid tumors).

According to another aspect, the present invention encompasses microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as described above for use in the treatment or prevention of diseases, particularly cancers or conditions with a dysregulated immune response or other conditions associated with abnormal DGKζ signaling, particularly liquid and solid tumors.

According to another aspect, the present invention encompasses the use of a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as described above in a method for treating or preventing a disease, particularly a cancer or condition with a disordered immune response or other conditions associated with abnormal DGKξ signaling (particularly liquid and solid tumors).

According to another aspect, the present invention encompasses the use of a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as described above in a method for treating or preventing a disease, particularly a cancer or condition with a disordered immune response or other conditions associated with abnormal DGKξ signaling (particularly liquid and solid tumors).

According to another aspect, the present invention encompasses the use of a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as described above for the preparation of a pharmaceutical composition, preferably a medicament, for the prevention or treatment of a disease, particularly a cancer or condition with a disordered immune response or other conditions associated with abnormal DGKξ signaling (particularly fluid and solid tumors).

According to another aspect, the present invention encompasses a method of treating or preventing a disease, particularly a cancer or condition with a disordered immune response or other diseases associated with abnormal DGKζ signaling (particularly liquid and solid tumors), using an effective amount of a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as described above.

According to another aspect, the present invention covers pharmaceutical compositions, in particular pharmaceutical preparations, comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as described above and one or more excipients (in particular one or more pharmaceutically acceptable excipients). Known procedures for preparing such pharmaceutical compositions in suitable dosage forms can be used.

The present invention furthermore encompasses pharmaceutical compositions, in particular medicaments, comprising at least one microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide according to the invention, together with one or more pharmaceutically suitable excipients, and their use for the purposes mentioned above.

The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide according to the present invention may be systemically and/or locally active. For this purpose, it can be administered in a suitable manner, such as, for example, orally, parenterally, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginally, dermally, transdermally, conjunctivally, auricularly or as an implant or stent.

For these administration routes, the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide according to the present invention can be administered in a suitable administration form.

For oral administration, the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoroanilino)propionamide according to the present invention can be formulated into a method known in the art to rapidly and/or improve the delivery of the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoroanilino)propionamide of the present invention. The invention relates to a dosage form of the present invention, for example, tablets (uncoated or coated tablets, for example, with a delayed dissolving or insoluble enteric or controlled release coating), orally disintegrating tablets, film/wafers, film/lyophilized preparations, capsules (for example, hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions or aerosols.

Parenteral administration can be achieved by avoiding an absorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intracavitary) or by including absorption (e.g. intramuscularly, subcutaneously, intradermally, percutaneously or intraperitoneally). Administration forms suitable for parenteral administration are, in particular, preparations for injection and infusion in the form of suspensions, emulsions, lyophilized products or sterile powders.

Examples of suitable administration routes are pharmaceutical forms for inhalation [especially powder inhalers, nebulizers], nasal drops, nasal sprays; tablets/films/paper capsules/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, eye inserts, ear drops, ear sprays, ear powders, ear washes, ear tampon; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milks, pastes, foams, dusting powders, implants or stents.

The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide according to the present invention can be incorporated into the administration form. This can be achieved in a manner known per se by mixing with a pharmaceutically suitable excipient. Pharmaceutically suitable excipients include, in particular, ● fillers and carriers (e.g. cellulose, microcrystalline cellulose (such as, for example, Avicel ^® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ^® )), ● ointment bases (e.g. petroleum jelly, wax, triglycerides, wax, lanolin, lanolin, hydrophilic ointments, polyethylene glycol), ● bases for suppositories (e.g. polyethylene glycol, cocoa butter, hard fat), ● solvents (e.g. water, ethanol, isopropyl alcohol, glycerol, propylene glycol, medium-chain long triglyceride fatty oils, liquid polyethylene glycol, wax), ● surfactants, emulsifiers, dispersants or wetting agents (e.g. sodium lauryl sulfate), lecithin, phospholipids, fatty alcohols (e.g. Lanette ^® ), sorbitan fatty acid esters (e.g. Span ® ), polyoxyethylene sorbitan fatty acid esters (e.g. Tween ^® ), polyoxyethylene fatty acid glycerides (e.g. Cremophor ^® ), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers ^{(e.g. Pluronic ® )} , buffers, acids and bases (e.g. phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, tromethamine, triethanolamine), isoosmotic agents (e.g. glucose, sodium chloride), adsorbents (e.g. highly dispersed silica), tackifiers, gel formers, thickeners and/or binders (e.g. polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g. ^Carbopol® ); alginates, gelatin), disintegrants (e.g. modified starch, sodium carboxymethylcellulose, sodium glycolate starch (e.g. ^Explotab® ), cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose (croscarmellose) (e.g. AcDiSol ^® )), ● flow regulators, lubricants, slip agents and release agents (for example magnesium stearate, stearic acid, talc, highly disperse silica (such as, for example, Aerosil ^® )), ● coating materials (for example sugar, insect glue) and film formers for rapidly or modified dissolving films or diffusion films (for example polyvinyl pyrrolidone (such as, for example, Kollidon ^® ), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates, such as, for example, Eudragit ^® )), ● capsule materials (e.g. gelatin, hydroxypropyl methylcellulose), ● synthetic polymers (e.g. polylactide, polyglycolide, polyacrylate, polymethacrylate (such as (e.g.) Eudragit ^® ), polyvinyl pyrrolidone (such as (e.g.) Kollidon ^® ), polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and copolymers and block copolymers thereof), ● plasticizers (e.g. polyethylene glycol, propylene glycol, glycerol, triacetine, triacetate citrate, dibutyl phthalate), ● penetration enhancers, ● Stabilizers (e.g. antioxidants, such as, for example, ascorbic acid, palmitic acid ascorbate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate), ● preservatives (e.g. p-hydroxybenzoates, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), ● colorants (e.g. inorganic pigments, such as, for example, iron oxides, titanium dioxide), ● flavoring agents, sweeteners, taste- and/or odor-masking agents.

The present invention further relates to a pharmaceutical composition comprising at least one microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide according to the present invention, together with one or more pharmaceutically suitable excipients, and to its use according to the present invention.

Based on standard laboratory techniques known to evaluate the suitability of microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide for the treatment of cancer or conditions with a dysregulated immune response or other disorders associated with aberrant DGKζ signaling, the above-mentioned molecule was tested by standard toxicity tests and by using the above-mentioned molecule to determine the activity of the molecule in mammals. The effective dose of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide of the present invention for treating each desired indication can be readily determined by standard pharmacological assays for the treatment of the identified conditions and by comparing such results with those of known active ingredients or agents used to treat such conditions. The amount of active ingredient to be administered in the treatment of one of these conditions may vary widely depending on considerations such as the particular microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide and the dosage unit employed, the mode of administration, the duration of treatment, the age and sex of the patient being treated, and the nature and extent of the condition being treated.

The total amount of microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide to be administered will generally be in the range of about 0.001 mg/kg to about 200 mg/kg of body weight per day, and preferably about 0.01 mg/kg to about 20 mg/kg of body weight per day. Clinically useful dosing schedules will vary from one to three times daily dosing to once every four weeks. In addition, "drug holidays" (in which the patient is not given the drug for a specific period of time) may be beneficial to the overall balance between pharmacological effects and tolerability. A unit dose may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered one or more times per day or less than once per day. The average daily dose administered by injection (including intravenous, intramuscular, subcutaneous and parenteral injection) and using infusion techniques will preferably be 0.01 to 200 mg/kg total body weight. The average daily rectal dose regimen will preferably be 0.01 to 200 mg/kg total body weight. The average daily vaginal dose regimen will preferably be 0.01 to 200 mg/kg total body weight. The average daily topical dose regimen will preferably be 0.1 to 200 mg administered one to four times a day. The transdermal concentration will preferably be the concentration required to maintain a daily dose of 0.01 to 200 mg/kg. The average daily inhalation dose regimen will preferably be 0.01 to 100 mg/kg total body weight.

Of course, each patient's specific initial and ongoing dosage regimen will vary depending on the nature and severity of the condition as determined by the attending physician, the activity of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combination, and the like. The desired treatment mode and dosage amount of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide or a pharmaceutically acceptable salt or ester or combination thereof of the present invention can be determined by one skilled in the art using known therapeutic tests.

Experimental Section Table 2: Abbreviations

The following table lists the abbreviations used in this article. XRPD X-ray powder diffraction DSC Differential scanning calorimetry PSD Particle size distribution HPLC High performance liquid chromatography UPLC Ultra performance liquid chromatography ee or ee Enantiomeric excess w/w Weight to weight v/v Volume to volume ELSD Evaporative light scattering detector MS Mass spectrometry NMR Nuclear magnetic resonance RT, rt Room temperature _tR Retention time SDS Sodium dodecyl sulfate PMMA Poly(methyl methacrylate)

Various aspects of the present invention described in this application are illustrated by the following examples, which are not intended to limit the present invention in any way.

The example test experiments described herein are used to illustrate the present invention and the present invention is not limited to the examples given. Experimental Section - Materials and Methods HPLC and LC/MS Methods: Methods HPLC 1 : Preparative HPLC :

Instrumentation: Pump: Labomatic HD-5000 or HD-3000, head HDK 280, low pressure gradient module ND-B1000; manual syringe valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 µm, 125x30 mm; solvent: solvent A: water + 0.2 vol% ammonia (32%), solvent B: acetonitrile; gradient: 0.00 to 0.50 min 15% B (150 ml/min), 0.50 to 6.00 min 15 to 55% B (150 ml/min), 6.00 to 6.10 min 55 to 100% B (150 ml/min), 6.10 to 8.00 min 100% B (150 ml/min); UV: 361 nm Method HPLC2 : Analytical UPLC/MS :

Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Solvent: Solvent A: Water + 0.2 vol% ammonia (32%), Solvent B: Acetonitrile; Gradient: 0 to 1.6 min 1 to 99% B, 1.6 to 2.0 min 99% B; Flow rate 0.8 mL/min; Temperature: 60°C; Injection: 2 µL; DAD scan: 210 to 400 nm; ELSD method HPLC3 : Analytical chiral HPLC :

Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SB 3µ, 100x4.6; Solvent A: Hexane + 0.1 vol% diethylamine; Solvent B: 2-propanol; Isocratic: 60%A+40%B; Flow rate: 1.4 ml/min; Temperature: 25°C; UV: 254 nm Method HPLC4 : Chemical purity, Examples 3 and 4 , and Reference Example 2 : equipment: HPLC (with a pressure range up to 600 bar and a retention volume of about 850 µL) with thermostatically controlled column oven, UV detector and data evaluation system (e.g. Agilent 1260) Column: Waters Acquity BEH Shield C18 Length: 50 mm, ID: 2.1 mm, Particle size: 1.7 µm Maximum pressure: 600 bar Typical starting pressure: 500 bar Solvent: A: 1580 mg ammonium bicarbonate + 80 µL formic acid (98+%) / 1L Milli-Q water (compressible: solvent type) B: acetonitrile (compressible: solvent type) gradient: Time(min) B (%) 0.00 5.0 1.00 5.0 4.50 45.0 7.50 60.0 8.50 80.0 9.50 80.0 10.00 5.0 11.00 5.0 The percentage of mobile phase A is the difference between B (%) and 100%. Balance time: 1 min (under starting conditions) Flow Rate: 0.7 mL/min Pulling speed: 200 µL/min Injection volume: 2.5 µL (RT) Needle Wash: Flushing port cycle (7 s) Solvent: Methanol Column temperature: 40℃ Data sampling rate: 20 Hz (＞ 0.013 min (0.25 s response time) Detection wavelength: 270 nm, bandwidth: 4 nm Margin of negative absorbance: 100 mAU Detector unit path: 10 mm Narrow seam: 4 nm Sample solvent: Acetonitrile Sample / calibration solution: Dissolve the sample with sample solvent at a concentration of approximately 0.25 mg/mL (e.g., material weighing exactly 25 mg dissolved in 100 mL) and fill to the calibration mark. Method HPLC5 : Enantiomeric excess, Examples 3 and 4 , and Reference Example 2 : equipment: Ultra-high performance liquid chromatography, using a thermostatically controlled column oven, UV detector and data evaluation system, with a retention volume of approximately 200 µL (e.g. Agilent 1290) Column: Daicel Chiralpak IB N-3 Length: 150 mm, Inner diameter: 4.6 mm, Particle size: 3.0 µm Maximum pressure: 300 bar Typical starting pressure: 210 bar Column temperature: 25℃ Mobile phase: A: n-heptane/ethanol + 0.1% TFA (50% + 50%; V:V) (compressibility: solvent type used) Flow Rate: 1.50 mL/min Isoconcentration: A (%)：100 Run time: 8.0 min Detector unit path: 10 mm Detection wavelength: 265 nm, bandwidth: 4 nm Data sampling rate: 2.5 Hz (＞ 0.1 min (2 s response time)) Margin of negative absorbance: 100 mAU Narrow seam: 4 nm Injection volume: 3.0 µL (RT) Pulling speed: 200 µL/min Needle Wash: Flushing port cycle (7 s) Solvent: Ethanol Sample solvent: Ethanol Sample solution: Dissolve the sample with sample solvent at a concentration of approximately 1.0 mg/mL (e.g. weighing exactly 25 mg and dissolved in 25 mL) of material and fill to the calibration mark. Method HPLC6 : Preparative chiral HPLC :

Instruments: Labomatic HD3000, Knauer Pump 100, Labcol Vario 4000 Plus, Knauer DAD 2600; Column: Linear Starch SB 5µ 250x50 mm Nr.34; Solvent A: Hexane + 0.1 vol% diethylamine (99%); Solvent B: 2-propanol; Isocratic: 60%A + 40%B; Flow rate 150.0 ml/min, starting from 16 min 180 ml/min; UV @ 254 nm Particle size distribution (PSD)

Method PSD1 : Particle size distribution (PSD) was determined by laser diffraction using a Malvern Panalytical Mastersizer 3000. 0.1% Span 85 in heptane was used as the dispersion medium. The samples were sonicated for 45 seconds at 40% intensity.

Method PSD2a : Particle size distribution (PSD) is determined by laser diffraction using a Sympatec Helos device. Water with a small amount of surfactant is used as the dispersion medium. The sample is ultrasonicated for 240 seconds.

Method PSD2b : Particle size distribution (PSD) is determined by laser diffraction using a Sympatec Helos device. Paraffin is used as the dispersion medium. The sample is ultrasonicated for 240 seconds.

Method PSD 3 : Particle size analysis by laser diffraction using Sympatec (HELOS) with Baysilone (Element 14 PDMS 10-A) as dispersion medium. The samples were sonicated for 90 seconds at 80% intensity (60 s rest) and stirred with a magnetic stirrer at 800 rpm. The measurements were performed 3 times (30 s rest) and the arithmetic mean was calculated.

Method PSD 4 : Particle size analysis was determined by laser diffraction using a Malvern Panalytical Mastersizer 3000. Water with a drop of Tween 80 was used as the dispersion medium. The sample was sonicated for 180 seconds. Differential Scanning Calorimetry (DSC) Method DSC1 :

Differential Scanning Calorimetry (DSC) was performed using a Mettler Toledo TGA/DSC 3+. The instrument was purged with nitrogen at a flow rate of 20 ml min ^-1 . Approximately 1 to 15 mg of each sample was placed in an aluminum crucible and heated starting from 25°C at a heating rate of 20°C min ^-1 . No sample preparation was performed. Method DSC2 :

Differential Scanning Calorimetry (DSC) was performed using a Mettler Toledo TGA/DSC 3+. The instrument was purged with nitrogen at a flow rate of 30 ml min ^-1 . Approximately 1 to 15 mg of each sample was placed in an aluminum crucible and heated starting from 25°C at a heating rate of 10 or 20°C min ^-1 . No sample preparation was performed. Method DSC 3 :

Differential Scanning Calorimetry (DSC) was performed using a Mettler Toledo DSC3. The calorimeter was purged with nitrogen at a flow rate of 50 ml.min ^-1 . Approximately 3 to 5 mg of sample was placed in an aluminum crucible without sample preparation. The temperature range was -10 to 230°C with a heating rate of 20°C.min ^-1 . X- ray Powder Diffraction (XRPD) Method XRPD1 :

X-ray powder diffraction (XRPD) data were recorded on a Bruker D2 PHASER diffraction instrument with a LYNXEYE-2 detector using Cu Kα1 radiation (1.54060 Å). All samples were prepared and measured at ambient temperature on Si-single crystal low-background sample holders (open or with PMMA domes). Data were collected in Bragg-Brentano (θ/2θ) horizontal geometry between 3 and 40° ( 2θ ) or 4 and 40° ( 2θ ) with 0.02° steps at 0.3 s step ^-1 . The X-ray tube was operated at 30 kV and 10 mA. Method XRPD2 :

X-ray powder diffraction (XRPD) data were recorded on a PANalytical X'Pert PRO diffractometer using monochromatic Cu-K α1 radiation at generator settings of 40 kV and 40 mA. Samples were collected in transmission mode, prepared as a thin layer between two foils. The scan range was between 2° and 40° 2θ at 25 sec/step with 0.013° step. Method XRPD3 :

X-ray powder diffraction (XRPD) data were recorded on a STOE STADI P diffraction instrument using monochromatic Cu-Kα 1 radiation, position sensitive detector, at generator settings of 40 kV and 40 mA. Samples were collected in transmission mode, prepared as a thin layer between two foils. The scanning range was between 2° and 40° 2θ at 15 sec/step with 0.5° step. Comparison of Dissolution of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide (material from Example 3) compared to materials from Reference Examples 1 and 2 Dissolution Properties Methods Sample

The following batches are provided for comparative experiments: The product produced by Example 3 , i.e., microcrystalline (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide produced using the process according to the present invention The product produced by Reference Example 1 , i.e., a batch of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide produced by jet milling of a crystallization batch and containing a portion of amorphous material The product produced by Reference Example 2 , i.e., a coarse crystal batch of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide

Phosphate buffer pH 6.8 with 0.1% SDS was used as dissolution medium. The 100% level was set to 201.5 µg/ml. Based on previous solubility data of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, the thermodynamic solubility of this compound from the crystallization batch should result in a release of approximately 20%. The higher weight was used to be able to detect possible supersaturation of the batch studied. Calibration

Calibration and measurements were performed using the µDissolver from PION, a small-scale dissolution device with an in-situ UV probe that allows high time resolution. A five-point calibration from 0 to 207 µg/ml was recorded in phosphate buffer pH 6.8 with 2% SDS. The detection wavelength was set to 255 to 268 nm (method range, second derivative). Measurement

2.015 mg (± 0.1 mg) of the corresponding drug substance batch was transferred to the µDiss container and 10 ml of phosphate buffer pH 6.8 with 0.1% SDS was added. The dissolution profile was recorded over approximately five and a half hours. Each sample was measured in duplicate (n=2). For the batch from Reference Example 2, the in-situ UV probe of one container was blocked by particles during the measurement, so this batch was studied only from a single container (n=1). Experimental Part - Examples Example 1 : Preparation of (R)-2-(N-[4- amino -5-(4- methoxybenzyl ) thiazol -2- yl ]-4- fluoroanilino ) propionamide ( screening of process variants ) (R)-2-(N-[4- amino -5-(4- methoxybenzyl ) thiazol -2- yl ]-4- fluoroanilino ) propionamide Example 1a

[4-Amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (100 mg, 0.29 mmol, CAS 697232-63-6, WO2021/214019, see also Example 1 step 1 below) was dissolved in N,N-dimethylformamide (2.1 mL), followed by the addition of potassium carbonate (K ₂ CO ₃ , 201 mg, 1.46 mmol) and (2S)-2-bromopropionamide (53.1 mg, 0.35 mmol, CAS 41137-34-2, purchased from Enamine). The reaction mixture was stirred at rt for 24 h, filtered and purified by preparative HPLC (Method HPLC1) to give 73.8 mg (0.18 mmol, 61% yield) of the title compound in 88% ee. Example 1b

[4-Amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (50 mg, 0.145 mmol) was dissolved in isopropanol/acetone 3/1 (1.2 mL), followed by the addition of N,N,N,N-tetramethylguanidine (25 mg, 0.22 mmol) and (2S)-2-bromopropionamide (26.6 mg, 0.17 mmol). The reaction mixture was stirred at rt for 48 h and at 50 °C for 2 h, filtered and purified by preparative HPLC (Method HPLC1) to give 22.7 mg (0.05 mmol, 38% yield) of the title compound in 61% ee. Example 1c

[4-Amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (50 mg, 0.145 mmol) was dissolved in 1-methyl-2-pyrrolidone (1.3 mL), followed by the addition of potassium carbonate (100 mg, 0.73 mmol) and (2S)-2-bromopropionamide (26.6 mg, 0.17 mmol). The reaction mixture was stirred at rt for 48 h, filtered and purified by preparative HPLC (Method HPLC1) to give 27 mg (0.06 mmol, 44% yield) of the title compound in 76% ee. Example 1d

[4-Amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (50 mg, 0.145 mmol) was dissolved in N,N-dimethylformamide (1.2 mL), followed by the addition of potassium bicarbonate (KHCO ₃ , 73 mg, 0.73 mmol) and (2S)-2-bromopropionamide (26.6 mg, 0.17 mmol). The reaction mixture was stirred at rt for 48 h and at 50° C. for 2 h, filtered and purified by preparative HPLC (Method HPLC1) to give 27 mg (0.06 mmol, 44% yield) of the title compound in 63% ee. Example 1e

[4-Amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (100 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (2.1 mL), followed by the addition of potassium carbonate (201 mg, 1.46 mmol) and (2S)-2-bromopropionamide (53.1 mg, 0.35 mmol). The reaction mixture was stirred at rt for 5 h, filtered and purified by preparative HPLC (Method HPLC1) to give 73.8 mg (0.18 mmol, 61% yield) of the title compound in 91% ee. Example 1f

[4-Amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (50 mg, 0.145 mmol) was dissolved in N,N-dimethylformamide (1.2 mL), followed by the addition of N,N,N,N-tetramethylguanidine (25 mg, 0.22 mmol) and (2S)-2-bromopropionamide (26.6 mg, 0.17 mmol). The reaction mixture was stirred at rt for 24 h, filtered and purified by preparative HPLC (Method HPLC1) to give 26 mg (0.06 mmol, 43.6% yield) of the title compound in 86% ee. Example 1g

[4-Amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (65 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (1.4 mL), followed by the addition of potassium carbonate (133 mg, 0.96 mmol) and (S)-4-methylbenzenesulfonic acid 1-amino-1-propionyl-2-yl ester (56 mg, 0.23 mmol). The reaction mixture was stirred at rt for 24 h and at 60 °C for 2 h, filtered and purified by preparative HPLC (Method HPLC1) to give 46 mg (0.11 mmol, 58% yield) of the title compound in 88% ee. Example 1h

[4-Amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (71.5 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (1.4 mL), followed by the addition of potassium carbonate (144 mg, 1.04 mmol) and (S)-4-methylbenzenesulfonic acid 1-amino-1-propionyl-2-yl ester (61 mg, 0.25 mmol). The reaction mixture was stirred at rt for 4 h and at 60 °C for 1 h, filtered and purified by preparative HPLC (Method HPLC1) to give 24 mg (0.06 mmol, 28% yield) of the title compound in 94% ee. Example 1i

[4-Amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (71.5 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (1.4 mL), followed by the addition of N,N,N,N-tetramethylguanidine (36 mg, 0.31 mmol) and (S)-4-methylbenzenesulfonic acid 1-amino-1-propionyl-2-yl ester (61 mg, 0.25 mmol). The reaction mixture was stirred at rt for 2 h and at 60 °C for 1 h, filtered and purified by preparative HPLC (Method HPLC1) to give 24 mg (0.06 mmol, 28% yield) of the title compound in 95% ee.

Analytical data of (R)-2-(N-[4- amino -5-(4- methoxybenzyl ) thiazol -2- yl ]-4- fluoroanilino ) propanamide as obtained in Examples 1a to 1i : LC/MS (method HPLC2): t _R = 1.06 min/MS (ESIpos): m/z = 415.5 [M+H] ⁺ Analytical chiral HPLC (method HPLC3): t _R = 5.92 min (Example 1a; t _R of Examples 1b to 1i is in the range of 5.9 to 6.2 minutes; the (S)-enantiomer is found to elute at t _R 3.49 to 3.55 minutes) ¹ H-NMR (400 MHz, DMSO- d 6): δ ppm = 1.16 (d, 3 H), 3.75 (s, 3 H), 5.06 (q, 1 H), 6.93 (d, 2 H), 7.22 - 7.27 (m, 1 H), 7.34 (dd, 2 H), 7.48 (d, 2 H), 7.57 (s, 1 H), 7.64 (dd, 2 H), 7.79 - 8.38 (m, 2 H). Example 2 : (R) -2- (N-[4- amino -5-(4- methoxybenzyl ) thiazol -2- yl ]-4- fluoroanilino ) propanamide is crystallized to obtain the microcrystalline form of the present invention

Weigh 2.5 g of solid (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide into a 100 mL crystallization vessel. Add 26.74 g of acetone and 2.98 g of water. Stir the suspension at 20°C for 10 minutes to obtain an API solution. In a second 100 mL crystallization vessel, precool 59.42 g of water to 5°C and stir. Add the API solution over 30 minutes onto the precooled water while maintaining the temperature at 5°C. The resulting suspension was separated by filtration and the filter cake was rinsed with displacement wash of acetone/H ₂ O 70 wt % (5.0 g) and then with displacement wash of H ₂ O (5.0 g). The wet filter cake was dried at 60° C. in vacuo. Yield: 89.9%.

XRPD analysis (method XRPD1) of the (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide thus obtained did not show any evidence of the presence of amorphous material or differences in the crystalline form compared to WO 2021/214019 ( FIG. 1 ) (see FIG. 9 , Table 16 therein). DSC (method DSC1) indicated full crystallinity and also did not show any evidence of the presence of amorphous material ( FIG. 2 ). The PSD determined by method PSD1 was found to have x10 / x50 / x90 of 1.8 / 4.3 / 12.6 μm. Example 3 : Preparation of microcrystalline (2R)-2-(N-[4- amino -5-(4- methoxybenzyl ) thiazol -2- yl ]-4- fluoroanilino ) propionamide

A suspension of [4-amino-2-(4-fluoroanilino)thiazol-5-yl]-(4-methoxyphenyl)methanone (120 g, 349 mmol), (2S)-2-bromopropionamide (63.7 g, 419 mmol, 1.2 eq., 95% enantiomeric excess) and potassium phosphate (K ₃ PO ₄ , 148 g, 699 mmol, 2.0 eq.) in acetonitrile (1200 mL) was heated to 60° C. and stirred at this temperature for 1 hour. The temperature was then lowered to 20° C. over 40 min, and water (1200 mL) was added over 20 min. The resulting triphasic mixture was stirred at 20 °C for 3 hours, filtered, and the filter cake was then washed with water (3 x 240 mL) to afford (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide (124 g wet, 99.14% purity, 99.2% enantiomeric excess) as a light yellow solid. The water content of the wet filter cake was determined and found to be 16%, equivalent to 20 mL of residual water contained in the wet filter cake. This amount was taken into account in the subsequent microcrystallization step.

The wet filter cake was dissolved in a mixture of acetone (1350 mL) and water (130 mL) at ambient temperature to give a solution with a small amount of residual solid. The mixture was filtered and the filtrate was added to water (2000 mL) at 4-10 °C over 38 min. The resulting dispersed off-white suspension was filtered and the filter cake was washed with water (2 x 150 mL) and then dried in vacuo at 50 °C to provide (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide (90.3 g, 216 mmol, 62% yield, 99.12% purity, 99.3% enantiomeric excess) as an off-white agglomerated powder. The PSD determined by method PSD2a was found to be (x10 / x50 / x90): 1.2 / 4.6 / 16.1 μm).

Chemical purity and enantiomeric excess were determined according to HPLC methods 4 and 5 (supra) as described above.

Chemical purity (HPLC method 4): t _R = 5.4 min.

Enantiomeric excess (HPLC method 5): t _R = 2.9 min ((2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide) t _R = 2.3 min ((2S)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide) XRPD analysis (method XRPD1) of the (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide obtained in this way did not show any evidence of the presence of amorphous material or differences in the crystalline form compared to WO 2021/214019 ( FIG. 3 ). DSC (method DSC1) indicated full crystallinity and also showed no evidence of the presence of amorphous material (Figure 4). The dissolution of this material was only slightly slower than the dissolution of the material obtained by jet milling the coarse crystalline material (see Reference Example 1) but substantially faster than the coarse crystalline counterparts disclosed in Reference Example 2 (Figures 5, 6). Preparation of starting materials for Example 3 : Preparation of [4-amino-2-(4-fluoroanilino)thiazol-5-yl]-(4-methoxyphenyl)methanone:

A mixture of 1-fluoro-4-isothiocyanatobenzene (300 g, 1.96 mol) and triethylamine (297 g, 2.94 mol, 1.5 equiv) in acetonitrile (0.90 L) is warmed to 60°C. A solution of cyanamide (90.6 g, 2.15 mol, 1.1 equiv) in acetonitrile (1.35 L) is added to this mixture over 1 hour. After another hour, a solution of 2-bromo-1-(4-methoxyphenyl)ethanone (449 g, 1.96 mol, 1.0 equiv) in acetonitrile (2.25 L) is added at 60°C over 75 min. After another 15 min, the suspension is cooled to 20°C over 0.5 h and stirred at this temperature for another 0.5 h. The mixture was filtered, the precipitate was washed with _H2O and dried in vacuo at 50°C to give [4-amino-2-(4-fluoroanilino)thiazol-5-yl]-(4-methoxyphenyl)methanone (606 g, 1.75 mol, 89% yield, 99.0% purity) as a yellow or orange solid. Preparation of (2S)-2-bromopropionamide:

A mixture of (2S)-2-bromopropionic acid (200 g, 1.31 mol, 88% ee, purchased from ABCR) and thionyl chloride (218 g, 1.83 mol, 1.4 equiv) was heated to 50 °C. After 18 hours, the crude acyl chloride was diluted with 2-methyltetrahydrofuran (1.85 L) and added to 30% aqueous ammonia solution (381 g, 3.27 mol, 2.5 equiv) at -15 to 7 °C over 75 min. After the addition was complete, the temperature was raised to 20 °C and water (200 mL) was added. The layers were separated and the aqueous layer was extracted with 2-methyltetrahydrofuran. The combined organic layers were washed with saturated aqueous sodium chloride solution and a portion of the solvent was removed in vacuo at 40 °C. n-Heptane was added, the resulting suspension was cooled to 0 to 5°C, maintained at this temperature for 1 hour, filtered, and the precipitates were then washed with n-heptane. The filter cake was dried in vacuo at 35°C to give (2S)-2-bromopropionamide (147 g, 967 mmol, 74% yield, 99.65% purity, 95% enantiomeric excess) as a colorless solid. Example 4 : Preparation of microcrystalline (2R)-2-(N-[4- amino -5-(4- methoxybenzyl ) thiazol -2- yl ]-4- fluoroanilino ) propionamide

(2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide powder (essentially anhydrous, prepared according to the protocol described in Example 3) (180 g) was added to a mixture of acetone (877 g) and water (175.5 g) and heated up to 55° C., resulting in a solution with a small amount of residual solids. The mixture was filtered with a K300 20 μm filter cloth and the filtrate was cooled down to 35° C. within 1 hour. 35 g of a nanosuspension containing 79.8 wt % water, 10 wt % (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, 8 wt % PVP K12, 2 wt % HPC Klucel ELF and 0.2 wt % SDS (prepared by the method disclosed in Example 1.1 of EP4154872A1 described in European Patent Application No. 22196150.1) was added as a seed material. Subsequently, the suspension was cooled down to 20° C. within 1 hour. In order to increase the yield, 1165.5 g of water was continuously added within 1 hour and the stirring time was then 1 hour. The resulting dispersed white suspension was filtered through a pressure filter and PP 2703 filter cloth. The filter cake was washed with water (2 x 800 mL) and dried in vacuo at 50 °C to provide (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide (164.55 g, 91.4% yield, 99.59% purity, 99.74% enantiomeric excess) as a white agglomerated powder. The PSD determined by Method PSD4 was found to be (x10 / x50 / x90): 3.22 / 6.87 / 13.2 μm ( FIG. 13 ).

XRPD analysis (method XRPD1) of the thus obtained (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide did not show any evidence of the presence of amorphous material or difference in crystalline form compared to the disclosure of WO 2021/214019 ( FIG. 15 ); similarly, DSC analysis (method DSC1) did not show any evidence of the presence of amorphous material ( FIG. 14 ).

Compared to the dissolution of the material obtained from Example 3, the dissolution of the material is at least faster or equal. Specifically, according to the pH measurement, the same amount of the material as in Example 3 (-▲-) and Example 4 (- Tablets of microcrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide obtained as described in Eur. 2.9.3., using acetate buffer pH 4.5 containing 2% SDS (sodium dodecyl sulfate) as dissolution medium ( FIG. 16 ). A paddle apparatus as specified in the US pharmacopeia (USP apparatus 2 (paddle)) with a stirrer speed of 50 rpm and a total medium volume of 900 mL was used. Experimental Section - Reference Examples for Comparison with Examples According to the Invention Reference Example 1 : Partial Amorphization of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide Produced by Jet Milling Jet Milling Protocol

For micronization of the compound, an LSM Zero air jet mill was used.

The compound prepared as described below (4.00 g) was sieved through a 1 mm manual sieve and added in small portions to the air jet mill. Micronization was performed for about 1 hour at room temperature (23° C., 40% relative humidity) using a syringe pressure of 8 bar, a milling pressure of 6 bar and nitrogen as the air jet medium.

Particle size analysis (method PSD3), DSC (method DSC2) and XRPD analysis (method XRPD2) of the compound after the micronization process were performed and the yield (3.78 g, 94.5%) was determined. The PSD of the material thus obtained, determined by method PSD3, was found to be (x10 / x50 / x90) 2.55 / 11.08 / 25.95 μm.

(R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide as obtained by the chemical synthesis described below and used for jet milling is a crystalline solid characterized by the diffraction pattern shown in FIG7 (obtained by method XRPD2) and by thermal behavior as characterized by method DSC2 ( FIG8 ), in which a single endothermic event (melting) occurs at 195° C. (onset).

The partial amorphization that occurs during jet milling can be clearly detected by differential scanning calorimetry (DSC, Method DSC2), where localized recrystallization of amorphous material is seen in exothermic events between 100 and 140°C (Figure 9). Direct comparison of the XRPD data (obtained using Method XRPD2) of the material before and after jet milling also shows a reduced level of crystallinity in the jet milled material (the latter resulting in the lower image in Figure 10) (Figure 10). The material used for jet milling was prepared as follows: Step 1: [4-Amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone

1-Fluoro-4-isothiocyanatobenzene (51.175 g, 98%, 327.4 mmol, CAS 1544-68-9, Aldrich) was dissolved in acetonitrile (1930 mL, Honeywell). Cyanamide (16.52 g, 393 mmol, CAS 420-04-2, Aldrich) was added at room temperature followed by DBU (48.9 mL, 327.4 mmol, Sigma-Aldrich). The reaction mixture was stirred for 45 minutes and then additional DBU (24.4 mL, 163.7 mmol) was added at room temperature followed by 2-bromo-1-(4-methoxyphenyl)ethan-1-one (75 g, 327.4 mmol, CAS 2632-13-5, Fluka and Aldrich) as a solution in acetonitrile (570 mL). The reaction mixture was stirred at rt for 48 hours as a suspension. A large amount of water was added, the precipitate was filtered off, washed with water, suspended in water, and dried by freeze drying to give 122.57 g (quantitative yield, 91% purity) of a solid which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm = 3.81 (s, 3 H) 7.01 (d, 2 H) 7.21 (dd, 2 H) 7.59 - 7.65 (m, 2 H) 7.66 (d, 2 H) 8.12 (br s, 2 H) 10.76 (br s, 1 H). LC/MS (method HPLC2): t _R = 1.07 min; MS (ESIpos) m/z = 344.2 [M+H] ⁺ . Step 2: rac-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide

[4-Amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (87.36 g, 254.4 mmol) was dissolved in N,N-dimethylformamide (1863 mL, Aldrich), followed by the addition of potassium carbonate (175.8 g, 1272 mmol, Riedel-de-Haen) and rac-2-bromopropionamide (46.4 g, 305.3 mmol, CAS 5875-25-2, Aldrich). The reaction mixture was stirred at rt for 3 days. Water was added and the precipitate was filtered off, washed with water, suspended in water, and dried by freeze drying to give 82.6 g (199.29 mmol, 78% yield) of the title compound. ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ ppm = 1.16 (d, 3 H), 3.75 (s, 3 H), 5.06 (q, 1 H), 6.93 (d, 2 H), 7.22 - 7.27 (m, 1 H), 7.34 (dd, 2 H), 7.48 (d, 2 H), 7.57 (s, 1 H), 7.64 (dd, 2 H), 7.79 - 8.38 (m, 2 H). LC/MS (method HPLC2): t _R = 1.06 min/MS (ESIpos): m/z = 415.5 [M+H] ⁺ Step 3: (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide

Rac-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide (82.60 g, 199.3 mmol) was separated by chiral HPLC to yield 33.0 g (79.62 mmol, 39.95%) of S-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide (enantiomer 1) and 38.8 g (93.61 mmol, 46.97%) of R-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide (enantiomer 2 with minor impurities). R-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide was suspended in methyl tert-butyl ether (500 mL, Aldrich) and stirred for 16 days. The suspension was filtered and the solid was washed with methyl tert-butyl ether. Water was added and the precipitate was filtered off, washed with water, suspended in water, and dried by freeze drying to give 35.7 g (84.44 mmol, 42.4% yield) of the title compound as a crystalline material, which is characterized as shown below and as discussed above in the context of Figures 7 and 8. Preparative chiral HPLC ( method HPLC6) Enantiomer 1 t _R = 10.2 to 12.1 min Enantiomer 2 t _R = 14.6 to 21.4 min Analytical chiral HPLC ( method HPLC3) : Enantiomer 2, (R), t _R = 5.99 min ¹ H-NMR (400 MHz, DMSO- d 6): δ ppm = 1.16 (d, 3 H), 3.75 (s, 3 H), 5.06 (q, 1 H), 6.93 (d, 2 H), 7.22 - 7.27 (m, 1 H), 7.34 (dd, 2 H), 7.48 (d, 2 H), 7.57 (s, 1 H), 7.64 (dd, 2 H), 7.79 - 8.38 (m, 2 H). [α] _D ²⁰ = +150.65° (chloroform) Reference Example 2 : Coarse Crystals of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide

Crude crystals of (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide were obtained by thoroughly mixing to homogeneity three qualitatively equivalent subbatches of (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide solid, each of which was produced according to the following procedure: [4-amino-2-(4-fluoroanilino)thiazol-5-yl]-(4-methoxyphenyl)methanone (120 g, 349 mmol), (2S)-2-bromopropanamide (63.7 g, 419 mmol, 1.2 eq., 90% enantiomeric excess) and potassium phosphate (K ₃ PO ₄ , 148 g, 699 mmol, 2.0 equiv) in acetonitrile (1200 mL) was heated to 60 °C and stirred at this temperature for 1 hour. The temperature was then lowered to 20 °C over 40 min, and water (1200 mL) was added over 20 min. The resulting three-phase mixture was stirred at 20 °C for 3 hours and then filtered. The filter cake was washed with water (3 x 240 mL) and dried in vacuo at 50 °C to provide (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide (105 g, 252 mmol, 72% yield, 99.74% purity, 99.0% enantiomeric excess) as a light yellow solid. PSD determined by Method PSD2b was found to be (x10 / x50 / x90): 5.6 / 34 / 131 μm.

XRPD analysis (method XRPD3) of the crude crystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide thus obtained did not show any evidence of amorphous material or a difference in crystalline form compared to WO 2021/214019 ( FIG. 11 ). DSC (method DSC3) indicated full crystallinity and also did not show any evidence of amorphous material ( FIG. 12 ).

Figure 1: XRPD of the material obtained in Example 2 (Method XRPD1)

Figure 2: DSC of the material obtained in Example 2 (method DSC1)

Figure 3: XRPD of the material obtained in Example 3 (method XRPD1) (lower panel with peak picking) Table 1: Peak list corresponding to Figure 3 (lower panel): No. Location Strength 1 7.3 160 2 7.6 181 3 7.9 584 4 8.2 136 5 9.2 288 6 12.2 92 7 12.5 129 8 13.5 232 9 14.0 209 10 14.2 40 11 14.6 368 12 14.9 161 13 15.2 154 14 15.3 184 15 15.8 124 16 16.3 137 17 18.4 79 18 19.0 112 19 19.4 89 20 19.5 66 twenty one 20.0 44 twenty two 20.2 63 twenty three 20.6 246 twenty four 21.2 329 25 21.5 46 26 22.7 78 27 22.8 149 28 22.9 131 29 23.8 43 30 24.5 79 31 25.1 37 32 25.8 37 33 26.1 51 34 26.6 83 35 27.1 71 36 28.3 53 37 28.4 42 38 31.2 45 39 31.7 50 40 32.6 38 41 33.6 32 42 38.7 28

Figure 4: DSC of the material obtained in Example 3 (method DSC1)

Figure 5. Comparison of dissolution profiles in phosphate buffer (pH 6.8) + 0.1% SDS; the thermodynamic solubility of the crystalline material is approximately 20%; 100% dissolution corresponds to 201.5 µg/mL. The materials analyzed are (i) material from Reference Example 1 after jet milling (▬     ▬     ▬     ▬     ▬     ▬), (ii) material from Example 3 (▬  ●  ▬  ●  ▬  ●), and (iii) material from Reference Example 2 (▬ ▬ ▬ ▬ ▬ ▬ ▬). The Y-axis correlates to the amount dissolved (%) and the X-axis correlates to time (in minutes).

Figure 6. Zoom-in showing the first hour of the comparison of the dissolution profiles shown in Figure 5, with the y-axis cropped to 30%

Figure 7. XRPD of the material obtained from Reference Example 1 before jet milling (Method XRPD2)

Figure 8. DSC of the material obtained from Reference Example 1 before jet milling (Method DSC2)

Figure 9. DSC of the material obtained from Reference Example 1 after jet milling (Method DSC2)

Figure 10 Comparative XRPD of the material of Reference Example 1 before (upper diffraction pattern) and after (lower diffraction pattern) self-jet milling (Method XRPD2)

Figure 11: XRPD of material obtained from Reference Example 2 (Method XRPD 3)

Figure 12: DSC of the material obtained from Reference Example 2 (Method DSC3)

Figure 13: Particle size distribution of the material obtained from Example 4 (Method PSD 4)

Figure 14: DSC of the material obtained from Example 4 (Method DSC1)

Figure 15: XRPD of material obtained from Example 4 (Method XRPD 1)

Figure 16: Containing equal amounts of Comparison of the dissolution profiles of microcrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide tablets obtained as described in the present invention. The Y-axis is related to the amount of dissolution (%) and the X-axis is related to the time (in minutes).

Claims (26)

A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide wherein the presence of an amorphous form is less than 15% and the particle size distribution is as follows: x10 is <5 µm, x50 is <10 µm, and x90 is <35 µm. A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as claimed in claim 1, wherein the particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm. A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as claimed in claim 1, wherein the particle size distribution is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm. A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as claimed in claim 1, 2 or 3 wherein the enantiomeric excess is at least 95%. A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as claimed in claim 1, 2, 3 or 4, wherein the presence of the amorphous form is less than 5%. A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as claimed in claim 1, 2, 3, 4 or 5, wherein the particle size distribution is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm. A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as claimed in claim 1, 3, 4 or 5, wherein the particle size distribution is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm. A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as claimed in claim 1, 2, 4 or 5, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 µm, x50 is in the range of 3 to 7 µm, and x90 is in the range of 8 to 20 µm. A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as claimed in claim 1, 3, 4 or 5, wherein the enantiomeric excess is at least 98%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 0.3 to 4 µm, x50 is in the range of 4 to 10 µm, and x90 is in the range of 10 to 20 µm. A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as claimed in claim 1, 2, 3, 4, 5, 6 or 8, wherein the enantiomeric excess is at least 99%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 1 to 2 µm, x50 is in the range of 4 to 5.5 µm, and x90 is in the range of 10 to 18 µm. A microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as claimed in claim 1, 3, 4, 5, 7 or 9, wherein the enantiomeric excess is at least 99%, the presence of amorphous form is less than 5%, and the particle size distribution is as follows: x10 is in the range of 1 to 4 µm, x50 is in the range of 4 to 8 µm, and x90 is in the range of 12 to 18 µm. A method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the method comprising the steps of: dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in a solvent or a solvent mixture, then mixing the resulting solution with an anti-solvent, then separating and drying the resulting precipitate, to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide. The method of claim 12, comprising the steps of: adding a solution of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in a dipolar aprotic solvent and/or a protic solvent, as appropriate, to an antisolvent, and separating and drying the resulting precipitate, to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide. The method of claim 12 or 13, comprising the steps of: adding a filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in a mixture of acetone and water at a temperature in the range of 4°C to 10°C for a period of time in the range of 30 minutes to 1 hour, wherein the ratio of acetone to water is in the range of 8:1 (v/v) to 12:1 (v/v) of acetone to water, and separating and drying the resulting precipitate, to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide. The method of claim 12, comprising the steps of: 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in a solvent, 3) creating supersaturation, 4) adding a nanosuspension comprising other (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, an anti-solvent, at least one surfactant and at least one polymer, 5) followed by one or more of the following sub-steps: a. cooling, b. adding an anti-solvent, and c. evaporating the solvent , 6) separating and drying the resulting precipitate, To obtain (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in microcrystalline form. The method of claim 12 or 15, comprising the steps of: 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in acetone containing water in the range of 10 to 30% v/v, and optionally filtering, 3) creating supersaturation by cooling, the temperature reduction being in the range of 5°C to 30°C, 4) adding a nanosuspension comprising other (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, water, at least one surfactant and at least two polymers, 5) followed by a. Cool, then b. add water, 6) separate and dry the resulting precipitate, to obtain microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide. The method of claim 12 or 13, comprising the following steps i. allowing an intermediate compound of formula (II) (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, ii. dissolving the crude product produced in step i. in a dipolar aprotic solvent and/or a protic solvent and then optionally filtering, iii. adding the solution or filtrate produced in step ii. to an antisolvent, and iv. separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide. The method of claim 12, 13 or 17, comprising the following steps i. allowing an intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates at a temperature in the range of 20 to 80° C. in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone and isopropanol for a period of time in the range of 30 minutes to 24 hours, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, ii. dissolving the crude product produced from step (i) in a mixture of acetone and water and then filtering, the ratio of acetone to water being in the range of 8:1 (v/v) to 12:1 (v/v) in favor of acetone, iii. adding the filtrate to water at a temperature in the range of 0°C to 20°C for a time in the range of 20 minutes to 1.5 hours; and iv. separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide. The method of claim 12, 13, 14, 17 or 18, comprising the following steps i. allowing an intermediate compound of formula (II) (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, reacting in acetonitrile at a temperature in the range of 50 to 70°C for a period of time in the range of 1 to 2 hours in the presence of 1.5 to 5 equivalents of potassium phosphate, followed by lowering the temperature to 20°C over a period of time in the range of up to one hour, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide, ii. dissolving the crude product produced from step (i) in a mixture of acetone and water and then filtering, the ratio of acetone to water being in the range of 8:1 (v/v) to 12:1 (v/v) in favor of acetone, iii. adding the filtrate to water at a temperature in the range of 4°C to 10°C for a time in the range of 30 minutes to 1 hour; and iv. separating and drying the resulting precipitate to obtain a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide. The method of claim 12 or 15, comprising the following steps: 1) allowing an intermediate compound of formula (II) (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, 2) dissolving the crude product produced by step 1) in a solvent, 3) creating supersaturation, 4) adding a nanosuspension comprising other (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, an anti-solvent, at least one surfactant and at least one polymer, 5) followed by one or more of the following sub-steps: a. cooling, b. adding an anti-solvent, and c. evaporating the solvent , 6) separating and drying the resulting precipitate, To obtain (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in microcrystalline form. The method of claim 12, 15, 16 or 20, comprising the steps of: 1) allowing an intermediate compound of formula (II) to (II) and the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates at a temperature in the range of 20 to 80° C. in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone and isopropanol for a period of time in the range of 30 minutes to 24 hours, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, 2) dissolving the crude product from step 1) in acetone containing water in the range of 10 to 30% v/v and optionally filtering, 3) creating supersaturation by cooling, the temperature reduction being in the range of 5°C to 30°C, 4) adding a nanosuspension comprising further (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, water, at least one surfactant and at least two polymers, 5) followed by a. cooling, followed by b. adding water, 6) The resulting precipitate was separated and dried to obtain microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide. The method of claim 12, 15, 16, 20 or 21, comprising the steps of: 1) allowing an intermediate compound of formula (II) to (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C in acetonitrile for a period of time in the range of 1 to 2 hours, optionally followed by lowering the temperature to 20°C over a period of time in the range of up to one hour, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, 2) dissolving the crude product from step 1) in acetone containing water in the range of 10 to 30% v/v at a temperature in the range of 40°C to 70°C and optionally filtering, 3) creating supersaturation by cooling, the temperature reduction being in the range of 15°C to 25°C, 4) adding a saturated mixture comprising further (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide (5 to 20% w/w), water (60 to 90% w/w), at least one surfactant (0.05 to 1% w/w) and at least two polymers (each independently 0.5 to 15% w/w), wherein the at least one surfactant comprises an alkali metal salt of a _C8 - _C20 -alkyl sulfate, and the at least two polymers comprise hydroxypropyl cellulose and polyvinyl pyrrolidone, and wherein the amount of the nanosuspension is in the range of 1 to 6% w/w of the supersaturated solution produced by step 3), 5) followed by a. cooling, the temperature reduction being in the range of 5°C to 25°C, and then b. adding water, 6) separating and drying the resulting precipitate, To obtain (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide in microcrystalline form. A pharmaceutical composition comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide as claimed in any one of claims 1 to 11 and one or more pharmaceutically acceptable excipients. A method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide, the method comprising the following steps to allow the intermediate compound of formula (II) (II) react with the intermediate compound of formula (III) (III) wherein LG is a leaving group as defined above, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propionamide. The method of claim 24, comprising the following steps: (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate, at a temperature in the range of 40 to 80° C., in a solvent selected from N,N-dimethylformamide and acetonitrile for a period of time in the range of 30 minutes to 6 hours, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 90%. The method of claim 24 or 25, comprising the following steps: (II) and the intermediate compound of formula (III) (III) wherein LG is a bromine atom, reacting in acetonitrile at a temperature in the range of 50 to 70°C for a period of time in the range of 1 to 2 hours in the presence of 1.5 to 5 equivalents of potassium phosphate, followed by lowering the temperature to 20°C over a period of time in the range of up to one hour, thereby obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzyl)thiazol-2-yl]-4-fluoroanilino)propanamide in an enantiomeric excess of at least 95%.