EA041037B1 - AMORPHOUS AND CRYSTALLINE FORMS OF IDO INHIBITORS - Google Patents

Description

Cross-reference to related applications

The present application claims priority under U.S. Provisional Application No.

62/527855, filed June 30, 2017, the contents of which are hereby incorporated by reference in their entirety.

Field of invention

The present invention relates to solid forms of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6fluoroquinolin-4-yl)cyclohexyl)propanamide and its salts and hydrates, processes for their preparation, pharmaceutical compositions containing these compounds, and methods of treatment using these compositions.

BACKGROUND OF THE INVENTION (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, also referred to herein as Compound 1, has the following structure :

Compound 1 is a potent inhibitor of indolamine 2,3-dioxygenase (IDO; also known as IDO1), which is the target gene for IFN-γ (interferon gamma) and is involved in immunomodulation. The possibility of using compound 1 in the treatment of cancer and other diseases is currently being studied. Compound 1 was previously described in WO 2016/073770.

The compound, in free base, hydrate, solvate or salt form, may exist in an amorphous form and/or in one or more crystalline forms that have different physical properties, such as different X-ray diffraction patterns (XRPD or PXRD) and different temperature characteristics. The free base, hydrate, solvate, and salt forms of a compound may also differ in their stability, preparation, dosage form, dissolution profile, bioavailability, and the like.

There is a need for new forms of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4yl)cyclohexyl)propanamide having desirable and favorable chemical and physical properties. There is also a need for reliable and reproducible methods for the production, purification and preparation of dosage forms of compound 1 (and its hydrates, solvates, salts and hydrated salt forms) that meet the goals of commercialization. The present invention addresses these and other important issues.

The essence of the invention

The present invention relates to solid forms of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6fluoroquinolin-4-yl)cyclohexyl)propanamide (compound 1), including solid forms of the free base ( R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, solid forms of monohydrate (R)-N-(4-chlorophenyl)- 2-(( 1 S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, solid salt forms (R)-N-(4-chlorophenyl)-2-((1S,4S)-4 -(6-fluoroquinolin-4-yl)cyclohexyl)propanamide formed with methanesulfonic acid and (R)-N-(4-chlorophenyl)-2((1S,4S)-4-(6-fluoroquinoline) salt monohydrate solid forms -4-yl)cyclohexyl)propanamide formed with methanesulfonic acid. Also described are compositions containing these solid forms, as well as methods for their preparation and use in therapy.

Brief description of the drawings

In FIG. 1 is an X-ray powder diffraction pattern of form 2 of the free base monohydrate of compound 1.

In FIG. 1A shows the ss NMR spectrum of form 2 of the free base monohydrate of compound 1.

In FIG. 1B shows the FT-IR spectrum of Compound 1 Free Base Monohydrate Form 2.

In FIG. 1C is a Differential Scanning Calorimetry (DSC) thermogram of Compound 1 Free Base Monohydrate Form 2.

In FIG. 1D is a Thermogravimetric Analysis (TGA) thermogram of Compound 1 Free Base Monohydrate Form 2.

In FIG. 1E shows the Fourier-Raman spectrum of form 2 of the free base monohydrate of compound 1.

In FIG. 2 shows an X-ray powder diffraction pattern of the free base form 4 of compound 1.

In FIG. 2A shows the ss NMR spectrum of form 4 of the free base of compound 1.

In FIG. 2B is a DSC thermogram of form 4 of compound 1 free base.

In FIG. 2C is a TGA thermogram of form 4 of compound 1 free base.

- 1 041037

In FIG. Figure 3 shows the powder X-ray diffraction pattern of the amorphous free base of compound 1.

In FIG. 3A shows the ss NMR spectrum of the amorphous free base of compound 1.

In FIG. 3B shows the FT-IR spectrum of the amorphous free base of compound 1.

In FIG. 3C shows the Fourier-Raman spectrum of the amorphous free base of compound 1.

In FIG. 4 shows an X-ray powder diffraction pattern of form 1 of the salt of compound 1, in which there is one molecule of compound 1 per molecule of methanesulfonic acid (MSA salt of compound 1).

In FIG. 4A shows the ss NMR spectrum of the MSA salt form 1 of compound 1.

In FIG. 4B shows the FT-IR spectrum of form 1 of the MSA salt of compound 1.

In FIG. 4C is a DSC thermogram of form 1 of the MSA salt of compound 1.

In FIG. 4D shows the Fourier-Raman spectrum of form 1 of the MSA salt of compound 1.

In FIG. 4E is a TGA thermogram of Compound 1 MSA salt Form 1.

In FIG. 5 shows an X-ray powder diffraction pattern of an amorphous salt of compound 1 formed with methanesulfonic acid (MSA).

In FIG. 5A shows the ss NMR spectrum of the amorphous MSA salt of compound 1.

In FIG. 5B shows the Fourier-Raman spectrum of an amorphous MSA salt of compound 1.

In FIG. 6 shows an X-ray powder diffraction pattern of form 2 of the MSA salt monohydrate of compound 1.

In FIG. 6A is a DSC thermogram of Form 2 of the MSA salt monohydrate of Compound 1.

In FIG. 6B is a TGA thermogram of Form 2 of the MSA salt monohydrate of Compound 1.

In FIG. Figure 7 shows the microdissolution profiles of form 1 MSC salt of compound 1, HCl salt of compound 1 (amorphous), crystalline HCl salt of compound 1 in FaSSIF (Fasted State Simulated Intestinal Fluid) and FeSSIF (Fed State Simulated Intestinal Fluid) in an amount of 150 mg, simulating human dose.

In FIG. 8 shows the microdissolution profiles of compound 1 MSA salt form 1, compound 1 free base (amorphous) and compound 1 free base hydrate form 2 in FaSSIF and FeSSIF media, in the amount of 0.2 mg/ml, n=3-4.

In FIG. 9 shows the microdissolution profiles of Compound 1 MSA salt form 1 and Compound 1 MSA salt monohydrate form 2.

Detailed description of the invention

The present invention relates to solid forms of Compound 1, such as Compound 1 (as free base), Compound 1 monohydrate (as free base), and Compound 1 salt formed with methanesulfonic acid (MSA), Compound 1 MSA salt monohydrate, as well as to the preparation of such solid forms, to pharmaceutical compositions containing such solid forms, and to methods of treating diseases mediated by IDO using such solid forms. The names of the described solid forms should not be construed as a limitation to any other substance having similar or identical physical and chemical characteristics, but rather, these names should be considered as identifiers, which should be interpreted in accordance with the characteristic information given in this description.

Free base hydrate of compound 1.

According to one embodiment, this invention relates to the solid form of compound 1 (as free base), which is a monohydrate. For example, the solid form of compound 1 free base monohydrate contains approximately 1 molecule of water per molecule of compound 1 free base.

According to preferred aspects of the present invention, the solid hydrate form of Compound 1 (as free base) is the crystalline form of Compound 1 monohydrate (as free base), referred to herein as Compound 1 Free Base Monohydrate Form 2. Compound 1 Free Base Monohydrate Form 2 has desired stability profile.

Compound 1 free base monohydrate Form 2 may have an X-ray diffraction pattern containing one peak, or at least one peak whose position, expressed in degrees 2Θ, is selected from 9.4, 12.4, 17.2, 17.6, 20 ,1, 21.1 and 21.6 degrees 2Θ ±0.2 degrees 2θ. Form

- 2 041037 free base monohydrate of compound 1 can also be characterized by an X-ray diffraction pattern containing two peaks, the positions of which, expressed in degrees 2θ, are selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21, 1 and 21.6 degrees 2θ ±0.2 degrees 2θ. The free base monohydrate form 2 of Compound 1 can also be characterized by an X-ray diffraction pattern containing three peaks whose positions, expressed in degrees 2θ, are selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1 and 21.6 degrees 2θ±0.2 degrees 2θ. Compound 1 free base monohydrate form 2 can also be characterized by an X-ray diffraction pattern containing four peaks whose positions, expressed in degrees 2θ, are selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1 and 21.6 degrees 2Θ ±0.2 degrees 2θ. Compound 1 free base monohydrate form 2 can also be characterized by an X-ray diffraction pattern containing five peaks whose positions, expressed in degrees 2θ, are selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1 and 21.6 degrees 2θ±0.2 degrees 2θ. Compound 1 free base monohydrate form 2 can also be characterized by an X-ray diffraction pattern containing six peaks whose positions, expressed in degrees 2θ, are selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1 and 21.6 degrees 2θ±0.2 degrees 2θ. Form 2 of the free base monohydrate of compound 1 can also be characterized by an X-ray diffraction pattern containing peaks whose positions, expressed in degrees 2θ, correspond to 9.4, 12.4, 17.2, 17.6, 20.1, 21.1 and 21 .6 degrees 2θ ±0.2 degrees 2θ.

Diffraction peak positions of compound 1 free base monohydrate form 2, at room temperature, based on a high quality diffraction pattern obtained with a rotating capillary diffractometer (Cu Ka), 2Θ-calibrated according to NIST (National Institute of Standards and Technology) or using other suitable standards are given in table. 1 and table. 1A.

Table 1. Characteristic positions of the diffraction peaks form 2 of the free base monohydrate of compound 1

Table 1A. Compound 1 Free Base Monohydrate Form 2 Peak List

- 3 041037

Compound 1 free base monohydrate Form 2 may have an X-ray diffraction pattern containing at least one peak selected from the peaks shown in Table 1. 1A.

Compound 1 free base monohydrate Form 2 may also have an X-ray diffraction pattern substantially the same as that shown in FIG. 1.

In table. Figure 2 shows X-ray diffraction data for a single crystal of form 2 of the free base monohydrate of compound 1.

Table 2. X-ray diffraction data for a single crystal of form 2 of the free base monohydrate of compound 1

Temperature room temperature Wavelength 1.54178 A Crystal system, space group Monoclinic, С2 Unit cell parameters a = 25.404(1) A alpha = 90° b = 10.0423(6) A beta = 91.851(3)° c = 8.8156(5) A gamma = 90° Volume 2247.8(2) A ³ Calculated Density 1.267 g/ ^cm3 Formula units per unit cell 4

In table. Figure 3 shows the atomic coordinates of form 2 of the free base monohydrate of compound 1.

Table 3. Atomic coordinates of form 2 of the free base hydrate of compound 1

Atom X At Z A tom X At Z joint venture 0.9315(1) 0.7764(2) -0.4727(1) C24 0.7470(2) 1.0312(4) 0.3017(6) F1 0.4666(1) 0.3834(3) 0.2165(4) O1W 0.8172(1) 0.5088(3) 0.1604(4) N1 0.7695(1) 0.8741(3) -0.0183(3) H1 0.7416 0.9123 -0.0557 N2 0.4216(1) 0.9155(3) 0.2075(3) H2 0.8691 0.7960 0.0244 01 0.8056(1) 0.7905(3) 0.2000(3) FROM 0.9319 0.7664 -0.1577 C1 0.8090(1) 0.8444(3) -0.1225(3) H5 0.8247 0.8411 -0.4862 C2 0.8601(1) 0.8075(4) -0.0778(4) H6 0.7622 0.8801 -0.3067 NW 0.8974(1) 0.7881(5) -0.1872(4) H8 0.6974 0.9391 0.1446 C4 0.8841(1) 0.8006(4) -0.3377(4) H9 0.7312 0.7526 0.3674 C5 0.8337(2) 0.8338(4) -0.3835(4) NUDE 0.5817 0.7234 0.3860 C6 0.7963(1) 0.8565(3) -0.2758(4) NPA 0.6648 0.6214 0.2884 C7 0.7699(1) 0.8502(3) 0.1316(3) hub 0.6881 0.6774 0.1388 C8 0.7248(1) 0.9096(3) 0.2179(4) H12A 0.5951 0.6822 0.1260 C9 0.7015(1) 0.8014(4) 0.3205(4) H12B 0.6182 0.8263 0.1086 SU 0.5836(1) 0.7989(4) 0.3160(3) H13A 0.6637 0.7852 0.5232 joint venture 0.6690(1) 0.7014(4) 0.2284(5) H13B 0.6882 0.9267 0.5007 C12 0.6145(1) 0.7526(3) 0.1786(4) H14A 0.6202 0.9822 0.3276

- 4 041037

C13 0.6687(1) 0.8556(5) 0.4498(4) H14B 0.5965 0.9403 0.4829 C14 0.6155(1) 0.9081(4) 0.3965(3) H18 0.4511 1.0918 0.2116 C15 0.5276(1) 0.8384(3) 0.2725(3) H19 0.5371 1.0361 0.2734 C16 0.4875(1) 0.7398(3) 0.2481(3) H20 0.5314 0.5689 0.2656 C17 0.4351(1) 0.7839(4) 0.2203(3) H21 0.3594 0.7174 0.1913 C18 0.4595(2) 1.0022(4) 0.2239(5) H22 0.3777 0.4937 0.1995 C19 0.5123(1) 0.9688(4) 0.2591(5) H24A 0.7618 1.0915 0.2303 C20 0.4974(2) 0.6011(4) 0.2490(4) H24V 0.7738 1.0035 0.3741 C21 0.3940(1) 0.6887(4) 0.2044(4) H24C 0.7192 1.0750 0.3536 C22 0.4047(2) 0.5560(4) 0.2082(4) H1W 0.846(3) 0.485(7) 0.174(6) C23 0.4566(2) 0.5159(4) 0.2253(4) H2W 0.817(3) 0.598(8) 0.159(7)

The ss NMR spectrum of the free base monohydrate of compound 1 is shown in FIG. 1A. The ss NMR spectrum of form 2 of the free base hydrate of compound 1 contains the following peaks:

ppm (±0.2)

180.4

160.0

153.1

148.2

143.6

139.5

131.3

127.9

123.7

122.1

119.7

118.3

106.5 42.0 40.4 33.3 31.6 29.9 28.4 25.0 18.3

The FT-IR spectrum of Compound 1 Free Base Monohydrate Form 2 is shown in FIG. 1b. The FT-IR spectrum of compound 1 free base monohydrate contains at least the following peaks:

The DSC thermogram of Compound 1 Free Base Monohydrate Form 2 is shown in FIG. 1C.

- 5 041037

The TGA thermogram of Compound 1 Form 2 Compound 1 Free Base Monohydrate is shown in FIG. 1D.

The Fourier-Raman spectrum of Compound 1 free base monohydrate form 2 is shown in FIG. 1E.

The Fourier-Raman spectrum of compound 1 free base monohydrate contains at least the following peaks:

The free base monohydrate form 2 of Compound 1 may be present in substantially pure form, ie about 90% pure or greater based on the weight of the compound, as measured by HPLC (High Performance Liquid Chromatography). For example, Compound 1 free base monohydrate form 2 may be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% pure, or 100% pure. The rest of the material may include other solid forms of compound 1, and/or reactive impurities, and/or process impurities that occur during the preparation of this compound.

Mixtures of Compound 1 Free Base Monohydrate Form 2 with other solid forms of Compound 1 are also included within the scope of the present invention. In appropriate embodiments, such mixtures may contain less than 90% (by weight of the mixture) of Compound 1 Free Base Monohydrate Form 2. For example, mixtures may contain 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35%, 30%, 25%, 20%, 15%, 10%, or approximately 5% (by weight of mixture) Compound 1 Free Base Monohydrate Form 2.

Free base compound 1.

According to one embodiment, this invention relates to a crystalline form of Compound 1 (as free base), referred to herein as Form 4. Free base Form 4 of Compound 1 has a desirable workability and a desirable stability profile that is sufficient for industrial solid dosage forms. scale.

Form 4 of the free base of compound 1 may be characterized by an X-ray diffraction pattern containing one peak, or at least one peak, the position of which, expressed in degrees 2θ, is selected from 7.6, 12.0, 13.5, 14.4, 17, 6, 20.1, 20.7 and 22.0 degrees 2Θ ±0.2 degrees 2θ. Form 4 of the free base of compound 1 can also be characterized by an X-ray diffraction pattern containing two peaks whose positions, expressed in degrees 2θ, are selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ ±0.2 degrees 2θ. Form 4 of the free base of compound 1 can also be characterized by an X-ray diffraction pattern containing three peaks whose positions, expressed in degrees 2θ, are selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2Θ ±0.2 degrees 2θ. Form 4 of the free base of compound 1 can also be characterized by an X-ray diffraction pattern containing four peaks whose positions, expressed in degrees 2θ, are selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2Θ ±0.2 degrees 2θ. Form 4 of the free base of compound 1 can also be characterized by an X-ray diffraction pattern containing five peaks whose positions, expressed in degrees 2θ, are selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ ±0.2 degrees 2θ. Form 4 of the free base of compound 1 can also be characterized by an X-ray diffraction pattern containing six peaks whose positions, expressed in degrees 2θ, are selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ ±0.2 degrees 2θ. Form 4 of the free base of compound 1 can also be characterized by an X-ray diffraction pattern containing seven peaks whose positions, expressed in degrees 2θ, are selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ ±0.2 degrees 2θ. Form 4 of the free base of compound 1 can also be characterized by an X-ray diffraction pattern containing peaks whose positions, expressed in degrees 2θ, correspond to 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20, 7 and 22.0 degrees 2Θ ±0.2 degrees 2θ.

The diffraction peak positions of form 4 of the free base of compound 1, at room temperature, based on a high quality diffraction pattern obtained with a rotating capillary diffractometer (Cu Ka), 2θ-calibrated according to NIST or using other suitable standards, are given in Table . 4 and 4A.

Table 4. Characteristic positions of the diffraction peaks of form 4 of the free base of compound 1

- 7 041037

Form 4 of the free base of compound 1 may be characterized by an x-ray diffraction pattern containing at least one peak selected from the peaks shown in table. 4A.

Form 4 of the free base of Compound 1 can also be characterized by an X-ray diffraction pattern essentially the same as that shown in FIG. 2.

In table. Figure 5 shows X-ray diffraction data for a single crystal of form 4 of the free base of compound 1.

Table 5. X-ray diffraction data for a single crystal of form 4 of the free base of compound 1

Temperature room temperature Wavelength 1.54178 A Crystal system, space group Monoclinic, Ρ2ι Unit Cell Parameters a = 8.648(1) A alpha = 90 b = 5.1322(8) A beta = 97.105(8)° c = 23.367(3) A gamma = 90 Volume 1029.1(3) A ³ Calculated Density 1.326 g/ ^cm3 Formula units per unit cell 2

In table. Figure 6 shows the atomic coordinates of form 4 of the free base of compound 1.

Table 6. Atomic coordinates of form 4 of the free base of compound 1

Atom X Y Z Atom X Y Z joint venture 0.8004(2) 0.2652(4) 0.3629(1) C23 0.6753(5) 0.4174(9) 0.4575(2) F1 1.1246(3) 0.2782(6) 1.0468(1) C24 0.5211(5) 0.240(1) 0.7147(2) N1 0.7171(4) 0.1912(6) 0.6093(1) H1 0.7215 0.0364 0.6234 N2 1.3913(4) -0.2846(7) 0.8863(1) H1A 0.7526 0.1423 0.7150 01 0.6832(4) 0.6147(5) 0.6310(1) NZA 1.1521 0.4342 0.7533 C1 0.6913(4) 0.3024(7) 0.7082(1) NZV 1.0261 0.2182 0.7367 C2 0.6971(4) 0.3875(7) 0.6464(1) H4 1.0728 0.4680 0.8455 NW 1.0494(4) 0.3737(7) 0.7598(1) H5A 0.8570 0.0628 0.8117 C4 1.0496(4) 0.3071(7) 0.8235(1) H5B 0.8818 0.1838 0.8738 C5 0.8839(4) 0.2214(7) 0.8332(1) H6A 0.7850 0.5844 0.8384 C6 0.7634(4) 0.4316(8) 0.8142(1) H6B 0.6607 0.3682 0.8199 C7 0.7625(4) 0.5106(7) 0.7505(1) H7 0.6984 0.6678 0.7441 C8 0.9293(4) 0.5839(7) 0.7407(1) H8A 0.9313 0.6185 0.6999 C9 1.1730(4) 0.1091(7) 0.8455(1) H8B 0.9586 0.7432 0.7616 SU 1.2521(4) -0.0343(8) 0.8098(2) NUDE 1.2343 -0.0059 0.7703 joint venture 1.3606(4) -0.225(1) 0.8317(2) NO 1.4139 -0.3145 0.8056 C12 1.3155(4) -0.1434(7) 0.9241(2) H13 1.4131 -0.3452 0.9942 C13 1.3477(4) -0.2058(9) 0.9829(2) H15 1.0783 0.3420 0.9392 C14 1.2089(4) 0.0605(7) 0.9063(1) H17 1.3073 -0.1052 1.0623 C15 1.1460(4) 0.2041(8) 0.9493(1) H19 0.9042 -0.0731 0.4520 C16 1.1854(5) 0.1387(8) 1.0055(2) H20 0.8739 -0.0965 0.5487 C17 1.2845(5) -0.0653(9) 1.0234(2) H22 0.5913 0.5216 0.5312 C18 0.7706(5) 0.243(1) 0.4346(2) H23 0.6237 0.5453 0.4343 C19 0.8427(5) 0.0488(9) 0.4681(2) H24A 0.4588 0.3933 0.7070 C20 0.8239(5) 0.0343(9) 0.5259(2) H24V 0.5139 0.1805 0.7532 C21 0.7315(4) 0.2123(7) 0.5498(1) H24C 0.4841 0.1055 0.6877 C22 0.6556(4) 0.4029(8) 0.5156(2)

- 8 041037 ss NMR spectrum is shown in FIG. 2A. The ss NMR spectrum of form 4 of the free base of the compound contains the following peaks:

ppm (±0.2)

180.3

176.2

159.1

153.1

147.9

143.6

139.6

137.0

131.2

127.9

123.8

119.8

118.1

109.0

106.4

42.1

40.4

38.4

35.4

33.3

31.6

29.9

28.4

25.1

20.1

18.3

The DSC thermogram of Compound 1 Free Base Form 4 is shown in FIG. 2b.

The TGA thermogram of Compound 1 Free Base Form 4 is shown in FIG. 2C.

The amorphous free base of Compound 1 is also included within the scope of the present invention. The PXRD pattern of the amorphous free base of Compound 1 is shown in FIG. 3. The amorphous free base spectrum of compound 1 obtained using solid state NMR spectroscopy is shown in FIG. 3A. The ss NMR spectrum of the amorphous free base of compound 1 contains the following peaks:

ppm (±0.2)

177.4

160.6

150.6 146.0 139.2 128.9 120.1 107.3 41.2 29.9 17.1

The FT-IR spectrum of the amorphous free base of compound 1 is shown in FIG. 3b. The FT-IR spectrum of the amorphous free base of compound 1 contains the following peaks:

cm ¹ (± 1)

2933

2862

1689

1660 1596 1514 1492 1400 1244 1091

The Fourier-Raman spectrum of the amorphous free base of compound 1 is shown in FIG. 3C. The Fourier-Raman spectrum of the amorphous free base of compound 1 contains the following peaks:

Compound 1 free base form 4 may be present in substantially pure form, ie about 90% pure or greater based on the weight of the compound as determined by HPLC analysis. For example, Free Base Form 4 of Compound 1 may be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% pure, or 100% pure. The remainder of the material may include other solid forms of Compound 1 and/or reactive impurities and/or process impurities arising from the preparation of this compound.

Mixtures of Compound 1 Free Base Form 4 with other solid forms of Compound 1 are also included within the scope of the present invention. In appropriate embodiments, such mixtures may contain less than 90% (by weight of the mixture) of Compound 1 Free Base Form 4. For example, mixtures may contain 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35 , 30, 25, 20, 15, 10 or approximately 5% (by weight of the mixture) form 4 of the free base of compound 1.

The amorphous free base of Compound 1 may be present in substantially pure form, ie about 90% pure or greater based on the weight of the compound as determined by HPLC analysis. For example, the amorphous free base of compound 1 may be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% pure, or 100% pure. The rest of the material may include other solid forms of compound 1, and/or reactive impurities, and/or process impurities that occur during the preparation of this compound.

Mixtures of the amorphous free base of Compound 1 with other solid forms of Compound 1 are also included within the scope of the present invention. In appropriate embodiments, such mixtures may contain less than 90% (by weight of the mixture) of Compound 1 amorphous free base. For example, mixtures may contain 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 30, 25, 20, 15, 10, or approximately 5% (by weight of the mixture) of compound 1 amorphous free base.

MSC-salt of compound 1.

According to one embodiment, this invention relates to crystalline forms of the salt of compound 1 formed with methanesulfonic acid (MSA). According to some aspects of the present invention, the crystalline form of the MSA salt of compound 1 is unsolvated. According to other aspects of the present invention, the crystalline form of the MSA salt of Compound 1 is anhydrous (ie, anhydrous). According to other aspects of the present invention, the crystalline form of the MSA salt of Compound 1 is unsolvated and non-hydrated (ie, anhydrous).

According to preferred aspects of the present invention, the MSA salt of Compound 1 is a mono-MSA salt of Compound 1. According to particularly preferred aspects of the present invention, the crystalline form of the mono-MSA salt of Compound 1 is referred to herein as Form 1. Mono-MSA salt of Compound 1, in particular Form 1 of the mono-MSA salt of Compound 1 has a higher oral bioavailability, when administered as a solid dosage form, compared to the free base of Compound 1.

Compound 1 MSA salt form 1 may have an X-ray diffraction pattern containing one peak, or at least one peak whose position, expressed in degrees 2θ, is selected from 12.2, 12.6, 13.4, 14.8, 16 .4, 16.8, 19.6 and 24.0 degrees 2Θ ±0.2 degrees 2θ. MSA salt form 1 of compound 1 can also be characterized by an X-ray diffraction pattern containing two peaks whose positions, expressed in degrees 2θ, are selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8 , 19.6 and 24.0

- 10 041037 degrees 2θ ±0.2 degrees 2θ. MSA salt form 1 of compound 1 can also be characterized by an X-ray diffraction pattern containing three peaks whose positions, expressed in degrees 2θ, are selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8 , 19.6 and 24.0 degrees 2Θ ±0.2 degrees 2θ. MSA salt form 1 of compound 1 can also be characterized by an X-ray diffraction pattern containing four peaks whose positions, expressed in degrees 2θ, are selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8 , 19.6 and 24.0 degrees 2θ ±0.2 degrees 2θ. MSA salt form 1 of compound 1 can also be characterized by an X-ray diffraction pattern containing five peaks whose positions, expressed in degrees 2θ, are selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8 , 19.6 and 24.0 degrees 2Θ ±0.2 degrees 2θ. MSA salt form 1 of compound 1 can also be characterized by an X-ray diffraction pattern containing six peaks whose positions, expressed in degrees 2θ, are selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8 , 19.6 and 24.0 degrees 2θ ±0.2 degrees 2θ. MSA salt form 1 of compound 1 can also be characterized by an X-ray diffraction pattern containing seven peaks whose positions, expressed in degrees 2θ, are selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8 , 19.6 and 24.0 degrees 2Θ ±0.2 degrees 2θ. MSA salt form 1 of compound 1 can also be characterized by an X-ray diffraction pattern containing peaks whose positions, expressed in degrees 2θ, correspond to 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19 .6 and 24.0 degrees 2θ ±0.2 degrees 2θ.

The positions of the diffraction peaks of form 1 of the MSA salt of compound 1, at room temperature, based on a high quality diffractogram obtained with a rotating capillary diffractometer (Cu Ka), 2θ-calibrated according to NIST requirements or using other suitable standards, are given in tab. 7 and tab. 7A.

Table 7. Characteristic positions of diffraction

- 11 041037

Form 1 MSC-salt of compound 1 may be characterized by an x-ray diffraction pattern containing at least one peak selected from the peaks shown in table. 7A.

MSA salt form 1 of Compound 1 can also have an X-ray diffraction pattern substantially the same as that shown in FIG. 4.

In table. Figure 8 shows X-ray diffraction data for a single crystal of form 1 of the MSA salt of compound 1.

Table 8. X-ray diffraction data for a single crystal of form 1 MSA salt of compound 1

Temperature room temperature Wavelength 1.54178 A Crystal system, space group Rhombic, Ρ2ι2ι2ι Unit cell parameters a = 10.4855(2) A alpha = 90 b = 14.1015(3) A beta = 90 c = 16.9033(4) A gamma = 90° Volume 2499.34(9) A ³ Calculated Density 1.347 g/ ^cm3 Formula units per unit cell 4

In table. Figure 9 shows the atomic coordinates of form 1 of the MSA salt of compound 1.

- 12041037

Table 9. Atomic coordinates of form 1 MSA salt of compound 1

Atom X Y Z Atom X Y Z joint venture 0.6693(1) 0.6888(1) 0.0394(1) O1S 0.3834(3) 0.510(1) 0.8927(2) F1 0.6567(3) 0.9364(2) 0.7979(2) O2S 0.1583(3) 0.5000(2) 0.8844(2) N1 0.3065(3) 0.7782(2) 0.2968(2) O3S 0.2810(4) 0.3638(2) 0.9191(2) N2 0.3061(4) 0.6553(2) 0.7924(2) Hl 0.2803 0.7310 0.3245 01 0.2978(6) 0.9365(2) 0.2854(2) H2 0.5669 0.5861 0.1681 C1 0.5541(4) 0.7114(2) 0.1116(2) H3 0.4229 0.6230 0.2668 C2 0.5277(4) 0.6452(2) 0.1691(2) H5 0.3697 0.8798 0.1718 NW 0.4422(4) 0.6679(2) 0.2283(2) H6 0.5092 0.8415 0.0711 C4 0.3844(3) 0.7563(2) 0.2316(2) H8 0.1885 0.8062 0.4207 C5 0.4097(4) 0.8209(3) 0.1715(2) H9A 0.0403 0.9524 0.3520 C6 0.4935(4) 0.7983(3) 0.1115(2) H9B -0.0091 0.8743 0.4105 C7 0.2683(5) 0.8647(2) 0.3206(2) H9C 0.0279 0.8470 0.3235 C8 0.1851(4) 0.8680(2) 0.3942(2) H10 0.2454 1.0024 0.4193 C9 0.0484(5) 0.8872(4) 0.3676(4) H11A 0.4082 0.9754 0.5034 SU 0.2364(3) 0.9441(2) 0.4503(2) hub 0.4217 0.8976 0.4377 joint venture 0.3691(3) 0.9189(3) 0.4815(2) H12A 0.4516 0.8321 0.5659 C12 0.3663(3) 0.8414(3) 0.5450(2) H12B 0.3384 0.7822 0.5216 C13 0.2757(3) 0.8687(2) 0.6127(2) H13 0.3070 0.9285 0.6349 C14 0.1436(3) 0.8876(3) 0.5803(2) H14A 0.0869 0.9055 0.6231 C15 0.1489(4) 0.9669(3) 0.5192(2) H14B 0.1103 0.8304 0.5560 C16 0.2826(4) 0.7953(2) 0.6779(2) H15A 0.0636 0.9785 0.4993 C17 0.3809(4) 0.7999(2) 0.7367(2) H15B 0.1784 1.0245 0.5447 C18 0.3907(4) 0.7275(2) 0.7945(2) H19 0.1559 0.6002 0.7422 C19 0.2134(5) 0.6503(3) 0.7400(3) H20 0.1355 0.7148 0.6435 C20 0.2003(4) 0.7200(3) 0.6808(2) H21 0.4730 0.9209 0.7031 C21 0.4745(4) 0.8715(3) 0.7395(2) H23 0.6375 0.8000 0.8914 C22 0.5667(4) 0.8681(3) 0.7955(2) H24 0.4927 0.6791 0.8893 C23 0.5741(5) 0.7981(3) 0.8530(2) H1S1 0.1887 0.4703 1.0460 C24 0.4881(5) 0.7276(3) 0.8521(2) H1S2 0.2642 0.5634 1.0267 CIS 0.2647(6) 0.4955(4) 1.0224(3) H1S3 0.3381 0.4706 1.0492 sis 0.2704(1) 0.4633(1) 0.9229(1) H2N 0.317(4) 0.602(3) 0.831(2)

The ss NMR spectrum of form 1 of the MSA salt of compound 1 is shown in FIG. 4A. The ss NMR spectrum of form 1 of the MSA salt of compound 1 contains the following peaks:

- 13041037 ppm (±0.2) 178.4 168.2 162.1 142.7 140.5 137.3 131.3 129.3 125.7

123.7 122.8 118.7

114.1 43.4 41.8 40.0 35.8 32.0 28.1 25.1 17.5

The FT-IR spectrum of Compound 1 MSA salt Form 1 is shown in FIG. 4b. The FT-IR spectrum of form 1 of the MSC salt of compound 1 contains the following peaks:

The DSC thermogram of form 1 of the MSC salt of compound 1 is shown in FIG. 4C. DSC thermogram of form 1 of the salt of compound 1 formed with methanesulfonic acid indicates that there is a variable endothermic transition at ~245-249°C, corresponding to melting accompanied by decomposition of the substance. Form 1 MSC salt of compound 1 is a crystalline anhydrous substance, the melting and decomposition of which begins at approximately 245-249°C (according to DSC-endotherm).

The Fourier-Raman spectrum of form 1 of the MSA salt of compound 1 is shown in FIG. 4D. Typical Fourier peaks of the Raman spectrum are shown in the following table:

- 14 041037

The TGA thermogram of Compound 1 MSA salt Form 1 is shown in FIG. 4E. The TGA thermogram of form 1 of the MSA salt of compound 1 corresponds to the pure form, essentially free of water and residual solvents.

Amorphous forms of the MSA salt of Compound 1 are also included within the scope of the present invention. The PXRD pattern of the amorphous MSC salt of Compound 1 is shown in FIG. 5. ss NMR spectrum of the amorphous MSA salt of compound 1 is shown in FIG. 5A. The ss NMR spectrum of the amorphous MSA salt of compound 1 contains the following peaks:

rrsh (±0.2)

175.9

161.6

144.0

138.5

135.0

128.4

108.8

40.7

29.4

17.3

The Fourier-Raman spectrum of the amorphous MSA salt of compound 1 is shown in FIG. 5b. Typical peaks are shown in the following table.

- 15 041037

Compound 1 MSA salt Form 1 may be present in substantially pure form, ie about 90% pure or greater based on the weight of the compound as determined by HPLC analysis. For example, Form 1 MSA salt of Compound 1 may be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% pure, or 100% pure. The rest of the material may include other solid forms of compound 1, and/or reactive impurities, and/or process impurities that occur during the preparation of this compound.

Mixtures of Compound 1 MSA salt Form 1 with other solid forms of Compound 1 are also included within the scope of the present invention. In appropriate embodiments, such mixtures may contain less than 90% (by weight of the mixture) of Compound 1 MSA salt form 1. For example, mixtures may contain 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35%, 30%, 25%, 20%, 15%, 10%, or approximately 5% (by weight of the mixture) of compound 1 MSA salt form 1.

The amorphous MSA salt of Compound 1 may be present in substantially pure form, ie about 90% pure or greater based on the weight of the compound as determined by HPLC analysis. For example, an amorphous MSA salt of Compound 1 may be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% pure, or 100% pure. The rest of the material may include other solid forms of compound 1, and/or reactive impurities, and/or process impurities that occur during the preparation of this compound.

Mixtures of the amorphous MSA salt of Compound 1 with other solid forms of Compound 1 are also included within the scope of the present invention. In appropriate embodiments of the invention, such mixtures may contain less than 90% (by weight of the mixture) of the amorphous MSA salt of compound 1. For example, mixtures may contain 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35 , 30, 25, 20, 15, 10, or approximately 5% (by weight of the mixture) of the amorphous MSA salt of Compound 1.

Hydrate of the salt of compound 1 formed with methanesulfonic acid (MSA salts).

According to one embodiment, this invention relates to the solid form of the salt of compound 1 formed with methanesulfonic acid (MSA salts), which is a monohydrate. For example, the solid form of Compound 1 MSA salt monohydrate contains approximately 1 molecule of water per molecule of Compound 1 MSA salt.

According to preferred aspects of the present invention, the solid form of Compound 1 MSA salt monohydrate is the crystalline form of Compound 1 MSA salt monohydrate. Compound 1 MSA salt monohydrate has a desirable stability profile.

According to preferred aspects of the present invention, Compound 1 MSA salt monohydrate is the crystalline form of Compound 1 MSA salt monohydrate, referred to herein as Compound 1 MSA salt monohydrate form 2. Compound 1 MSA salt monohydrate form 2 is physically stable at room temperature and relative air humidity 95% for 5 days.

Form 2 of the MSA salt monohydrate of Compound 1 can be characterized by an X-ray diffraction pattern containing one peak, or at least one peak, the position of which, expressed in degrees 2Θ, is selected from 9.3, 11.8, 14.3, 15.6, 17.7; 20.5; 22.2; in 20 degrees, selected from 9.3, 11.8, 14.3, 15.6,

- 16041037

17.7, 20.5, 22.2, 23.2 and 24.1 degrees 2Θ ±0.2 degrees 2Θ. Form 2 of the MSA salt monohydrate of compound 1 can also be characterized by an X-ray diffraction pattern containing three peaks whose positions, expressed in degrees 2θ, are selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20, 5, 22.2, 23.2 and 24.1 degrees 2Θ ±0.2 degrees 2θ. Form 2 of the MSA salt monohydrate of compound 1 can also be characterized by an X-ray diffraction pattern containing four peaks whose positions, expressed in degrees 2Θ, are selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20, 5, 22.2, 23.2 and 24.1 degrees 2Θ ±0.2 degrees 2Θ. Form 2 of the MSA salt monohydrate of compound 1 can also be characterized by an X-ray diffraction pattern containing five peaks whose positions, expressed in degrees 2Θ, are selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20, 5, 22.2, 23.2 and 24.1 degrees 2Θ ±0.2 degrees 2Θ. Form 2 of the MSA salt monohydrate of compound 1 can also be characterized by an X-ray diffraction pattern containing six peaks whose positions, expressed in degrees 2Θ, are selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20, 5, 22.2, 23.2 and 24.1 degrees 2Θ ±0.2 degrees 2Θ. Form 2 of the MSA salt monohydrate of compound 1 can also be characterized by an X-ray diffraction pattern containing seven peaks whose positions, expressed in degrees 2Θ, are selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20, 5, 22.2, 23.2 and 24.1 degrees 2Θ ±0.2 degrees 2Θ. Form 2 of the MSA salt monohydrate of compound 1 can also be characterized by an X-ray diffraction pattern containing eight peaks whose positions, expressed in degrees 2Θ, are selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20, 5, 22.2, 23.2 and 24.1 degrees 2Θ ±0.2 degrees 2Θ. Form 2 of the MSA salt monohydrate of compound 1 can also be characterized by an X-ray diffraction pattern containing peaks whose positions, expressed in degrees 2Θ, correspond to 9.3, 11.8, 14.3, 15.6, 17.7, 20.5, 22.2, 23.2 and 24.1 degrees 2Θ ±0.2 degrees 2Θ.

The positions of the diffraction peaks of form 2 of the MSA salt monohydrate of compound 1, at room temperature, based on a high quality X-ray diffraction pattern obtained with a rotating capillary diffractometer (Cu Ka), 2Θ-calibrated according to NIST requirements or using other suitable standards, are given in table. 10 and 10A.

Table 10. Characteristic positions of diffraction peaks of Form 2 of MSA salt monohydrate of compound 1 degrees 2θ±0.2 9.3 11.8 14.3 15.6 17.7 20.5 22.2 23.2 24.1 Table 10A . List of peaks of form 2 of MSA salt monohydrate of compound 1 degrees t20±0.2 9.3 9.6

- 17 041037

Form 2 monohydrate MSA-salt of compound 1 may be characterized by an x-ray diffraction pattern containing at least one peak selected from the peaks shown in table. 10A.

Form 2 of the MSA salt monohydrate of Compound 1 can also have an X-ray diffraction pattern substantially the same as that shown in FIG. 6. The structure of the single crystal form 2 of the MSA salt hydrate of compound 1 was successfully determined and had the following parameters: crystal system: rhombic; space group: P212121; unit cell parameters and calculated volume: a = 10.44447(13) A, b = 12.99925(13) A, c = 18.94899(14) A, α = 90°, β = 90°, γ = 90 °, V \u003d 2572.71 (5) A ³ ; molecular weight according to the formula of the compound: 525.02 g mol ^-1 , Z = 4 and the density calculated from it: 1.355 g cm ^-3 . Form 2 of the MSA salt monohydrate of Compound 1 is the mesylate (MSA) salt monohydrate of Compound 1. The XRPD pattern of Form 2 of the MSA salt of Compound 1 indicates that this material consists of a crystalline substance.

The DSC thermogram of Form 2 of the MSA salt monohydrate of Compound 1 is shown in FIG. 6A.

The TGA thermogram of Form 2 of the MSA salt monohydrate of Compound 1 is shown in FIG. 6b.

The TGA thermogram of Form 2 of the MSA salt monohydrate of compound 1 indicates that there is a loss of approximately 3.5% of the mass during heating to a temperature of approximately 100°C. The weight loss corresponds to approximately one mole of water per mole of API.

The DSC thermogram of Compound 1 MSA monohydrate Form 2 indicates the presence of a wide endotherm over a temperature range of approximately 90-150° C., consistent with the dehydration of Compound 1 MSA monohydrate Form 2 observed in the TGA thermogram.

Form 2 of the MSA salt monohydrate of Compound 1 may be present in substantially pure form, ie about 90% pure or greater, based on the weight of the compound, as determined by HPLC analysis. For example, the MSA salt monohydrate form 2 of Compound 1 may be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% pure, or 100% pure. The rest of the material may include other solid forms of compound 1, and/or reactive impurities, and/or process impurities that occur during the preparation of this compound.

Mixtures of Form 2 MSA salt monohydrate of Compound 1 with other solid forms of Compound 1 are also included within the scope of the present invention. In appropriate embodiments, such mixtures may contain less than 90% (by weight of the mixture) of Compound 1 MSA monohydrate form 2. For example, mixtures may contain 85, 80, 75, 70, 65, 60, 55, 50, 45, 40 , 35, 30, 25, 20, 15, 10, or approximately 5% (by weight of the mixture) form 2 of the MSA salt monohydrate of compound 1.

Samples of the crystalline forms described in this application (for example, form 4 free base

Compound 1, Compound 1 free base hydrate form 2, Compound 1 MSA salt form 1, Compound 1 MSA salt monohydrate form 2) can be substantially pure in terms of phase homogeneity, indicating the presence of a dominant amount of one crystalline form; and optionally a minor amount of one or more other crystalline forms. The presence of more than one crystalline form in a sample can be determined using techniques such as powder X-ray diffractometry (PXRD) or solid state nuclear magnetic resonance spectroscopy (ss NMR). For example, the presence of additional peaks in an experimental PXRD pattern compared to a simulated PXRD pattern may indicate the presence of more than one crystal form in a sample. A simulated PXRD diffraction pattern can be calculated from single crystal X-ray diffraction data, see Smith, D.K., A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns, Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963). In a preferred embodiment of the invention, the crystalline form is substantially pure in terms of phase homogeneity, i.e. 10% or less, preferably 5% or less, and more preferably 2% or less of the total peak area in the experimentally obtained PXRD diffraction pattern is occupied by additional peaks that absent from the simulated PXRD pattern. Most preferably, the crystalline form is substantially pure in terms of phase homogeneity and, in its experimental PXRD pattern, 1% or less of the total peak area is occupied by additional peaks that are not present in the simulated PXRD pattern.

Various solid forms described in this application can be identified using various analytical techniques known to the average person skilled in the art. Such techniques include, but are not limited to, solid state nuclear magnetic resonance (ss NMR) spectroscopy, powder x-ray diffraction (PXRD), differential scanning calorimetry (DSC), and/or thermogravimetric analysis (TGA).

One of ordinary skill in the art will appreciate that the resulting x-ray diffraction pattern may contain a measurement error, which depends on the measurement conditions used. In particular, it is well known that the intensities in an X-ray diffraction pattern may vary depending on the measurement conditions used. In addition, it should be understood that the relative intensities may also vary depending on the experimental conditions, and, accordingly, the exact order of intensity should not be taken into account. In addition, the measurement error of the diffraction angle in a standard X-ray diffraction pattern is usually approximately ±0.2 degrees 2θ, and such a value of the measurement error should be taken into account with respect to the aforementioned diffraction angles. Therefore, it is to be understood that the crystalline forms of the present invention are not limited to crystalline forms that have X-ray diffraction patterns. completely identical to the X-ray diffraction patterns shown in the figures attached to this description. Any crystalline forms that have X-ray diffraction patterns substantially identical to the X-ray diffraction patterns shown in the accompanying figures are included within the scope of the present invention. The average person skilled in the art is able to appreciate the significant identity of the x-ray diffraction patterns.

Solid forms of compound 1 (and solid forms of its hydrates and salt forms) described in this application can be obtained in the form of pharmaceutical compositions and/or can be used in therapeutic and/or prophylactic methods. These procedures include, without limitation, administration of Compound 1 solid forms, Compound 1 hydrate solid forms (including Compound 1 monohydrate administration), Compound 1 MSA salt solid forms, and Compound 1 MSA salt solid hydrate forms, alone or in combination with one or more than one other pharmaceutically active agent, including agents that can be used in the treatment of the disorders described in this application.

Therapeutic use

Compounds and pharmaceutical compositions according to the present invention can be used to treat or prevent any diseases or pathological conditions that are sensitive to the enzymatic activity of IDO. These diseases and conditions include viral and other infections (eg, skin infections, GI infections, urinary tract infections, urinary tract infections, systemic infections), proliferative diseases (eg, cancer), and autoimmune diseases (eg, rheumatoid arthritis, lupus vulgaris). The compounds and pharmaceutical compositions of the invention may be administered to animals, preferably mammals (eg pets, cats, dogs, mice, rats) and more preferably humans. Any route of administration may be used to deliver a compound or pharmaceutical composition to a patient. According to some embodiments of the present invention, the compound or pharmaceutical composition is administered orally. According to other embodiments of the present invention, the compound or pharmaceutical composition is administered parenterally.

- 19 041037

The compounds of the present invention can modulate the activity of the indolamine-2,3-dioxygenase (IDO) enzyme. The term modulate is intended to refer to the ability to increase or decrease the activity of an enzyme or receptor. Accordingly, the compounds of the invention may be used in methods for modulating IDO, comprising contacting the enzyme with any one or more than one compound or any one or more compositions described herein. In some embodiments, the compounds of the present invention may act as IDO inhibitors. In other embodiments, compounds of the invention may be used to modulate IDO activity in a cell or in an individual in need of modulation of the enzyme by administering a modulating (eg, inhibitory) amount of a compound of the invention.

Compound 1 can inhibit the activity of the enzyme indolamine-2,3-dioxygenase (IDO). For example, Compound 1 can be used to inhibit IDO activity in a cell or in an individual in need of modulation of the enzyme by administering an inhibitory amount of Compound 1.

Additionally, the present invention provides methods for inhibiting tryptophan degradation in a system containing cells expressing IDO, such as a tissue, living organism, or cell culture. In some embodiments, the present invention provides methods for altering (eg, increasing) the level of extracellular tryptophan in a mammal by administering an effective amount of Compound 1 in the form of a composition of the invention. There are standard techniques in the art for measuring tryptophan levels and tryptophan degradation.

Additionally, the present invention provides methods for inhibiting immunosuppression, such as IDO-mediated immunosuppression, in a patient by administering to the patient an effective amount of compound 1, such as described herein. IDO-mediated immunosuppression is associated, for example, with various types of cancer, tumor growth, metastasis, viral infection and viral replication.

Additionally, the present invention provides methods for treating diseases associated with activity or expression, including abnormal activity and/or overexpression, IDO, in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a solid form of the compound 1 (or its hydrate or salt) according to the present invention or a pharmaceutical composition containing this compound. Examples of diseases may include any disease, disorder or pathological condition that is directly or indirectly associated with the expression or activity of the IDO enzyme, such as increased expression or abnormal activity. An IDO-associated disease may also include any disease, disorder, or condition that can be prevented, ameliorated, or treated by modulating enzyme activity. Examples of IDO-associated diseases include cancer, viral infection such as HIV infection, hepatitis C virus (HCV) infection, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataract, organ transplant consequences (e.g. transplant rejection). organ) and autoimmune diseases, including asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus.

It is understood that in the context of this description, the term cell refers to a cell that is in vitro, ex vivo or in vivo. In some ex vivo embodiments of the present invention, the cell may be part of a tissue sample extracted from an organism, such as a mammal. According to some variants of implementation of the present invention in vitro, the cell may be a cell in cell culture. In some in vivo embodiments of the present invention, the cell is a living cell of an organism, such as a mammal.

In the context of this description, the term contacting refers to the association of these groups in an in vitro system or in vivo system. For example, contacting an IDO enzyme with a compound of the invention includes administering a compound of the present invention to an individual or patient, such as a human having IDO, as well as, for example, administering a solid form of Compound 1 of the invention to a sample containing a cell or purified preparation containing the IDO enzyme. .

The term IDO inhibitor refers to an agent capable of inhibiting indolamine-2,3-dioxygenase (IDO) activity and thereby attenuating IDO-mediated immunosuppression. An IDO inhibitor can inhibit IDO1 and/or IDO2 (INDOL1). The IDO inhibitor may be a reversible or irreversible IDO inhibitor. A reversible IDO inhibitor is a compound that reversibly inhibits the activity of an IDO enzyme at a catalytic site or a non-catalytic site, and an irreversible IDO inhibitor is a compound that irreversibly impairs the activity

- 20 041037 IDO enzyme.

The types of cancer that can be treated using the solid forms and compositions of the present invention include, without limitation, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, stomach cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers. Examples of such types of cancers include neuroblastoma, intestinal carcinoma such as rectal carcinoma, colon carcinoma, familial adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, laryngeal carcinoma, subpharyngeal carcinoma, tongue carcinoma, salivary carcinoma carcinoma of the stomach, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, renal parenchymal carcinoma, ovarian carcinoma, cervical carcinoma, carcinoma of the corpus uteri, endometrial carcinoma, chorionic carcinoma, pancreatic carcinoma, prostate carcinoma, testicular carcinoma , breast carcinoma, urinary organ carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphatic l leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia/lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, biliary carcinoma bladder, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma.

Accordingly, in other embodiments, the present invention provides a method for treating an autoimmune disease comprising administering to a patient in need of such treatment a solid form of a compound or composition of the present invention. Examples of such autoimmune diseases include, without limitation, collagen diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sharp's syndrome, CREST syndrome (calcification, Raynaud's syndrome, esophageal dysmotility, telangiectasia), dermatomyositis, vasculitis (Wegener's disease), and Sjögren's syndrome. , kidney diseases such as Goodpasture's syndrome, rapidly progressive glomerulonephritis and type II membranous proliferative glomerulonephritis, endocrine diseases such as type I diabetes, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoimmune parathyroidism (parathyroidism), pernicious anemia, gonadal insufficiency , idiopathic Addison's disease, hyperthyroidism, Hashimoto's thyroiditis and primary myxedema, skin diseases such as pemphigus vulgaris, bullous pemphigoid, herpes pregnant, epidermolysis bullosa and severe erythema multiforme, liver diseases such as biliary primary cirrhosis, autoimmune chronic cholangitis, autoimmune hepatitis type 1, autoimmune hepatitis type 2, primary sclerosing cholangitis, neuronal diseases such as multiple sclerosis, myasthenia gravis, myasthenic Eaton-Lambert syndrome, acquired neuromyotomy, Guillain-Barre syndrome (Miller Fisher syndrome), stiff man syndrome , cerebellar degeneration, ataxia, opsoclonus, sensory neuropathy and achalasia, blood diseases such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (Werlhof's disease), infectious diseases with associated autoimmune reactions such as AIDS, malaria and Chagas disease.

One or more additional pharmaceutical agents or treatments such as, for example, an antiviral agent, a chemotherapeutic or other anticancer agent, an immunostimulant, an immunosuppressant, ionizing radiation, antitumor and antiviral vaccines, cytokine therapy (for example, IL2 and GM-CSF), and /or a tyrosine kinase inhibitor may optionally be used in combination with the compounds of the present invention for the treatment of IDO-associated diseases, disorders or conditions. These agents may be used in combination with the compounds of the present invention in a single dosage form, or the agents may be administered simultaneously or sequentially in separate dosage forms.

Suitable chemotherapeutic or other anticancer agents include, for example, alkylating agents (including but not limited to nitrogen mustards, ethyleneimine derivatives, alkylsulfonates, nitrosoureas, and triazenes) such as uramustine, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobromane , triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Agents suitable for use in combination with the compounds of the present invention in the treatment of melanoma include dacarbazine (DTIC), optionally together with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the Dartmouth regimen, which consists of DTIC, BCNU, cisplatin, and tamoxifen; a combination of cisplatin, vinblastine and DTIC, mozolomide, or YERVOY®. The compounds of the invention may also be used in combination with immunotherapeutic drugs in the treatment of melanoma, including cytokines such as interferon alpha, interleukin 2 and tumor necrosis factor (TNF).

The compounds of the invention can also be used in combination with vaccine therapy in the treatment of melanoma. Melanoma vaccines are somewhat similar to antiviral vaccines, which are used to prevent diseases caused by viruses such as polio, measles, and mumps. Weakened melanoma cells or parts of melanoma cells called antigens can be injected into a patient to stimulate the body's immune system to kill the melanoma cells.

For the treatment of melanomas localized to the arms and legs, a combination of agents including one or more compounds of the invention may also be used in combination with an isolated hyperthermic limb perfusion technique. According to this treatment protocol, the blood circulation of the manipulated limb is temporarily separated from the blood circulation system in the rest of the body and high doses of chemotherapeutic drugs are injected into the artery that feeds this limb, thus ensuring the delivery of high doses to the site occupied by the tumor, and not exposing the internal organs to the action these doses, which otherwise could cause severe side effects. Typically, the liquid is heated to 102-104°F (38.9-40.0°C). Melphalan is the drug most commonly used in this chemotherapeutic modality. Another agent called tumor necrosis factor (TNF) can also be used.

Suitable chemotherapeutic or other anticancer agents include, for example, antimetabolites (including, but not limited to, folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine , fludarabine phosphate, pentostatin and gemcitabine.

Suitable chemotherapeutic or other anticancer agents further include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, anticancer antibiotics, enzymes, lymphokines, and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, araC, paclitaxel (Taxol), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrozole, letrazole, capecitabine, reloxafine, and droloxafine.

Suitable cytotoxic agents are also cytotoxic agents such as epidophyllotoxin (epidophyllotoxin); an antitumor enzyme; topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur and hematopoietic growth factors.

Other anticancer agents include therapeutic antibodies such as trastuzumab (HERCEPTIN®), antibodies against costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies against cytokines (IL-1O or TGF-β).

Other anticancer agents also include anticancer agents that block immune cell migration, such as chemokine receptor antagonists, including CCR2 and CCR4.

Other anti-cancer agents also include anti-cancer agents that enhance the immune system, such as adjuvants or adaptive T-lymphocyte transfer agents.

Cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

Pharmaceutical compositions according to the invention may optionally include at least one signal transduction inhibitor (STI). A signal transduction inhibitor is an agent that selectively inhibits one or more steps in signaling pathways critical to the normal functioning of cancer cells and thereby induces their apoptosis. Suitable STIs include, without limitation: (i) bcr/abl kinase inhibitors such as, for example, STI 571 (GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (IRESSA®, SSI-774) and antibodies (Imclone: C225 [Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)] and Abgenix: ABX-EGF); (iii) her-2/neu receptor inhibitors such as farnesyl transferase inhibitors (FTIs) such as, for example, L-744832 (Kohl et al., Nat. Med., 1(8):792-797 (1995)) ; (iv) inhibitors of the Akt family of kinases or the Akt pathway, such as, for example, rapamycin (see, for example, Sekulic et al., Cancer Res., 60:3504-3513 (2000)); (v) cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-O1 (see, for example, Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (2003)); and (vi) phosphatidylinositol kinase inhibitors such as, for example, LY294002 (see, for example, Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994)). Alternatively, at least one STI and at least one IDO inhibitor may be in separate pharmaceutical compositions. According to a specific embodiment of the present invention, at least one IDO-22 041037 inhibitor (such as compound 1, or a solid form thereof, or a solid form of a hydrate or salt of this compound) and at least one STI may be administered to a patient simultaneously or sequentially. In other words, at least one IDO inhibitor may be administered first, at least one STI may be administered first, or at least one IDO inhibitor and at least one STI may be administered simultaneously. In addition, when more than one IDO inhibitor and/or STI is used, these compounds may be administered in any order.

The present invention further provides a pharmaceutical composition for the treatment of a chronic viral infection in a patient, comprising at least one IDO inhibitor (such as compound 1 or a solid form of a hydrate or salt of this compound), optionally at least one chemotherapeutic drug, and optionally at least one antiviral agent, in a pharmaceutically acceptable carrier. Pharmaceutical compositions may include at least one IDO inhibitor according to the present invention in addition to at least one known IDO inhibitor. According to a specific embodiment of the present invention, at least one of these IDO inhibitors of the pharmaceutical composition is Compound 1, or a solid form thereof, or a solid form of a hydrate or salt of this compound).

Also provided is a method for treating a chronic viral infection in a patient by administering an effective amount of the above pharmaceutical composition.

According to a specific embodiment of the present invention, at least one IDO inhibitor and at least one chemotherapeutic agent may be administered to a patient simultaneously or sequentially. In other words, at least one IDO inhibitor may be administered first, at least one chemotherapeutic agent may be administered first, or at least one IDO inhibitor and at least one STI may be administered simultaneously. In addition, when more than one IDO inhibitor and/or chemotherapeutic agent is used, these compounds may be administered in any order. Likewise, any antiviral agent or STI may also be administered at any time relative to the administration of the IDO inhibitor.

Chronic viral infections that may be treated with the combination therapy of the present invention include, but are not limited to, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella-zoster virus, Coxsackie virus, human immunodeficiency virus (HIV). Notably, for the treatment of parasitic infections (eg malaria) the aforementioned methods can also be used, in which already known compounds suitable for the treatment of parasitic infections are optionally used instead of antiviral agents.

According to another embodiment of the invention, pharmaceutical compositions containing at least one IDO inhibitor according to the present invention can be administered to a patient to prevent arterial restenosis occurring, for example, after balloon endoscopy or stenting. According to a specific embodiment of the present invention, the pharmaceutical composition further comprises at least one taxane (eg, paclitaxel (Taxol); see, for example, Scheller et al., Circulation, 110:810-814 (2004)).

Suitable antiviral agents considered candidates for use in combination with the solid forms of the present invention may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs.

Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [6c(POM)-PMEA]; lobukavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and called beta-b-2',3'-dicleoxy-5-fluoro-cytidene); DAPD, ((-)-beta-O-2,6-diamino-purine dioxolane) and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MkC-442 (1-(ethoxy-methyl)-5-(1methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione) and (+)-calanolide A (NSC-675451) and B Typical suitable protease inhibitors include saquinavir (Ro 31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfinavir (AG-1343), amprenavir (141W94), lasinavir (lasinavir) (BMS-234475); DMP-450, BMS-232623, ABT-378 and AG-1549 Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project #11607.

Combinations with an immuno-oncological agent.

The present invention further provides methods of treatment in which the solid form of Compound 1, or the solid form of a hydrate or salt of Compound 1, is administered together with one or more immuno-oncological agents. The immuno-oncological agents used in these methods, also known as immunotherapeutic anti-cancer agents, are effective in enhancing, stimulating and/or upregulating the immune response in a subject.

According to one aspect of the present invention, sequential administration means that the solid form of Compound 1, or the solid form of the hydrate or salt of Compound 1, is administered prior to administration.

- 23 041037 immuno-oncological agent. According to another aspect of the present invention, the solid form of Compound 1, or the solid form of a hydrate or salt of Compound 1, is administered simultaneously with the immuno-oncological agent. According to another aspect of the present invention, sequential administration implies that the solid form of Compound 1, or the solid form of a hydrate or salt of Compound 1, is administered after administration of the immuno-oncological agent.

According to another aspect of the present invention, the solid form of Compound 1, or the solid form of a hydrate or salt of Compound 1, may be presented as a formulation further containing an immuno-oncological agent.

Immuno-oncological agents include, for example, small molecule drugs, antibodies, or other biological or small molecules. Examples of biological immuno-oncological agents include, without limitation, cancer vaccines, antibodies, and cytokines. According to one aspect of the present invention, the antibody is a monoclonal antibody. According to another aspect of the present invention, the monoclonal antibody is a humanized antibody or a human antibody.

According to one aspect of the present invention, the immuno-oncological agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal to T cells, both of which (often referred to as immune checkpoint regulators) cause an increase in antigen-specific T-cell responses.

Several stimulatory and inhibitory molecules belong to the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, including B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 ( ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA) and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to related receptors belonging to the TNF receptor family including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI , APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α/TNFe, TNFR2, TNa, LTeR, lymphotoxin α 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

According to another aspect of the present invention, the immuno-oncological agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-P, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate immune response.

According to one aspect of the present invention, T cell responses can be stimulated by the combination of a solid form of compound 1, or a solid form of a hydrate or salt of compound 1, and one or more agents selected from (i) a protein antagonist that inhibits T cell activation (e.g. immune checkpoint inhibitor) such as CTLA-4, PD-1, PD-L1, PD-L2, AG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1 and TIM-4, and (ii) a protein agonist that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

Other agents that can be used in combination with the solid form of compound 1, or the solid form of the hydrate or salt of compound 1, for the treatment of cancer include inhibitory receptor antagonists located on NK cells (natural killer cells), or activating receptor agonists, located on NK cells. For example, a solid form of compound 1, or a solid form of a hydrate or salt of compound 1, can be used in combination with KIR (immunoglobulin-like killer cell receptor) antagonists such as lirilumab.

Other combination therapy agents include agents that inhibit or deplete macrophages or monocytes, including (but not limited to) CSF-1R receptor (colony stimulating factor receptor) antagonists such as anti-CSF-1R receptor antagonist antibodies, including RG7155 (WO 11/70024 , WO 11/107553, WO 11/131407, WO 13/87699, WO 13/119716, WO 13/132044) or FPA-008 (WO 11/140249, WO 13/169264, WO 14/036357).

According to another aspect of the present invention, the solid form of Compound 1, or the solid form of a hydrate or salt of Compound 1, may be used in conjunction with one or more of agonistic agents that bind positive co-stimulatory receptors, blocking agents that impair signal transduction through inhibitory receptors, antagonists and with one or more agents that systemically increase the incidence of anti-cancer T cells, an agent that bypasses various immunosuppressive pathways in the tumor microenvironment (eg, blocks inhibitory receptor recruitment (eg, PD-L1/PD-1 interactions), depletes or inhibits Tregs (regulatory T cells) (for example, anti-CD25 monoclonal antibody (eg daclizumab) or depletion using microbead-bound antibodies against ex vivo CD25-positive cells can be used here), inhibits metabolic enzymes such as IDO, or eliminates/prevents anergy and depletion of T-cells), and an agent that triggers the activation of the innate immune response and/or inflammation at the site of the tumor.

According to one aspect of the present invention, the immuno-oncological agent is a CTLA-4 receptor antagonist, such as an anti-CTLA-4 antagonist antibody. Suitable anti-CTLA-4 antibodies include, for example, YERVOY® (ipilimumab) or tremelimumab.

According to another aspect of the present invention, the immuno-oncological agent is a PD-1 (Programmed Cell Death Protein 1) antagonist, such as an anti-PD-1 antagonist antibody. Suitable anti-PD-1 antibodies include, for example, OPDIVO® (nivolumab), KEYTRUDA® (pembrolizumab) or MEDI-0680 (AMP-514; WO 2012/145493). These immuno-oncological agents may also include pidilizumab (CT-011), although the specificity of its binding to PD-1 is questionable. Another approach to target the PD-1 receptor is to use the recombinant AMP-224 protein, which consists of the extracellular domain of the PD-L2 protein (B7-DC) fused to an IgG1 Fc fragment.

According to another aspect of the present invention, the immuno-oncological agent is a PD-L1 protein antagonist, such as an anti-PD-L1 antagonist antibody. Suitable anti-PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO 2010/077634), durvalumab (MEDI4736), BMS-936559 (WO 2007/005874) and MSB0010718C (WO 2013/79174).

According to another aspect of the present invention, the immuno-oncological agent is a LAG-3 (lymphocyte activation gene 3) protein antagonist, such as an anti-LAG-3 antagonist antibody. Suitable anti-LAG3 antibodies include, for example, BMS-986016 (WO 10/19570, WO 14/08218) or IMP-731 or IMP-321 (WO 08/132601, WO 09/44273).

According to another aspect of the present invention, the immuno-oncological agent is a CD137 receptor (4-1BB) agonist, such as an anti-CD137 agonist antibody. Suitable anti-CD137 antibodies include, for example, urelumab and PF-05082566 (WO 12/32433).

According to another aspect of the present invention, the immuno-oncological agent is a GITR (glucocorticoid-inducible receptor superfamily of tumor necrosis factor receptor) receptor agonist, such as an anti-GITR agonist antibody. Suitable anti-GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO 06/105021, WO 09/009116) and MK-4166 (WO 11/028683).

According to another aspect of the present invention, the immuno-oncological agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO 2006/122150, WO 07/75598, WO 08/36653, WO 08/36642), indoxymod or NLG-919 (WO 09/73620, WO 09/1156652, WO 11 /56652, WO 12/142237).

According to another aspect of the present invention, the immuno-oncological agent is an OX40 receptor agonist, such as an anti-OX40 agonist antibody. Suitable anti-OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

According to another aspect of the present invention, the immuno-oncological agent is an OX40L ligand antagonist, such as an anti-OX40 antagonist antibody. Suitable OX40L ligand antagonists include, for example, RG-7888 (WO 06/029879).

According to another aspect of the present invention, the immuno-oncological agent is a CD40 receptor agonist, such as an anti-CD40 agonist antibody. According to another embodiment of the present invention, the immuno-oncological agent is a CD40 receptor antagonist, such as an anti-CD40 antagonist antibody. Suitable anti-CD40 antibodies include, for example, lucatumumab or dacetuzumab.

According to another aspect of the present invention, the immuno-oncological agent is a CD27 receptor agonist, such as an anti-CD27 agonist antibody. Suitable anti-CD27 antibodies include, for example, varlilumab.

According to another aspect of the present invention, the immuno-oncological agent is MGA271 (to B7H3) (WO 11/109400).

The present invention also relates to pharmaceutical kits that can be used, for example, for the treatment or prevention of IDO-associated diseases or disorders, obesity, diabetes and other diseases mentioned in this description, comprising one or more than one container containing a pharmaceutical composition containing a therapeutically effective amount of a compound of the invention. Such kits may further include, if desired, one or more of the various standard pharmaceutical components used in the kits, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as is obvious to those skilled in the art. . The kit may also include instructions, in the form of inserts or labels, stating the amounts of components to be administered, recommendations for administration, and/or recommendations for mixing the components.

Combination therapy is contemplated to include the sequential administration of these therapeutic agents, that is, the administration of the therapeutic agents at different times, as well as the substantially simultaneous administration of these therapeutic agents, or at least two of the therapeutic agents. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form for single administration containing therapeutic agents in a fixed proportion, or multiple dosage forms for single administration, each containing one therapeutic agent. Sequential or substantially simultaneous administration of therapeutic agents may be by any suitable route, including, without limitation, oral routes of administration, intravenous routes of administration, intramuscular routes of administration, and direct absorption through mucosal tissues. Therapeutic agents may be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination may be administered by intravenous injection, while other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. Combination therapy may also include the administration of the therapeutic agents described above in another combination with other biologically active ingredients and non-drug treatments (eg, surgery or radiation therapy). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be administered at any suitable time until a beneficial effect is achieved from the combination of therapeutic agents and the non-drug treatment. For example, in appropriate cases, a positive result may persist for several days or even weeks, when non-drug treatment is temporarily excluded and only the administration of therapeutic agents remains.

Pharmaceutical compositions and dosages

The present invention also provides pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more of the solid forms described herein, together with one or more pharmaceutically acceptable carriers (auxiliaries) and/or diluents, and optionally , with one or more additional therapeutic agents.

The solid forms of the invention, in any of the uses described herein, may be administered in any suitable manner, such as orally, i.e., in the form of tablets, capsules (each of which includes sustained release or extended release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, dispersions obtained using spray drying), syrups and emulsions; sublingual; buccal; parenterally, eg, using subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (eg, as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal mucosa, for example using an inhalation spray; topically, for example in the form of a cream or ointment; or rectally, for example in the form of suppositories. These solid forms may be administered as such, but are usually administered together with a pharmaceutical carrier selected in consideration of the route of administration employed and standard pharmaceutical practice.

The phrase "pharmaceutically acceptable" as used herein refers to compounds, substances, compositions and/or dosage forms that, on the basis of medical evaluation, are suitable for use in contact with human and animal tissues, i.e., do not exhibit excessive toxicity, irritation, allergic reaction, or other disorders or complications commensurate with an acceptable benefit/risk ratio.

The phrase pharmaceutically acceptable carrier in the context of this description means a pharmaceutically acceptable substance, composition or base, such as a liquid or solid filler, diluent, excipient, auxiliary agent used in the manufacturing process of a drug (for example, a lubricant, talc, magnesium, calcium or zinc stearate or stearic acid) or a solvent encapsulating agent involved in the transfer or transport of a compound of the invention from one organ or body part to another organ or body part. Each carrier must be acceptable, i.e. compatible with the other ingredients of the formulation and harmless to the patient.

The term pharmaceutical composition means a composition containing a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. The phrase pharmaceutically acceptable carrier refers to a medium commonly used in the art for the delivery of biologically active agents to animals, in particular mammals, i.e., including an adjuvant, excipient or vehicle such as diluents, preservatives, excipients, agents that regulate flowability, leavening agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, flavoring agents

- 26 041037 agents, antibacterial agents, antifungal agents, lubricating agents and spreading agents, depending on the nature of the route of administration and dosage forms.

Pharmaceutically acceptable carriers are included in the preparation, taking into account a number of factors related to the competence of those of ordinary skill in the art. These factors include, without limitation, the type and nature of the active agent being formulated; characteristics of the subject to whom the agent-containing composition will be administered; the intended route of administration of the composition and the intended therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may include several different ingredients and excipients in addition to the active agent, such additional ingredients included in the formulation for a variety of reasons, such as stabilization of the active agent, binders, etc., are well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers and factors influencing their choice can be found in many readily available sources such as, for example, Allen, Jr., L.V. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

The mode of administration of solid forms according to the present invention, of course, will vary depending on such known factors as the pharmacodynamic characteristics of a particular agent and the method and route of its administration; biological species to which the recipient belongs, his age, sex, health, medical condition and body weight; nature and severity of symptoms; type of concurrent treatment; frequency of repetition of treatment; the route of administration, the functional parameters of the patient's kidneys and liver, and the desired effect.

As a general guide, the daily oral dose of each active ingredient required to achieve a therapeutic effect is usually in the range of from about 0.001 to about 5000 mg per day, preferably from about 0.01 to about 1000 mg per day, and most preferably from about 0 ,1 to approximately 250 mg per day. When administered intravenously, the most preferred doses are from about 0.01 to about 10 mg/kg/min at a constant infusion rate. The compounds of the present invention may be administered once a day as a single dose, or the total daily dose may be administered in divided doses of two, three or four divided doses.

The solid forms of the present invention are usually administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) selected according to the intended form of administration, which is, for example, oral tablets, capsules, elixirs, syrups. and the like, and in accordance with standard pharmaceutical practice.

Suitable dosage forms (pharmaceutical compositions) for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage form. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.1-95% (by weight) of the total weight of the composition.

A typical oral capsule contains at least one of the compounds of the present invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). This mixture is passed through a 60 mesh sieve and filled into a No. 1 gelatin capsule.

A typical injectable preparation is prepared by aseptically placing at least one of the compounds of the present invention (250 mg) into a test tube, followed by lyophilization and aseptic sealing. Before use, the contents of this tube are mixed with 2 ml of saline to obtain an injectable preparation.

Included within the scope of the present invention are pharmaceutical compositions containing as active ingredient at least one of the compounds of the present invention, in a therapeutically effective amount, alone or in combination with a pharmaceutical carrier. Optionally, the solid forms of the present invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents, such as an anti-cancer agent or other pharmaceutically active agent.

Regardless of the route of administration chosen, the solid forms of the present invention are prepared into pharmaceutically acceptable dosage forms using standard techniques known to those skilled in the art.

Actual dosage levels of active ingredients in the pharmaceutical compositions of the present invention may vary in order to obtain an amount of active ingredient that will be effective in achieving the desired therapeutic response in a particular patient, and depending on the composition and route of administration, but in any case not must be toxic to the patient.

The selected dosage level will generally depend on a number of factors, including the potency of the compound of the present invention used, the route of administration, the time of administration, the rate of excretion, or

- 27 041037 metabolism of the compound, rate and degree of absorption, duration of treatment, other drugs, compounds and/or substances used in combination with the compound according to the invention, age, sex, body weight, pathological condition, general health and medical history of the patient who treat, and other similar factors known in the medical field.

A physician or veterinarian of average skill in the art can readily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian might start by prescribing a lower dose level of the compounds of the invention used in a pharmaceutical composition than that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

In general, a suitable daily dose of a compound is that amount of the compound which is the lowest dose that will produce a therapeutic effect. The level of such an effective dose usually depends on the factors described above.

If desired, an effective daily dose of a compound may be administered as two, three, four, five, six or more sub-doses administered separately throughout the day at appropriate time intervals, optionally in unit dosage forms. According to some aspects of the present invention, the entire daily dose is administered at one time.

Although the compound of the present invention can be administered as such, it is still preferable to administer the compound as a pharmaceutical preparation (composition).

Definitions

Some aspects of the present invention relate to crystalline forms. The crystalline forms are characterized by an X-ray diffraction pattern with sharp maxima.

In the context of this description, amorphous refers to the solid form of the molecule and/or ions, which is not crystalline. The x-ray diffraction pattern of the amorphous solid lacks sharp peaks.

In the context of this description, the term hydrate refers to the crystalline form of the molecule, which additionally contains water molecules included in the crystalline structure. The water molecules in the hydrate may have an ordered arrangement and/or a disordered arrangement. The hydrate may contain a stoichiometric or non-stoichiometric amount of water molecules.

In the context of this description, the term patient refers to organisms in need of treatment using the methods according to the present invention. Such organisms preferably include (but are not limited to) mammals (eg, mice, monkeys, horses, cattle, pigs, dogs, cats, and the like), and most preferably humans.

In the context of this description, the term effective amount means that amount of a drug or pharmaceutical agent, i.e., a compound of the invention, that elicits a biological or therapeutic response in a tissue, system, animal, or human that is sought, for example, by a researcher or medical practitioner. In addition, the term therapeutically effective amount means any amount which, when compared with a corresponding subject who has not received such an amount, results in an improvement in the treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or in a reduction in the rate of progression of a disease or disorder. . An effective amount may be administered over one or more administrations, applications, or as one or more doses, and is not intended to be limited to a particular formulation or route of administration. The term also includes amounts effective in the sense of enhancing normal physiological function.

As used herein, the terms treat or treat refer to the treatment of a disease state in a mammal, especially a human, and include: (a) preventing the onset of the disease state in the mammal, in particular where such mammal is predisposed to developing the disease state but the diagnosis has not yet been made. delivered; (b) easing the disease state, ie stopping its development, and/or (c) alleviating the disease state, ie regressing the disease state.

Aspects of the invention

Aspect 1. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4.

Aspect 2. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, Form 4 according to Aspect 1, characterized by powder x-ray a diffraction pattern containing at least one peak whose position, expressed in degrees 2θ, is selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0 degrees 2θ ±0.2 degrees 2θ.

Aspect 3. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4 according to Aspect 1, characterized by powder X-ray diffraction pattern containing two peaks whose positions, expressed in degrees 2θ, are selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ ± 0.2 degrees 2θ.

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Aspect 4. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4 according to Aspect 1, characterized by X-ray powder diffraction pattern containing three peaks, the positions of which, expressed in degrees 2θ, are selected from 7.6, 12.0,

13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ ±0.2 degrees 2θ.

Aspect 5. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4 according to Aspect 1, characterized by powder X-ray diffraction pattern containing four peaks whose positions, expressed in degrees 2θ, are selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ ± 0.2 degrees 2θ.

Aspect 6 Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate Form 2.

Aspect 7. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate, form 2 according to aspect 6, characterized by powder x-ray diffraction pattern containing at least one peak, the position of which, expressed in degrees 2θ, is selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1 and 21.6 degrees 2θ ± 0.2 degrees 2θ.

Aspect 8. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate, form 2 according to aspect 6, characterized by powder x-ray diffraction pattern containing two peaks whose positions, expressed in degrees 2θ, are selected from 9.4, 12.4, 17.2, 17.6,20.1,21.1 and 21.6 degrees 2θ ±0.2 degrees 2θ.

Aspect 9. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate, form 2 according to aspect 6, characterized by powder x-ray diffraction pattern containing three peaks whose positions, expressed in degrees 2θ, are selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1 and 21.6 degrees 2θ ±0.2 degrees 2θ.

Aspect 10. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate, form 2, according to aspect 6, characterized by powder x-ray diffraction pattern containing four peaks whose positions, expressed in degrees 2θ, are selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1 and 21.6 degrees 2θ ±0.2 degrees 2θ.

Aspect 11. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)methanesulfonic acid propanamide Form 1.

Aspect 12. Crystalline methanesulfonic acid (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 1 according to Aspect 11, characterized by powder x-ray diffraction pattern containing at least one peak, the position of which, expressed in degrees 2θ, is selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6 and 24 .0 degrees 2θ ±0.2 degrees 2θ.

Aspect 13. Crystalline methanesulfonic acid (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 1 according to Aspect 11, characterized by powder x-ray diffraction pattern containing two peaks whose positions, expressed in degrees 2θ, are selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6 and 24.0 degrees 2θ ±0.2 degrees 2θ.

Aspect 14. Methanesulfonic acid crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 1 according to Aspect 11, characterized by powder x-ray diffraction pattern containing three peaks whose positions, expressed in degrees 2θ, are selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6 and 24.0 degrees 2θ ±0.2 degrees 2θ.

Aspect 15. Crystalline methanesulfonic acid (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 1 according to Aspect 11, characterized by powder x-ray diffraction pattern containing four peaks whose positions, expressed in degrees 2θ, are selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6 and 24.0 degrees 2θ ±0.2 degrees 2θ.

Aspect 16 Amorphous methanesulfonic acid (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide.

Aspect 17. Pharmaceutical composition containing crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, form 4, crystalline (R )-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate Form 2 or crystalline (R)-N-(4-chlorophenyl )-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)methanesulfonic acid propanamide Form 1, or a combination thereof, and a pharmaceutically acceptable carrier.

Aspect 18. The pharmaceutical composition according to aspect 17, further comprising amorphous (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, amorphous ( R)-N(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)methanesulfonic acid propanamide or a combination thereof.

Aspect 19 The pharmaceutical composition of Aspect 17 further comprising amorphous (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide.

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Aspect 20. A method of treating cancer in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of crystalline (R)-N-(4-chlorophenyl)-2((1S,4S)-4-(6-fluoroquinoline-4- yl)cyclohexyl)propanamide, form 4, crystalline (R)-N-(4chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate, form 2, or crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid Form 1, or combinations thereof.

Aspect 21. The method according to aspect 20, wherein the cancer is prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck , skin (including melanoma and basal carcinoma), mesothelial lining, white blood cells (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, lung (including small cell lung and non-small cell carcinoma), adrenal, thyroid, kidney or bones; or is glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, cutaneous basal cell carcinoma, or seminoma of the testis.

Aspect 22 The method of Aspect 20 further comprising administering amorphous (R)-N-(4chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, amorphous (R) -N-(4-chlorophenyl)2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid; or combinations thereof.

Aspect 23 The method of aspect 20 further comprising administering an immune checkpoint inhibitor.

Aspect 24. The method of aspect 20 wherein the immune checkpoint inhibitor is ipilimumab (YERVOY™), nivolumab (OPDIVO™), pembrolizumab (KEYTRUDA™), or a combination thereof.

Aspect 25. A method for modulating indolamine-2,3-dioxygenase activity, comprising contacting indolamine-2,3-dioxygenase with crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6fluoroquinoline -4-yl)cyclohexyl)propanamide, form 4, crystalline (R)-N-(4-chlorophenyl)-2((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate, form 2, or crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide of methanesulfonic acid, form 1;

or their combination;

optionally in combination with amorphous (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4yl)cyclohexyl)propanamide, amorphous (R)-N-(4-chlorophenyl methanesulfonic acid )-2-((1S,4S)-4-(6-fluoroquinolin-4yl)cyclohexyl)propanamide, or a combination thereof.

Examples

The following examples are provided to provide those of ordinary skill in the art with a complete description of the invention and a description of how to make and use the present invention, and are intended not to limit the scope of what the inventors consider to be their invention, but are also intended to that the examples do not mean that the experiments described below were performed or that the examples describe all experiments that can be performed. It is to be understood that the descriptions of the examples, in this sense, do not necessarily imply their execution, rather that the descriptions given can be used to obtain data and the like. on the nature of the compounds described in this application. Although efforts have been made to maintain accuracy in the indication of numerical values (for example, quantities, temperatures, and so on), it should be taken into account that some experimental errors and deviations are possible.

Methods.

Data for a single crystal.

X-ray diffraction data for a single crystal of form 1 of the MSA salt of compound 1 was recorded using a Bruker X8 APEX II CCD diffractometer equipped with a MICROSTAR-H microfocus X-ray generator (rotating anode) of monochromatic CuKa radiation (λ=1.54178 A). The single crystal was at room temperature during the recording of diffraction.

X-ray diffraction data for a single crystal of Compound 1 Free Base Monohydrate Form 2 and Compound 1 Free Base Form 4 were recorded using a Bruker X8 Prospector Ultra diffractometer equipped with an APEX II detector and a microfocus X-ray source of monochromatic CuKa radiation (λ=1.54178 A) IμS. The single crystals were kept at room temperature during diffraction recording.

X-ray diffraction data for a single crystal of form 2 of the MSA salt hydrate of compound 1 were recorded using a Rigaku SuperNova diffractometer equipped with a Dectris Pilatus 200K detector and a microfocus X-ray generator (with a sealed tube) of monochromatic CuKα radiation. The single crystal was at room temperature during the recording of diffraction. Indexing and the process of measuring the intensity of reflections were carried out under the control of the CrysAlisPro l,171,38,41r software package (Rigaku OD, 2015).

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The indexing and reflection intensity measurement process was carried out under the control of the APEX2 software package (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). The final unit cell parameters were determined using the complete data set. Direct methods were used to solve the structures, the structures were refined by minimizing the sum of squares of the elements of the full matrix using the SHELXTL software package (GM Sheldrick, SHELXTL v6, 14, Bruker AXS, Madison, WI USA.). Structural refinements included minimizing the following function: Σw(|Fo| - |Fc|) ² , where w is an appropriate error weight for observed intensities, Fo is a structure factor based on measured reflections, and Fc is a structure factor based on calculated reflections. The agreement between the refined model of the crystal structure and the experimental X-ray diffraction pattern was estimated using the residual factors R = Σ||Fo|-|Fc||/Σ|Fo| and wR = [Σw(|Fo|-|Fc|) ² / Σw|Fo|] ^1/2 . Difference Fourier maps were checked at all stages of refinement. To refine all non-hydrogen atoms, the anisotropic thermal displacement parameters were used. The parameters of hydrogen atoms were usually calculated using idealized geometry, introduced isotropic temperature factors, and included in the structure factor calculations with fixed parameters. In a few exceptional cases, hydrogen atoms were localized based on difference Fourier maps and refined isotropically, for example, the hydrogen atoms of water in the structure of form 2 of the free base hydrate of compound 1 and the acidic hydrogen atom of methanesulfonic acid in the structure of form 1 of the MSA salt of compound 1.

PXRD (PANalytical).

The PXRD diffraction pattern of the amorphous free base of compound 1 and the amorphous MSA salt of compound 1 was recorded using an Empyrean powder X-ray diffractometer (PANalytical) with CuKa radiation: λ = 1.541 A. This diffractometer is equipped with a ceramic tube, for which the power level was set, determined by the voltage value 45 kV and a current value of 40 mA, and a PIXcel 1D RTMS detector. The optical system for the formation of incident beams consisted of a Soller slit of 0.02 radians, a beam mask of 10 mm; 1° anti-scattering slit and automatic divergence slit set to irradiated length up to 10 mm. The optical system for the formation of diffracted beams consisted of a Soller slit of 0.02 radians; automatic anti-scattering slot, set to the irradiated length up to 10 mm; Ni-K-Beta filter and ~2.9° detector window. Data was recorded in continuous scan mode in reflection geometry during rotation, in the angle range 2θ 2-40°, with a step of 0.033-040°, the net counting time was ~317 s/step. More than 200 mg of the powdered sample was packed into the pour sample holders.

PXRD (GADDS-NB) Capillary.

PXRD diffraction patterns were obtained using a Bruker C2 GADDS diffractometer. The following X-ray radiation parameters were set: Cu Κα (40 kV, 40 mA). The distance from the sample to the detector was 15 cm. The samples were placed in sealed glass capillaries <1 mm in diameter. The capillary was rotated during the entire period of diffraction registration. Diffraction was recorded over a 2θ range of approximately 2<2θ<32°, and the sample exposure time was at least 1000 seconds. The resulting 2D diffraction lines were integrated to give conventional 1D PXRD patterns with a 2θ step of 0.05° over a 2θ range of approximately 2-32°.

Differential Scanning Calorimetry (DSC).

Compound 1 free base hydrate, Compound 1 free base, and Compound 1 MSC salt using differential scanning calorimetry (DSC) were analyzed on a TA Instrument calorimeter (model Q2000 or Q1000). A sample (approximately 1-10 mg) was weighed into an aluminum cuvette to the nearest hundredth of a milligram and then transferred to the DSC calorimeter. The calorimeter was purged with nitrogen gas (50 ml/min). The data were recorded in the range from room temperature to 300°C (temperature increase rate was 10°C/min). DSC plots were built in such a way that the endothermic peaks were directed downwards.

DSC analysis of the MSA salt hydrate of compound 1 was performed using a TA Instruments 2920 differential scanning calorimeter. Temperature calibration was performed using indium metal, in accordance with NIST requirements. The sample was placed in an aluminum cuvette of the DSC calorimeter, the cuvette was closed with a lid, the lid was hermetically sealed, and a microhole was made in it with a laser, and then the mass was accurately determined (3.7940 mg). A weighed aluminum cuvette, configured as a sample cuvette, was placed in the cell on the reference side. The analysis was performed by raising the temperature from -30°C to 300°C at a rate of 10°C/min.

Thermogravimetric analysis (TGA).

Thermogravimetric analysis (TGA) of compound 1 free base hydrate, compound 1 free base and compound 1 MSA salt was performed on a TA Instrument thermogravimetric analyzer (model Q5000 or Q500). The sample (approximately 10-30 mg) was placed in a pre-calibrated platinum cuvette. The mass of the sample was determined with an accuracy of one thousandth of a milligram. The oven was purged with nitrogen gas (100 ml/min). The data were recorded in the interval

- 31 041037 from room temperature to 300°C (temperature increase rate was 10°C/min).

TG analysis of the MSA salt hydrate of compound 1 was performed using a TA Instruments Q5000 thermogravimetric analyzer. Temperature calibration was performed using nickel and alumel. The sample (5.6360 mg) was placed in an aluminum cuvette. The sample was hermetically sealed, the cuvette lid was pierced, and then the cuvette was placed in the TG oven. The furnace was heated under a nitrogen atmosphere. The analysis was performed by raising the temperature from ambient temperature to 350° C. at a rate of 10° C./min.

Solid state nuclear magnetic resonance spectroscopy (ss NMR).

Solid-state C13-NMR experiments using the technique of cross-polarization and magic angle rotation of the sample (CPMAS) were performed on a Bruker AV III spectrometer operating at a proton frequency of 500 MHz. A solid sample was rotated in a ZrO ₂ rotor 4 mm in diameter at a speed of 13 kHz. The contact time was 4 ms and increased on the proton channel from 50 to 100% (AE Bennett et al., J. Chem. Phys., 1995, 103, 6951), (G. Metz, X. Wu and SO Smith, J. Magn. Reson. A., 1994, 110, 219-227). The relaxation delay maintained at 5 x 1H T1 API was 20 s. The proton spin decoupling technique used a TPPM (Two Pulse Phase Modulation) sequence with a pulse width of 4.3 μs (nominal bandwidth: 58 kHz). The spectral bandwidth was 300 ppm. centered at 100 ppm The number of points accumulated was 2048 (which gave a digital resolution of 36 Hz), and 8192 were filled with zeros before apodization. Another 2048 free induction decays were added. Chemical shifts in the spectrum were determined indirectly from the TMS (tetramethylsilane) signal using 3-methylglutaric acid (D. Barich, E. Gorman, M. Zell, and E. Munson, Solid State Nuc. Mag. Res., 2006, 30, 125-129). Approximately 80 mg of sample was used in each experiment. The temperature value was set to 280°K.

FT infrared spectroscopy.

FTIR spectroscopy was performed using an IS50-ATR spectrometer with attenuated total internal reflection (ATR). The spectra were recorded using the reflection mode with a resolution of 4 cm ^-1 and the number of scans 64. The spectra were recorded with a resolution of 4 cm ^-1 and the number of scans 64.

Fourier-Raman spectroscopy.

Fourier Raman spectra were obtained with a resolution of 4 cm ^-1 and a number of scans of 64 using a Nicolet iS50 Fourier Raman spectrometer integrated with a high sensitivity InGaS detector. The laser excitation wavelength was 1064 nm. The laser power was 0.5 W.

Stability testing. chromatographic conditions.

VPLC options.

VHPLC system: Waters AcQuity BSM or H-Class VHPLC system equipped with a Waters UV/Vis detector.

Column: Ascentis Express C18, 150 mm x 2.1 mm (id), particle size 2.7 µm.

Detector wavelength: 218 nm.

VHPLC detector limit time: normal.

VHPLC - sampling frequency: 20 Hz.

VHPLC - bandpass: resolution 1.2 nm.

Flow rate: 0.5 ml/min.

Injection volume 1 µl.

Column temperature: 30°C.

Chromatography time: ~14 min.

Sample temperature: 5°C.

Mobile phase A: water:acetonitrile:TFA (95:5:0.05).

Mobile phase B: water:acetonitrile:TFA (5:95:0.05).

VHPLC: list of gradients defined by the program.

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Mobile phase composition Time (min) %A %IN gradient profile 0 85 15 Elementary 0.5 85 15 isocratic mode 5.5 45 55 Linear 8.0 35 65 Linear 10 0 100 Linear 10.5 85 15 Linear 14 85 15 isocratic mode

Typical retention time of compound 1: retention time (min) 5.66; relative retention time (min) 1.00.

Microdissolution.

Microdissolution experiments were performed in a pION pDiss Profiler microdissolution apparatus (pION pDiss Profiler) with a fiber optic UV monitoring system, as follows.

Probes: 2.5 mm probe (path length 5 mm).

Volume: 15 ml.

Mixing: 150 rpm.

Temperature: 37°C (solution and apparatus bath).

Blank: instant FaSSIF/FeSSIF.

Standards: 6 standard concentrations (0, 5, 15, 25, 50, 100, 200 µg/ml).

Vehicle: 10 mg/ml DMSO.

Wavelength: 280 nm, control wavelength 450 nm.

Example 1 Compound 1

Compound 1 can be prepared using the techniques described in WO 2016/073770, incorporated herein by reference.

Example 2 Compound 1 free base, amorphous.

132.0 g of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6fluoroquinolin-4-yl)cyclohexyl)propanamide hydrate and 610 g of ethyl acetate were added to a 1 L round bottom flask. This suspension was heated until all the solid had dissolved. The resulting solution was concentrated to dryness under vacuum. The resulting solid was dried under vacuum at 50° C. to yield 126.0 g of (R)-N-(4-chlorophenyl)-2((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide as a white solid (yield: 99.6%).

Example 3 Compound 1 Free Base Hydrate Form 2

13.75 kg of acetonitrile, then 2.68 kg of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) were introduced into a 50 L chemical reactor, coated on the inside with enamel, under a nitrogen atmosphere, and washed with 2.0 kg acetonitrile. 2.03 kg of N-methylimidazole was added followed by 1.95 kg of acetonitrile. 2.48 kg of (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid was added followed by 1.05 kg of acetonitrile. This mixture was held for 0.5 h, then 1.21 kg of 4-chloroaniline and then 1.0 kg of acetonitrile were added. The temperature of the mixture was maintained at 20° C. until the reaction was complete according to HPLC analysis. The resulting solution was then heated to 60° C. and 9.25 kg of water was added. The solution was then cooled to 40° C., the mixture was held for 1 hour, seed crystals (32 g) were added and washed with water:acetonitrile (2:1; 1.15 kg) and the resulting suspension was held for 1 hour. The suspension was then cooled to 20° C. and 25.75 kg of water was added. The suspension was filtered and the filter cake was washed three times with water:acetonitrile (2:1; 6.9 kg). The filter cake was dried under vacuum at 50° C. to give 3.33 kg of (R)-N-(4chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-propanamide hydrate in as a white solid (yield: 94.1%).

Example 4 Compound 1 Free Base Hydrate Form 2

250 mg of the amorphous free base of compound 1 was dissolved at a temperature of 40-50°C in 2 ml of an organic solvent, such as ethanol, acetone, acetonitrile or tetrahydrofuran. Water (2 ml) was added in portions of 0.5 ml, after adding 1 ml of water an emulsion was obtained due to the release of oil. Keeping this emulsion resulted in crystallization. The formed crystals

- 33 041037 were filled using a Buchner filter funnel.

Example 5 Compound 1 Free Base Form 4

15.0 g of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6fluoroquinolin-4-yl)cyclohexyl)propanamide hydrate and 176 g of acetonitrile, and stirred until all the solid dissolved. The resulting solution was concentrated to dryness under vacuum. Another portion of acetonitrile (176 g) was added and again the solution was concentrated to dryness in vacuo. Added 134 g of ethyl acetate, and kept until a homogeneous solution, and again concentrated to dryness under vacuum. After removing all the solvent, 50 g of ethyl acetate was added. This solution was heated to 40°C and kept under stirring on a magnetic stirrer. Seed crystals (220 mg) were added and then 144 g of heptane were added over 45 minutes. This suspension was gradually cooled to 20° C. and another portion of heptane (27 g) was added. Then the temperature of the suspension was cyclically changed by heating to 50°C and gradual cooling to 20°C. The suspension was kept overnight. The solid was filtered off and dried under vacuum to give 12.0 g of (R)-N-(4chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide as a white solid substances (yield: 84.5%).

Example 6 Compound 1 Free Base Form 4

250 mg of the free base of compound 1 was dissolved in 1 ml of ethyl acetate at 40°C. 700 μl of heptane was added and then approximately 10 mg of compound 1 free base form 4 seed crystals. This resulted in the formation of a suspension. The resulting suspension was kept for 10 min, and then another portion of heptane (3 ml) was added. The suspension was held for approximately 1 hour, then filtered using a Buechner funnel and dried overnight in a vacuum oven at 50°C.

Example 7 Compound 1 Free Base Form 4

100 mg Form 2 Compound 1 free base was dried in a vacuum oven overnight at 50° C. to dehydrate this material. The material was then suspended at 65° C. in 1 ml heptane overnight. A few hours later, a phase transition occurred, and then the conversion to form 4 of the free base of compound 1.

Example 8 Salt of compound 1 formed with methanesulfonic acid (MSA), amorphous.

2.6 g of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4yl)cyclohexyl)propanamide methanesulfonate and 0.1 l of methanol were added to a glass tube. This mixture was stirred at room temperature until the solid dissolved and a clear sprayable solution was obtained. The 2.6% (w/v) sprayable solution was then spray dried at 65° C. to remove the methanol solvent using heated nitrogen gas through a two-fluid spray nozzle (2050 LC/64AC, Spraying Systems Co.) using custom made small scale spray dryer. The following spray drying parameters were used: solution spray rate - 1.3 ml per minute, N ₂ gas inlet flow rate - 32 standard liters per minute, N ₂ inlet temperature 65°C. Inside the spray dryer, the solid was collected on filter paper 4. 2.3 g of spray-dried white solid was collected from the filter paper and transferred to a glass tube. The spray-dried solid was dried under vacuum overnight in a glass tube at room temperature.

Example 8A. Salt of compound 1 formed with methanesulfonic acid (MSA), amorphous.

An amorphous MSA salt of compound 1 was obtained by rotary evaporation of form 1 of the MSA salt of compound 1 in dichloromethane. The resulting substance was recrystallized to obtain form 1 MSA salt of compound 1 after temperature stress at 60°C.

Example 9. Salt of compound 1 formed with methanesulfonic acid (MSA), form 1.

In a chemical reactor with a volume of 1 l, 50 g of the free base of compound 1 were dissolved in 500 ml of ethyl acetate at 25°C with stirring at a speed of 500 rpm. A solution of MSA (1 molar equivalent) in ethyl acetate (250 ml) was prepared and this solution was pumped into the chemical reactor over 2 hours. The resulting suspension was held for 30 minutes. The crystals were separated using a Buechner filter funnel, dried overnight in an oven at 50°C.

Example 10. Salt of compound 1 formed with methanesulfonic acid (MSA), form 1.

349 g of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and 2 liters of acetonitrile were added to a 10-liter chemical reactor coated on the inside with enamel under a nitrogen atmosphere. 245 g of N-methylimidazole was added and then 0.3 l of acetonitrile. 300 g of (R)-2-((1S,4S)-4-(6fluoroquinolin-4-yl)cyclohexyl)propanoic acid was added followed by 0.3 L of acetonitrile. This mixture was held for 0.5 h, then 139 g of 4-chloroaniline and then 0.4 l of acetonitrile were added. The temperature of the mixture was maintained at 20° C. until the reaction was complete according to HPLC analysis. The resulting solution was then heated to 60° C. and 1.2 L of water was added. The solution was then cooled to 40° C., seed crystals (3 g) were added and the resulting slurry was held for 1 hour. The slurry was then cooled to 20° C. and 2.7 L of water was added. The suspension was filtered and the filter cake was washed three times with water/acetonitrile (2:1; 3 L). The filter cake was dissolved in 5.1 L of ethyl acetate and this solution was distilled to a volume of 4.2 L at 41° C. under vacuum. The suspension was cooled to 20° C., seed crystals (4.14 g) were added and a solution of 95.7 g of methanesulfonic acid in 2.9 L of ethyl acetate was added. The suspension was then filtered, washed twice with 1.65 L of ethyl acetate and dried under vacuum at 50° C. to obtain 445 g of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6- fluoroquinolin4-yl)cyclohexyl)propanamide methanesulfonate as a white solid (yield: 88%).

Example 11 MSA salt monohydrate of compound 1, form 2.

Compound 1 MSA salt monohydrate form 2 can be prepared by suspending Compound 1 MSA salt form 1 at a water activity of 60% (expressed in relative humidity units) at room temperature in an ethanol/water mixture (85/15 v/v). Single crystals of MSA salt form 2 of compound 1 were grown by evaporating a solution of form 1 of MSA salt of compound 1 in methanol/acetonitrile (8/92 v/v) at ambient temperature.

Example 12 MSA salt form 1 of compound 1: solid state stability.

To study the effect of temperature, humidity and light on Form 1 of the MSA salt of the compound, a 112-month stability study was performed. See table below. In this study, one batch of drug substance was used, packaged in double LDPE (low density polyethylene) bags, placed in a 0.6 L HDPE (high density polyethylene) container with a lid and gasket. Compound 1 MSA salt form 1 remained stable for at least 12 months when stored under long term storage conditions at 5°C and 25°C/60% relative humidity (OBB), 6 months when stored under accelerated aging conditions at 40 °C/75% OBB and 3 months when stored under stress at 50°C.

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The results of the photostability study showed that there is no need to protect this medicinal substance from light. Compound 1 MSC salt Form 1 can be stored at or below 25°C.

no Stability study Storage conditions Time As-is analysis (%) Adjusted analysis (%) 0 Start 79.0 ¹ 97.0 ¹ 1 Long term storage 5°C 1 month 81.9 100.5 3 months 82.4 101.1 6 months 81.2 99.6 12 months 81.7 100.5 2 25°C/60% RH 1 month 82.1 100.8 3 months 81.7 100.4 6 months 81.2 99.7 12 months 81.1 99.8 3 accelerated aging 40°C/75% RH 2 weeks 80.7 99.1 1 month 82.3 101.0 3 months 81.5 100.1 6 months 81.8 100.4 4 Stress -20°C 1 month 82.4 101.1 5 40°C/75% RH 2 weeks 80.9 99.3 1 month 81.6 100.3 3 months 81.4 99.9 6 months 80.3 98.6 6 50°C 2 weeks 80.8 99.2 1 month 82.0 100.7 3 months 82.2 100.9 7 2°C/HIL/UVAexposure 4 days 80.8 99.2 25°C/HIL/UVAexposure 2 weeks 78.7 96.8 25°C/HIL/UVA protection 4 days 81.1 99.5 25°C/HIL/UVA protection 2 weeks 80.4 98.7

¹ average of 2 results

There were essentially no deviations in the analysis as is or adjusted from the initial value as is 79.0% or the initial value corrected 97.0% in studies numbered 1, 2, 3 and 5, except that there was some variability . A non-significant increase was present in the as-is and adjusted analyzes from baseline values of 79.0% and 97.0%, respectively, in study numbers 6 (up to 82.0% and 100.7%, respectively) and 4 (up to 82.0%, respectively). .4% and 101.1% respectively).

There were essentially no deviations in total impurities from a baseline of 0.57% in study numbers 4, 1, 2, and 3. A decrease in total impurities from a baseline of 0.57% was observed in study numbers 3 (down to 0.48 %) and 6 (up to 0.50%). The main reason for this decrease was the decrease in 4-chloroaniline from 0.09% initially to <0.05% in study numbers 3 and 6.

There were no deviations in the amount of enantiomeric impurities of compound 1 from the initial value <0.05% in studies with numbers 1 and 2.

There were essentially no moisture content deviations from baseline <0.1% w/w in study numbers 1 and 2.

The color and appearance (white or yellowish powder or powder with lumps) was maintained throughout all studies.

After the study with any number on the XRD-diffraction pattern, there were no changes.

There were essentially no deviations after Compound 1 MSA salt form 1 was subjected to minimal exposure according to ICH Q1B guidelines. When the exposure was about 3.5 times the minimum ICH exposure, a slight increase in total impurities was observed, predominantly due to impurities that increased by less than 0.10%. The post-drug adjusted value in the analysis was 96.8%. There were no other changes for all other properties tested. The results of the photostability study showed that it is not necessary to protect this medicinal substance from light.

Form 1 of the MSC salt of compound 1 remained physically stable under stress conditions, including grinding with organic solvents and water and stress at a relative humidity of 75% and a temperature of 40°C for 5 days.

Example 13 Form 1 MSA salt of compound 1, solubility versus pH.

The pH dependence of the solubility of form 1 of the MSA salt of compound 1 was studied using NaOH (1N or 10N aqueous solution) and HCl (concentrated or 1N aqueous solution), pH was adjusted at a temperature of 22±3°C. Measurements were made using an Orion ATI Model 370 pH meter. Approximately 20-30 mg of Compound 1 MSA salt form 1 was weighed into each of eleven 10cc type I glass vials. 5 ml of the prepared aqueous acid and base solution was added to each vial. Each vial was capped, shaken and sonicated for better mixing. The pH of each sample was recorded.

The samples were vigorously stirred overnight at room temperature at 300 rpm. After stirring for 24 hours, the pH of each sample (as a suspension) was recorded. The suspensions were filtered through a 0.2 µm Acrodisc syringe filter. The clear filtrates were collected and shaken for better mixing. The pH of each filtrate was recorded. The pH of the suspension and the filtrate were almost the same.

A 1.0 ml aliquot of each filtrate was placed in a flask and diluted 25 times with 50% acetonitrile/50% Milli-Q water to bring the volume of the flask to 25 ml. Aliquots were transferred to an automatic HPLC pipette to analyze the concentration of Compound 1.

Samples were analyzed using the following HPLC method.

Column: Waters YMC Pro-Pack C18; Part # AS12S05-1546WT, S-5um, 150x4.6mm (ID).

mobile phase.

Solvent A: water/0.05% TFA.

Solvent B: acetonitrile/0.05% TFA.

Flow rate: 1.0 ml/min.

Column temperature: room temperature.

Detector wavelength: 250 nm.

Injection volume: 10 µl.

Working concentration: approximately 100 mcg/ml.

Sample/Standard Diluent: 50% Acetonitrile/50% Milli-Q Water.

Typical connection 1.

Retention time: 15.5 min (RRT (relative retention time) 1.0).______

HPLC Program: Gradient Time (min) Flow rate (ml/shminsh) % A % IN 0 1.0 95 5 24 1.0 10 90 27 1.0 95 5 thirty 1.0 95 5

Preparation of an external standard: 25.4 mg of Compound 1 MSC salt Form 1 was weighed into a 25 ml type I glass vial. 20 ml of 100% acetonitrile was added to the vial. The vial was closed, shaken and sonicated. Not all of the solid dissolved. The resulting suspension was transferred to a 250 ml glass volumetric flask and the glass vial was washed with 50% acetonitrile/50% Milli-Q water (4x20 ml), transferring each portion of the wash mixture to the volumetric flask. All solid dissolved. A mixture of 50% acetonitrile/50% water Milli Q was added to the volumetric flask, bringing the final volume of the solution to 250 ml, the flask was shaken to obtain a standard solution with a concentration of 101.5 μg/ml.

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In general, the obtained profiles were profiles typical of weak bases, from which it followed that the solubility of the free base is 1-2 µg/ml, the solubility in water (natural pH ~2.5) is ~130 µg/ml, pH- dependent maximum solubility is reached at pH ~2 and is ~560 μg/ml, and the solubility decreases at pH values below 2 (73 μg/ml at pH 1 and 24 μg/ml at pH 0.5). These results are shown in the table below.

*Medium simulating intestinal fluid after a meal **Wednesday simulating intestinal fluid on an empty stomach

Example 14 Microdissolution in FaSSiF/FeSSiF.

MSA salt form 1 of compound 1 had a higher rate and degree of dissolution compared to the amorphous form or the HCl salt (amorphous and crystalline) in both FeSSiF and FaSSiF. The dissolution rate of Compound 1 MSA salt form 1 indicated rapid absorption. See fig. 7.

Form 1 MSC-salt of compound 1 had a higher rate and degree of dissolution compared to the free base of compound 1 (amorphous). See fig. 8.

Example 15 Microdissolution in FaSSiF/FeSSiF.

The dissolution of MSA salt form 1 of compound 1 and MSA salt form 2 of compound 1 monohydrate in FaSSIF and FeSSIF media were analyzed. Target doses of 150 mg were added to 250 ml (0.60 mg/ml API equivalent) of FaSSIF (pH 6.5) and FeSSIF (pH 5).

AUC values and dissolution rates appear to be similar for Compound 1 MSA salt form 1 and Compound 1 MSA salt monohydrate form 2 in FaSSIF and FeSSIF media. There are no statistically significant differences in AUC, but there are statistically significant differences in dissolution rates, namely, form 2 of the MSC salt monohydrate of compound 1 dissolves slightly faster in FaSSIF medium. Forms 1 and 2 have similar solubility peaks in FaSSIF medium. The solubility behavior in the FeSSIF medium is similar to the solubility behavior in the FaSSIF medium, but the numerical values are 3 times higher. Form 1 MSC-salt of compound 1 has a coefficient reflecting the effect of food intake, equal to 3.10. Both forms have a constant coefficient reflecting the effect of food intake. Form 2 of the MSC salt hydrate of Compound 1 has a coefficient reflecting the effect of food intake, equal to 3.49. See table below and FIG. 9. MSA salt form 2 of compound 1 and MSA salt form 1 of compound 1 appear to have similar dissolution profiles.

MSC-salt Compounds 1 AUC (mcg, min/ml) Dissolution rate (µg/ml/min) Solubility Peak (µg/mL) Average SD %CV Average SD speed Average Form 1 FaSSiF 14988.073 1160.442 7.742 2,460 0.466 100.877 Form 1 FeSSiF 46410.396 2091.297 4.506 38.850 9.664 271.564 Form 2 FaSSiF 14315.281 657.354 4.592 4.449 0.654 91.325 Form 2 FeSSiF 50014.687 5376.308 10.749 47.996 3.879 287.395

p-value (Form 2 v. Form 2, FaSSIF) AUC=0.352, rate=0.003 p-value (Form 2 v. Form 2, FeSSIF) AUC=0.329, rate=0.139

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Example 16 Microdissolution in FaSSiF/FeSSiF media.

In this study, we analyzed the differences in the dissolution of the free base of the compound (amorphous), form 2 of the free base of compound 1 and form 1 of the MSA salt of compound 1 in media

FaSSIF and FeSSIF.

The peak solubility of form 1 of the MSA salt of compound 1 in FaSSIF and FeSSIF media is 4-5 times higher than the peak of solubility of form 2 of the free base. This difference is statistically significant (p<0.05). The rate of dissolution of form 1 of the MSA salt of compound 1 in FeSSIF is 38 vs. 23 mcg/ml/min. In the FeSSIF medium, the dissolution rate and degree are increased for all APIs (active pharmaceutical ingredients). The coefficient reflecting the effect of food intake is approximately 3.5 for the MSA salt, 5 for the amorphous free base, and ∼3.5 for the form 2 free base.

Example 17. Grinding in a jet mill.

Particle size reduction can be achieved by jet milling using the 0202 Jet-o-Mizer loop Mill system. To ensure particle collision, high pressure nitrogen gas is fed into the grinding chamber through two milling nozzles. The feed rate of the drug into the mill is controlled by an auto-feeder, which feeds the drug into the feed funnel of the mill visually at a constant feed rate. High-pressure nitrogen gas is supplied through a venturi nozzle to introduce the medicinal substance from the mill hopper into the grinding chamber, and this pressure is called venturi pressure. Before grinding, the mill and vent pressures are adjusted to the desired level and maintained at the same level until the product disappears from the hopper. The vent pressure is typically set 10 psi above the mill pressure. The micronized medicinal substance exits through the outlet of the grinding chamber and enters the product collection device, which consists of a block that combines a cyclone and a carrier with a porous fabric filter. The grinding parameters can be changed depending on the analyzed sample. Grinding allows to obtain particles whose size falls in the range from 12.7 μm to 24.0 μm (D90, as determined using laser scattering). Grinding parameters and physical properties are shown in the table below.

Milling parameters and physical properties of milled Form 1 MSC salt Compound 1 Matter properties Parameters 0202 Jet Mill Color and appearance white solid Feeding speed range (kg/h) 1.18-2.22 Mill pressure range (psi) 20-65 Mill pressure range (bar) 20-65 D50 (µm) 6.2-9.8 D90 (µm) 12.7-24.0 Surface area (m ² /g) 2.08-3.63 Bulk density (g/ml) (for sample with D90 = 22.3 µm) 0.193

Example 18 Stability - Compound 1 Free Base Form 4

The solid state stability of Compound 1 Free Base Form 4 was studied. After storage for at least 2 weeks, no change was found. The results of these experiments are shown in the table below.

Compound 1 free base form 4 remained chemically stable for at least 4 weeks.

stressful conditions 2 weeks Area (%) 4 weeks Area (%) RT/RL* 99.75% 99.70% 25°C/60% relative air humidity 99.78% 99.77% 40°C/75% relative air humidity (outdoor) 99.79% 98.46% 40°C/75% relative humidity (indoor) 99.78% 99.71 50°C 99.68% 99.74% High Intensity Light (HIL) 99.77% 99.58%

*room temperature/room light

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Claims (14)

Example 19 Stability - Compound 1 Free Base Hydrate Form 2 The solid state stability of compound 1 free base monohydrate form 2 was studied. The results of these experiments are shown in the table below. There were no changes in the PXRD patterns of all samples after storage for 4 weeks or 8 weeks. There were no changes in the DSC/TGA thermograms of all samples after storage for 4 weeks. No evidence of shape change, dehydration, or transition to an amorphous state was found after 8 weeks of storage. There were no changes in the TGA thermograms of all samples after storage for 8 weeks. Compound 1 free base hydrate form 2 remained chemically stable for at least 13.5 weeks when stored at elevated temperature and under the humidity conditions tested. stressful conditions 4 weeks Area (%) 8 weeks Area (%) 13.5 weeks Area (%) RT/RL* 99.90% 99.90% 99.78% 25°C/60% relative humidity 99.90% 99.90% 99.73% 40°C/75% relative humidity (open) 99.90% 99.90% 99.63% 40°C/75% relative humidity (closed) 99.90% 99.90% 99.62% 50°C 99.90% 99.04% 99.79% Light high intensity (HIL) 99.1% ND ND *room temperature, room light Example 20. The amorphous substance of the MSC salt of compound 1 was converted into form 1 of the MSC salt of compound 1 after heat stress at 60°C for 9 days. Compound 1 MSA salt monohydrate form 2 was converted to Compound 1 MSA salt monohydrate form 1 and Compound 1 MSA monohydrate form 2 after storage for 6 days under stress conditions at 75% relative humidity and 40°C. Partial conversion to form 2 of the MSA salt monohydrate of compound 1 at a relative air humidity of 75% suggests that this amorphous, according to X-ray diffraction pattern, substance may have a higher rate of conversion to form 2 of the MSA salt of compound 1 than to form 1 MSC salts of compound 1. Example 21 Stability - Compound 1 free base. In order to find out what form changes could take place in Compound 1 Free Base Monohydrate Form 2, Compound 1 Free Base Form 4, and Compound 1 Amorphous Free Base, experiments were performed using heat. The amorphous free base of compound 1 was heated in the temperature range from 67°C to 150°C. There was no crystallization. Melt/cool experiments using Compound 1 free base form 4 resulted in glass formation with several small, birefringent acicular particles, although the resulting XRPD diffraction patterns did not provide evidence that a crystalline material had formed. Heating form 2 of the free base monohydrate of compound 1 for ~2 h at ~100°C led to a noticeable change in birefringence, but did not change the XRPD pattern. Heating to ~125°C caused the sample to melt. After cooling the resulting liquid sample on dry ice, a glass was obtained that did not have the properties of birefringence, which was consistent with the X-ray diffraction pattern characteristic of an amorphous substance. Additional experiments on heating form 2 of the free base monohydrate of compound 1, in which this substance was heated in the temperature range from ~79 to 80°C for 1 day or at ~75°C in a stream of nitrogen gas for ~20 h, led to partial transformation into other crystalline forms. Form 2 of compound 1 free base monohydrate appears to be thermodynamically stable at high relative humidity and RT. Several experiments were performed to study the dehydration of hydrated forms at ~0% relative air humidity. Compound 1 free base monohydrate form 2 became unstable after storage overnight at 0% relative humidity. CLAIM 1. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4, characterized by an X-ray powder diffraction pattern containing at least three peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2Θ±0.2 degrees 2θ. - 40 041037 2. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide form 4 according to claim 1, characterized by an X-ray powder diffraction pattern, containing three peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ±0.2 degrees 2θ. 3. Crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide form 4 according to claim 1, characterized by a powder x-ray diffraction pattern, containing four peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ±0.2 degrees 2θ. 4. Pharmaceutical composition containing crystalline (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide form 4, characterized by powder X-ray diffraction pattern, containing at least three peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0 degrees 2θ±0.2 degrees 2θ, and a pharmaceutically acceptable carrier. 5. Pharmaceutical composition according to claim 4, additionally containing amorphous (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, amorphous ( R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)methanesulfonic acid propanamide, or a combination thereof; or additionally containing amorphous (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4yl)cyclohexyl)propanamide. 6. Pharmaceutical composition according to claim 4, where the pharmaceutical composition is a solid dosage form. 7. Pharmaceutical composition according to claim 6, wherein the solid dosage form is a tablet, pill or capsule. 8. A method of treating cancer in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of crystalline (R)-N-(4-chlorophenyl)-2((1S,4S)-4-(6-fluoroquinoline-4- yl)cyclohexyl)propanamide Form 4, characterized by an X-ray powder diffraction pattern containing at least three peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ ±0.2 degrees 2θ. 9. The method according to claim 8, characterized in that the cancer is a cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck , skin (including melanoma and basal carcinoma), mesothelial lining, white blood cells (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, lung (including small cell lung and non-small cell carcinoma), adrenal, thyroid, kidney or bones; or is glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, cutaneous basal cell carcinoma, or seminoma of the testis. 10. The method of claim 8, further comprising introducing amorphous (R)-N-(4-chlorophenyl)-2((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, amorphous (R methanesulfonic acid )-N-(4-chlorophenyl)-2-((1S,4S)-4(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, or combinations thereof. 11. The method of claim 8, further comprising administering an immune checkpoint inhibitor, optionally wherein the immune checkpoint inhibitor is ipilimumab, nivolumab, pembrolizumab, or a combination thereof. 12. The method of claim 8, wherein Form 4 is characterized by an X-ray powder diffraction pattern containing three peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ ±0.2 degrees 2θ; or where Form 4 is characterized by an X-ray powder diffraction pattern containing four peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ±0 ,2 degrees 2θ. 13. The method according to claim 8, where form 4 is characterized by an X-ray powder diffraction pattern containing three peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ ±0.2 degrees 2θ. 14. The method of claim 8, wherein Form 4 is characterized by an X-ray powder diffraction pattern containing four peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0 degrees 2θ ±0.2 degrees 2θ. -