Amorphous and crystalline forms of IDO inhibitors

Abstract

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

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 62 / 527,855, filed June 30, 2017, the entire contents of which are incorporated herein by reference.

[0002] (Technical field) This specification describes solid form and its salts and hydrates, methods for their preparation, pharmaceutical compositions containing them and methods of using them.

[0003] (Prior Art) (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is designated herein as Compound 1 and has the following structure: [ka] It has.

[0004] Compound 1 is a potent inhibitor of indoleamine 2,3-dioxygenase (IDO; also known as IDO1), an IFN-γ target gene that plays a role in immune regulation. Compound 1 is being investigated as a treatment for cancer and other diseases. Compound 1 was previously described in WO2016 / 073770.

[0005] The compounds may be present in amorphous form as free bases, hydrates, solvates or salts. form and / or one or more crystals form and each may exhibit different physical properties, such as different X-ray diffraction patterns (XRPD or PXRD) and different temperature characteristics. formThey may also differ with respect to their individual stability, processing methods, formulations, dissolution profiles, bioavailability, and the like.

[0006] Novel (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamides with desired beneficial chemical and physical properties form Furthermore, in order to facilitate commercialization, Compound 1 (and its hydrates, solvates, salts and hydrated salts) is required. form There is also a need for reliable and reproducible methods for producing, purifying, and formulating . The present invention is directed to these and other important aspects.

[0007] (Summary of the Invention) The present invention is a solid form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide (compound 1), e.g., solid form The free base of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, solid form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate, solid form Methanesulfonate salt of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide and solid form The solid described relates to the methanesulfonate monohydrate of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide. form Compositions comprising the compounds are also described, as well as methods for their preparation and use in therapy. [Brief explanation of the drawings]

[0008] [Figure 1]FIG. 1 shows the powder X-ray diffraction analysis for Form 2 of the free base monohydrate of Compound 1. [Figure 2] FIG. 1A shows the ssNMR spectrum for Form 2 of the free base monohydrate of Compound 1. [Figure 3] FIG. 1B shows the FT-IR for Form 2 of the free base monohydrate of Compound 1. [Figure 4] FIG. 1C shows a differential scanning calorimetry (DSC) thermogram for Form 2 of the free base monohydrate of Compound 1. [Figure 5] FIG. 1D shows the thermogravimetric analysis (TGA) thermogram for the free base monohydrate Form 2 of Compound 1. [Figure 6] FIG. 1E shows the FT-Raman spectrum for the free base monohydrate form 2 of Compound 1. [Figure 7] FIG. 2 shows the powder X-ray diffraction analysis for Form 4 of the free base of Compound 1. [Figure 8] FIG. 2A shows the ssNMR spectrum for the free base form 4 of compound 1. [Figure 9] FIG. 2B shows the DSC thermogram for Form 4 of the free base of Compound 1. [Figure 10] FIG. 2C shows the TGA thermogram for Form 4 of the free base of Compound 1. [Figure 11] FIG. 3 shows the powder X-ray diffraction analysis for amorphous Compound 1 free base. [Figure 12] FIG. 3A shows the ssNMR spectrum for amorphous Compound 1 free base. [Figure 13] FIG. 3B shows the FT-IR spectrum for amorphous Compound 1 free base. [Figure 14] FIG. 3C shows the FT-Raman spectrum for amorphous Compound 1 free base. [Figure 15] FIG. 4 shows the powder X-ray diffraction analysis for Form 1 of the mono-methanesulfonic acid salt (MSA salt) of Compound 1. [Figure 16]FIG. 4A shows the ssNMR spectrum for Form 1 of the MSA salt of Compound 1. [Figure 17] FIG. 4B shows the FT-IR spectrum for Form 1 of the MSA salt of Compound 1. [Figure 18] FIG. 4C shows the DSC thermogram for Form 1 of the MSA salt of Compound 1. [Figure 19] FIG. 4D shows the FT-Raman spectrum for Form 1 of the MSA salt of Compound 1. [Figure 20] FIG. 4E shows the TGA thermogram for Form 1 of the MSA salt of Compound 1. [Figure 21] FIG. 5 shows the powder X-ray diffraction analysis for the methanesulfonic acid (MSA) salt of amorphous Compound 1. [Figure 22] FIG. 5A shows the ssNMR spectrum for the MSA salt of amorphous Compound 1. [Figure 23] FIG. 5B shows the FT-Raman spectrum for the MSA salt of amorphous Compound 1. [Figure 24] FIG. 6 shows the powder X-ray diffraction analysis for Form 2 of the MSA salt monohydrate of Compound 1. [Figure 25] FIG. 6A shows the DSC thermogram for Form 2 of the MSA salt monohydrate of Compound 1. [Figure 26] FIG. 6B shows the TGA thermogram for Form 2 of the MSA salt monohydrate of Compound 1. [Figure 27] FIG. 7 shows the microsolubility profiles for Form 1 of the MSA salt of Compound 1, Compound 1HCl (amorphous), and the crystalline form of Compound 1HCl at a simulated 150 mg human dose in FaSSI and FeSSIF. [Figure 28] FIG. 8 shows the microsolubility profiles for Compound 1 MSA salt Form 1, Compound 1 free base (amorphous), and Compound 1 free base hydrate Form 2 at 0.2 mg / mL (n=3-4) in FaSSIF and FeSSIF. [Figure 29]FIG. 9 shows microsolubility data for Form 1 of the MSA salt of Compound 1 and Form 2 of the MSA salt monohydrate of Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present disclosure provides a solid form of Compound 1. form , for example, Compound 1 (free base), the monohydrate (free base) of Compound 1 and the methanesulfonic acid (MSA) salt of Compound 1, the monohydrate MSA salt of Compound 1, and the solids form The production of said solid form and a pharmaceutical composition comprising said solid form The present invention relates to a method for treating IDO-mediated diseases using the disclosed solids. form The names should not be construed as limitations with respect to other substances having similar or identical physical and chemical properties, but rather, these names should be understood as identifiers to be interpreted in accordance with the characterization information disclosed herein.

[0010] [ka]

[0011] Compound 1 free base hydrate In one embodiment, the present invention provides a solid form of Compound 1 (free base) that exists as a monohydrate. form For example, the solid form of the free base monohydrate of Compound 1 form contains approximately one molecule of water per molecule of Compound 1 free base.

[0012] In a preferred embodiment, a solid form The hydrate of Compound 1 (free base) is a crystalline form of Compound 1 (free base) monohydrate. form of the free base monohydrate of Compound 1 form 2. The free base monohydrate of Compound 1 is form 2 has a desirable stability profile.

[0013] Compound 1 free base monohydrate form 2 may be characterized by an X-ray diffraction pattern having one or at least one peak selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6° 2θ ± 0.2° 2θ. form Compound 2 can also be characterized by an X-ray diffraction pattern having two peaks selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6° 2θ ± 0.2° 2θ. form Compound 2 may also be characterized by an X-ray diffraction pattern having three peaks selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6° 2θ ± 0.2° 2θ. form Compound 2 may also be characterized by an X-ray diffraction pattern having four peaks selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6° 2θ ± 0.2° 2θ. form 2 may also be characterized by an X-ray diffraction pattern having five peaks selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6° 2θ ± 0.2° 2θ. form Compound 2 may also be characterized by an X-ray diffraction pattern having six peaks selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6° 2θ ± 0.2° 2θ. form 2 may be characterized by an X-ray diffraction pattern with peaks at 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6 degrees 2θ±0.2 degrees 2θ.

[0014] of the free base monohydrate of Compound 1 at room temperature based on high-quality patterns collected on a diffractometer (CuKα) equipped with a spinning capillary, with 2θ calibrated using NIST or other appropriate standards. form The diffraction peak positions for 2 are shown in Table 1 and Table 1A.

[0015] Table 1. Compound 1 free base monohydrate form Characteristic diffraction peak positions for 2 [Table 1]

[0016] Table 1A. Compound 1 free base monohydrate form Peak list about 2 [Table 2]

[0017] Compound 1 free base monohydrate form 2 may be characterized by an X-ray diffraction pattern having at least one peak selected from the peaks listed in Table 1A.

[0018] Compound 1 free base monohydrate form 2 may be characterized by an X-ray diffraction pattern substantially as shown in FIG.

[0019] Table 2 shows the free base monohydrate of Compound 1. form Single crystal X-ray data for 2 is shown. Table 2. Compound 1 free base monohydrate form Single crystal X-ray data for 2 [Table 3]

[0020] Table 3 shows the free base monohydrate of Compound 1. form The atomic coordinates for 2 are shown. Table 3. Free base hydrate of Compound 1 form Atomic coordinates of 2 [Table 4]

[0021] The ssNMR spectrum of the free base monohydrate of Compound 1 is shown in Figure 1A. form ssNMR of 2 gives the following peaks: [Table 5]

[0022] Compound 1 free base monohydrate form The FT-IR spectrum of 2 is shown in Figure 1B. The FTIR of the free base monohydrate of compound 1 gives at least the following peaks: [Table 6]

[0023] Compound 1 free base monohydrate form The DSC thermogram of 2 is shown in Figure 1C.

[0024] Compound 1 free base monohydrate form The TGA thermogram of 2 is shown in Figure 1D.

[0025] Compound 1 free base monohydrate form The FT-Raman spectrum of 2 is shown in Figure IE. The FT-Raman spectrum of the free base monohydrate of compound 1 gives at least the following peaks: [Table 7]

[0026] Compound 1 free base monohydrate form 2 was substantially pure based on the weight of the compound as determined by HPLC (High Performance Liquid Chromatography). form For example, the free base monohydrate of Compound 1 may be present in a concentration of about 90% or more, i.e., may have a purity of about 90% or more. form 2 may have a purity of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%. The remaining material may be another solid form of Compound 1. formand / or may contain reaction impurities and / or processing impurities resulting from its production.

[0027] Compound 1 free base monohydrate form Another solid of 2 and compound 1 form Also within the scope of the present invention are mixtures of Compound 1 with less than 90% of the free base monohydrate of Compound 1, based on the weight of the mixture. form For example, the mixture may comprise 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or about 5% by weight of the free base monohydrate of Compound 1. form It may include 2.

[0028] Compound 1 free base In one embodiment, the present disclosure provides a crystalline form of Compound 1 (free base). form This is referred to herein as form 4. The free base of Compound 1 form 4 has desirable operational and stability properties sufficient to allow for the manufacture of solid dosage forms on a commercial scale.

[0029] of the free base of Compound 1 form 4 may be characterized by an X-ray diffraction pattern having one or at least one peak selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0° 2θ ± 0.2° 2θ. form 4 may also be characterized by an X-ray diffraction pattern having two peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0° 2θ ± 0.2° 2θ. form 4 may also be characterized by an X-ray diffraction pattern having three peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0° 2θ ± 0.2° 2θ. form4 may also be characterized by an X-ray diffraction pattern having four peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0° 2θ ± 0.2° 2θ. form 4 may also be characterized by an X-ray diffraction pattern having five peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0° 2θ ± 0.2° 2θ. form 4 may also be characterized by an X-ray diffraction pattern having six peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0° 2θ ± 0.2° 2θ. form 4 may also be characterized by an X-ray diffraction pattern having seven peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0° 2θ ± 0.2° 2θ. form 4 may also be characterized by an X-ray diffraction pattern with angles of 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0 degrees 2θ±0.2 degrees 2θ.

[0030] of the free base monohydrate of Compound 1 at room temperature based on high-quality patterns collected on a diffractometer (CuKα) equipped with a spinning capillary, with 2θ calibrated using NIST or other appropriate standards. form The diffraction peak positions for 4 are shown in Tables 4 and 4A.

[0031] Table 4. Free base of Compound 1 form Characteristic diffraction peak positions for 4 [Table 8]

[0032] Table 4A. Compound 1 free base form Peak list about 4 [Table 9]

[0033] of the free base of Compound 1 form 4 may be characterized by an X-ray diffraction pattern having at least one peak selected from the peaks listed in Table 4A.

[0034] of the free base of Compound 1 form 4 may be characterized by an X-ray diffraction pattern substantially as shown in FIG.

[0035] Table 5 shows the free base of Compound 1. form Single crystal X-ray data for 4 is shown. Table 5. Compound 1 free base form Single crystal X-ray data for 4 [Table 10]

[0036] Table 6 shows the free base of Compound 1. form The atomic coordinates for 4 are shown. Table 6. Compound 1 free base form Atomic coordinates of 4 [Table 11]

[0037] The ssNMR spectrum is shown in Figure 2A. form 4 gives rise to the following peaks: [Table 12]

[0038] of the free base of Compound 1 form The DSC thermogram of 4 is shown in Figure 2B.

[0039] of the free base of Compound 1 form The TGA thermogram of 4 is shown in Figure 2C.

[0040] Amorphous Compound 1 free base is also within the scope of the present invention. The PXRD of amorphous Compound 1 free base is shown in Figure 3. The solid state NMR of amorphous Compound 1 free base is shown in Figure 3A. The ssNMR of amorphous Compound 1 free base gives the following peaks: [Table 13]

[0041] The FT-IR spectrum of amorphous Compound 1 free base is shown in Figure 3B. The FT-IR spectrum of amorphous Compound 1 free base gave the following peaks: [Table 14]

[0042] The FT-Raman spectrum of amorphous Compound 1 free base is shown in Figure 3C. The FT-Raman spectrum of amorphous Compound 1 free base gives the following peaks: [Table 15]

[0043] of the free base of Compound 1 form 4 is a substantially pure compound having a purity of about 90% or greater based on the weight of the compound as determined by HPLC. form For example, the free base of Compound 1 may be form 4 may have a purity of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%. The remaining material may be another solid form of Compound 1. form and / or may contain reaction impurities and / or processing impurities resulting from the manufacture thereof.

[0044] of the free base of Compound 1 form Another solid of 4 and compound 1 form Also within the scope of the present invention are mixtures of Compound 1. In these embodiments, such mixtures contain less than 90% of the free base of Compound 1, based on the weight of the mixture. formFor example, the mixture may contain 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or about 5% by weight of the free base of Compound 1. form 4 may be included in the mixture.

[0045] The amorphous Compound 1 free base is substantially pure, having a purity of about 90% or greater, based on the weight of the compound, as determined by HPLC. form For example, the amorphous Compound 1 free base may have a purity of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%. The remaining material may be another solid form of Compound 1. form and / or may contain reaction impurities and / or processing impurities resulting from its production.

[0046] Amorphous Compound 1 free base and another solid form of Compound 1 form Also within the scope of the present invention are mixtures of amorphous Compound 1. In these embodiments, such mixtures may contain less than 90% amorphous Compound 1 free base, based on the weight of the mixture. For example, the mixtures may contain 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or about 5% amorphous Compound 1 free base by weight.

[0047] MSA salt of compound 1 In one embodiment, the present disclosure provides a crystalline form of the methanesulfonic acid (MSA) salt of Compound 1. form In one aspect, a crystal of the MSA salt of Compound 1 form In another embodiment, the crystalline form of the MSA salt of Compound 1 is form is non-hydrated (i.e., anhydrous). In yet another aspect, the crystalline form of the MSA salt of Compound 1 form is non-solvated and non-hydrated (i.e., anhydrous).

[0048] In a preferred embodiment of the present invention, the MSA salt of Compound 1 is a mono-MSA salt of Compound 1. In a particularly preferred embodiment, the crystal of the mono-MSA salt of Compound 1 formis used herein form 1. The mono-MSA salt of Compound 1, particularly the mono-MSA salt of Compound 1, form 1 has high oral bioavailability compared to the free base of Compound 1 when administered as a solid dosage form.

[0049] MSA salt of compound 1 form Compound 1 may be characterized by an X-ray diffraction pattern having one or at least one peak selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0° 2θ ± 0.2° 2θ. form Compound 1 may also be characterized by an X-ray diffraction pattern having two peaks selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0° 2θ ± 0.2° 2θ. form Compound 1 may also be characterized by an X-ray diffraction pattern having three peaks selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0° 2θ ± 0.2° 2θ. form Compound 1 can also be characterized by an X-ray diffraction pattern having four peaks selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0° 2θ ± 0.2° 2θ. form Compound 1 can also be characterized by an X-ray diffraction pattern having five peaks selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0° 2θ ± 0.2° 2θ. form Compound 1 may also be characterized by an X-ray diffraction pattern having six peaks selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0° 2θ ± 0.2° 2θ. form Compound 1 may also be characterized by an X-ray diffraction pattern having seven peaks selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0° 2θ ± 0.2° 2θ. form1 may also be characterized by an X-ray diffraction pattern with peaks at 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0 degrees 2θ±0.2 degrees 2θ.

[0050] of the MSA salt of compound 1 at room temperature based on high-quality patterns collected on a diffractometer (CuKα) equipped with a spinning capillary, with 2θ calibrated using NIST or other appropriate standards. form The diffraction peak positions for 1 are shown in Tables 7 and 7A.

[0051] Table 7. MSA salt of Compound 1 form Characteristic diffraction peak positions for 1 [Table 16] Table 7A. MSA salt of Compound 1 form Peak list about 1 [Table 17]

[0052] MSA salt of compound 1 form 1 may be characterized by an X-ray diffraction pattern having at least one peak selected from the peaks listed in Table 7A.

[0053] MSA salt of compound 1 form 1 may be characterized by an X-ray diffraction pattern substantially as shown in FIG.

[0054] Table 8 shows the MSA salt of Compound 1 form Single crystal X-ray data for 1 is shown. Table 8: MSA salt of Compound 1 form Single crystal X-ray data for 1 [Table 18]

[0055] Table 9 shows the MSA salt of Compound 1 form The atomic coordinates of 1 are shown. Table 9. MSA salt of compound 1 form Atomic coordinates of 1 [Table 19]

[0056] MSA salt of compound 1 form The ssNMR of 1 is shown in Figure 4A. form ssNMR of 1 gives the following peaks: [Table 20]

[0057] MSA salt of compound 1 form The FT-IR spectrum of 1 is shown in Figure 4B. form 1 gives rise to the following FT-IR peaks: [Table 21]

[0058] MSA salt of compound 1 form The DSC thermogram of 1 is shown in Figure 4C. form The DSC thermogram of 1 shows a variable endothermic transition at ∼245–249 °C, corresponding to dissolution with decomposition. form 1 is a crystalline anhydrous material with melting and decomposition at approximately 245-249°C (onset) (based on DSC endotherm).

[0059] MSA salt of compound 1 form The FT-Raman spectrum of 1 is shown in Figure 4D. Representative FT-Raman peaks are shown in the table below: [Table 22]

[0060] MSA salt of compound 1 form The TGA thermogram of 1 is shown in Figure 4E. form The TGA thermogram of 1 shows anhydrous solubility essentially free of water and residual solvent. form matches.

[0061] Within the scope of the present invention are amorphous forms of the MSA salt of Compound 1. form The PXRD of the MSA salt of amorphous Compound 1 is shown in Figure 5. The ssNMR spectrum of the MSA salt of amorphous Compound 1 is shown in Figure 5A. The MSA salt of amorphous Compound 1 gives rise to the following ssNMR peaks: [Table 23]

[0062] The FT-Raman spectrum of the MSA salt of amorphous Compound 1 is shown in Figure 5B. Representative peaks are shown in the table below. [Table 24]

[0063] MSA salt of compound 1 form 1 was substantially pure as determined by HPLC. form The MSA salt of Compound 1 may be present in a concentration of about 90% or more, i.e., may have a purity of about 90% or more based on the weight of the compound. form 1 may have a purity of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%. The remaining material may be another solid form of Compound 1. form and / or may contain reaction and / or processing impurities resulting from its production.

[0064] MSA salt of compound 1 form 1 and another solid of compound 1 form Also within the scope of the present invention are mixtures of the MSA salt of Compound 1. In these embodiments, such mixtures contain less than 90% of the MSA salt of Compound 1, based on the weight of the mixture. formFor example, the mixture may comprise 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or about 5% by weight of the MSA salt of Compound 1. form It may include 1.

[0065] The amorphous MSA salt of Compound 1 was substantially pure as determined by HPLC. form The remaining material may be present in a concentration of about 90%, i.e., about 90% or greater purity based on the weight of the compound. For example, the MSA salt of amorphous Compound 1 may have a purity of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%. form and / or may contain reaction and / or processing impurities resulting from its production.

[0066] Amorphous MSA salt of Compound 1 and other solids of Compound 1 form Also within the scope of the present invention are mixtures of the MSA salt of amorphous Compound 1. In these embodiments, such mixtures may contain less than 90% of the MSA salt of amorphous Compound 1, based on the weight of the mixture. For example, the mixture may contain 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or about 5% of the MSA salt of amorphous Compound 1 by weight of the mixture.

[0067] Methanesulfonate salt (MSA salt) hydrate of compound 1 In one embodiment, the present disclosure provides a solid that is a monohydrate. form The methanesulfonic acid (MSA salt) of compound 1 of the formula (I) is used. For example, the solid form The monohydrate of the MSA salt of Compound 1 contains approximately one molecule of water per molecule of the MSA salt of Compound 1.

[0068] In a preferred embodiment, a solid of the monohydrate MSA salt of Compound 1 form is a crystal of the MSA salt monohydrate of compound 1. form The MSA salt monohydrate of Compound 1 has a desirable stability profile.

[0069] In a preferred embodiment of the present invention, the monohydrate of the MSA salt of Compound 1 is a crystalline monohydrate of the MSA salt of Compound 1. form which is herein referred to as the MSA salt monohydrate of Compound 1 form 2. The MSA salt monohydrate of Compound 1 form 2 is physically stable at room temperature and 95% relative humidity for 5 days.

[0070] MSA salt monohydrate of compound 1 form 2 may be characterized by an X-ray diffraction pattern having one or at least one peak selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20.5, 22.2, 23.2, and 24.1°2θ±0.2°2θ. form 2 can be characterized by an X-ray diffraction pattern having two peaks selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20.5, 22.2, 23.2, and 24.1°2θ±0.2°2θ. form 2 can be characterized by an X-ray diffraction pattern having three peaks selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20.5, 22.2, 23.2, and 24.1°2θ±0.2°2θ. form 2 can be characterized by an X-ray diffraction pattern having four peaks selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20.5, 22.2, 23.2, and 24.1°2θ±0.2°2θ. form 2 can be characterized by an X-ray diffraction pattern having five peaks selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20.5, 22.2, 23.2, and 24.1°2θ±0.2°2θ. form 2 can be characterized by an X-ray diffraction pattern having six peaks selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20.5, 22.2, 23.2, and 24.1°2θ±0.2°2θ. form2 can be characterized by an X-ray diffraction pattern having seven peaks selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20.5, 22.2, 23.2, and 24.1°2θ±0.2°2θ. form 2 can be characterized by an X-ray diffraction pattern having eight peaks selected from 9.3, 11.8, 14.3, 15.6, 17.7, 20.5, 22.2, 23.2, and 24.1°2θ±0.2°2θ. form 2 may be characterized by an X-ray diffraction pattern with peaks at 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.

[0071] of the MSA salt monohydrate of compound 1 at room temperature based on high-quality patterns collected on a spinning capillary diffractometer (CuKα) with 2θ calibrated using NIST or other appropriate standards. form The diffraction peak positions for 2 are shown in Table 10 and Table 10A.

[0072] Table 10. MSA salt monohydrate of compound 1 form Characteristic diffraction peak positions for 2 [Table 25] Table 10A. MSA salt monohydrate of Compound 1 form Peak list about 2 [Table 26]

[0073] MSA salt monohydrate of compound 1 form 2 may be characterized by an X-ray diffraction pattern having at least one peak selected from the peaks listed in Table 10A.

[0074] MSA salt monohydrate of compound 1 formCompound 2 can also be characterized by an X-ray diffraction pattern substantially as shown in Figure 6. form The single crystal structure of 2 has been successfully determined. The crystal system is orthorhombic and the space group is P212121. The lattice parameters and calculated volume are: a = 10.44447(13) Å, b = 12.99925(13) Å, c = 18.94899(14) Å, α = 90°, β = 90°, γ = 90°, V = 2572.71(5) Å. 3 The formula weight is 525.02g mol -1 (Z=4) and 1.355 g cm -3 The density (calculated value) of the MSA salt monohydrate of compound 1 was form 2 is the monohydrate of the mesylate (MSA) salt of Compound 1. form The XRPD pattern of 2 showed the material to consist of crystalline material.

[0075] MSA salt monohydrate of compound 1 form The DSC thermogram of 2 is shown in Figure 6A.

[0076] MSA salt monohydrate of compound 1 form The TGA thermogram of 2 is shown in Figure 6B.

[0077] MSA salt monohydrate of compound 1 form TGA data for 2 showed a weight loss of about 3.5 wt % by approximately 100° C. The weight loss corresponds to about 1 mole of water per mole of API.

[0078] MSA salt monohydrate of compound 1 form The DSC data for 2, as seen in TGA, reveals that the broad endotherm observed in the range of approximately 90-150 °C corresponds to the MSA salt monohydrate of compound 1. form It was shown that this corresponds to the dehydration of 2.

[0079] Compound 1MSA monohydrate form 2 was substantially pure as determined by HPLC. formFor example, the MSA monohydrate of Compound 1 may be present in a purity of about 90% or more, based on the weight of the compound. form 2 may have a purity of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%. The remaining material may be another solid form of Compound 1. form and / or may contain reaction and / or processing impurities resulting from its production.

[0080] Compound 1MSA monohydrate form Another solid of 2 and compound 1 form Also within the scope of the present invention are mixtures of Compound 1 MSA monohydrate and 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or about 5% by weight of the mixture. In these embodiments, such mixtures may contain less than 90% amorphous MSA salt of Compound 1, based on the weight of the mixture. For example, the mixture may contain 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or about 5% by weight of the mixture of MSA monohydrate of Compound 1. form It may include 2.

[0081] The crystals described herein form (e.g., the free base of Compound 1) form 4. Hydrate of the free base of Compound 1 form 2. MSA salt of compound 1 form 1. MSA salt monohydrate of compound 1 form 2) The sample may be provided in a substantially pure homogeneous phase, but may contain only one single crystal. form is present in a predominant amount, and optionally one or more other crystals form indicates that small amounts of more than one crystal may be present in the sample. form The presence of one or more crystalline compounds in a sample can be determined by techniques such as powder X-ray diffraction (PXRD) or solid-state nuclear magnetic resonance spectroscopy (ssNMR). For example, the presence of extra peaks in a comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern can indicate the presence of one or more crystalline compounds in a sample. formSimulated PXRD can be calculated from single crystal X-ray data. See Smith, DK, "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963). Preferably, crystal form The crystals have a substantially pure homogeneous phase in which the experimentally measured PXRD pattern exhibits extra peaks not present in the simulated PXRD pattern that account for less than 10%, preferably less than 5%, and more preferably less than 2% of the total peak area. Most preferred are crystals having a substantially pure homogeneous phase in which the experimentally measured PXRD pattern exhibits extra peaks not present in the simulated PXRD pattern that account for 1% or less of the total peak area. form is.

[0082] The various solids described herein form can be distinguished from one another by using a variety of analytical techniques known to those skilled in the art, including, but not limited to, solid-state magnetic resonance (ssNMR) spectroscopy, X-ray powder diffraction (PXRD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA).

[0083] Those skilled in the art will understand that an X-ray diffraction pattern may be obtained with measurement errors depending on the measurement conditions used. In particular, it is generally known that the intensities in an X-ray diffraction pattern may vary depending on the measurement conditions used. It should also be understood that the relative intensities may also vary depending on the experimental conditions, so the exact order of the intensities should not be considered. Furthermore, the measurement error of the diffraction angle for a conventional X-ray diffraction pattern is usually about ±0.2°2θ, and it should be considered that such a measurement error exists in the diffraction angle. As a result, the crystal of the present invention formis a crystal that provides an X-ray diffraction pattern that is completely identical to the X-ray diffraction pattern shown in the accompanying drawings disclosed herein. form It should be understood that the present invention is not limited to any crystal that provides an X-ray diffraction pattern substantially identical to the pattern disclosed in the accompanying drawings. form Also within the scope of the present invention are the ability to determine substantial identity in terms of X-ray diffraction patterns within the skill of one in the art.

[0084] The solid form of Compound 1 described herein form (and its hydrates and salts form Solid form ) may be formulated into pharmaceutical compositions and / or used in therapeutic and / or prophylactic methods. These methods include administering solid forms of Compound 1 form administration of a solid hydrate of Compound 1 (e.g., a monohydrate of Compound 1); form , a solid MSA salt of Compound 1 form and the solid MSA salt hydrate of compound 1 form These include, but are not limited to, administering the compound of formula (I) alone or in combination with one or more other pharmaceutically active agents, such as agents that may be useful in treating the diseases described herein.

[0085] Treatment application The compounds and pharmaceutical compositions of the present invention are useful in the treatment or prevention of any disease or condition that is sensitive to the enzymatic activity of IDO. These include viral and other infectious diseases (e.g., skin infections, GI infections, urinary tract infections, genitourinary infections, systemic infections), proliferative diseases (e.g., cancer), and autoimmune diseases (e.g., rheumatoid arthritis, lupus). The compounds and pharmaceutical compositions can be administered to animals, preferably mammals (e.g., livestock, cats, dogs, mice, rats), more preferably humans. Any method of administration can be used to deliver the compounds or pharmaceutical compositions to patients. In some embodiments, the compounds or pharmaceutical compositions are administered orally. In other embodiments, the compounds or pharmaceutical compositions are administered parenterally.

[0086] The compounds of the present invention can modulate the activity of the enzyme indoleamine-2,3-dioxygenase (IDO). The term "modulate" is meant to refer to the ability to increase or decrease the activity of the enzyme or receptor. Thus, the compounds of the present invention can be used in methods of modulating IDO by contacting the enzyme with any one or more compounds or compositions. In certain embodiments, the compounds of the present invention can act as inhibitors of IDO. In further embodiments, the compounds of the present invention can be used to modulate the activity of IDO in cells or individuals in need of enzyme modulation by administering a modulating (e.g., inhibiting) amount of the compound of the present invention.

[0087] Compound 1 can inhibit the activity of the enzyme indoleamine-2,3-dioxygenase (IDO). For example, Compound 1 can be used to inhibit the activity of IDO in cells or individuals in need of modulation of the enzyme by administering an inhibitory amount of Compound 1.

[0088] The present invention further provides a method for inhibiting the degradation of tryptophan in a system containing cells that express IDO, such as tissue, living organ or cell culture.In some embodiments, the present invention provides a method for modifying (e.g., increasing) extracellular tryptophan levels in mammals by administering an effective amount of Compound 1 in the compositions provided herein.Methods for measuring tryptophan levels and tryptophan degradation are common methods for those skilled in the art.

[0089] The present invention is a method of inhibiting immunosuppression, e.g., IDO-mediated immunosuppression, by administering to a patient an effective amount of Compound 1. IDO-mediated immunosuppression is associated with, for example, cancer, tumor growth, metastasis, viral infection, and viral replication.

[0090] The present invention provides a therapeutically effective amount or dose of a solid form of Compound 1 (or a hydrate or salt thereof) of the present invention. formor a pharmaceutical composition thereof to an individual (e.g., a patient) in need of such treatment, thereby providing a method for treating a disease associated with IDO activity or expression (e.g., abnormal activity and / or overexpression). Examples of diseases include any disease, disorder, or condition directly or indirectly associated with IDO enzyme expression or activity, e.g., overexpression or abnormal activity. IDO-associated diseases can also include any disease, disorder, or condition that can be prevented, alleviated, or cured by modulating enzyme activity. Examples of IDO-associated diseases include cancer, viral infections, e.g., HIV infection, HCV infection, depression, neurodegenerative disorders, e.g., Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplants (e.g., organ transplant rejection), and autoimmune diseases, e.g., asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus.

[0091] As used herein, the term "cell" refers to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell may be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell may be a cell in cell culture. In some embodiments, an in vivo cell is a cell that is living within an organism, such as a mammal.

[0092] As used herein, the term "contacting" refers to bringing together the specified components in an in vitro system or an in vivo system. For example, "contacting" an IDO enzyme with a compound of the present invention refers to administering a compound of the present invention to an individual or patient, e.g., a human, having IDO, as well as administering an individual of Compound 1 of the present invention to an individual or patient, e.g., a human. form The present invention relates to the introduction of a nucleotide sequence into a sample containing cells or into a purified preparation containing the IDO enzyme.

[0093] The term "IDO inhibitor" refers to a drug that inhibits the activity of indoleamine 2,3-dioxygenase (IDO), thereby reversing IDO-mediated immunosuppression. IDO inhibitors can inhibit IDO1 and / or IDO2 (INDOL1). IDO inhibitors may be reversible or irreversible IDO inhibitors. A "reversible IDO inhibitor" is a compound that reversibly inhibits IDO enzyme activity at the catalytic or non-catalytic site, and an "irreversible IDO inhibitor" is a compound that reversibly inactivates IDO enzyme activity.

[0094] Solids of Compound 1 of the Present Invention form The types of cancer that can be treated using include, but are not limited to, brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, blood cancer, lung cancer, and bone cancer. Examples of such cancer types include neuroblastoma, intestinal cancer, e.g., rectal cancer, colon cancer, familial polyposis coli and hereditary non-polyposis, colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenoma malignum, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, malignant melanoma, brain tumors, e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, These include, but are not limited to, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0095] Thus, according to another embodiment, the present invention provides a solid form of the compound of the present invention. formAlternatively, a method for treating an autoimmune disease by providing the composition to a patient in need thereof is provided. Examples of such autoimmune diseases include collagen diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sharp's syndrome, CREST syndrome (calcinosis, Raynaud's syndrome, esophageal motility disorders, telangiectasia), dermatomyositis, vasculitis (Wegener's granulomatosis; Morbus Wegener's), and Sjogren's syndrome, kidney diseases such as Goodpasture's syndrome, rapidly progressive glomerulonephritis and membranochondrogenic glomerulonephritis type II, endocrine diseases such as type I diabetes, autoimmune polyendocrine disease type I (APECED), autoimmune parathyroid disease, pernicious anemia, gonadal failure, idiopathic adrenal insufficiency, hyperthyroidism, Hashimoto's disease, and primary myxedema, skin diseases such as pemphigus vulgaris, bullous pemphigoid, herpes gestationis, epidermolysis bullosa, and erythema multiforme major, and liver diseases. Diseases include, for example, primary biliary cirrhosis, autoimmune cholangitis, autoimmune type 1 hepatitis, autoimmune type 2 hepatitis, primary sclerosing cholangitis, neurological diseases such as multiple sclerosis, myasthenia gravis, Lambert-Eaton myasthenic syndrome, acquired neuromyotonia, Guillain-Barré syndrome (Fisher syndrome), stiff-person syndrome, cerebellar degeneration, ataxia, opsoclonus, sensory neuropathy and achalasia, blood diseases such as autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura (Morbus Werlhof), and autoimmune reaction-related infectious diseases such as AIDS, malaria and Chagas disease.

[0096] One or more additional pharmaceutical agents or treatments, such as antiviral agents, chemotherapeutic or other anti-cancer agents, immunostimulants, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapeutics (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors, may optionally be used in combination with the compounds of the present invention for the treatment of IDO-related diseases, disorders, or conditions. form or the agents may be administered simultaneously or sequentially in separate dosage forms.

[0097] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, but not limited to, nitrogen mustards, ethylenimine derivatives, alkylsulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0098] Suitable agents for use in combination with the compounds of the invention in the treatment of malignant melanoma include dacarbazine (DTIC), optionally in combination with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; cisplatin, vinblastine, and DTIC, temozolomide, or YERVOY®. The compounds of the invention may also be combined with immunotherapeutic agents, such as cytokines, e.g., interferon alpha, interleukin 2, and tumor necrosis factor (TNF), in the treatment of malignant melanoma.

[0099] The compound of the present invention can be used in combination with vaccine therapy in the treatment of melanoma.Anti-melanoma vaccine is similar in some respects to the antiviral vaccine that can be used to prevent diseases caused by viruses, such as polio, mizzle and mumps.Weakened melanoma cells or melanoma cells (so-called antigens) can also be administered to stimulate the body's immune system to destroy melanoma cells.

[0100] Malignant melanoma limited to the arms or legs may be treated with a combination of drugs, including one or more compounds of the present invention, using the hyperthermic limb perfusion technique. This treatment protocol involves temporarily separating the involved limb from the rest of the body and injecting high doses of chemotherapy into the limb's arterial bloodstream, providing a high dose to the tumor area without exposing internal organs to doses that could cause serious side effects. The fluid is usually warmed to 102°-104°F. Melphalan is the drug most frequently used in this chemotherapy. It may be administered with another drug called tumor necrosis factor (TNF).

[0101] Suitable chemotherapy or other anti-cancer agents include, for example, antimetabolites (such as, for example, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as, but not limited to, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0102] Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and derivatives thereof (e.g., vinca alkaloids, antitumor agents, antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (taxol), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide, and teniposide.

[0103] Other cytotoxic agents include Navelbine, CPT-11, Anastrozole, Letrazole, Capecitabine, Reloxafine and Droloxafine.

[0104] Suitable cytotoxic agents are, for example, epidophyllo toxins; anti-neoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitory agents; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0105] Other anti-cancer agents include antibody therapeutics (e.g., trastuzumab (HERCEPTIN (登録商標) )), antibodies against costimulatory molecules (e.g., CTLA-4, 4-1BB and PD-1), or antibodies against cytokines (IL-1O or TGF-β).

[0106] Other anti-cancer agents also include those that block immune cell migration to chemokine receptors (eg, CCR2 and CCR4), eg, antagonists.

[0107] Other anti-cancer agents include those that enhance the immune system (eg, adjuvants or adoptive T-cell transfer).

[0108] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

[0109] The pharmaceutical compositions of the present invention may optionally include at least one signal transduction inhibitor (STI), which is an agent that selectively inhibits one or more essential steps in a signal transduction pathway for the normal function of cancer cells, thereby resulting in apoptosis. Suitable STIs include, but are not limited to: (i) bcr / abl kinase inhibitors, such as STI 571 (GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors, such as 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 farnesyltransferase inhibitors (FTIs), e.g., L-744,832 (Kohl et al., Nat. Med., 1(8):792-797(1995)); (iv) inhibitors of Akt family kinases or the Akt pathway, such as rapamycin (e.g., Sekulic et al., Cancer Res., 60:3504-3513(2000)); (v) cell cycle kinase inhibitors, such as flavopiridol and UCN-O1 (see, e.g., Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56(2003)); and (vi) phosphatidylinositol kinase inhibitors, such as LY294002 (see, e.g., Vlahos et al., J. Biol. Chem., 269:5241-5248(1994)). Alternatively, at least one STI and at least one IDO inhibitor may be present in separate pharmaceutical compositions. In certain embodiments of the present invention, at least one IDO inhibitor (e.g., Compound I or a solid form thereof) may be present in separate pharmaceutical compositions. form , or a solid of its hydrate or salt form) and at least one STI may be administered to a patient simultaneously or sequentially. In other words, the at least one IDO inhibitor may be administered first, the at least one STI may be administered first, or the at least one IDO inhibitor and at least one STI may be administered simultaneously. Furthermore, when more than one IDO inhibitor and / or STI is used, the compounds may be administered in any order.

[0110] The present invention provides a method for treating a chronic viral infection in a patient, comprising administering to the patient at least one IDO inhibitor (e.g., a solid form of Compound 1 or a hydrate or salt thereof) in a pharmaceutically acceptable carrier. form The present invention further provides a pharmaceutical composition comprising at least one IDO inhibitor of the present invention, optionally at least one chemotherapeutic agent, and optionally at least one antiviral agent. The pharmaceutical composition may comprise at least one IDO inhibitor of the present invention and at least one established (known) IDO inhibitor. In certain embodiments, the at least one IDO inhibitor in the pharmaceutical composition is Compound 1 or a solid form thereof. form , or a solid of its hydrate or salt form is.

[0111] Also provided is a method for treating a chronic viral infection in a patient by administering an effective amount of the pharmaceutical composition.

[0112] In certain embodiments of the present invention, at least one IDO inhibitor and at least one chemotherapeutic agent are administered to patients simultaneously or sequentially.In other words, at least one IDO inhibitor can be administered first, or at least one chemotherapeutic agent can be administered first, or at least one IDO inhibitor and at least one STI can be administered simultaneously.In addition, when one or more IDO inhibitors and / or chemotherapeutic agents are used, the compounds can be administered in any order.Similarly, any antiviral agent or STI can be administered at any time compared to the administration of IDO inhibitor.

[0113] Chronic viral infections that may be treated using the combinatorial therapy of the present invention include, but are not limited to, diseases caused by hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella-zoster virus, coxsackievirus, and human immunodeficiency virus (HIV). Of note, parasitic infections (e.g., malaria) may also be treated using the above methods. Compounds known to treat parasitic infections may be added in place of antiviral agents, if appropriate.

[0114] In yet another embodiment, the pharmaceutical composition of the present invention comprising at least one IDO inhibitor can be administered to a patient to prevent arterial restenosis (e.g., arterial restenosis after balloon endoscopy or stent placement).In certain embodiments, the pharmaceutical composition can further comprise at least one taxane (e.g., paclitaxel (taxol); see, for example, Scheller et al., Circulation, 110:810-814(2004)).

[0115] The solid of the present invention form Suitable antiviral agents that may be considered for use in combination with may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral agents.

[0116] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C, which stands for β-L-2',3'-dicreoxy-5-fluoro-citidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and rhodenosine (FddA). Representative and suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Representative and suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nalfenavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0117] Combination with cancer immunotherapy agents Further provided herein is a solid form of Compound 1. form or a solid hydrate or salt of Compound 1 form is administered in combination with one or more cancer immunotherapeutic agents. As used herein, a cancer immunotherapeutic agent, also known as a cancer immunotherapy, is effective in enhancing, stimulating, and / or upregulating an immune response in a patient.

[0118] In one embodiment, the solid form of Compound 1 form or a solid hydrate or salt of Compound 1 form is administered sequentially prior to administration of the cancer immunotherapeutic agent. form or a solid hydrate or salt of Compound 1 form In another embodiment, a solid dose of Compound 1 is administered simultaneously with a cancer immunotherapeutic agent. form or a solid hydrate or salt of Compound 1 form is administered sequentially after the administration of the cancer immunotherapy agent.

[0119] In another embodiment, the solid form of Compound 1 form or a solid hydrate or salt of Compound 1 form may be co-administered with a cancer immunotherapeutic agent.

[0120] Cancer immunotherapeutic agents include, for example, small molecule drugs, antibodies, or other biological or small molecule drugs. Examples of biological cancer immunotherapeutic agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one embodiment, the antibody is a monoclonal antibody. In another embodiment, the monoclonal antibody is a humanized or human antibody.

[0121] In one embodiment, the cancer immunotherapeutic agent is either (i) an agonist of a stimulatory (e.g., costimulatory) receptor or (ii) an antagonist of an inhibitory signal to T cells (e.g., co-inhibitor), both of which result in amplification of antigen-specific T cell responses (often also referred to as immune checkpoint modulators).

[0122] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or costimulatory receptors is the B7 family, which includes 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 costimulatory or costimulatory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, 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, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3 , EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0123] In another embodiment, the cancer immunotherapeutic agent is a cytokine that inhibits or stimulates T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) to stimulate an immune response.

[0124] In one embodiment, the T cell response is determined by administering Compound 1 to a patient. form or a solid hydrate or salt of Compound 1 form, and one or more of (i) proteins that inhibit T cell activation, such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-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. Antagonist of (e.g., immune checkpoint inhibitors ) and (ii) can be stimulated by a combination of agonists of proteins that stimulate 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.

[0125] Compound 1 solids for the treatment of cancer form or a solid hydrate or salt of Compound 1 form Other agents that can be combined with include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the solid phase of Compound 1 form or a solid hydrate or salt of Compound 1 form may be combined with an antagonist of KIR, such as lirilumab.

[0126] Further agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, such as, but not limited to, CSF-1R antagonists, e.g., CSF-1R antagonist antibodies such as RG7155 (e.g., WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (e.g., WO11 / 140249, WO13 / 169264, WO14 / 036357).

[0127] In another embodiment, the solid form of Compound 1 form or a solid hydrate or salt of Compound 1 formmay be used in conjunction with one or more agonist agents that bind positive costimulatory receptors, blockers or antagonists that attenuate signaling through inhibitory receptors, as well as one or more agents that systemically increase the frequency of anti-tumor T cells, agents that suppress intrinsic immune suppressive pathways in the tumor microenvironment (e.g., by blocking binding of inhibitory receptors such as PD-L1 / PD-1 interaction), agents that deplete or inhibit Tregs (e.g., with anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 beads), agents that inhibit metabolic enzymes such as IDO or reverse / restore immune unresponsiveness or depletion of T cells, and agents that initiate innate immune activation and / or inflammation at the tumor site.

[0128] In one embodiment, the cancer immunotherapeutic agent is a CTLA-4 antagonist, e.g., an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY® (ipilimumab) or tremelimumab.

[0129] In another embodiment, the cancer immunotherapeutic agent is a PD-1 antagonist, e.g., an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO® ( Nivolumab ), KEYTRUDA (registered trademark) ( Pembrolizumab ) or MEDI-0680 (AMP-514; WO 2012 / 145493). Cancer immunotherapeutics may also include pidilizumab (CT-011), although its specificity for PD-1 binding is questionable. Another approach to targeting the PD-1 receptor is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224.

[0130] In another embodiment, the cancer immunotherapeutic agent is a PD-L1 antagonist, e.g., an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0131] In another embodiment, the cancer immunotherapeutic agent is a LAG-3 antagonist, for example, an antagonistic LAG-3 antibody.Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218) or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0132] In another embodiment, the cancer immunotherapeutic agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0133] In another embodiment, the cancer immunotherapeutic agent is a GITR agonist, for example, an agonistic GITR antibody.Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683).

[0134] In another embodiment, the cancer immunotherapeutic agent is IDO antagonist.Suitable IDO antagonist includes for example INCB-024360 (WO2006 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximob or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

[0135] In another embodiment, the cancer immunotherapeutic agent is an OX40 agonist, e.g., an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0136] In another embodiment, the cancer immunotherapeutic agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0137] In another embodiment, the cancer immunotherapeutic agent is a CD40 agonist, for example, an agonistic CD40 antibody. In yet another embodiment, the cancer immunotherapeutic agent is a CD40 antagonist, for example, an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0138] In another embodiment, the cancer immunotherapeutic agent is a CD27 agonist, e.g., an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, valilumab.

[0139] In another embodiment, the cancer immunotherapeutic agent is MGA271 (against B7H3) (WO11 / 109400).

[0140] The present invention encompasses pharmaceutical kits useful in the treatment or prevention of, for example, IDO-related diseases or disorders, obesity, diabetes, and other diseases mentioned herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention. Those skilled in the art will readily appreciate that such kits can further include one or more of various conventional pharmaceutical kit components, such as one or more containers containing pharmaceutically acceptable carriers, additional containers, if desired. The kits may also include instructions, such as an insert or label, indicating the amounts of components to be administered, guidelines for administration, and / or guidelines for mixing the components.

[0141] Combination therapy is intended to include administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different times, as well as administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the patient one single dosage form with a fixed ratio of each therapeutic agent, or multiple single dosage forms for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal membranes. The therapeutic agents can be administered by the same or different routes. For example, a first therapeutic agent in a selected combination can be administered by intravenous injection, while another therapeutic agent in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered intravenously. Combination therapy can also include other biologically active ingredients and non-drug therapies (e.g., surgery or radiation therapy) in combination with the administration of the above-mentioned therapeutic agents. If the combination therapy further includes a non-drug treatment, the non-drug treatment can be administered at any suitable time, so long as the beneficial effect resulting from the synergistic action of the combined therapeutic and non-drug treatment is achieved, e.g., in suitable cases, this beneficial effect is achieved even when the non-drug treatment is temporarily suspended, perhaps for days or weeks, from the administration of the therapeutic agent.

[0142] Pharmaceutical Compositions and Dosages The present invention provides a therapeutically effective amount of one or more solids according to the present invention. form and optionally formulated with one or more pharmaceutically acceptable carriers (excipients) and / or diluents, and optionally with one or more additional therapeutic agents as described above.

[0143] The solid of the present invention formFor any of the uses described herein, the compounds may be administered by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained-release or extended-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally (e.g., subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., injectable sterile aqueous or non-aqueous solutions or suspensions)); intranasally, e.g., to the nasal mucosa by inhalation spray; topically, e.g., by cream or ointment; or rectally (e.g., in the form of a suppository). They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the route of administration and standard pharmaceutical practice.

[0144] The term "pharmaceutically acceptable" means that the compound, material, composition, and / or dosage form is suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of ordinary medical judgment, commensurate with a reasonable benefit / risk ratio.

[0145] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, auxiliary (e.g., lubricant, magnesium, calcium, or zinc stearate or stearic acid), or solvent encapsulant, that is involved in carrying or delivering a compound of interest from one organ or part of the body to another organ or part of the body. Each carrier is "acceptable" in the sense of being compatible with the other ingredients in the formulation and not deleterious to the patient.

[0146] The term "pharmaceutical composition" refers to a composition comprising a compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" is a medium, i.e., an adjuvant, excipient, or vehicle generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal, and varies depending on the method of administration and the nature of the dosage form, but includes, for example, a diluent, a preservative, a filler, a flow regulator, a disintegrating agent, a wetting agent, an emulsifier, a suspending agent, a sweetener, a flavor, a fragrance, an antibacterial agent, an antifungal agent, a lubricant, and a dispensing agent.

[0147] Pharmaceutically acceptable carriers are formulated according to many factors well known to those skilled in the art. These include, but are not limited to, the type and nature of the active agent to be formulated; the subject to whom the composition containing the agent 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 various solid and semi-solid dosage forms. Such carriers can contain many different ingredients and additives in addition to the active agent, and such additional ingredients, well known to those skilled in the art, are included in the formulation for various reasons (e.g., stabilization of the active agent, binders, etc.). Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in many readily available sources, such as Allen, Jr. LV, et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0148] The solid of the present invention form The dosage regimen will, of course, vary depending on known factors, such as the pharmacokinetic properties of the particular agent and its method and route of administration; the species, age, sex, health, medical condition and weight of the recipient; the nature and severity of symptoms; type of concomitant treatment; frequency of treatment; route of administration, the patient's renal and hepatic function and the desired effect.

[0149] As a general guide, the daily dosage of each active ingredient, when used to achieve the desired effect, ranges from about 0.001 to about 5000 mg / day, preferably from about 0.01 to about 1000 mg / day, and most preferably from about 0.1 to about 250 mg / day. The most preferred dosage for intravenous administration is in the range of about 0.01 to about 10 mg / kg / minute by continuous infusion. The compounds of the present invention may be administered in a single dose daily, or in divided doses with the total daily dosage being administered two, three, or four times daily.

[0150] The solid of the present invention form is typically administered in admixture with a pharmaceutical diluent, excipient or carrier (collectively referred to herein as a pharmaceutical carrier) appropriately selected in accordance with common pharmaceutical practice depending on the desired form of administration, e.g., oral tablets, capsules, elixirs, syrups, and the like.

[0151] Dosage forms (pharmaceutical compositions) suitable for administration contain about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.1 to 95% by weight of the total weight of the composition.

[0152] A typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and packed into a No. 1 gelatin capsule.

[0153] A typical injectable formulation is prepared by aseptically placing at least one compound of the present invention (250 mg) into a vial, aseptically lyophilizing it, and sealing it. At the time of use, the contents of the vial are mixed with 2 mL of saline to prepare an injectable formulation.

[0154] The present invention includes within its scope pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the invention as the active ingredient, alone or in combination with a pharmaceutical carrier. form can be used alone or in combination with other compounds of the invention or one or more other therapeutic agents, such as an antidiabetic agent or another pharmacologically active substance.

[0155] Regardless of the route of administration selected, the solid form can be administered in pharmaceutically acceptable dosages by conventional methods known to those skilled in the art. form It is formulated in

[0156] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient that is not toxic to the patient and is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0157] The selected dosage level will depend upon a variety of factors, including the activity of the compound of the invention employed, the route of administration of the compound, the time of administration, the rate of excretion or metabolism, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or materials used in combination with the compound of the invention employed, the age, sex, weight, symptoms, health and medical history of the patient being treated, and factors known in the medical arts.

[0158] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start dosages of the compounds of the invention used in the pharmaceutical composition at lower levels than needed to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0159] Generally, a suitable daily dose of the compound will be the lowest effective dose that produces a therapeutic effect in an amount of the compound. Such an effective amount will generally depend upon the factors described above.

[0160] If necessary, the effective daily dose of the compound may be administered as a single dose at appropriate intervals throughout the day, as appropriate. formIn some embodiments of the invention, the dosage is a single administration per day.

[0161] While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0162] (definition) Certain aspects of the present invention relate to crystalline form Regarding crystals form produces an X-ray diffraction pattern with a sharp maximum.

[0163] As used herein, "amorphous" refers to a solid of molecules and / or ions that is not crystalline. form Amorphous solids do not exhibit X-ray diffraction patterns with sharp maxima.

[0164] As used herein, a "hydrate" refers to a crystalline form of a molecule that further contains water incorporated into the crystalline structure. form The water molecules in a hydrate may be in an ordered and / or disordered arrangement. Hydrates may contain either stoichiometric or non-stoichiometric amounts of water molecules.

[0165] As used herein, the term "patient" refers to an organism treated by the methods of the present invention, preferably including, but not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably humans.

[0166] As used herein, the term "effective amount" refers to the amount of a drug or pharmaceutical preparation, i.e., the amount of a compound of the present invention, that elicits the biological or medicinal response of a tissue, organ, animal, or human that is anticipated, for example, by a researcher or medical professional. Furthermore, the term "therapeutically effective amount" refers to any amount that results in an improvement in the treatment, cure, prevention, or mitigation of a disease, disorder, deficiency, or side effect, or a reduction in the rate of progression of a disease or disorder, when compared to a corresponding patient who has not received such amount. An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited by the formulation or route of administration. The term also encompasses within its scope an amount effective to enhance normal physiological function.

[0167] As used herein, the term "treating" or "treatment" encompasses the treatment of a disease state in a mammal, particularly a human, and includes: (a) preventing a disease state from occurring in a mammal, particularly where the mammal has not yet been diagnosed with the disease but is susceptible to developing the disease state; (b) inhibiting a disease state, i.e., arresting its onset; and / or (c) alleviating a disease state, i.e., causing regression of the disease state.

[0168] Aspects Aspect 1. Crystals form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide form 4. Embodiment 2. The crystal of embodiment 1, characterized by a powder X-ray diffraction pattern including at least one peak selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0°2θ±0.2°2θ. form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide form 4. Embodiment 3. The crystal of embodiment 1, characterized by a powder X-ray diffraction pattern including two peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0 °2θ ± 0.2 °2θ. form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide form 4. Embodiment 4. The crystal of embodiment 1, characterized by a powder X-ray diffraction pattern including three peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0°2θ±0.2°2θ. form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide form 4. Embodiment 5. The crystal of embodiment 1, characterized by a powder X-ray diffraction pattern including four peaks selected from 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0 °2θ ± 0.2 °2θ. form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide form 4. Aspect 6. Crystals form of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate form 2. Embodiment 7. The crystal of embodiment 6, characterized by a powder X-ray diffraction pattern including at least one peak selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6 °2θ±0.2 °2θ. form of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate form 2. Embodiment 8. The crystal of embodiment 6, characterized by a powder X-ray diffraction pattern including two peaks selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6°2θ±0.2°2θ. form of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate form 2. Embodiment 9. The crystal of embodiment 6, characterized by a powder X-ray diffraction pattern including three peaks selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6°2θ±0.2°2θ. form of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate form 2. Embodiment 10: The crystal of embodiment 6, characterized by a powder X-ray diffraction pattern including four peaks selected from 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6°2θ±0.2°2θ. form of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate form 2. Aspect 11. Crystals form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid form 1. Embodiment 12. The crystal of embodiment 11, characterized by a powder X-ray diffraction pattern including at least one peak selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0°2θ±0.2°2θ. form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid form 1. Embodiment 13: The crystal of embodiment 11, characterized by a powder X-ray diffraction pattern including two peaks selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0°2θ±0.2°2θ. form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid form 1. Embodiment 14: The crystal of embodiment 11, characterized by a powder X-ray diffraction pattern including three peaks selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0°2θ±0.2°2θ. form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid form 1. Embodiment 15: The crystal of embodiment 11, characterized by a powder X-ray diffraction pattern including four peaks selected from 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6, and 24.0°2θ±0.2°2θ. form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid form 1. Aspect 16. Amorphous quality of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid. Aspect 17. crystal form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide form 4; crystal formof (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate form 2; or crystal form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid form 1; or combinations thereof; and a pharmaceutically acceptable carrier. Aspect 18. Amorphous quality (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, amorphous quality (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid or combinations thereof, 18. The pharmaceutical composition of embodiment 17, further comprising: Aspect 19. Amorphous quality 18. The pharmaceutical composition of embodiment 17, further comprising (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide of the formula: Aspect 20. A therapeutically effective amount of: crystal form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide form 4; crystal form of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate form 2; or crystal form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid form 1; or administering the combination to a patient in need of cancer treatment. A method for treating cancer in a patient in need thereof. Embodiment 21. The method of embodiment 20, wherein the cancer is cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (e.g., melanoma and basal cell carcinoma), mesothelium, white blood cells (e.g., lymphoma and leukemia), esophagus, breast, muscle, connective tissue, lung (e.g., small cell lung cancer and non-small cell carcinoma), adrenal gland, thyroid, kidney, or bone; or glioma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma (e.g., Kaposi's sarcoma), choriocarcinoma, basal cell carcinoma of the skin, or seminoma. Aspect 22. Amorphous quality (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, amorphous quality (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid, or a combination thereof. Embodiment 23 The method of embodiment 20, further comprising an immune checkpoint inhibitor. Embodiment 24 The method of embodiment 20, wherein the immune checkpoint inhibitor comprises ipilimumab (YERVOY®), nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), or a combination thereof. 25. Indoleamine 2,3-dioxygenase is crystal form (R)-N-(4-chlorophenyl)-2-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide form 4; crystal formof (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate form 2; or crystal form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid form 1; Or a combination of these, Optionally, amorphous quality in combination with (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)propanamide methanesulfonic acid, or a combination thereof; A method for modulating the activity of indoleamine 2,3-dioxygenase, comprising contacting [Example]

[0169] The following examples are provided to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of the inventions that the inventors regard as their inventions, nor are they intended to represent all experiments that can be performed or that can be performed. It is understood that the exemplary descriptions set forth in the present tense need not necessarily be performed, but rather that the descriptions may be performed to produce the data and properties described herein. Efforts have been made to determine accuracy with respect to the numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0170] method Single crystal data MSA salt of compound 1 form Single-crystal X-ray data for 1 were collected using a Bruker X8 APEX II CCD diffractometer (MICROSTAR-H microfocus, equipped with a rotating pair-anode X-ray generator with monochromated Cu Kα radiation (λ = 1.54178 Å)). The single crystal was kept at room temperature during data collection.

[0171] Compound 1 free base monohydrate form 2 and the free base of compound 1 form Single-crystal X-ray data for 4 were collected using a Bruker X8 Prospector Ultra diffractometer equipped with an APEX II detector and a 1 μS microfocus X-ray source with monochromated Cu Kα radiation (λ = 1.54178 Å). The single crystal was kept at room temperature during data collection.

[0172] MSA salt hydrate of compound 1 form Single-crystal X-ray data for 2 were collected using a Rigaku SuperNov diffractometer equipped with a Dectris Pilatus 200K detector and a microfocus sealed-tube X-ray generator with monochromatic Cu Kα radiation. The single crystal was kept at room temperature during data collection. Indexing and processing of the measured intensity data were performed using the software suite CrysAlisPro 1.171.38.41r (Rigaku OD, 2015).

[0173] Indexing and processing of the measured intensity data was performed using the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). Final unit cell parameters were determined using the entire data set. The structure was solved by direct methods and refined by full-matrix least-squares using the SHELXTL software program package (GM Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA). The structure was refined by Σw(|F o |-|F c |) 2where w is an appropriate weighting factor based on the error in the measured intensity, and F o is the structure coefficient based on the measured reflection, and F c where |Fo|-|Fc|| / Σ|Fo| and wR=[Σw(|Fo|-|Fc|) 2 / Σw|Fo|] 1 / 2 The differential Fourier maps were examined at every refinement step. All non-hydrogen atoms were refined with anisotropic thermal displacement parameters. Hydrogen atoms were generally calculated with idealized geometry, assigned isotropic temperature factors, and included in the structure factor calculations with fixed parameters. Hydrogen atoms (e.g., the free base hydrate of Compound 1) were generally calculated with idealized geometry, assigned isotropic temperature factors, and included in the structure factor calculations with fixed parameters. form The hydrogen atoms of water in the structure of 2 and the MSA salt of compound 1 form Some exceptions existed when the nuclei (such as the acidic hydrogen atoms of the methanesulfonic acid in the structure of 1) were located from the difference Fourier map and refined isotropically.

[0174] PXRD (PANalytical) amorphous quality The free base and amorphous forms of Compound 1 qualityThe PXRD pattern for the MSA salt of compound 1 was recorded on an Empyrean (PANalytical) X-ray powder diffractometer using Cu Kα radiation at λ = 1.541 Å. The powder diffractometer was equipped with a ceramic tube and a RTMS PIXcel 1D detector set at 45 kV and 40 mA power levels. The incident optics consisted of a 0.02 rad Soller slit, a 10 mm beam mask, a 1° anti-scatter slit, and an automatic divergence slit set to the 10 mm irradiation wavelength. The diffraction optics consisted of a 0.02 rad Soller slit, an automatic anti-scatter slit set to the 10 mm irradiation wavelength, a Ni-K-β filter, and a ~2.9° detector window. Data were collected in reflector geometry, spinning in continuous scan mode, over a 2θ range of 2–40°, stepwise from 0.033–0.40°, with a net measurement time of ~317 s per step. Powder samples greater than 200 mg were packed into a backfill sample holder.

[0175] PXRD(GADDS-NB) Capillary PXRD data were obtained using a Bruker C2 GADDS. The radiation was Cu Kα (40 KV, 40 mA). The sample-detector distance was 15 cm. The samples were placed in a 1000 nm diameter tube. < The sample was placed in a 1 mm sealed glass capillary. The capillary was rotated during data collection. Data were collected over approximately 20 min with a sample exposure time of at least 1000 s. < 2θ < The resulting two-dimensional diffraction arcs were integrated to generate a typical one-dimensional PXRD pattern in the range of approximately 2 to 32° 2θ with a step size of 0.05° 2θ.

[0176] Differential scanning calorimetry (DSC) Differential scanning calorimetry (DSC) experiments for the free base hydrate of Compound 1, the free base of Compound 1, and the MSA salt of Compound 1 were performed using a TA Instrument-model Q2000 or Q1000. Samples (approximately 1-10 mg) were weighed into aluminum pans and recorded to exactly 100 mg before transferring the samples to the DSC. The instrument was purged with nitrogen gas at 50 mL / min. Data were collected between room temperature and 300 °C at a heating rate of 10 °C / min. The DSC plots showed a descending endothermic peak.

[0177] DSC for Compound 1MSA hydrate was performed using a TA Instruments 2920 Differential Scanning Calorimeter. Temperature calibration was performed using NIST-traceable indium metal. The sample was placed in an aluminum DSC pan, covered with a lid, sealed, and laser-punched with a pinhole, and the weight was accurately recorded (3.7940 mg). A weighed aluminum pan designated as the sample pan was placed on the reference side of the cell. Analysis was performed from -30°C to 300°C at 10°C / min.

[0178] Thermogravimetric analysis (TGA ) Thermogravimetric analysis (TGA) experiments for the free base hydrate of Compound 1, the free base of Compound 1, and the MSA salt of Compound 1 were performed using a TA Instrument-model Q5000 or Q500. Samples (approximately 10-30 mg) were placed in pre-tared platinum pans. Sample weights were accurately measured and recorded by the instrument to the nearest 1,000 milligrams. The furnace was purged with nitrogen gas at 100 mL / min. Data were collected from room temperature to 300 °C at a heating rate of 10 °C / min.

[0179] 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 pan. The sample was sealed, the lid was pierced, and then placed in a TG furnace. The furnace was heated under nitrogen. The analysis was performed from ambient temperature to 350°C at 10°C / min.

[0180] Solid-state nuclear magnetic resonance (ssNMR) carbon 13 Cross-polarization magic-angle spinning (CPMAS) solid-state NMR experiments were performed on a Bruker AV III instrument scanning at a proton frequency of 500 MHz. Solid samples were spun at 13 kHz in a 4 mm ZrO rotor. The contact time was 4 ms, and the proton channel was ramped 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 delay time was 5x the API, which is 20 s. 1 The H T1 was maintained. Proton decoupling was performed using a TPPM sequence with a 4.3 μs pulse (58 nominal bandwidth). The spectral width was 300 ppm centered at 100 ppm. 2048 data points were acquired (representing a digital resolution of 36 Hz) and zero-filled to 8192 before apodization. 2048 free induction decays were simultaneously superimposed. This spectrum was indirectly compared to TMS 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 for each experiment. The temperature was set to 280 K.

[0181] Fourier transform infrared spectroscopy (FT-Infra-Red) Fourier transform infrared spectroscopy was performed by attenuated total reflectance (ATR) using an IS50-ATR spectrometer. Spectra were recorded at 4 cm -1 Spectra were collected using reflectance mode at a resolution of 4 cm and 64 scans. -1 and collected using reflectance mode at a resolution of 64 scans.

[0182] FT-Raman FT-Raman spectra were recorded using a Nicolet iS50 FT-Raman spectrometer equipped with a highly sensitive InGaS detector at 4 cm -1 The images were acquired at a resolution of 64 scans. The laser excitation wavelength was 1064 nm. The laser power was 0.5 W.

[0183] Stability test chromatography conditions : VHPLC parameters VHPLC system: Waters AcQuity BSM or H-Class VHPLC system with Waters UV / Vis detector. Column: Ascentis Express C18, 150 mm x 2.1 mm id, 2.7 um particle size. Detection wavelength: 218 nm VHPLC detection time constraints: Normal VHPLC sampling rate: 20 Hz VHPLC bandwidth: 1.2 nm resolution Flow rate: 0.5 mL / min Injection volume: 1uL Column temperature: 30℃ Run time: ~14 minutes Sample temperature: 5℃ Mobile phase A: Water:Acetonitrile:TFA (95:5:0.05) Mobile phase B: water:acetonitrile:TFA (5:95:0.05)

[0184] VHPLC Gradient Program List [Table 27] Typical retention times for compound 1: Retention time (min) 5.66; Relative retention time (min) 1.00

[0185] Microdissolution Microdissolution experiments were performed on a pION μDiss Profiler microdissolution instrument (pION μDiss Profiler) using a fiber optic UV monitoring system as follows: Probe: 2.5 mm probe (5 mm path length) Capacity: 15ml Stirring: 150 rpm Temperature: 37°C (bath temperature of solution and equipment) 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, baseline 450 nm

[0186] Example 1. Compound 1 Compound 1 can be prepared using the methods described in WO2016 / 073770, which is incorporated herein by reference.

[0187] Example 2: Compound 1 Free Base, Amorphous A 1 L round-bottom flask was charged with (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide hydrate (132.0 g) and ethyl acetate (610 g). The slurry was heated until all solids dissolved. The solution was concentrated to dryness under vacuum. The resulting solid was dried under vacuum at 50° C. to give (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide (126.0 g, 99.6% yield) as a white solid.

[0188] Example 3: Compound 1 free base hydrate form 2 A 50 L glass-fired reaction vessel was charged under a nitrogen blanket with 13.75 kg acetonitrile, followed by 2.68 kg N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), followed by a 2.0 kg acetonitrile rinse. 2.03 kg N-methylimidazole was added, followed by 1.95 kg acetonitrile. 2.48 kg (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid was added, followed by 1.05 kg acetonitrile. The mixture was held for 0.5 hours, and then 1.21 kg 4-chloroaniline was charged, followed by 1.0 kg acetonitrile. The mixture was maintained at 20°C until the reaction was complete as determined by HPLC analysis. The solution was then heated to 60°C and charged with water (9.25 kg). The solution was then cooled to 40°C, the mixture was aged for 1 hour, seed crystals (32 g) were added, rinsed with 1.15 kg of 2:1 water:acetonitrile, and the resulting slurry was maintained for 1 hour. The slurry was then cooled to 20°C, and 25.75 kg of water was added. The slurry was filtered, and the cake was washed three times with 6.9 kg of 2:1 water:acetonitrile. The cake was dried under vacuum at 50°C to provide 3.33 kg of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide hydrate as a white solid (94.1% yield).

[0189] Example 4: Compound 1 free base hydrate form 2 Amorphous Compound 1 free base (250 mg) was dissolved in an organic solvent (2 mL), such as ethanol, acetone, acetonitrile, or tetrahydrofuran, at 40°C to 50°C. Water (2 mL) was added in 0.5 mL portions. After the addition of water (1 mL), an emulsion was observed, with the oil releasing. Crystallization occurred upon aging of the emulsion. The crystals were isolated using a Buchner funnel.

[0190] Example 5: Preparation of the free base of Compound 1 form 4 A 500 mL round-bottom flask was charged with (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide hydrate (15.0 g) and acetonitrile (176 g) and stirred until all solids were dissolved. The solution was concentrated to dryness under vacuum. Additional acetonitrile (176 g) was added and the solution was concentrated to dryness under vacuum. Ethyl acetate (134 g) was added and stirred until a homogeneous solution was formed and again concentrated to dryness under vacuum. After all solvent was removed, ethyl acetate (50 g) was added. The solution was heated to 40° C. and stirred magnetically. Seed crystals (220 mg) were added and heptane (144 g) was added over 45 minutes. The slurry was gradually cooled to 20° C. and additional heptane (27 g) was added. The slurry was then temperature cycled by heating to 50° C. and gradually cooling to 20° C. The slurry was stirred overnight. The solid was filtered and dried under vacuum to give (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide (12.0 g, 84.5% yield) as a white solid.

[0191] Example 6: Preparation of the free base of Compound 1 form 4 The free base of compound 1 (250 mg) was dissolved in ethyl acetate (1 mL) at 40° C. Heptane (700 μL) was added, followed by the addition of the free base of compound 1. formSeed crystals of 4 (approximately 10 mg) were added, which resulted in the formation of a slurry. The slurry was aged for 10 minutes, and then additional heptane (3 mL) was added. The slurry was aged for approximately 1 hour, then isolated on a Buchner funnel and dried under vacuum in an oven at 50° C. overnight.

[0192] Example 7: Preparation of the free base of Compound 1 form 4 of the free base of Compound 1 form 2 (100 mg) was dried in a vacuum oven overnight at 50 °C to dehydrate the material. The material was then slurried in heptane (1 mL) at 65 °C overnight. A phase transition occurred after several hours, after which the free base of compound 1 was obtained. form Converted to 4.

[0193] Example 8: Methanesulfonic acid (MSA) salt of Compound 1, amorphous To a glass vial was added (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate (2.6 g) and methanol (0.1 L). The mixture was stirred at room temperature until the solid dissolved, resulting in a clear spray solution. The 2.6% (w / v) spray solution was then spray-dried at 65°C through a two-fluid spray nozzle (2050 LC / 64AC, Spraying Systems Co.) in a custom-built small-scale spray dryer using heated nitrogen gas from the methanol solvent. The applied spray-drying parameters were as follows: solution spray rate / 1.3 mL / min, standard 32 L / min inlet N2 gas flow rate, 65°C inlet N2 temperature. Within the spray dryer, the solid material was collected on a 4" filter paper. The spray-dried white solid (2.3 g) was collected from the filter paper and transferred to a glass vial. The spray-dried solid was vacuum dried and allowed to dry in the glass vial at room temperature overnight.

[0194] Example 8A: Methanesulfonic acid (MSA) salt of Compound 1, amorphous MSA salt of compound 1 form Amorphous MSA salt of Compound 1 was obtained by rotary evaporation of 1 / dichloromethane. This material was then heated to 60°C to obtain the amorphous MSA salt of Compound 1. form It was recrystallized to 1.

[0195] Example 9: Methanesulfonic acid (MSA) salt of Compound 1 form 1 The free base of compound 1 (50 g) was dissolved in ethyl acetate (500 mL) in a 1 L reaction vessel at 25° C. with stirring at 500 RPM. A solution of 1 molar equivalent of MSA in ethyl acetate (250 mL) was prepared and pumped into the reaction vessel over 2 hours. The resulting slurry was aged for 30 minutes. The crystals were isolated using a Buchner funnel and dried overnight in an oven at 50° C.

[0196] Example 10: Methanesulfonic acid (MSA) salt of Compound 1 form 1 A 10 L glass-lined reaction vessel was charged with N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (349 g) and acetonitrile (2 L) under a nitrogen atmosphere. N-methylimidazole (245 g) was added, followed by acetonitrile (0.3 L). (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid (300 g) was added, followed by acetonitrile (0.3 L). The mixture was held for 0.5 hours, and then 4-chloroaniline (139 g) was charged, followed by acetonitrile (0.4 L). The mixture was maintained at 20 °C until the reaction was determined to be complete by HPLC analysis. The solution was then heated to 60 °C and water (1.2 L) was charged. The solution was then cooled to 40°C, seeded (3 g), and the resulting slurry was maintained for 1 hour. The slurry was then cooled to 20°C and charged with water (2.7 L). The slurry was filtered, and the cake was washed three times with 2:1 water / acetonitrile (3 L). The cake was dissolved with ethyl acetate (5.1 L), and the solution was distilled under vacuum at 41°C to a volume of 4.2 L. The slurry was cooled to 20°C, seeded (4.14 g), and a solution of methanesulfonic acid (95.7 g) in ethyl acetate (2.9 L) was added. The slurry was then filtered, washed twice with ethyl acetate (1.65 L), and dried under vacuum at 50° C. to give (R)—N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate (445 g, 88% yield) as a white solid.

[0197] Example 11: MSA salt monohydrate of Compound 1 form 2 MSA salt monohydrate of compound 1 form 2 was dissolved in ethanol / water (85 / 15 v / v) at room temperature with a water activity of 60% relative humidity to obtain the MSA salt of compound 1. form The MSA salt hydrate of compound 1 can be prepared by slurrying the compound. form Single crystals of 2 were prepared by precipitation of the MSA salt of compound 1 in 8 / 92 v / v methanol / acetonitrile at ambient temperature. form Growth was achieved by evaporating a solution of 1.

[0198] Example 12: MSA salt of Compound 1 form 1: Solid-state stability A 12-month stability study of the MSA salt of Compound 1 form The effects of temperature, humidity, and light on Compound 1 were tested. See the table below. The test consisted of one batch of drug packaged in a double LDPE bag and placed in a 0.6 L HDPE bag with a lid and gasket. form 1 remained stable for at least 12 months of storage under long-term conditions at 5°C and 25°C / 60% relative humidity (RH), for 6 months under accelerated conditions at 40°C / 75% RH, and for 3 months under stress conditions at 50°C. Data from photostability studies indicated that the drug does not need to be protected from light. The MSA salt of compound 1 form 1 can be stored at or below 25°C. [Table 28]

[0199] Although there was some variability, no substantial change in the "as is" assay or "corrected" from the initial assay "as is" value of 79.0% or assay "corrected" value of 97.0% was observed for Tests Nos. 1, 2, 3, and 5. Slight increases were observed for Tests Nos. 6 (to 82.0% and 100.7%, respectively) and 4 (to 82.4% and 101.1%, respectively) from the initial assay "as is" and assay "corrected" values ​​of 79.0% and 97.0%, respectively.

[0200] No substantial change in total impurities from the initial value of 0.57% was observed for runs 4, 1, 2, and 3. A decrease in total impurities from the initial value of 0.57% was observed for runs 3 (to 0.48%) and 6 (to 0.50%), primarily due to a decrease in 4-chloroaniline from the initial value of 0.09% to <0.05% for both conditions.

[0201] For Tests 1 and 2, no change in Compound 1 enantiomeric impurity was observed from the initial value of <0.05%.

[0202] For tests no. 1 and 2, essentially no change in moisture content was observed from a starting value of <0.1% w / w.

[0203] The color and appearance (white or off-white powder or powder with clumps) was maintained throughout the study.

[0204] No change in the XRD pattern was observed for all test numbers after testing.

[0205] MSA salt of compound 1 form No substantial changes were observed when 1 was exposed to the minimum ICH Q1B exposure. A slight increase in total impurities was observed with approximately 3.5 minimum ICH exposures, primarily due to an increase in impurities at levels below 0.10%. The assay value corrected for the exposed drug was observed to be 96.8%. No other changes were observed in the other tested attributes. Photostability data indicated that the drug does not need to be protected from light.

[0206] MSA salt of compound 1 form 1 was physically stable under stress conditions, such as milling with organic solvents and water and stressing at 40°C for 5 days at 75% relative humidity.

[0207] Example 13: MSA salt of Compound 1 form 1, pH solubility MSA salt of compound 1 form The pH solubility of 1 was tested at 22±3°C using NaOH (1N or 10N aqueous solution) and HCl (concentrated or 1N aqueous solution) for pH adjustment. Measurements were performed using an Orion ATI Model 370 pH meter. The MSA salt of compound 1 formApproximately 20-30 mg of 1 was weighed into each of eleven 10 cc Type I glass vials. To each vial, various aqueous acidic and basic solutions (5 mL) were added. Each vial was stoppered and thoroughly mixed by vortexing and sonication. The pH of each sample was recorded.

[0208] The samples were vigorously stirred overnight at ambient room temperature at 300 rpm. After 24 hours of stirring, the pH of each sample (as a suspension) was recorded. The suspensions were filtered through a 0.2 micron Acrodisc syringe filter. The clear filtrates were collected, vortexed, and thoroughly mixed, and the pH of each filtrate was recorded. The pH of the suspensions and filtrates was nearly identical.

[0209] Each aliquot (1.0 mL) of the filtrate was diluted 25 times with 50% acetonitrile / 50% Milli-Q Water, qw, to a total volume of 25 mL in each flask. The aliquots were transferred to the autosampler of the HPLC to assay the concentration of Compound 1.

[0210] The samples were assayed using the following HPLC method: Column: Waters YMC Pro-Pack C18; Part # AS12S05-1546WT, S-5 μm, 150 x 4.6 mm ID Mobile phase Solvent A: Water with 0.05% TFA Solvent B: Acetonitrile w / 0.05% TFA Flow rate: 1.0 mL / min Column temperature: ambient temperature RT Detector wavelength: 250 nm Injection volume: 10 μL Treatment concentration: approximately 100 mcg / mL Sample / standard diluent: 50% acetonitrile / 50% Milli-Q Water Typical Compound 1 Retention time: 15.5 minutes (RRT 1.0) [Table 29]

[0211] External standard preparation: 25.4 mg of the MSA salt of Compound 1 in a 25 mL Type I glass vial form 1 was weighed out. 100% acetonitrile (20 mL) was added to the vial. The vial was stoppered, vortexed, and sonicated. Not all solids dissolved. The suspension was transferred to a 250 mL glass volumetric flask, and the glass vial was washed with 4 x 20 mL 50% acetonitrile / 50% Milli-Q Water, with each wash transferred to the volumetric flask. All solids dissolved. The QS volumetric flask was brought to a final volume of 250 mL with 50% acetonitrile / 50% Milli-Q Water to obtain a standard solution at 101.5 mcg / mL.

[0212] The overall profile was typical of a weak base, showing a solubility of 1-2 mcg / mL for the free base, ~130 mcg / mL in water (originally pH ~2.5), a pH maximum of ~560 mcg / mL at pH ~2, and decreasing solubility below pH 2 (73 mcg / mL at pH 1, 24 mcg / mL at pH 0.5). The results are shown in the table below. [Table 30]

[0213] Example 14: Microdissolved FaSSiF / FeSSiF MSA salt of compound 1 form 1 is amorphous form or HCl salts (amorphous and crystalline form ) shows a rapid rate and extent of dissolution in both FeSSiF and FaSSiF. form The dissolution rate of 1 suggests rapid absorption. See Figure 7. form 1 exhibits a more rapid rate and extent of dissolution compared to the free base (amorphous) of Compound 1. See Figure 8.

[0214] Example 15: Microdissolved FaSSiF / FeSSiF of MSA salt of Compound 1 in FaSSIF and FeSSIF form 1 and MSA salt monohydrate form The dissolution of 2 was evaluated. Target doses were 150 mg / 250 mL (0.60 mg / mL API equivalent) in FaSSIF (pH 6.5) and FeSSIF (pH 5).

[0215] AUC and dissolution rate values ​​were calculated for the MSA salt of Compound 1 in FaSSIF and FeSSIF. form 1 and the MSA salt monohydrate of compound 1 form Although there was no statistical difference in AUC values, there was a statistically significant difference in dissolution rate, with the MSA salt monohydrate of Compound 1 being significantly different from that of Compound 2. form 2 was slightly faster in FaSSIF. form has a similar solubility peak in FaSSIF. This behavior is similar and three times higher in FeSSIF. form The food effect ratio to 1 was 3.10. form The food efficacy ratio for Compound 1 MSA salt hydrate was constant. form The food efficacy ratio of Compound 2 was 3.49. See the table below and Figure 9. form 2 is the MSA salt of compound 1 form It can be seen that it has a dissolution profile similar to that of 1. [Table 31]

[0216] Example 16: Microdissolved FaSSiF / FeSSiF This study demonstrated the activity of the free base (amorphous) of Compound 1 in FaSSIF and FeSSIF. quality ), the free base of Compound 1 form 2 and the MSA salt of compound 1 form The difference in dissolution of 1 was evaluated.

[0217] MSA salt of compound 1 form The peak solubility of 1 is form The MSA salt of compound 1 in FeSSIF was 4-5 times higher than that in FaSSIF and FeSSIF. This was statistically significant (p<0.05). form The dissolution rate for 1 is 38 vs. 23 ug / mL / min. In FeSSIF, the rate and extent of dissolution is increased for all APIs. The FE ratio for the MSA salt is approximately 3.5, the amorphous free base is 5, and the free base is 1. form 2 is ~3.5.

[0218] Example 17: Jet Mill Particle size reduction can be achieved by jet milling using an 0202 Jet o Mizer loop mill. Particle collision is achieved by supplying nitrogen gas at high pressure to the milling chamber through two grinding nozzles. The drug substance feed rate to the mill is controlled by a feeder that delivers drug from the mill's feeder hopper to the milling chamber at a visually constant feed rate. High-pressure nitrogen gas is supplied through a venturi nozzle to inject drug from the mill feed hopper into the milling chamber, which is indicated as venturi pressure. The grinding pressure and venturi pressure are adjusted to the desired level after milling begins, and both are maintained at the same level even if product backflow from the feeder hopper is observed. The venturi pressure is typically adjusted to a grinding pressure greater than 10 PSI. The micronized drug exits the mill chamber outlet into a product recovery unit consisting of a combine cyclone and porous fabric filter media assembly. Milling parameters can be adjusted based on sample analysis. Particle sizes ranging from 12.7 μm to 24.0 μm (D90 by laser light scattering) are achieved by this milling operation. Milling parameters and physical properties are shown in the table below. [Table 32]

[0219] Example 18: Stability of Compound 1 Free Base form 4 of the free base of Compound 1 form The solid state stability of 4 was tested. The results of these experiments are shown in the table below. No changes were observed for at least two weeks.

[0220] of the free base of Compound 1 form 4 was chemically stable for at least 4 weeks. [Table 33]

[0221] Example 19: Stability of Compound 1 Free Base Hydrate form 2 Compound 1 free base monohydrate form The solid-state stability of 2 was tested. The experimental results are shown in the table below. No changes in PXRD were observed in any samples over 4 or 8 weeks. No changes in DSC / TGA were observed in any samples over 4 weeks. After 8 weeks form Changes, dehydration or amorphous quality There was no evidence of formation of . There was no change in TGA at 8 weeks in all samples.

[0222] Compound 1 free base hydrate form 2 was chemically stable for at least 13.5 weeks at the elevated test temperature and humidity conditions. [Table 34]

[0223] Example 20 amorphous quality The MSA material of Compound 1 was found to be a soluble form of MSA salt of Compound 1 after 9 days of heat stress at 60°C. formThe MSA salt monohydrate of compound 1 was converted to 1. form 2 is the MSA salt of compound 1 after 6 days of stress at 40°C and 75% relative humidity. form 1 and the MSA salt monohydrate of compound 1 form At 75% relative humidity, the MSA salt monohydrate of compound 1 was converted to 2. form 2, which is amorphous. quality The substance is the MSA salt of compound 1 form MSA salt hydrate of compound 1 form It was suggested that 2 may have a faster conversion rate to 2.

[0224] Example 21: Stability - Compound 1 Free Base The heating test was carried out on the free base monohydrate of Compound 1. form 2. Compound 1 free base form 4 and Amorphous All possible reactions occurring in the free base of Compound 1 form This was done to test the changes.

[0225] Amorphous The free base of Compound 1 was heated at 67°C to 150°C. No crystallization was observed. form Melt / quench experiments starting with 4 resulted in a glass containing some fine birefringent particles, but the resulting XRPD pattern showed no evidence of crystalline material.

[0226] Compound 1 free base monohydrate form Heating 2 at ∼100 °C for ∼2 h resulted in an observable change in birefringence, but not by XRPD. form No change. Heating to ~125°C resulted in the sample becoming liquid. Cooling the liquid sample on dry ice revealed the amorphous phase of the X-ray. of The corresponding non-birefringent glass was obtained. The material was heated at 79-80°C or 75°C for 1 day under nitrogen gas flow. form Additional heating experiments on 2 revealed different crystals at both temperatures. formPartial conversion of the free base monohydrate of compound 1 to form 2 is thermodynamically stable at high relative humidity and RT. form It would be.

[0227] Many experiments were performed at hydration temperatures of ~0% RH. form The free base monohydrate of compound 1 was prepared to investigate the dehydration of form 2 is unstable after being kept at 0% RH overnight. form was converted to.

Claims

1. A crystal of crystalline form 4 of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, characterized by a powder X-ray diffraction pattern containing peaks at 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0°2θ±0.2°2θ.

2. 20. A pharmaceutical composition comprising a crystal of crystalline Form 4 of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, characterized by an X-ray powder diffraction pattern containing peaks at 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7, and 22.0 °2θ ± 0.2 °2θ, and a pharma- ceutical acceptable carrier.

3. The pharmaceutical composition of claim 2, 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)propanamide methanesulfonic acid, or a combination thereof.

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

5. The pharmaceutical composition according to any one of claims 2 to 4 for treating cancer.

6. 6. The pharmaceutical composition of claim 5, wherein the cancer is cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal cell carcinoma), mesothelium, white blood cells (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, lung (including small cell lung carcinoma and non-small cell carcinoma), adrenal gland, thyroid, kidney or bone; or glioma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma (including Kaposi's sarcoma), choriocarcinoma, basal cell carcinoma of the skin or seminoma.

7. 7. The pharmaceutical composition of claim 5 or 6, further comprising an immune checkpoint inhibitor.

8. 8. The pharmaceutical composition of claim 7, wherein the immune checkpoint inhibitor is ipilimumab, nivolumab, pembrolizumab, or a combination thereof.

9. 5. The pharmaceutical composition according to any one of claims 2 to 4 for modulating the activity of indoleamine 2,3-dioxygenase, optionally 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)propanamide methanesulfonic acid, or a combination thereof.

10. 3. The pharmaceutical composition of claim 2, which is in a solid dosage form.

11. 11. The pharmaceutical composition of claim 10, wherein the solid dosage form is a tablet, pill or capsule.

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