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 Jun. 30, 2017, which is hereby incorporated by reference in its entirety.

[0002] (Technical Field) This specification relates to the (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide of a solid Form , as well as salts and hydrates thereof, methods for their preparation, pharmaceutical compositions containing them, and methods of using them.

[0003] (Background Art) (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide is shown herein as Compound 1 and has the following structure:

Chemical Formula

[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 studied as a treatment for cancer and other diseases. Compound 1 has been previously described in WO2016 / 073770.

[0005] The compound can exist as a free base, hydrate, solvate or salt, in amorphous Form and / or one or more crystalline Form forms, each of which can exhibit various physical properties, such as different X-ray diffraction patterns (XRPD or PXRD) and different temperature properties. The free base, hydrates, solvates and salts of the compound FormThey may also differ with respect to their individual stability, method of treatment, formulation, dissolution profile, bioavailability, etc.

[0006] There is a need for novel (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide having the desired beneficial chemical and physical properties. Form In addition, in order to smoothly proceed with commercialization, a reliable and reproducible method for the production, purification, and formulation of Compound 1 (and its hydrates, solvates, salts, and hydrates Form ) is also needed. The present invention relates to such aspects as well as other important aspects.

[0007] (Summary of the Invention) The present invention relates to solid Form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide (Compound 1), for example, the free base of solid Form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, the monohydrate of solid Form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, the methanesulfonate of solid Form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, and the methanesulfonate monohydrate of solid Form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide. Compositions containing the described solids Form are also described, as well as methods for their production and methods for their use in treatment.

Brief Description of the Drawings

[0008]

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DETAILED DESCRIPTION OF THE INVENTION

[0009] The present disclosure relates to solids of Compound 1 Form , for example, Compound 1 (free base), the monohydrate of Compound 1 (free base) and the methanesulfonic acid (MSA) salt of Compound 1, the MSA salt monohydrate of Compound 1, and the manufacture of said solids Form said solids Form pharmaceutical compositions comprising said solids Form and methods of treating IDO-mediated diseases using said solids Form The names of the disclosed solids should not be understood as limitations with respect to other substances having similar or identical physical and chemical properties. Rather, these names should be understood as identifiers to be interpreted in accordance with the information on the characteristic analysis disclosed herein.

[0010]

Chemical Formula

[0011] Free base hydrate of Compound 1 In one embodiment, the present invention relates to a solid of Compound 1 (free base) present as a monohydrate. Form For example, the solid of the free base monohydrate of Compound 1 Form contains about 1 molecule of water per molecule of the free base of Compound 1.

[0012] In a preferred embodiment, the hydrate of Compound 1 (free base) of the solid Form is a crystal of the free base monohydrate of Compound 1 Form which is shown herein as Form 2 of the free base monohydrate of Compound 1. The Form 2 of the free base monohydrate of Compound 1 has the desired stability profile.

[0013] For the free base monohydrate of Compound 1Form 2 can be characterized by an X-ray diffraction pattern having one peak 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. The free base monohydrate of Compound 1 Form 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. Also, the free base monohydrate of Compound 1 Form 2 can 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. The free base monohydrate of Compound 1 Form 2 can 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. The free base monohydrate of Compound 1 Form 2 can 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. The free base monohydrate of Compound 1 Form 2 can 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. The free base monohydrate of Compound 1 Form 2 can be characterized by an X-ray diffraction pattern having peaks at 9.4, 12.4, 17.2, 17.6, 20.1, 21.1, and 21.6° 2θ ± 0.2° 2θ.

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

[0015] Table 1. For the free base monohydrate of Compound 1 Form Characteristic diffraction peak positions for 2 [Table 1]

[0016] Table 1A. For the free base monohydrate of Compound 1 Form Peak list for 2 [Table 2]

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

[0018] For the free base monohydrate of Compound 1 Form 2 can be characterized by an X-ray diffraction pattern substantially as shown in Figure 1.

[0019] Table 2 shows the single crystal X-ray data for 2 of the free base monohydrate of Compound 1. Form Table 2. Single crystal X-ray data for 2 of the free base monohydrate of Compound 1 For the free base monohydrate of Compound 1 Form Single crystal X-ray data for 2 [Table 3]

[0020] Table 3 shows the atomic coordinates for 2 of the free base monohydrate of Compound 1. Form Table 3. Atomic coordinates of 2 of the free base monohydrate of Compound 1 For the free base monohydrate 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. The Form ssNMR of 2 gives the following peaks:

Table 5

[0022] The free base monohydrate of Compound 1 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] The free base monohydrate of Compound 1 Form The DSC thermogram of 2 is shown in Figure 1C.

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

[0025] The free base monohydrate of Compound 1 Form The FT-Raman spectrum of 2 is shown in Figure 1E. The FT-Raman of the free base monohydrate of Compound 1 gives at least the following peaks:

Table 7

[0026] The free base monohydrate of Compound 1 Form 2 is substantially pure Form by weight of the compound, as determined by HPLC (high performance liquid chromatography), i.e., it can be present with a purity of about 90% or more. For example, the Form 2 of the free base monohydrate of Compound 1 can have a purity of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%. The residual substances are other solids of Compound 1 Formand / or reaction impurities and / or processing impurities resulting from its production may be included.

[0027] of the free base monohydrate of Compound 1 Form 2 and another solid of Compound 1 Form The mixture with is also within the scope of the present invention. In these embodiments, such a mixture may contain less than 90% of the free base monohydrate of Compound 1 based on the weight of the mixture. Form 2 may be included. 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 free base monohydrate of Compound 1. Form 2 may be included.

[0028] free base of Compound 1 In one embodiment, the present specification relates to crystals of Compound 1 (free base), Form which are shown herein as Form 4. The 4 of the free base of Compound 1 has desirable handling and stability properties that may fully enable the production of solid dosage forms on a commercial scale. Form 4 may be characterized by an X-ray diffraction pattern having one peak 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. The 4 of the free base of Compound 1

[0029] of the free base of Compound 1 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. The 4 of the free base of Compound 1 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. The 4 of the free base of Compound 1 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. The 4 of the free base of Compound 1 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. The free base of Compound 1 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. The free base of Compound 1 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. The free base of Compound 1 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. The free base of Compound 1 Form 4 may also be characterized by an X-ray diffraction pattern having 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0° 2θ ± 0.2° 2θ.

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

[0031] Table 4. Characteristic diffraction peak positions for 4 of the free base of Compound 1 Form Characteristic diffraction peak positions for 4 [Table 8]

[0032] Table 4A. Peak list for 4 of the free base of Compound 1 Form Peak list for 4 [Table 9]

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

[0034] Of the free base of Compound 1 Form 4 can be characterized by an X-ray diffraction pattern that is substantially as shown in Figure 2.

[0035] Table 5 shows the single crystal X-ray data for 4 of the free base of Compound 1. Form For 4 Table 5. Single crystal X-ray data for 4 of the free base of Compound 1 Form For 4

Table 10

[0036] Table 6 shows the atomic coordinates for 4 of the free base of Compound 1. Form For 4 Table 6. Atomic coordinates of 4 of the free base of Compound 1 Form For 4

Table 11

[0037] The ssNMR spectrum is shown in Figure 2A. Of the free base of Compound 1 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] The free base of amorphous compound 1 is also within the scope of the present invention. The PXRD of the free base of amorphous compound 1 is shown in Figure 3. The solid-state NMR of the free base of amorphous compound 1 is shown in Figure 3A. By ssNMR of the free base of amorphous compound 1, the following peaks are obtained: [Table 13]

[0041] The FT-IR spectrum of the free base of amorphous compound 1 is shown in Figure 3B. By the FT-IR spectrum of the free base of amorphous compound 1, the following peaks were obtained: [Table 14]

[0042] The FT-Raman spectrum of the free base of amorphous compound 1 is shown in Figure 3C. By the FT-Raman spectrum of the free base of amorphous compound 1, the following peaks are obtained: [Table 15]

[0043] The free base of compound 1 Form 4 is substantially pure with a purity of about 90% or more, based on the weight of the compound, as determined by HPLC Form and can be present therein. For example, the free base of compound 1 Form 4 can have a purity of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%. The residual substances can include other solids of compound 1 Form and / or reaction impurities and / or processing impurities resulting from the production thereof.

[0044] The free base of compound 1 Form 4 and another solid of compound 1 Form The mixture of is also within the scope of the present invention. In these embodiments, such a mixture contains less than 90% of the free base of compound 1, based on the weight of the mixture Formmay contain 4. 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 wt% of the free base of Compound 1 Form may contain 4 in the mixture.

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

[0046] A mixture of the free base of amorphous Compound 1 and another solid of Compound 1 Form is also within the scope of the present invention. In these embodiments, such a mixture may contain less than 90% of the free base 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 wt% of the free base of amorphous Compound 1.

[0047] The MSA salt of Compound 1 In one embodiment, the present specification relates to crystals of the methanesulfonic acid (MSA) salt of Compound 1 Form In certain aspects, the crystals of the MSA salt of Compound 1 Form are non-solvates. In another aspect, the crystals of the MSA salt of Compound 1 Form are non-hydrates (i.e., anhydrous). In yet another aspect, the crystals of the MSA salt of Compound 1 Form are non-solvates and non-hydrates (i.e., anhydrous).

[0048] In a preferred embodiment of the present specification, the MSA salt of Compound 1 is the mono-MSA salt of Compound 1. In particular, in a preferred embodiment, the crystals of the mono-MSA salt of Compound 1 Formis as described in this specification Form is shown as 1. The mono-MSA salt of Compound 1, particularly the Form 1, when administered as a solid dosage form, has a higher oral bioavailability compared to the free base of Compound 1.

[0049] The Form 1 of the MSA salt of Compound 1 can be characterized by an X-ray diffraction pattern having one peak 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. The Form 1 of the MSA salt of Compound 1 can 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. The Form 1 of the MSA salt of Compound 1 can 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. The Form 1 of the MSA salt of Compound 1 can also be characterized by an X-ray analysis 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. The Form 1 of the MSA salt of Compound 1 can also be characterized by an X-ray analysis 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. The Form 1 of the MSA salt of Compound 1 can 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. The Form 1 of the MSA salt of Compound 1 can 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. The Form1 may also be characterized by an X-ray diffraction pattern having peaks at 12.2, 12.6, 13.4, 14.8, 16.4, 16.8, 19.6 and 24.0° 2θ ± 0.2° 2θ.

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

[0051] Table 7. Characteristic diffraction peak positions for the MSA salt of Compound 1 Form for 1

Table 16

Table 17

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

[0053] for the MSA salt of Compound 1 Form 1 may be characterized by an X-ray diffraction pattern substantially as shown in Figure 4.

[0054] Table 8 shows the single crystal X-ray data for the MSA salt of Compound 1 Form for 1. Table 8: Single crystal X-ray data for the MSA salt of Compound 1 Form for 1

Table 18

[0055] Table 9 shows the Form atomic coordinates of 1 of the MSA salt of Compound 1. Table 9. Atomic coordinates of 1 of the MSA salt of Compound 1 Form

Table 19

[0056] The ssNMR of 1 of the MSA salt of Compound 1 Form is shown in Figure 4A. The ssNMR of 1 of the MSA salt of Compound 1 Form yields the following peaks by ssNMR:

Table 20

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

Table 21

[0058] The DSC thermogram of 1 of the MSA salt of Compound 1 Form is shown in Figure 4C. The DSC thermogram of 1 of methanesulfonic acid of Compound 1 Form shows a variable endothermic transition corresponding to melting with decomposition at ~245 - 249 °C. The DSC thermogram of 1 of the MSA salt of Compound 1 Form 1 is a crystalline anhydrous substance that melts and decomposes at approximately 245 - 249 °C (onset) (based on the endotherm of DSC).

[0059] The FT-Raman spectrum of 1 of the MSA salt of Compound 1 Form is shown in Figure 4D. Representative FT-Raman peaks are shown in the following table:

Table 22

[0060] ​The MSA salt of Compound 1 Form The TGA thermogram of 1 is shown in Figure 4E. The MSA salt of Compound 1 Form The TGA thermogram of 1 is substantially free of water and residual solvents, anhydrous Form in agreement with.

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

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

[0063] The MSA salt of Compound 1 Form 1 can exist in substantially pure form, as determined by HPLC, i.e., it can have a purity of about 90% or more based on the weight of the compound. For example, the MSA salt of Compound 1 Form 1 can have a purity of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%. The residual substances can include another solid of Compound 1 Form and / or reaction impurities and / or processing impurities resulting from its manufacture. Form

[0064] The MSA salt of Compound 1 Form 1 and another solid of Compound 1 Form mixtures are also within the scope of the present invention. In these embodiments, such mixtures, based on the weight of the mixture, contain less than 90% of the MSA salt of Compound 1 Form ​It may contain 1. 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 wt% of the MSA salt of Compound 1 Form It may contain 1.

[0065] The MSA salt of amorphous Compound 1 is substantially pure as determined by HPLC Form and may be present therein, i.e., may have a purity of about 90% or more 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%. The residual substances may include another solid of Compound 1 Form and / or reaction impurities and / or processing impurities resulting from its production.

[0066] A mixture of the MSA salt of amorphous Compound 1 and another solid of Compound 1 Form is also within the scope of the present invention. In these embodiments, such a mixture 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 wt% of the MSA salt of amorphous Compound 1.

[0067] Methanesulfonate (MSA salt) hydrate of Compound 1 In one embodiment, the present specification relates to the methanesulfonic acid (MSA salt) of Compound 1 which is a monohydrate Form solid. For example, the MSA salt monohydrate of Compound 1 Form solid contains about 1 molecule of water per molecule of the MSA salt of Compound 1.

[0068] In a preferred embodiment, the solid of the MSA salt monohydrate 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 desired stability profile.

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

[0070] The Form 2 of the MSA salt monohydrate of Compound 1 can be characterized by an X-ray diffraction pattern having one peak 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. The Form 2 of the MSA salt monohydrate of Compound 1 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. The Form 2 of the MSA salt monohydrate of Compound 1 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. The Form 2 of the MSA salt monohydrate of Compound 1 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. The Form 2 of the MSA salt monohydrate of Compound 1 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. The Form 2 of the MSA salt monohydrate of Compound 1 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. The 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. The MSA salt monohydrate of Compound 1 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. The MSA salt monohydrate of Compound 1 Form 2 can be characterized by an X-ray diffraction pattern having peaks at 9.3, 11.8, 14.3, 15.6, 17.7, 20.5, 22.2, 23.2 and 24.1° 2θ ± 0.2° 2θ.

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

[0072] Table 10. For the MSA salt monohydrate of Compound 1 Form Characteristic diffraction peak positions for 2

Table 25

Table 26

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

[0074] For the MSA salt monohydrate of Compound 1 Form2 can also be characterized by an X-ray diffraction pattern substantially as shown in Figure 6. The hydrate of the MSA salt of Compound 1 Form The single crystal structure of 2 was successfully determined. This crystal system is orthorhombic, and the space group is P2 1 2 1 2 1 as follows: 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 525.02 g mol -1 (Z = 4), and the calculated density is 1.355 g cm -3 . The hydrate of the MSA salt monohydrate of Compound 1 Form 2 is the monohydrate of Compound 1 mesylate (MSA) salt. The hydrate of the MSA salt monohydrate of Compound 1 Form The XRPD pattern of 2 showed a substance consisting of a crystalline material.

[0075] The hydrate of the MSA salt monohydrate of Compound 1 Form The DSC thermogram of 2 is shown in Figure 6A.

[0076] The hydrate of the MSA salt monohydrate of Compound 1 Form The TGA thermogram of 2 is shown in Figure 6B.

[0077] The hydrate of the MSA salt monohydrate of Compound 1 Form The TGA data of 2 showed a weight loss of approximately 3.5 wt% up to approximately 100 °C. The weight loss corresponds to approximately 1 mole of water molecules per mole of API.

[0078] The hydrate of the MSA salt monohydrate of Compound 1 Form The DSC data of 2 showed that, as seen in the TGA, the broad endotherm observed in the range of approximately 90 - 150 °C corresponded to the dehydration of the hydrate of the MSA salt monohydrate of Compound 1 Form of 2.

[0079] The MSA monohydrate of Compound 1 FormAs determined by HPLC, it can exist in substantially pure Form , i.e., it can exist with a purity of about 90% or more, based on the weight of the compound. For example, the Form 2 of the MSA monohydrate of Compound 1 can have a purity of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%. The residual substances can include another solid of Compound 1 Form and / or reaction impurities and / or processing impurities resulting from its production.

[0080] The Form 2 of the MSA monohydrate of Compound 1 and another solid of Compound 1 Form The mixture is also within the scope of the present invention. In these embodiments, such a mixture can contain less than 90% of the amorphous MSA salt of Compound 1, based on the weight of the mixture. For example, the mixture can contain 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10 or about 5% by weight of the Form 2 of the MSA monohydrate of Compound 1.

[0081] The crystals described herein Form (e.g., the Form 4 of the free base of Compound 1, the Form 2 of the hydrate of the free base of Compound 1, the Form 1 of the MSA salt of Compound 1, the Form 2 of the MSA salt monohydrate of Compound 1) samples can be provided in a substantially pure homogeneous phase, but it is shown that a dominant amount of one single crystal Form is present and, if desired, one or more other crystals Form can be present in small amounts. The presence of more than one crystal Form in the sample can be determined by techniques such as powder X-ray diffraction (PXRD) or solid-state nuclear magnetic resonance spectroscopy (ssNMR). For example, in the comparison of the experimentally measured PXRD pattern with the simulated PXRD pattern, the presence of extra peaks indicates the presence of one or more crystals Formcan be shown. The simulated PXRD can be calculated from single crystal X-ray data. See Smith, D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963). Preferably, the crystal Form has a substantially pure and homogeneous phase such that the experimentally measured PXRD pattern, which gives rise to extra peaks not present in the simulated XRPD pattern, is shown to be less than 10%, preferably less than 5%, more preferably less than 2% of the total peak area. Most preferably, the crystal has a substantially pure and homogeneous phase such that the measured PXRD pattern, which gives rise to extra peaks not present in the simulated PXRD pattern, is shown to be 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 various analytical techniques known to those skilled in the art. Such techniques include, but are not limited to, solid state nuclear 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 X-ray diffraction patterns can be obtained with measurement errors depending on the measurement conditions used. In particular, it is generally known that the intensity in an X-ray diffraction pattern can vary depending on the measurement conditions used. It should also be understood that since the relative intensity can also vary depending on the experimental conditions, the exact order of the intensities should not be considered. Furthermore, the measurement error of the diffraction angle for conventional X-ray diffraction patterns is usually about ±0.2° 2θ, and such a degree of measurement error should be considered to exist in the above-mentioned diffraction angles. As a result, the crystals of the present invention FormA crystal that provides an X-ray diffraction pattern that is 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 thereto. Any crystal that provides an X-ray diffraction pattern that is substantially identical to the pattern disclosed in the accompanying drawings Form also falls within the scope of the present invention. The ability to determine substantial identity with respect to X-ray diffraction patterns is within the scope of those skilled in the art.

[0084] The solid of Compound 1 described herein Form (and its hydrates and salts Form in solid form Form ) may be formulated into a pharmaceutical composition and / or used in a method of treatment and / or prevention. These methods include administration of the solid of Compound 1 Form , the solid of a hydrate of Compound 1 (e.g., the monohydrate of Compound 1 Form , the solid of the MSA salt of Compound 1 Form and the solid of the MSA salt hydrate of Compound 1 Form , either alone or in combination with one or more other pharmaceutically active agents, such as agents that may be useful in the treatment of the diseases described herein, but are not limited thereto.

[0085] Therapeutic applications 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 may be administered to animals, preferably mammals (e.g., livestock, cats, dogs, mice, rats), more preferably humans. Any method of administration may be used to deliver the compound or pharmaceutical composition to the patient. In certain embodiments, the compound or pharmaceutical composition is administered orally. In other embodiments, the compound or pharmaceutical composition is administered parenterally.

[0086] The compounds of the present invention can modulate the activity of the enzyme indoleamine-2,3-dioxygenase (IDO). The term "modulate" means the ability to increase or decrease an enzyme or receptor. Thus, the compounds of the present invention can be used in a method 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 a further embodiment, the compounds of the present invention can be used by administering a modulating (e.g., inhibiting) amount of the compound of the present invention to modulate the activity of IDO in a cell or individual in which modulation of the enzyme is needed.

[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 a cell or individual in which modulation of the enzyme is needed by administering an inhibitory amount of Compound 1.

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

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

[0090] The present invention relates to a solid of a therapeutically effective amount or dose of Compound 1 of the present invention (or its hydrate or salt) FormAlso provided is a method for treating a disease associated with the activity or expression of IDO (e.g., abnormal activity and / or overexpression) by administering such a pharmaceutical composition to an individual (e.g., a patient) in need of such treatment. Examples of diseases include any disease, disorder, or condition that is directly or indirectly related to the expression or activity of the IDO enzyme, e.g., overexpression or abnormal activity. IDO-related diseases may also include any disease, disorder, or condition that can be prevented, alleviated, or cured by modulating the enzyme activity. Examples of IDO-related 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 transplantation (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 a part of a tissue sample excised from an organism, e.g., 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, e.g., a mammal.

[0092] As used herein, the term "contact" means bringing together a given component in an in vitro or in vivo system. For example, "contacting" an IDO enzyme with a compound of the invention means administering the compound of the invention to an individual or patient having IDO, e.g., a human, and also, for example, introducing a solid of Compound 1 of the invention Form into a sample containing cells or a purified preparation containing the IDO enzyme.

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

[0094] The solid of Compound 1 of the present invention Form Cancer types that can be treated using this include, but are not limited to, brain tumors, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, blood cancer, lung cancer, and bone cancer. Examples of such cancer types include neuroblastoma, intestinal cancer such as rectal cancer, colorectal cancer, familial adenomatous polyposis cancer and hereditary non-polyposis, colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, malignant adenoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer of the uterine body, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, malignant melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral primitive neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic 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 cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal malignant melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma, but are not limited to these.

[0095] That is, according to another embodiment, the present invention relates to the solid of the compound of the present invention FormAlso provided is a method of treating an autoimmune disease by providing the composition to a patient in need thereof. Exemplary autoimmune diseases include collagen diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sharp syndrome, CREST syndrome (calcinosis, Raynaud's syndrome, esophageal motility disorder, telangiectasia), dermatomyositis, vasculitis (Wegener's granulomatosis; Morbus Wegener's), and Sjogren's syndrome; kidney diseases such as Goodpasture's syndrome, rapidly progressive glomerulonephritis, and membranoproliferative glomerulonephritis type II; endocrine diseases such as type I diabetes, autoimmune polyendocrine disease type I (APECED), autoimmune hypoparathyroidism, pernicious anemia, gonadal dysgenesis, 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; liver diseases such as primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis type 1, autoimmune hepatitis type 2, and 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, idiopathic thrombocytopenic purpura (Morbus Werlhof); autoimmune reaction-related infectious diseases such as AIDS, malaria, and Chagas disease.

[0096] One or more other pharmaceutical agents or treatment methods, such as antiviral agents, chemotherapeutic agents or other anti-cancer agents, immunostimulants, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapeutics (e.g., IL2 and GM-CSF) and / or tyrosine kinase inhibitors can, if desired, be used in combination with the compounds of the invention for the treatment of IDO-related diseases, disorders or symptoms. The agents can be combined with the compounds of the present application in a single dosage Form form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0097] Suitable chemotherapeutic agents or other anti-cancer agents include, for example, alkylating agents (such as, but not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes), such as, but not limited to, uracil mustard, chloromethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine and temozolomide.

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

[0099] The compounds of the present invention may also be used in combination with vaccine therapy in the treatment of melanoma. Anti-melanoma vaccines are in some respects similar to anti-viral vaccines that can be used to prevent diseases caused by viruses such as polio, mumps and measles. It is also possible to administer attenuated melanoma cells or melanoma cells (so-called antigens) to stimulate the body's immune system to destroy melanoma cells.

[0100] Malignant melanoma limited to the wrist or leg may be treated using a combination of agents comprising one or more of the compounds of the present invention using hyperthermic isolated limb perfusion technology. This treatment protocol temporarily separates the affected limb from the rest of the body and delivers a high dose of chemotherapeutic agent into the arterial blood flow of the limb by injection, providing a high dose to the tumor region without exposing the internal organs to dosages that can cause serious side effects. Typically, this fluid is warmed to 102°-104°F. Melphalan is the most frequently used agent in this chemotherapy. It may be administered in combination with another agent called tumor necrosis factor (TNF).

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

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

[0103] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, reloxafine and droloxafine.

[0104] Suitable cytotoxic agents include, for example, epidophyllotoxin; antineoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0105] Other anticancer agents include antibody therapeutic agents (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-10 or TGF-β).

[0106] Other anticancer agents also include those that block the migration of immune cells to chemokine receptors (e.g., CCR2 and CCR4), such as antagonists.

[0107] Other anticancer agents include those that enhance the immune system (e.g., adjuvants or adoptive T cell transfer).

[0108] Anticancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

[0109] The pharmaceutical composition of the present invention may optionally include at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more essential steps in a signal transduction pathway in the normal function of cancer cells, thereby causing 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 farnesyl transferase inhibitors (FTIs), such as L-744,832 (Kohl et al., Nat. Med., 1(8):792-797 (1995)); (iv) inhibitors of the Akt family kinase or the Akt pathway, such as rapamycin (see, for example, Sekulic et al., Cancer Res., 60:3504-3513 (2000)); (v) cell cycle kinase inhibitors, such as flavopiridol and UCN-O1 (see, for example, Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (2003)); and (vi) phosphatidylinositol kinase inhibitors, such as LY294002 (see, for example, Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994)). Alternatively, at least one STI and at least one IDO inhibitor may be present in separate pharmaceutical compositions. In certain embodiments of the present invention, at least one IDO inhibitor (e.g., Compound I or its solid Form , or a solid of its hydrate or salt FormAnd at least one STI can be administered to the patient simultaneously or sequentially. In other words, at least one IDO inhibitor can be administered first, or at least one STI can be administered first, or at least one IDO inhibitor and at least one STI can be administered simultaneously. Further, if one or more IDO inhibitors and / or STIs are used, this compound can be administered in any order.

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

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

[0112] In certain embodiments of the present invention, at least one IDO inhibitor and at least one chemotherapeutic agent are administered to the patient 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. Additionally, if 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 the IDO inhibitor.

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

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

[0115] The solid of the present invention Form Suitable antiviral agents that can be considered for use in combination 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 (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also called β-L-D4C and named β-L-2',3'-dideoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6-diaminopurine dioxolane); and rodenosine (FddA). Representative and suitable NNRTIs include nevirapine (BI-RG-587); delavirdine (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); nelfinavir (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 number 11607.

[0117] Combination with cancer immunotherapeutic agents Also provided herein is a solid of Compound 1 Form or a solid of a hydrate or salt of Compound 1 Form which is a method of treatment administered together with one or more cancer immunotherapeutic agents. As used herein, cancer immunotherapeutic agents are also known as cancer immunotherapies and are effective in enhancing, stimulating and / or upregulating the immune response in a patient.

[0118] In one embodiment, the solid of Compound 1 Form or the solid of a hydrate or salt of Compound 1 Form is sequentially administered before the administration of the cancer immunotherapeutic agent. In another embodiment, the solid of Compound 1 Form or the solid of a hydrate or salt of Compound 1 Form is administered simultaneously with the cancer immunotherapeutic agent. In yet another embodiment, the solid of Compound 1 Form or the solid of a hydrate or salt of Compound 1 Form is sequentially administered after the administration of the cancer immunotherapeutic agent.

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

[0120] Examples of cancer immunotherapeutic agents include, for example, small molecule drugs, antibodies or other biologic agents or small molecule formulations. 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 (i) an agonist of a stimulatory factor (e.g., a co-stimulatory factor) receptor or (ii) an antagonist of an inhibitory signal to T cells (e.g., a co-inhibitory factor), both of which result in the amplification of an antigen-specific T cell response (often also referred to as an immune checkpoint regulator).

[0122] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory 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 co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes 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 aspect, a cancer immunotherapeutic agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF and another immunosuppressive cytokine) or a cytokine that stimulates T cell activation for stimulating an immune response.

[0124] In one aspect, the T cell response is the solid of Compound 1 Form or the solid of a hydrate or salt of Compound 1 Formand one or more proteins that inhibit T cell activation, such as (i) 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) 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, and can be stimulated by a combination thereof.

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

[0126] Another agent for combination therapy is an agent that inhibits or depletes macrophages or monocytes, including but not limited to, for example, CSF-1R antagonists, such as 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 aspect, the solid of Compound 1 Form or the solid of the hydrate or salt of Compound 1 Formis used together with one or more agonist agents that bind to positive co-stimulatory receptors, blockers, antagonists that attenuate signaling via inhibitory receptors, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that suppress innate immunosuppressive pathways in the tumor microenvironment (e.g., blocking the binding of inhibitory receptors such as the PD-L1 / PD-1 interaction), agents that deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or depleting or inhibiting with ex vivo anti-CD25 beads), agents that inhibit metabolic enzymes such as IDO or reverse / recover T cell immune unresponsiveness or depletion, and agents that initiate innate immune activation and / or inflammation at the tumor site.

[0128] In one aspect, 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 aspect, 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® ( Pembrolizumab ) or MEDI-0680 (AMP-514; WO 2012 / 145493). The cancer immunotherapeutic agent may also include pidilizumab (CT-011) (although its specificity for PD-1 binding is in question). Another approach 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, so-called AMP-224.

[0130] In another aspect, the cancer immunotherapy agent is a PD-L1 antagonist, such as 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 aspect, the cancer immunotherapy agent is a LAG-3 antagonist, such as 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 aspect, the cancer immunotherapy 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 aspect, the cancer immunotherapy agent is a GITR agonist, such as 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 aspect, the cancer immunotherapy agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

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

[0136] In another aspect, 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 aspect, the cancer immunotherapeutic agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the cancer immunotherapeutic agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0138] In another aspect, the cancer immunotherapeutic agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varilumab.

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

[0140] The present invention includes, for example, pharmaceutical kits useful in the treatment or prevention of IDO-related diseases or disorders, obesity, diabetes and other diseases mentioned herein, which contain one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention. It will be readily understood by those skilled in the art that such kits can further include, if necessary, one or more various conventional pharmaceutical kit components, for example, containers containing one or more pharmaceutically acceptable carriers, additional containers. Instructions such as inserts or labels indicating the amount of the component to be administered, guidelines for administration and / or guidelines for mixing the components may be included in the kit.

[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 time points, and also these therapeutic agents or at least two of them are administered in a substantially simultaneous manner. Substantial simultaneous administration can be achieved, for example, by administering to a patient in one single dosage form at a fixed ratio of each therapeutic agent, or in a plurality of single dosage forms for each therapeutic agent. The sequential or substantial simultaneous administration of each therapeutic agent can be carried out, for example, by any suitable route such as the oral route, the intravenous route, the intramuscular route, and direct absorption through the mucosal membrane tissue, but is not limited thereto. The therapeutic agents can be administered by the same route or different routes. For example, the first therapeutic agent in a selected combination can be administered by intravenous injection, while another therapeutic agent within this combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. The combination therapy can further combine other biologically active ingredients and non-drug therapies (e.g., surgery or radiation therapy) to administer the above-described therapeutic agents. When this combination therapy further includes non-drug treatment, the non-drug treatment can be carried out at any appropriate time point as long as a useful effect resulting from the combined action of the therapeutic agent and the non-drug treatment is achieved. For example, in a preferred case, this useful effect is achieved even when the non-drug treatment is temporarily suspended, probably for several days or weeks, from the administration of the therapeutic agent.

[0142] Pharmaceutical Compositions and Dosage The present invention provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of one or more solids according to the present invention Form and, together with one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally together with one or more of the above-described other therapeutic agents, is formulated.

[0143] The solid of the present invention FormFor any and all uses described herein, by any suitable means, for example, orally, such as in tablets, capsules (each of which may include sustained release or extended release formulations), pills, powders, granules, elixirs, tinctures, suspensions (nanosuspensions, microsuspensions, spray dried dispersions), syrups and emulsions; sublingually; buccally; parenterally [for example, subcutaneous, intravenous, intramuscular or intrasternal injection, or infusion techniques (for example, injectable sterile aqueous or non-aqueous solutions or suspensions)]; intranasally, for example, to the nasal mucosa by inhalation spray; topically, for example, by creams or ointments; or rectally (for example, in the form of suppositories), may be administered. 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 criteria.

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

[0145] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid diluent, excipient, adjuvant (for example, lubricants, magnesium, calcium or zinc stearate or stearic acid), or a solvent encapsulating material involved in carrying or delivering the compound of interest from one organ or part of the body to another organ or another part of the body. Each carrier is "acceptable" in the sense that it is compatible with the other ingredients in the formulation and not harmful to the patient.

[0146] The term "pharmaceutical composition" means a composition comprising the compound of the present invention in combination with at least one further pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" is a medium generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal, i.e., an adjuvant, excipient or vehicle, which varies depending on the method of administration and the nature of the dosage form, and includes, for example, diluents, preservatives, bulking agents, flow regulators, disintegrants, wetting agents, emulsifying agents, suspending agents, sweeteners, flavors, fragrances, antibacterial agents, antifungal agents, lubricants and dispensing agents.

[0147] Pharmaceutically acceptable carriers are formulated according to numerous factors well known to those skilled in the art. These include, for example, but are not limited to, the type and nature of the active pharmaceutical agent to be formulated; the subject to which the composition containing the agent is 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 numerous different components and additives in addition to the active pharmaceutical agent, and such other components well known to those skilled in the art are included in the formulation for various reasons (e.g., stabilization of the active pharmaceutical agent, binder, etc.). Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in many readily available sources of information, such as Allen, Jr. L.V., et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0148] The solid Form dosage regimen of the present invention 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 status, medical condition and body weight of the recipient; the nature and extent of the symptoms; the type of concomitant therapy; the frequency of treatment; the route of administration, the renal and hepatic functions of the patient and the intended effect.

[0149] As a general guidance, when used to obtain the desired effect, the daily dosage of each active ingredient 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 ranges from about 0.01 to about 10 mg / kg / min in continuous infusion. The compounds of the present invention may be administered once a day or the total daily dosage may be administered in divided dosages 2, 3, or 4 times a day.

[0150] The solid of the present invention Form is typically administered in a mixture with a pharmaceutical diluent, excipient or carrier (collectively referred to herein as a pharmaceutical carrier) appropriately selected in accordance with general pharmaceutical standards according to the intended dosage form, for example, dosage forms such as oral tablets, capsules, elixirs and syrups.

[0151] Dosage forms suitable for administration (pharmaceutical compositions) contain from about 1 milligram to about 2000 milligrams of the 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 present invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and filled into No. 1 gelatin capsules.

[0153] A typical injectable preparation is produced by aseptically placing at least one compound of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing it. When in use, the contents of the vial are mixed with 2 mL of physiological saline to prepare an injectable preparation.

[0154] The present invention encompasses within its scope pharmaceutical compositions containing a therapeutically effective amount of at least one compound of the present invention as an active ingredient, alone or in combination with a pharmaceutical carrier. Optionally, the solid of the present inventionForm It can be used alone or in combination with other compounds of the present invention or one or more other therapeutic agents, such as antidiabetic agents or other pharmacologically active substances.

[0155] Regardless of the selected route of administration, the solid of the present invention Form is formulated into a pharmaceutically acceptable dosage Form by conventional methods known to those skilled in the art.

[0156] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention is not toxic to the patient and may be varied so as to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0157] The selected dosage level depends on a variety of factors including the activity of the compound of the present invention being used, 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 agents, compounds and / or materials used in combination with the compound of the present application, age, sex, weight, symptoms, state of 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 necessary effective amount of the pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the compound of the present invention used in the pharmaceutical composition at a level lower than the required amount and gradually increase the dosage until the desired therapeutic effect is achieved and the desired effect is achieved.

[0159] Generally, the appropriate daily dosage of a compound is the minimum dosage effect at which the amount of the compound produces a therapeutic effect. Such effective amounts generally depend on the factors described above.

[0160] If necessary, the effective daily dosage of the compound can be administered as a single dose, at appropriate intervals throughout the day, as appropriate. FormIt may also be administered separately at doses divided into 2, 3, 4, 5, 6 or more. In certain embodiments of the invention, the dosing is once daily.

[0161] While the compounds of the present invention can be administered alone, it is preferred to administer the compounds as pharmaceutical formulations (compositions).

[0162] (Definition) Certain aspects of the present specification relate to crystals Form Crystals Form produce an X-ray diffraction pattern with sharp maxima.

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

[0164] As used herein, "hydrate" refers to a crystal of a molecule that further contains water incorporated into its crystal structure Form The water molecules in the hydrate may be present in a regular arrangement and / or an irregular arrangement. The hydrate may contain either a stoichiometric or non-stoichiometric amount of water molecules.

[0165] As used herein, the term "patient" refers to an organism to be treated by the methods of the present invention. Such organisms preferably include mammals (e.g., mice, monkeys, horses, cows, pigs, dogs, cats, etc.), most preferably humans, but are not limited thereto.

[0166] As used herein, the term "effective amount" means the amount of a drug or pharmaceutical formulation that induces a biological or pharmaceutical response in a tissue, organ, animal, or human, as envisioned, for example, by a researcher or medical practitioner, i.e., the amount of a compound of the present invention. Further, the term "therapeutically effective amount" means any amount that, when compared to a corresponding patient to whom such amount has not been administered, results in an improvement in the treatment, cure, prevention, or alleviation of a disease, disorder, defect, or side effect, or a reduction in the rate of progression of a disease or disorder. An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to limit the formulation or route of administration. The term also includes amounts effective to enhance normal physiological functions.

[0167] As used herein, the term "treat" or "treatment" includes the treatment of a disease state in a mammal, particularly a human, and also includes the following: (a) preventing a disease state that occurs in a mammal, particularly when the mammal has not yet been diagnosed as having the disease but is susceptible to developing the disease state; (b) inhibiting the disease state, i.e., arresting its development; and / or (c) alleviating the disease state, i.e., bringing about regression of the disease state.

[0168] Aspect Aspect 1. Crystal Form of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4. Aspect 2. The crystal of Aspect 1, characterized by a powder X-ray diffraction pattern comprising 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 of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4. Aspect 3. The crystal of Aspect 1, characterized by a powder X-ray diffraction pattern comprising 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 of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4. Aspect 4. The crystal of Aspect 1, characterized by a powder X-ray diffraction pattern comprising 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 of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4. Aspect 5. The crystal of Aspect 1, characterized by a powder X-ray diffraction pattern comprising 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 of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4. Aspect 6. The crystal Form of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate Form 2. Aspect 7. The crystal of Aspect 6, characterized by a powder X-ray diffraction pattern comprising 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. Aspect 8. The crystal of Aspect 6, characterized by a powder X-ray diffraction pattern comprising 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. Aspect 9. The crystal of Aspect 6, characterized by a powder X-ray diffraction pattern comprising 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. Aspect 10. The crystal of Aspect 6, characterized by a powder X-ray diffraction pattern comprising 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. The crystal Form of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid Form 1. Aspect 12. The crystal of Aspect 11, characterized by a powder X-ray diffraction pattern comprising 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 of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid Form 1. Aspect 13. A crystal of Aspect 11, characterized by a powder X-ray diffraction pattern comprising 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 of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid Form 1. Aspect 14. A crystal of Aspect 11, characterized by a powder X-ray diffraction pattern comprising 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 of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid Form 1. Aspect 15. A crystal of Aspect 11, characterized by a powder X-ray diffraction pattern comprising 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 of (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 of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4; Crystal Form(R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate of Form 2; or crystal Form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid of Form 1; or a combination thereof; and a pharmaceutically acceptable carrier, a pharmaceutical composition. 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 a combination thereof, further comprising the pharmaceutical composition of Aspect 17. Aspect 19. Amorphous Quality (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, further comprising the pharmaceutical composition of Aspect 17. Aspect 20. A therapeutically effective amount of crystal Form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide of Form 4; crystal Form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate of Form 2; or crystal Form (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonic acid ofForm 1; or administering to a patient in need of cancer treatment a combination thereof, A method for treating cancer in a patient in need of cancer treatment. Aspect 21. The method of Aspect 20, wherein the cancer is prostate, colon, rectal, pancreatic, cervical, gastric, endometrial, brain, liver, bladder, ovarian, testicular, head, neck, skin (e.g., melanoma and basal cell carcinoma), mesothelium, leukocyte cells (e.g., lymphoma and leukemia), esophageal, breast, muscle, connective tissue, lung (e.g., small cell lung cancer and non-small cell cancer), adrenal, thyroid, kidney or bone cancer; or glioma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma (e.g., Kaposi's sarcoma), choriocarcinoma, skin basal cell carcinoma or seminoma. Aspect 22. The method of Aspect 20, further characterized by administering 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 methanesulfonate or a combination thereof. Quality of amorphous (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide, amorphous Quality of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate or a combination thereof. Aspect 23. The method of Aspect 20, further comprising an immune checkpoint inhibitor. Aspect 24. The method of Aspect 20, wherein the immune checkpoint inhibitor comprises ipilimumab (YERVOY®), nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®) or a combination thereof. Aspect 25. Indoleamine 2,3-dioxygenase, crystalline Form of (R)-N-(4-chlorophenyl)-2-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide Form 4; crystalline FormOf (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide monohydrate Form 2; or crystals Form Of (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide methanesulfonate Form 1; or a combination thereof, optionally, amorphous Quality Of (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 methanesulfonate or a combination thereof, A method for regulating the activity of indoleamine 2,3-dioxygenase, characterized by contacting them.

Example

[0169] The following examples are described to provide a complete disclosure and description of the production and use methods of the present invention to those skilled in the art, and are not intended to limit the scope of the invention that the inventors regard as their inventions with respect to those inventions, nor are they intended to indicate that the following experiments are to be carried out or all the experiments that can be carried out. The exemplary descriptions described in the present tense do not necessarily have to be carried out. Rather, this description is understood to mean that the descriptions for the examples described in this article do not necessarily have to be carried out, but rather that this description can be carried out to create data and things of the nature described in this specification. Although efforts have been made to determine the accuracy of the numerical values used (for example, amounts, temperatures, etc.), some experimental errors and deviations should be taken into account.

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

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

[0172] for the MSA salt hydrate of Compound 1 Form Single crystal X-ray data for 2 was 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 carried out using the software suite CrysAlisPro 1.171.38.41r (Rigaku OD, 2015).

[0173] Indexing and processing of the measured intensity data were carried out using the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). The 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 (G. M. Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA.) The structure refinement was based on 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 factor based on the measured reflection, and F c The agreement between the refined crystal structure model and the experimental X-ray diffraction data involves the minimization of a function defined by the formula: ||Fo|-|Fc|| / Σ|Fo| and wR=[Σw(|Fo|-|Fc|) 2 / Σw|Fo|] 1 / 2 The difference 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., in 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 Hydrogen atoms of water in the structure of 2 and the MSA salt of compound 1 Form There were some exceptions when the structures of the 1 and 2 (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 form 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 irradiation: λ = 1.541 Å. This powder diffractometer was equipped with a ceramic tube and an RTMS PIXcel 1D detector set at output levels of 45 kV and 40 mA. The incident optical system consisted of a 0.02 rad solar slit; a 10 mm beam mask; a 1° anti-scatter slit; and an automatic divergence slit set at an irradiation wavelength of 10 mm. The diffracted optical system consisted of a 0.02 rad solar slit; an automatic anti-scatter slit set at an irradiation wavelength of 10 mm; a Ni-K-β filter; and a detector window of ~2.9°. Data were collected in reflection mode, in a continuous scan mode while spinning, over a 2θ range of 2 - 40°, with a stepwise of 0.033 - 040° and a net measurement time of ~317 s / step. A powder sample of more than 200 mg was packed into a backfill sample holder.

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

[0176] Differential scanning calorimetry (DSC) Differential scanning calorimetry (DSC) experiments on 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 (about 1 - 10 mg) were weighed in an aluminum pan and recorded accurately up to 100 mg before transferring the samples to the DSC. The instrument was purged with nitrogen gas at 50 mL / min. Data were collected from room temperature to 300 °C at a heating rate of 10 °C / min. The DSC plots showed descending endothermic peaks.

[0177] DSC for the Compound 1 MSA 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, the lid was sealed, and holes were made with a laser pinhole, and the weight was accurately recorded (3.7940 mg). The aluminum pan weighed and determined as the sample pan was placed on the reference side of the cell. The analysis was performed at 10 °C / min from -30 °C to 300 °C.

[0178] Thermogravimetric analysis (TGA ) Thermogravimetric analysis (TGA) experiments on 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 (about 10 - 30 mg) were placed in a pre-weighed platinum pan. The sample weight was accurately measured and recorded by the instrument up to 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 hydrate of Compound 1 was performed using a TA Instruments Q5000 thermogravimetric analyzer. Temperature calibration was performed using nickel and almel. The sample (5.6360 mg) was placed in an aluminum pan. The sample was sealed, holes were opened in the lid, and then it was placed in the TG furnace. The furnace was heated under nitrogen. The analysis was carried out 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 operating at a proton frequency of 500 MHz. The solid sample was rotated at 13 kHz in a 4 mm ZrO 2 rotor. The contact time was 4 milliseconds, and the proton channel was tilted 50 - 100% (A.E. Bennett et al, J. Chem. Phys., 1995, 103, 6951)(G. Metz, X. Wu and S.O. Smith, J. Magn. Reson. A., 1994, 110, 219 - 227). The delay time was maintained at 20 seconds, which is 5x the API of HT 1 H T 1 Proton decoupling was performed using a TPPM sequence with a 4.3 μs pulse (58 nominal bandwidth). The observed spectral width was from 100 ppm centered to 300 ppm. 2048 data points were acquired (showing a digital resolution of 36 Hz), and zero-filling to 8192 was performed before apodization. 2048 free induction decays were co-added simultaneously. This spectrum was compared indirectly 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 test. The temperature was set at 280 K.

[0181] F Fourier transform infrared spectroscopy was performed using an IS50-ATR spectrometer by the total reflection measurement method (ATR). Spectra were collected in reflection mode at a resolution of 4 cm -1 and 64 scans. Spectra were collected in reflection mode at a resolution of 4 cm -1 and 64 scans.

[0182] ​ FT-Raman spectra were obtained using a Nicolet iS50 FT-Raman spectrometer equipped with a high-sensitivity InGaS detector at a resolution of 4 cm -1 and 64 scans. The laser excitation wavelength was 1064 nm. The laser output was 0.5 W.

[0183] ​ : VHPLC parameters VHPLC system: Waters AcQuity BSM or H-Class VHPLC system equipped with a Waters UV / Vis detector Column: Ascentis Express C18, 150 mm x 2.1 mm i.d., 2.7 um particle size Detection wavelength: 218 nm VHPLC detection time constraint: Normal VHPLC sampling rate: 20 Hz VHPLC bandwidth: 1.2 nm resolution Flow rate: 0.5 mL / min Injection volume: 1 uL Column temperature: 30 °C Running time: ~14 minutes Sample temperature: 5 °C 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

[0185] ​ The microdissolution experiment was carried out in a pIon μDiss Profiler microdissolution instrument using an optical fiber UV monitoring system as follows: Probe: 2.5 mm probe (5 mm path length) Volume: 15 ml Stirring: 150 rpm Temperature: 37 °C (solution and instrument bath temperature) Blank: Instant FaSSIF / FeSSIF Standard: Six 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 method described in WO2016 / 073770, which is incorporated herein by reference.

[0187] Example 2: Free base of Compound 1, amorphous To a 1 L round-bottom flask were added (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 obtain (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: Of the free base hydrate of Compound 1 ​ 2 Into a 50 L glass-lined reaction vessel, under a nitrogen blanket, 13.75 kg of acetonitrile was added, followed by 2.68 kg of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), and rinsed with 2.0 kg of acetonitrile. Following 2.03 Kg of N-methylimidazole, 1.95 kg of acetonitrile was added. Following 2.48 Kg of (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid, 1.05 kg of acetonitrile was added. The mixture was held for 0.5 hour, followed by 1.21 kg of 4-chloroaniline and 1.0 kg of acetonitrile. The mixture was maintained at 20 °C until completion of the reaction was confirmed by HPLC analysis. The solution was then heated to 60 °C and water (9.25 kg) was added. 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 held 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 in vacuo at 50 °C to give 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: Of the free base hydrate of Compound 1 ​ 2 The free base (250 mg) of amorphous Compound 1 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 adding 1 mL of water, an emulsion was observed as oil separated out. The emulsion was aged, and crystallization occurred. The crystals were isolated using a Buchner funnel.

[0190] Example 5: Free base of Compound 1 ​ 4 Into a 500 mL round-bottom flask were placed (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide hydrate (15.0 g) and acetonitrile (176 g), and the mixture was stirred until all the solids dissolved. The solution was concentrated to dryness under vacuum. Additional acetonitrile (176 g) was added, and the solution was concentrated to dryness under vacuum again. Ethyl acetate (134 g) was added, and the mixture was stirred until it became a homogeneous solution and then concentrated to dryness again under vacuum. After removing all the solvents, ethyl acetate (50 g) was added. The solution was heated to 40 °C and stirred with a magnetic stirrer. A seed crystal (220 mg) was 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 heated to 50 °C and subjected to a temperature cycle of gradually cooling to 20 °C. The slurry was stirred overnight. The solid was filtered and dried under vacuum to obtain (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: Free base of Compound 1 ​ 4 The free base (250 mg) of Compound 1 was dissolved in ethyl acetate (1 mL) at 40 °C. Heptane (700 μL) was added, and then the free base of Compound 1 ​A seed crystal of 4 (about 10 mg) was added. Thereby, a slurry was formed. The slurry was aged for 10 minutes and then heptane (3 mL) was further added. The slurry was aged for approximately 1 hour and then isolated with a Buchner funnel and dried overnight in an oven at 50 °C under vacuum.

[0192] Example 7: Free base of Compound 1 ​ 4 Free base of Compound 1 ​ 2 (100 mg) was dried in a vacuum oven at 50 °C overnight to dehydrate this substance. The substance was then slurried in heptane (1 mL) at 65 °C overnight. A phase transition occurred after several hours, and then the free base of Compound 1 ​ was converted to 4.

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

[0194] Example 8A: Methanesulfonic acid (MSA) salt of Compound 1, amorphous Of the MSA salt of Compound 1 ​ By rotary evaporation of 1 / dichloromethane, the amorphous MSA salt of Compound 1 was obtained. This substance was recrystallized to 1 by thermal stress at 60 °C of the MSA salt of Compound 1 ​ 1

[0195] Example 9: Methanesulfonic acid (MSA) salt of Compound 1, ​ 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 1 molar equivalent solution of MSA in ethyl acetate (250 mL) was prepared and added to the reaction vessel by pump over 2 hours. The resulting slurry was aged for 30 minutes. The crystals were isolated by Buchner funnel and dried in an oven at 50 °C overnight.

[0196] Example 10: Methanesulfonic acid (MSA) salt of Compound 1, ​ 1 Into a 10 L glass-lined reaction vessel, under a nitrogen atmosphere, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (349 g) and acetonitrile (2 L) were charged. N-Methylimidazole (245 g) was then added, followed by acetonitrile (0.3 L). To (R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid (300 g), acetonitrile (0.3 L) was added. The mixture was held for 0.5 h, and 4-chloroaniline (139 g) was then added, followed by acetonitrile (0.4 L). The mixture was maintained at 20 °C by HPLC analysis until the reaction was determined to be complete. The solution was then heated to 60 °C, and water (1.2 L) was added. The solution was then cooled to 40 °C, seed crystals (3 g) were added, and the resulting slurry was held for 1 h. The slurry was then cooled to 20 °C, and water (2.7 L) was added. The slurry was filtered, and the cake was washed three times with 2:1 water / acetonitrile (3 L). This cake was dissolved in 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, seed crystals (4.14 g) were added, and a solution of methanesulfonic acid (95.7 g) / 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 obtain (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: The MSA salt monohydrate of Compound 1 ​ 2 The MSA salt monohydrate of Compound 1 ​ 2 can be prepared by slurrying 1 of the MSA salt of Compound 1 at room temperature with a water activity of 60% relative humidity in ethanol / water (85 / 15 v / v). The MSA salt hydrate of Compound 1 ​ The single crystal of 2 can be obtained from the MSA salt of Compound 1 at ambient temperature in methanol / acetonitrile at 8 / 92 v / v. ​ The single crystal of 2 can be obtained from the MSA salt of Compound 1 at ambient temperature in methanol / acetonitrile at 8 / 92 v / v.​ Growth was achieved by evaporating a solution of 1.

[0198] Example 12: MSA salt of compound 1 ​ 1:Solid-state stability A 12-month stability study of the MSA salt of Compound 1 ​ The effects of temperature, humidity and light on Compound 1 were tested. See table below. The test consisted of one batch of drug packed in a double LDPE bag and placed in a 0.6 L HDPE with a lid and gasket. ​ 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 ​ 1 may be stored at or below 25°C. [Table 28]

[0199] For runs 1, 2, 3 and 5, 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 runs 6 (to 82.0% and 100.7%, respectively) and 4 (to 82.4% and 101.1%, respectively), there was a slight increase from the initial assay "as is" and assay "corrected" values ​​of 79.0% and 97.0%, respectively.

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

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

[0202] For Test Nos. 1 and 2, no substantial change was observed in the moisture content from the starting value of <0.1% w / w.

[0203] Color and appearance (including white or off-white powder or powder in lumps) were maintained during the test.

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

[0205] For the MSA salt of Compound 1 ​ 1, no substantial change was observed when exposed to the minimum ICH Q1B exposure. When subjected to approximately 3.5 times the minimum ICH exposure, a slight increase was observed among the total impurities, mainly 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 for the other tested attributes. The data from the photostability test indicated that the drug does not need to be protected from light.

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

[0207] Example 13: For the MSA salt of Compound 1 ​ 1, pH solubility For the MSA salt of Compound 1 ​ 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. The measurements were carried out using an Orion ATI Model 370 pH meter. For the MSA salt of Compound 1 ​1 (approximately 20 - 30 mg) was weighed into each of 11 10 cc Type I glass vials. Various acidic and basic aqueous solutions (5 mL) were added to each vial. Each vial was stoppered, vortexed, and mixed thoroughly by sonication. The pH of each sample was recorded.

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

[0209] Each aliquot (1.0 mL) of the filtrate was diluted 25 - fold in each flask to 25 mL using 50% acetonitrile / 50% Milli - Q Water, q.w. The aliquot was transferred to the HPLC autosampler and the concentration of Compound 1 was assayed.

[0210] The samples were assayed using the following HPLC method: Column: Waters YMC Pro - Pack C18; Part # AS12S05 - 1546WT, S - 5μm, 150 x 4.6 mm ID Mobile Phase Solvent A: Water w / 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: 10μL 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] Adjustment of external standard: 25.4 mg of the MSA salt of Compound 1 in a 25 mL Type I glass vial ​ 1 was weighed. 100% Acetonitrile (20 mL) was added to the vial. The vial was co-stoppered, vortexed, and sonicated. Not all of the solid dissolved. The suspension was transferred to a 250 mL glass volumetric flask, and the glass vial was washed with 4 x 20 mL of 50% Acetonitrile / 50% Milli-Q Water, and each wash was transferred to the volumetric flask. All of the solid dissolved. Q.S. the volumetric flask to a final volume of 250 mL using 50% Acetonitrile / 50% Milli Q Water to obtain a standard solution at 101.5 mcg / mL.

[0212] The overall profile is typical of a weak base, showing a solubility of 1 - 2 mcg / mL for the free base, ~130 mcg / mL in water (initially pH ~2.5), ~560 mcg / mL at the pH maximum at pH ~2, and a decrease in 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: Microdissolution FaSSiF / FeSSiF of the MSA salt of Compound 1 ​ 1 is amorphous ​ or the HCl salt (amorphous and crystalline ​ ) shows rapid rate and extent of dissolution in both FeSSiF and FaSSiF compared to. The ​ dissolution rate of 1 of the MSA salt of Compound 1 suggests rapid absorption. See Figure 7. The ​ 1 of the MSA salt of Compound 1 shows a more rapid rate and extent of dissolution compared to the free base (amorphous) of Compound 1. See Figure 8.

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

[0215] The AUC and dissolution rate values appeared to be similar for the MSA salt of Compound 1 in FaSSIF and FeSSIF ​ 1 and for the MSA salt monohydrate of Compound 1 ​ 2. There was no statistical difference in the AUC values, but there was a statistical significance in the dissolution rate, with the MSA salt monohydrate of Compound 1 ​ 2 being slightly faster in FaSSIF. This ​ has similar solubility peaks in FaSSIF. This behavior is similar in FeSSIF, being 3-fold higher. The food effect ration for the MSA salt of Compound 1 ​ 1 was 3.10. The food effect ration for both ​ was constant. The food effect ration for the MSA salt hydrate of Compound 1 ​ 2 was 3.49. See the following table and Figure 9. The MSA salt hydrate of Compound 1 ​ 2 was found to have a dissolution profile similar to that of the MSA salt of Compound 1 ​ 1.

Table 31

[0216] Example 16: Microdissolution in FaSSiF / FeSSiF This test was used to determine the free base of Compound 1 (amorphous ​ ) in FaSSIF and FeSSIF, the ​ 2 of the free base of Compound 1 and the MSA salt of Compound 1​ The difference in the dissolution of 1 was evaluated.

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

[0218] Example 17: Jet Mill The reduction in particle size can be achieved by a jet mill using a 0202 Jet o Mizer loop Mill. Particle collisions are made possible by the supply of high - pressure nitrogen gas into the milling chamber through two grinding nozzles. The supply rate of the drug substance to the mill is controlled by a feeder that supplies the drug from the mill's feeder hopper to the milling chamber at a visually constant supply rate. The high - pressure nitrogen gas is supplied through a venturi nozzle to inject the drug from the mill feed hopper into the milling chamber, which is shown as the venturi pressure. The grinding pressure and the venturi pressure are adjusted to the desired levels after milling starts and both are maintained at the same level even if a back - flow of the product from the feeder hopper is observed. The venturi pressure is usually adjusted to a grinding pressure exceeding 10 PSI. The atomized drug is present within a product recovery unit consisting of a combined cyclone and an assembly of a porous fabric filter media through the mill chamber outlet. The milling parameters can be adjusted based on sample analysis. A particle size in the range of 12.7 μm - 24.0 μm (D90 by laser light scattering) is achieved by this milling operation. The milling parameters and physical properties are shown in the following table. ​

Table 32

[0219] Example 18: Stability - Free base of Compound 1 ​ 4 Free base of Compound 1 ​ The solid state stability of 4 of the free base of Compound 1 was tested. These experimental results are shown in the following table. No change was observed for at least two weeks.

[0220] Free base of Compound 1 ​ 4 was chemically stable for at least four weeks.

Table 33

[0221] Example 19: Stability - Hydrate of the free base of Compound 1 ​ 2 Monohydrate of the free base of Compound 1 ​ The solid state stability of 2 of the monohydrate of the free base of Compound 1 was tested. Their experimental results are shown in the following table. In all samples, no change in PXRD was observed during four or eight weeks. In all samples, no change in DSC / TGA was observed at four weeks. After eight weeks ​ change, dehydration or amorphous ​ formation evidence was not present. In all samples, there was no change in TGA at eight weeks.

[0222] Hydrate of the free base of Compound 1 ​ 2 was chemically stable for at least 13.5 weeks under high test temperature and humidity conditions.

Table 34

[0223] Example 20 Amorphous ​ The MSA substance of Compound 1 was the MSA salt of Compound 1 after 9 days of thermal stress at 60 °C ​was converted to 1. The MSA salt monohydrate of Compound 1 ​ 2 was the MSA salt of Compound 1 after 6 days of stress at 40 °C and 75% relative humidity ​ 1 and the MSA salt monohydrate of Compound 1 ​ was converted to 2. At 75% relative humidity, the MSA salt monohydrate of Compound 1 ​ was partially converted to 2, from which an X-ray amorphous ​ substance had a faster conversion rate to 2 of the MSA salt hydrate of Compound 1 than to 1 of the MSA salt of Compound 1, suggesting that form it might have. form it might have.

[0224] Example 21: Stability - Free Base of Compound 1 A heating test was carried out on the form 2 of the free base monohydrate of Compound 1, the form 4 of the free base of Compound 1 and amorphous any form changes that could occur in the free base of Compound 1 to test.

[0225] amorphous The free base of Compound 1 was heated at 67 °C to 150 °C. No crystallization was observed. Using the form 4 of the free base of Compound 1 to start the melt / quench test, it became a glass containing some fine birefringent particles, but the obtained XRPD pattern showed no evidence of a crystalline substance.

[0226] Heating the form 2 of the free base monohydrate of Compound 1 at ~100 °C for ~2 hours resulted in observable changes in birefringence, but there was no form change by XRPD. When heated to ~125 °C, the sample liquefied. By cooling the liquid sample on dry ice, a non-birefringent glass corresponding to an X-ray amorphous of substance was obtained. In an additional heating experiment on the form 2 of the free base monohydrate of Compound 1 heated at ~79 to 80 °C or ~75 °C for 1 day under a nitrogen gas flow, at both temperatures another crystal formPartial conversion occurred. The free base monohydrate of Compound 1 form 2 is thermodynamically stable at high relative humidity and RT form would be.

[0227] Numerous experiments were prepared to examine the dehydration of hydration at ~0%RH form of the free base monohydrate of Compound 1. form 2 became unstable form and converted to after being maintained at 0%RH overnight.

Claims

Claim 1 Crystals 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 comprising peaks at 7.6, 12.0, 13.5, 14.4, 17.6, 20.1, 20.7 and 22.0° 2θ ± 0.2° 2θ. Claim 2 A pharmaceutical composition comprising crystals 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 comprising 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 pharmaceutically acceptable carrier. The pharmaceutical composition according to 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 methanesulfonate or a combination thereof. The pharmaceutical composition according to claim 2, further comprising amorphous (R)-N-(4-chlorophenyl)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide. Claim 5 The pharmaceutical composition according to any one of claims 2 to 4 for treating cancer. Claim 6 The pharmaceutical composition according to 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 cancer and non-small cell cancer), adrenal gland, thyroid gland, kidney or bone; or glioma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma (including Kaposi's sarcoma), choriocarcinoma, skin basal cell carcinoma or testicular germ cell tumor. Claim 7 The pharmaceutical composition according to claim 5 or 6, further comprising an immune checkpoint inhibitor. Claim 8 The pharmaceutical composition according to claim 7, wherein the immune checkpoint inhibitor is ipilimumab, nivolumab, pembrolizumab or a combination thereof. Claim 9 A pharmaceutical composition according to any one of claims 2 to 4 for regulating the activity of indoleamine 2,3-dioxygenase, which may further comprise 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 methanesulfonate or a combination thereof.

10. The pharmaceutical composition according to claim 2, which is in a solid dosage form.

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

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