Crystalline forms of somatostatin modulators

Abstract

SOLUTION: Described herein are: pharmaceutically acceptable salts of a somatostatin modulator; crystalline forms of the pharmaceutically acceptable salts of the somatostatin modulator; methods of making such salts and crystalline forms, as well as pharmaceutical compositions and medicaments comprising such salts and crystalline forms, and methods of using such salts and crystalline forms in the treatment of conditions, diseases or disorders that will benefit from modulation of somatostatin activity.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 875,285, filed July 17, 2019, which is incorporated herein by reference in its entirety.

[0002] Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and formulations containing such compounds, and methods of using such compounds in the treatment of diseases, disorders, or conditions that would benefit from modulating somatostatin activity. [Background technology]

[0003] Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation through interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Six somatostatin receptor protein subtypes have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, and SSTR5), encoded by five different somatostatin receptor genes. Modulation of specific somatostatin receptor subtypes, or combinations thereof, is attractive for the treatment of diseases, disorders, or conditions that would benefit from modulation of somatostatin activity. Summary of the Invention

[0004] Disclosed herein is a compound that is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

[0005] In one aspect disclosed herein, the compound is an amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having an X-ray powder diffraction (XRPD) pattern showing a lack of crystallinity, a modulated differential scanning calorimetry thermogram substantially the same as that shown in FIG. 1 , a modulated differential scanning calorimetry thermogram having a glass transition temperature with an onset of about 166.6°C and a midpoint of about 169.3°C, a thermogravimetric analysis pattern substantially the same as that shown in FIG. 12, a thermogravimetric analysis pattern with a loss of 3.85% w / w between 40 and 170°C, or a combination thereof.

[0006] In another embodiment disclosed herein, the compound is a crystalline form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

[0007] In some embodiments disclosed herein, the compound is crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, crystalline Pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 3 , an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.20°2-theta, about 6.76°2-theta, about 17.14°2-theta, and about 21.70°2-theta, a differential scanning calorimetry thermogram substantially the same as that shown in FIG. 4 , with an onset of about 78.4°C and a peak at about 81.8°C, an onset of about 266.1°C and a peak at about 270.1°C, an onset of about 281.1°C and a peak at about 286.1°C, and an onset of about 294.6°C and a peak at about 297.7°C. a differential scanning calorimetry thermogram with four endothermic events having a peak; a thermogravimetric pattern substantially the same as that shown in FIG. 5a; a thermogravimetric pattern with a 2.28% w / w loss between 60 and 180°C; a dynamic water vapor sorption isotherm plot substantially the same as that shown in FIG. 6; a reversible water uptake (9.8% w / w) from 2% to 95% relative humidity (RH); an XRPD that switches to pattern B upon storage at 75% RH and 40°C for 7 days; an XRPD that switches to pattern B upon storage at 96% RH and 25°C for 3 days; an XRPD that remains unchanged after drying under dynamic vacuum at 50°C for 2 hours; an XRPD that switches to pattern P after heating to 255°C; a water content of 1.5% w / w; or a combination thereof.

[0008] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline hydrate pattern B. In some embodiments, 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline hydrate pattern B, is an X-ray powder diffraction pattern having substantially the same X-ray diffraction pattern reflections at about 5.58°2-theta, about 7.48°2-theta, about 15.94°2-theta, and about 25.13°2-theta as shown in FIG. Diffraction pattern, differential scanning calorimetry thermogram substantially similar to that shown in FIG. 8 or FIG. 10b, showing a broad endothermic event with an onset of about 86.3° C. and a peak of about 115.1° C., and an endothermic event with an onset of about 213.2° C. and a peak of about 221.8° C., or an endothermic event with an onset of about 205.6° C. and a peak of about 221.8° C., an exothermic event with an onset of about 243.0° C. and a peak of about 254.2° C., and an exothermic event with an onset of about 278.0° C. and a peak of about 280.0° C. a differential scanning calorimetry thermogram with an endothermic event with an onset of 0.0°C and a peak at approximately 288.2°C; a thermogravimetric analysis pattern substantially the same as that shown in Figure 9a or Figure 10; a thermogravimetric analysis pattern with a 2.9% w / w loss from 40°C to 205°C or a 4.23% w / w loss from 45°C to 175°C; a dynamic water vapor sorption isotherm plot substantially the same as that shown in Figure 11; and reversible water uptake from 2% to 95% relative humidity (RH). (3.2% w / w), an unchanged XRPD after DVS analysis at 95% RH and 25°C, an unchanged XRPD after storage at 75% RH and 40°C for 7 days, an unchanged XRPD after drying under dynamic vacuum at 50°C for 2 hours, an unchanged XRPD after storage under static vacuum at 50°C for 3 hours, an XRPD that switches to Pattern I after heating to 270°C, a water content of 4.2% w / w, or a combination thereof.

[0009] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline Pattern C. In some embodiments, the crystalline hydrate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline Pattern B has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 12 , an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 7.10°2-theta, about 17.44°2-theta, about 22.18°2-theta, and about 25.20°2-theta, a differential scanning calorimetry thermogram substantially the same as that shown in FIG. 13 , an exothermic event with an onset of about 192.8°C and a peak at about 213.3°C, and an onset of about 252.2°C. 14a); a thermogravimetric pattern substantially the same as that shown in FIG. 14b; a thermogravimetric pattern with a 0.12% w / w loss from 40°C to 140°C and an additional 0.62% w / w loss from 140°C to 290°C; an XRPD that does not change after storage at 75% RH and 40°C for 7 days; an XRPD that does not change after drying under dynamic vacuum at 50°C for 2 hours; an XRPD that switches to Pattern I after heating to 240°C; or a combination thereof.

[0010] In some embodiments disclosed herein, the compound is crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 15 , an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.74°2-theta, about 11.17°2-theta, about 20.83°2-theta, and about 21.65°2-theta, a differential scanning calorimetry thermogram substantially the same as that shown in FIG. 16 , an endothermic event having an onset of about 260.9°C and a peak at about 274.8°C, and an endothermic event having an onset of about 292.7°C and a peak at about 296.0°C, and a differential scanning calorimetry thermogram substantially the same as that shown in FIG. 17 . a thermogravimetric analysis pattern substantially the same as that shown in Figure 18a with a 0.19% w / w loss from 40°C to 185°C and an additional 0.67% w / w loss from 185°C to 290°C; a dynamic water vapor sorption isotherm plot substantially the same as that shown in Figure 18a; reversible water uptake (9.1% w / w) from 2% to 95% relative humidity (RH) with a 2.5% w / w water uptake from 15 to 75% RH; an XRPD that switches to pattern B after DVS analysis from 2% to 95% RH and 25°C; an XRPD that does not change after storage at 75% RH and 40°C for 7 days; an XRPD that does not change after drying under dynamic vacuum at 50°C for 2 hours; a water content of 0.29% w / w; or a combination thereof.

[0011] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline isopropanol solvate Pattern D. In some embodiments, the crystalline isopropanol solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Pattern D is characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 19 , an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.10°2-theta, about 6.70°2-theta, about 17.75°2-theta, and about 22.22°2-theta, an XRPD that switches to Pattern A after drying under dynamic vacuum at 50° C. for 2 hours, or a combination thereof.

[0012] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline tetrahydrofuran solvate Pattern E. In some embodiments, the crystalline tetrahydrofuran solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Pattern E is characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 20 , an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.42°2-theta, about 19.99°2-theta, and about 21.12°2-theta, an XRPD that switches to Pattern A after drying under dynamic vacuum at 50° C. for 2 hours, or a combination thereof.

[0013] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline methyl isobutyl ketone solvate Pattern F. In some embodiments, the crystalline methyl isobutyl ketone solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Pattern F is characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 21 , an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 5.63°2-theta, about 6.27°2-theta, about 20.55°2-theta, and about 22.33°2-theta, an XRPD that switches to Pattern I after drying under dynamic vacuum at 50° C. for 2 hours, or a combination thereof.

[0014] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline ethyl acetate solvate Pattern G. In some embodiments, the crystalline ethyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Pattern G is characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 22 , an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.62°2-theta, about 13.21°2-theta, about 19.79°2-theta, and about 21.72°2-theta, an XRPD that switches to Pattern I after drying under dynamic vacuum at 50° C. for 2 hours, or a combination thereof.

[0015] In some embodiments disclosed herein, the compound is crystalline isopropyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern H. In some embodiments, the crystalline isopropyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern H, is characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 23 , an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 5.66°2-theta, about 16.77°2-theta, and about 22.78°2-theta, an XRPD that switches to Pattern I after drying under dynamic vacuum at 50° C. for 2 hours, or a combination thereof.

[0016] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline pattern J. In some embodiments, 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline pattern J, is characterized as having an X-ray powder diffraction pattern substantially the same as that shown in Figure 24, an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.32°2-theta, about 6.72°2-theta, about 12.33°2-theta, and about 21.47°2-theta, or a combination thereof.

[0017] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline pattern K. In some embodiments, 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline pattern K, has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 25 , an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.42°2-theta, about 15.90°2-theta, about 19.59°2-theta, and about 21.52°2-theta, a differential scanning calorimetry thermogram substantially the same as that shown in FIG. 26 b. , a differential scanning calorimetry thermogram with an endothermic event with an onset of about 254.1°C and a peak at about 271.9°C, and an endothermic event with an onset of about 294.5°C and a peak at about 297.7°C; a thermogravimetric pattern substantially the same as that shown in Figure 26a; a thermogravimetric pattern with a 0.1% w / w loss from 40°C to 190°C and an additional 0.69% w / w loss from 190°C to 310°C; an XRPD that does not change after drying under dynamic vacuum at 50°C for 2 hours; or a combination thereof.

[0018] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline acetone solvate Pattern M. In some embodiments, the crystalline acetone solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Pattern M is characterized as having an X-ray powder diffraction pattern substantially the same as that shown in Figure 27, an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.67 °2-theta, about 14.63 °2-theta, about 22.14 °2-theta, and about 24.91 °2-theta, or a combination thereof.

[0019] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline acetonitrile solvate pattern N. In some embodiments, the crystalline acetonitrile solvate pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 28, an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.18°2-theta and about 17.21°2-theta, a differential scanning calorimetry thermogram substantially the same as that shown in FIG. 29b, a crystalline acetonitrile solvate pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline acetonitrile solvate pattern N. The compound is characterized as having a differential scanning calorimetry thermogram with an endothermic event with an onset and a peak at about 144.0°C, an endothermic event with an onset at about 179.7°C and a peak at about 193.5°C, and an endothermic event with an onset at about 192.4°C and a peak at about 211.1°C, a thermogravimetric analysis pattern substantially the same as that shown in Figure 29a, a thermogravimetric analysis pattern with a 5.44% w / w loss from 40°C to 220°C, an XRPD that does not change after drying under dynamic vacuum at 50°C for 2 hours, or a combination thereof.

[0020] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline hydrate pattern O. In some embodiments, the crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray powder diffraction pattern substantially the same as that shown in Figure 30, an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.56°2-theta, 15.87°2-theta, 18.43°2-theta, and about 24.80°2-theta, 31b; a differential scanning calorimetry thermogram with an endothermic event having an onset at about 206.9°C and a peak at about 217.6°C; a thermogravimetric analysis pattern with a 4.54% w / w loss from 40°C to 260°C; an XRPD that does not vary after drying under dynamic vacuum at 50°C for 2 hours; or a combination thereof.

[0021] In some embodiments disclosed herein, the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline pattern P. In some embodiments, 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline pattern P, is characterized as having an X-ray powder diffraction pattern substantially the same as that shown in Figure 32, an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.97°2-theta, about 17.26°2-theta, about 19.33°2-theta, and about 20.94°2-theta, an XRPD that does not change after drying under dynamic vacuum at 50°C for 2 hours, an XRPD that switches to pattern B upon storage at 96% RH and 25°C for 3 days, or a combination thereof.

[0022] In another aspect, disclosed herein is a pharmaceutical composition comprising 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or a solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises amorphous 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or a solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises crystalline 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile dimesylate, or a solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for oral administration to a mammal. In some embodiments, the pharmaceutical composition is in the form of a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule. In some embodiments, the pharmaceutical composition is for use in treating a disease or condition in a mammal that would benefit from modulation of somatostatin receptor subtype 2 (SSTR2) activity. In some embodiments, the disease or condition is acromegaly, neuroendocrine tumors, an ophthalmic disease or condition, a neurological disorder, nephropathy, a respiratory disease or condition, cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or a combination thereof.

[0023] In another aspect, disclosed herein are methods of treating a disease or condition in a mammal that would benefit from modulation of somatostatin receptor subtype 2 (SSTR2) activity, the method comprising administering 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or a solvate thereof, to a mammal in need thereof. In some embodiments, the disease or condition is acromegaly, a neuroendocrine tumor, an eye disease or condition, a neurological disorder, a nephropathy, a respiratory disease or condition, cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or a combination thereof.

[0024] In another aspect, disclosed herein are methods of treating a disease or condition in a mammal that would benefit from modulation of somatostatin receptor subtype 2 (SSTR2) activity, the method comprising administering to a mammal in need thereof a pharmaceutical composition comprising 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or a solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the disease or condition is acromegaly, a neuroendocrine tumor, an ophthalmic disease or condition, a neurological disorder, a nephropathy, a respiratory disease or condition, cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or a combination thereof.

[0025] In some embodiments, the mammal is a human.

[0026] Provided is an article of manufacture that includes packaging material; the somatostatin receptor modulator 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate or a solvate thereof within the packaging material; and a label indicating that the somatostatin receptor modulator is used for modulating the activity of a somatostatin receptor or for the treatment, prevention, or amelioration of one or more symptoms of a disease or disorder described herein. [Brief explanation of the drawings]

[0027] [Figure 1] Modulated reversible and irreversible heat flow DSC thermograms of amorphous compound A·2MSA are shown. [Figure 2a] The TGA pattern of amorphous compound A·2MSA is shown. [Figure 2b] The DSC thermogram of amorphous compound A·2MSA is shown. [Figure 3] The XRPD pattern of compound A·2MSA pattern A is shown. [Figure 4] The standalone DSC thermogram of Compound A·2MSA Pattern A is shown. [Figure 5a] The TGA pattern of Compound A·2MSA Pattern A is shown. [Figure 5b] The DSC thermogram of Compound A·2MSA Pattern A is shown. [Figure 6] DVS isotherm plot of compound A·2MSA pattern A. [Figure 7] The XRPD pattern of compound A·2MSA pattern B is shown. [Figure 8] The standalone DSC thermogram of compound A·2MSA pattern B is shown. [Figure 9a] The TGA pattern of Compound A·2MSA Pattern B is shown. [Figure 9b] The DSC thermogram of compound A·2MSA pattern B is shown. [Figure 10a]The TGA pattern of Compound A·2MSA Pattern B after storage at ambient conditions for 1 week is shown. [Figure 10b] DSC thermogram of Compound A·2MSA Pattern B after 1 week of storage at ambient conditions. [Figure 11] DVS isotherm plot of compound A·2MSA pattern B. [Figure 12] The XRPD pattern of compound A·2MSA pattern C is shown. [Figure 13] The standalone DSC thermogram of compound A·2MSA pattern C is shown. [Figure 14a] The TGA pattern of Compound A·2MSA Pattern C is shown. [Figure 14b] The DSC thermogram of Compound A·2MSA pattern C is shown. [Figure 15] The XRPD pattern of compound A·2MSA pattern I is shown. [Figure 16] The standalone DSC thermogram of compound A·2MSA pattern I is shown. [Figure 17a] The TGA pattern of Compound A·2MSA Pattern I is shown. [Figure 17b] The DSC thermogram of Compound A·2MSA Pattern I is shown. [Figure 18] DVS isotherm plot of compound A·2MSA pattern I. [Figure 19] The XRPD pattern of compound A·2MSA pattern D is shown. [Figure 20] The XRPD pattern of compound A·2MSA pattern E is shown. [Figure 21] The XRPD pattern of compound A·2MSA pattern F is shown. [Figure 22] The XRPD pattern of compound A·2MSA pattern G is shown. [Figure 23] The XRPD pattern of compound A·2MSA pattern H is shown. [Figure 24] The XRPD pattern of compound A·2MSA pattern J is shown. [Figure 25]The XRPD pattern of compound A·2MSA pattern K is shown. [Figure 26a] The TGA pattern of Compound A·2MSA Pattern K is shown. [Figure 26b] The DSC thermogram of compound A·2MSA pattern K is shown. [Figure 27] The XRPD pattern of compound A·2MSA pattern M is shown. [Figure 28] The XRPD pattern of compound A·2MSA pattern N is shown. [Figure 29a] The TGA pattern of Compound A·2MSA Pattern N is shown. [Figure 29b] The DSC thermogram of Compound A·2MSA Pattern N is shown. [Figure 30] The XRPD pattern of compound A·2MSA pattern O is shown. [Figure 31a] The TGA pattern of Compound A·2MSA Pattern O is shown. [Figure 31b] The DSC thermogram of compound A·2MSA pattern O is shown. [Figure 32] The XRPD pattern of compound A·2MSA pattern P is shown. DETAILED DESCRIPTION OF THE INVENTION

[0028] Somatostatin (SST), also known as somatotropin-releasing inhibitory factor (SRIF), was originally isolated as a 14-amino acid peptide from sheep hypothalamus (Brazeau et al., Science 179, 77–79, 1973). An N-terminally extended 28-amino acid peptide with similar biological activity to the 14-amino acid somatostatin was subsequently isolated (Pradayrol et al., FEBS Letters, 109, 55–58, 1980; Esch et al., Proc. Natl. Acad. Sci. USA, 77, 6827–6831, 1980). SST is a regulatory peptide produced by multiple cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SST acts via both endocrine and paracrine pathways to affect its target cells. Many of these effects are related to the inhibition of secretion of other hormones, most notably growth hormone (GH). They are produced by a wide variety of cell types in the central nervous system (CNS) and intestine and have multiple functions, including regulating the secretion of growth hormone (GH), insulin, and glucagon, as well as many other hormones that are antiproliferative.

[0029] These pleiotropic actions of somatostatin are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, and SSTR5), which are encoded by five different somatostatin receptor genes (Reisine and Bell, Endocr Rev. 16, 427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405, 1997). All receptors are members of the A-class subgroup of the GPCR superfamily. The SSTR2A receptor is the most widely expressed subtype in human tumors and is the predominant receptor that suppresses GH secretion. Unless otherwise specified, the term SSTR2 refers to SSTR2a.

[0030] It is possible to selectively modulate any one or a combination of somatostatin receptor subtypes. In some embodiments, selectively modulating any one or a combination of somatostatin receptor subtypes relative to other somatostatin receptor subtypes is useful in various clinical applications. In some embodiments, selectively modulating any one somatostatin receptor subtype relative to other somatostatin receptor subtypes reduces undesirable side effects in various clinical applications.

[0031] For example, modulation of SSTR2 activity mediates the release of growth hormone (GH) from the anterior pituitary gland and the inhibition of glucagon release from the pancreas. SSTR2 is also involved in many other biological functions, including, but not limited to, cell proliferation, nociception, inflammation, and angiogenesis. In some embodiments, selective SSTR2 modulators are used in the treatment of acromegaly, enteric neuroendocrine tumors, pain, neuropathy, nephropathy, and inflammation, as well as retinopathies caused by abnormal vascular growth. In other embodiments, selective SSTR2 modulators are used in the treatment of arthritis, pain, cancer, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, Cushing's disease, acute lung injury, acute respiratory distress syndrome, and ophthalmopathy, such as age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, and Graves' ophthalmopathy.

[0032] In some embodiments, SSTR4 agonists exhibit anti-inflammatory and anti-nociceptive effects.

[0033] In some embodiments, the SSTR3 agonist inhibits insulin secretion.

[0034] In some embodiments, SSTR5 agonists inhibit insulin secretion. Additionally, SSTR5 is involved in regulating growth hormone release.

[0035] Somatostatin peptides and their receptor subtypes are widely expressed in the brain, and disruption or reduction of their activity may be involved in several psychiatric and neurodegenerative disorders. For example, somatostatin concentrations in the cerebral cortex and hippocampus are reduced in patients with schizophrenia, and one of the most consistent neuropathological findings in this patient population is a loss of somatostatin-expressing cortical inhibitory interneurons. Somatostatin is also highly expressed in brain regions associated with seizures, suggesting an important role in epilepsy. Somatostatin levels are reduced in the hippocampus of patients with Alzheimer's disease and Parkinson's disease, suggesting restoration of its signaling as a potential drug target for neurodegeneration.

[0036] In one aspect, the compounds described herein are modulators of SSTR2. In some embodiments, the compounds described herein selectively modulate the activity of SSTR2 relative to other somatostatin receptors.

[0037] In some embodiments, the compounds described herein are amenable to oral administration to a mammal in need of treatment with a somatostatin modulator.

[0038] In some embodiments, the somatostatin receptor modulators described herein have utility across a wide range of therapeutic applications. In some embodiments, the somatostatin receptor modulators described herein are used in the treatment of a variety of diseases or conditions, including, but not limited to, acromegaly, neuroendocrine tumors, retinopathies and other eye diseases, neuropathy, nephropathy, respiratory diseases, cancer, pain, neurodegenerative diseases, inflammatory diseases, as well as psychiatric and neurodegenerative diseases. In some embodiments, the somatostatin receptor modulators described herein are used in the treatment of acromegaly in a mammal.

[0039] In some embodiments, the somatostatin receptor modulators described herein inhibit the secretion of various hormones and trophic factors in mammals. In some embodiments, the compounds are used to suppress the secretion of specific endocrine glands, including, but not limited to, GH, insulin, glucagon, and prolactin. Suppression of specific endocrine gland secretions is useful for treating conditions such as acromegaly; endocrine tumors, such as carcinoid, VIP adenoma, insulinoma, and glucagonoma; or diabetes and diabetes-related conditions, including retinopathy, neuropathy, and nephropathy. In some embodiments, the somatostatin receptor modulators described herein are used to suppress exocrine secretions in the pancreas, stomach, and intestine for the treatment of conditions such as pancreatitis, fistulas, bleeding ulcers, and diarrhea associated with diseases such as AIDS or cholera. Diseases involving autocrine or paracrine secretion of trophic factors such as IGF-1 (as well as multiple endocrine factors) that can be treated by administration of the compounds described herein include breast, prostate, and lung cancers (both small cell and non-small cell epidermoid), as well as hepatocellular carcinoma, neuroblastoma, adenocarcinoma (ductal type) of the colon and pancreas, chondrosarcoma, and melanoma, diabetic retinopathy, and atherosclerosis associated with vascular grafts and restenosis after angioplasty.

[0040] In some embodiments, the somatostatin receptor modulators described herein are used to inhibit mediators of neurogenic inflammation (e.g., substance P or tachykinins) and may be used in the treatment of rheumatoid arthritis; psoriasis; local inflammation such as that associated with sunburn, eczema, or other sources of itch; inflammatory bowel disease; irritable bowel syndrome; allergies, including asthma and other respiratory diseases. In other embodiments, the somatostatin receptor modulators described herein function as neuromodulators in the central nervous system, useful for the treatment of Alzheimer's disease and other forms of dementia, pain, and headaches. In some embodiments, the somatostatin receptor modulators described herein provide cytoprotection in disorders involving splanchnic blood flow, including liver cirrhosis and esophageal varices.

[0041] Compound A Compound A is a somatostatin modulator useful in the therapeutic methods described herein.

[0042] As used herein, the term Compound A refers to 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile, which has the chemical structure shown below.

[0043] [ka]

[0044] Described herein is the mesylate salt of Compound A. Unless otherwise specified, "mesylate salt" encompasses both "monomesylate salt" and "dimesylate salt."

[0045] In some embodiments, provided herein is a dimesylate salt of Compound A ("Compound A·2MSA"). In some embodiments, the dimesylate salt of Compound A is referred to as "3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate," "3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimethanesulfonic acid," or "3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimethanesulfonic acid salt."

[0046] [ka]

[0047] In some embodiments, Compound A·2MSA is amorphous.

[0048] In some embodiments, Compound A·2MSA is crystalline.

[0049] Amorphous Compound A·2MSA Provided herein are amorphous solid forms of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide compositions comprising an amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has the following characteristics: (a) X-ray powder diffraction (XRPD) pattern showing lack of crystallinity; (b) Modulated differential scanning calorimetry thermogram substantially the same as that shown in Figure 1; (c) a modulated differential scanning calorimetry thermogram having a glass transition temperature with an onset of about 166.6°C and a midpoint of about 169.3°C; (d) Thermogravimetric analysis pattern substantially the same as that shown in Figure 2a; (e) a thermogravimetric analysis pattern with a loss of 3.85% w / w between 40 and 170°C; or (f) a combination thereof.

[0050] In some embodiments, the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction (XRPD) pattern indicative of a lack of crystallinity. In some embodiments, the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a modulated differential scanning calorimetry thermogram substantially the same as that shown in FIG. 1 . In some embodiments, the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram having a glass transition temperature with an onset of about 166.6°C and a midpoint of about 169.3°C. In some embodiments, the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern substantially the same as that shown in Figure 2a. In some embodiments, the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern with a loss of 3.85% w / w between 40 and 170°C.

[0051] Crystal pattern A of compound A·2MSA Also provided herein is crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) X-ray powder diffraction pattern substantially the same as that shown in Figure 3; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.20°2-theta, about 6.76°2-theta, about 17.14°2-theta, and about 21.70°2-theta; (c) A differential scanning calorimetry thermogram substantially the same as that shown in Figure 4; (d) a differential scanning calorimetry thermogram with four endothermic events, having an onset of about 78.4°C and a peak at about 81.8°C, an onset of about 266.1°C and a peak at about 270.1°C, an onset of about 281.1°C and a peak at about 286.1°C, and an onset of about 294.6°C and a peak at about 297.7°C; (e) Thermogravimetric analysis pattern substantially the same as that shown in Figure 4; (f) Thermogravimetric analysis pattern with a 2.28% w / w loss between 60 and 180 °C; (g) Dynamic water vapor sorption isotherm plot substantially the same as that shown in Figure 6 ; (h) reversible water uptake (9.8% w / w) at 2%–95% relative humidity (RH); (i) XRPD switching to pattern B upon storage at 75% RH and 40°C for 7 days; (j) XRPD switching to pattern B upon storage at 96% RH and 25°C for 3 days. (k) XRPD unchanged after drying under dynamic vacuum at 50°C for 2 hours; (l) XRPD switching to pattern P after heating to 255 °C; (m) a water content of 1.5% w / w, or (n) Characterized as having any combination thereof.

[0052] In some embodiments, crystalline Pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 3. In some embodiments, crystalline Pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.20 °2-theta, 6.76 °2-theta, about 17.14 °2-theta, and 21.70 °2-theta. In some embodiments, crystalline Pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram substantially the same as that shown in Figure 4. In some embodiments, crystalline Pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram with four endothermic events, having an onset at about 78.4°C and a peak at about 81.8°C, an onset at about 266.1°C and a peak at about 270.1°C, an onset at about 281.1°C and a peak at about 286.1°C, and an onset at about 294.6°C and a peak at about 297.7°C. In some embodiments, crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern substantially the same as that shown in Figure 5a. In some embodiments, crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern with a loss of 2.28% w / w between 60 and 180 °C.In some embodiments, crystalline Pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a dynamic water vapor sorption isotherm plot substantially the same as that shown in FIG. 6. In some embodiments, crystalline Pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits reversible water uptake (9.8% w / w) at 2% to 95% relative humidity (RH). In some embodiments, crystalline Pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD switching to Pattern B upon storage at 75% RH and 40° C. for 7 days. In some embodiments, crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that switches to pattern B upon storage at 96% RH and 25° C. for 3 days. In some embodiments, crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that remains unchanged after drying under dynamic vacuum at 50° C. for 2 hours. In some embodiments, crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that switches to pattern P upon heating to 255° C. In some embodiments, crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a water content of 1.5% w / w.

[0053] In some embodiments, crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.76°2-theta. In some embodiments, crystalline pattern A is further characterized by X-ray diffraction pattern reflections at about 6.20°2-theta, about 17.14°2-theta, and about 21.70°2-theta. In some embodiments, crystalline pattern A is further characterized by at least one X-ray diffraction pattern reflection selected from about 13.51°2-theta, 18.21°2-theta, about 19.73°2-theta, about 22.02°2-theta, and 26.77°2-theta.

[0054] Crystalline hydrate pattern B of compound A·2MSA Also provided herein is crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) X-ray powder diffraction pattern substantially the same as that shown in Figure 7; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.58°2-theta, about 7.48°2-theta, about 15.94°2-theta, and about 25.13°2-theta; (c) a differential scanning calorimetry thermogram substantially the same as that shown in Figure 8 or Figure 10b; (d)—A differential scanning calorimetry thermogram with a broad endothermic event having an onset of about 86.3° C. and a peak of about 115.1° C., and an endothermic event having an onset of about 213.2° C. and a peak of about 221.8° C.; or—An endothermic event having an onset of about 205.6° C. and a peak of about 221.8° C., an exothermic event having an onset of about 243.0° C. and a peak of about 254.2° C., and an endothermic event having an onset of about 278.0° C. and a peak of about 288.2° C.; (e) a thermogravimetric analysis pattern substantially the same as that shown in Figure 9a or Figure 10a; (f) Thermogravimetric analysis pattern with a 2.9% w / w loss between 40°C and 205°C or a 4.23% w / w loss between 45°C and 175°C; (g) Dynamic water vapor sorption isotherm plot substantially the same as that shown in Figure 11; (h) reversible water uptake (3.2% w / w) at 2%–95% relative humidity (RH); (i) Unchanging XRPD after DVS analysis at 95% RH and 25°C; (j) XRPD unchanged after storage at 75% RH and 40°C for 7 days; (k) XRPD unchanged after drying under dynamic vacuum at 50°C for 2 hours; (l) XRPD unchanged after storage under static vacuum at 50°C for 3 hours; (m) XRPD switching to pattern I after heating to 270 °C; (n) a water content of 4.2% w / w, or (o) a combination thereof.

[0055] In some embodiments, the crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 7. In some embodiments, the crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.58 °2-theta, about 7.48 °2-theta, about 15.94 °2-theta, and about 25.13 °2-theta. In some embodiments, the crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram substantially the same as that shown in Figure 8. In some embodiments, the crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram with a broad endothermic event with an onset at about 86.3°C and a peak at about 115.1°C, and an endothermic event with an onset at about 213.2°C and a peak at about 221.8°C. In some embodiments, crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram substantially the same as that shown in Figure 10b. In some embodiments, crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram with an endothermic event with an onset of about 205.6°C and a peak at about 221.8°C, an exothermic event with an onset of about 243.0°C and a peak at about 254.2°C, and an endothermic event with an onset of about 278.0°C and a peak at about 288.2°C.In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern substantially the same as that shown in FIG. 9a. In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern with a loss of 2.9% w / w between 40 and 205° C. In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern substantially the same as that shown in FIG. 10a. In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern with a loss of 4.23% w / w between 45 and 175° C. In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a dynamic water vapor sorption isotherm plot substantially the same as that shown in FIG. In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits reversible water uptake (3.2% w / w) at 2% to 95% relative humidity (RH). In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits unchanged XRPD after DVS analysis at 95% RH and 25°C.In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a stable XRPD after storage at 75% RH and 40° C. for 7 days. In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a stable XRPD after drying under dynamic vacuum at 50° C. for 2 hours. In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a stable XRPD after storage under static vacuum at 50° C. for 3 hours. In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD switching to pattern I after heating to 270° C. In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a water content of 4.2% w / w.

[0056] In some embodiments, crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 15.94°2-theta. In some embodiments, crystalline hydrate pattern B is further characterized by X-ray diffraction pattern reflections at about 5.58°2-theta, about 7.48°2-theta, and about 25.13°2-theta. In some embodiments, crystalline hydrate pattern B is further characterized by at least one X-ray diffraction pattern reflection selected from about 11.91°2-theta, about 13.58°2-theta, about 14.17°2-theta, 15.51°2-theta, about 18.48°2-theta, about 20.91°2-theta, and 28.26°2-theta.

[0057] Crystal pattern C of compound A·2MSA Also provided herein is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline pattern C. Some embodiments provide a composition comprising 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline pattern C. In some embodiments, 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline pattern C is (a) An X-ray powder diffraction pattern substantially the same as that shown in FIG. 12; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 7.10°2-theta, about 17.44°2-theta, about 22.18°2-theta, and about 25.20°2-theta; (c) A differential scanning calorimetry thermogram substantially the same as that shown in Figure 13; (d) a differential scanning calorimetry thermogram with an exothermic event having an onset of about 192.8°C and a peak of about 213.3°C, an endothermic event having an onset of about 252.2°C and a peak of about 272.3°C, and an endothermic event having an onset of about 296.6°C and a peak of about 298.9°C; (e) Thermogravimetric analysis pattern substantially the same as that shown in Figure 14a; (f) Thermogravimetric analysis pattern with a 0.12% w / w loss between 40°C and 140°C and a further 0.62% w / w loss between 140°C and 290°C. (g) Unchanged XRPD after storage at 75% RH and 40°C for 7 days; (h) Unchanging XRPD after drying under dynamic vacuum at 50°C for 2 hours; (i) XRPD switching to pattern I after heating to 240°C, or (j) a combination thereof.

[0058] In some embodiments, crystalline pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 12. In some embodiments, crystalline pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 7.10 °2-theta, 17.44 °2-theta, about 22.18 °2-theta, and 25.20 °2-theta. In some embodiments, crystalline Pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram substantially the same as that shown in Figure 13. In some embodiments, crystalline Pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram with an exothermic event with an onset at about 192.8°C and a peak at about 213.3°C, an endothermic event with an onset at about 252.2°C and a peak at about 272.3°C, and an endothermic event with an onset at about 296.6°C and a peak at about 298.9°C. In some embodiments, crystalline pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern substantially the same as that shown in Figure 14a. In some embodiments, crystalline pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern with a 0.12% w / w loss from 40°C to 140°C and an additional 0.62% w / w loss from 140°C to 290°C.In some embodiments, crystalline pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a stable XRPD after storage at 75% RH and 40° C. for 7 days. In some embodiments, crystalline pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a stable XRPD after drying under dynamic vacuum at 50° C. for 2 hours. In some embodiments, crystalline pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that switches to pattern I after heating to 240° C.

[0059] In some embodiments, crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 17.44°2-theta. In some embodiments, crystalline pattern C is further characterized by X-ray diffraction pattern reflections at about 7.10°2-theta, about 22.18°2-theta, and about 25.20°2-theta. In some embodiments, crystalline pattern C is further characterized by at least one X-ray diffraction pattern reflection selected from about 13.91°2-theta, about 19.02°2-theta, about 20.79°2-theta, about 21.44°2-theta, about 23.32°2-theta, and 27.58°2-theta.

[0060] Crystal pattern of compound A·2MSA I Also provided herein is crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 15; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.74°2-theta, about 11.17°2-theta, about 20.83°2-theta, and about 21.65°2-theta; (c) A differential scanning calorimetry thermogram substantially the same as that shown in Figure 16; (d) a differential scanning calorimetry thermogram with an endothermic event having an onset of about 260.9°C and a peak at about 274.8°C, and an endothermic event having an onset of about 292.7°C and a peak at about 296.0°C; (e) Thermogravimetric analysis pattern substantially the same as that shown in Figure 17a; (f) Thermogravimetric analysis pattern with a 0.19% w / w loss between 40°C and 185°C and a further 0.67% w / w loss between 185°C and 290°C; (g) Dynamic water vapor sorption isotherm plot substantially the same as that shown in Figure 18; (h) reversible water uptake (9.1% w / w) at 2% to 95% relative humidity (RH) with 2.5% w / w water uptake at 15 to 75% RH; (i) XRPD switching to pattern B after DVS analysis from 2% to 95% RH and 25°C; (j) XRPD unchanged after storage at 75% RH and 40°C for 7 days; (k) XRPD unchanged after drying under dynamic vacuum at 50°C for 2 hours; (l) a water content of 0.29% w / w, or (m) a combination thereof.

[0061] In some embodiments, crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 15. In some embodiments, crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.74 °2-theta, about 11.17 °2-theta, about 20.83 °2-theta, and about 21.65 °2-theta. In some embodiments, crystalline Pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram substantially the same as that shown in Figure 16. In some embodiments, crystalline Pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram with an endothermic event having an onset at about 260.9°C and a peak at about 274.8°C, and an endothermic event having an onset at about 292.7°C and a peak at about 296.0°C. In some embodiments, crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric pattern substantially the same as that shown in Figure 17a. In some embodiments, crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric pattern with a 0.19% w / w loss from 40°C to 185°C and an additional 0.67% w / w loss from 185°C to 290°C.In some embodiments, crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a dynamic water vapor sorption isotherm plot substantially the same as that shown in Figure 18. In some embodiments, crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits reversible water uptake (9.1% w / w) from 2% to 95% relative humidity (RH), with 2.5% w / w water uptake from 15 to 75% RH. In some embodiments, crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that switches to pattern B after DVS analysis at 2% to 95% RH and 25° C. In some embodiments, crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that remains constant after storage at 75% RH and 40° C. for 7 days. In some embodiments, crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that remains constant after drying under dynamic vacuum at 50° C. for 2 hours. In some embodiments, crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a water content of 0.29% w / w.

[0062] In some embodiments, crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.74°2-theta. In some embodiments, crystalline pattern I is further characterized by X-ray diffraction pattern reflections at about 11.17°2-theta, about 20.83°2-theta, and about 21.65°2-theta. In some embodiments, crystalline pattern I is further characterized by at least one X-ray diffraction pattern reflection selected from about 13.50°2-theta, about 18.49°2-theta, about 19.21°2-theta, about 22.58°2-theta, and about 24.69°2-theta.

[0063] Crystalline isopropanol solvate of compound A·2MSA, pattern D Also provided herein is a crystalline isopropanol solvate pattern D of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising a crystalline isopropanol solvate pattern D of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the crystalline isopropanol solvate pattern D of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 19; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.10°2-theta, about 6.70°2-theta, about 17.75°2-theta, and about 22.22°2-theta; (c) XRPD switching to pattern A after drying under dynamic vacuum at 50°C for 2 hours, or (d) a combination thereof.

[0064] In some embodiments, the crystalline isopropanol solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern D, exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 19. In some embodiments, the crystalline isopropanol solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern D, exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.10 °2-theta, about 6.70 °2-theta, about 17.75 °2-theta, and about 22.22 °2-theta. In some embodiments, the crystalline isopropanol solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, pattern D, exhibits a stable XRPD that switches to pattern A after drying under dynamic vacuum at 50° C. for 2 hours.

[0065] In some embodiments, the crystalline isopropanol solvate Pattern D of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.10 °2-theta. In some embodiments, the crystalline isopropanol solvate Pattern D is further characterized by X-ray diffraction pattern reflections at about 6.70 °2-theta, about 17.75 °2-theta, and about 22.22 °2-theta. In some embodiments, the crystalline isopropanol solvate Pattern D is further characterized by at least one X-ray diffraction pattern reflection at about 13.31 °2-theta, about 19.17 °2-theta, and about 20.21 °2-theta.

[0066] Crystalline tetrahydrofuran solvate of compound A·2MSA, pattern E Also provided herein is a crystalline tetrahydrofuran solvate pattern E of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising a crystalline tetrahydrofuran solvate pattern E of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the crystalline tetrahydrofuran solvate pattern E of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 20; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.42°2-theta, about 19.99°2-theta, and about 21.12°2-theta; (c) XRPD switching to pattern A after drying under dynamic vacuum at 50°C for 2 hours, or (d) a combination thereof.

[0067] In some embodiments, the crystalline tetrahydrofuran solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern E, exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 20. In some embodiments, the crystalline tetrahydrofuran solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern E, exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.42 degrees two-theta, about 19.99 degrees two-theta, and about 21.12 degrees two-theta. In some embodiments, the crystalline tetrahydrofuran solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern E, exhibits a stable XRPD that switches to Pattern A after drying under dynamic vacuum at 50° C. for 2 hours.

[0068] In some embodiments, the crystalline tetrahydrofuran solvate Pattern E of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.42 degrees two-theta. In some embodiments, the crystalline tetrahydrofuran solvate Pattern E is further characterized by X-ray diffraction pattern reflections at about 19.99 degrees two-theta and about 21.12 degrees two-theta. In some embodiments, the crystalline tetrahydrofuran solvate Pattern E is further characterized by an X-ray diffraction pattern reflection at about 17.76 degrees two-theta.

[0069] Crystalline methyl isobutyl ketone solvate of compound A·2MSA, pattern F Also provided herein is a crystalline methyl isobutyl ketone solvate pattern F of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising a crystalline methyl isobutyl ketone solvate pattern F of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the crystalline methyl isobutyl ketone solvate pattern F of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 21; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.63°2-theta, about 6.27°2-theta, about 20.55°2-theta, and about 22.33°2-theta; (c) XRPD switching to pattern I after drying under dynamic vacuum at 50°C for 2 hours, or (d) a combination thereof.

[0070] In some embodiments, the crystalline methyl isobutyl ketone solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern F, exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 21. In some embodiments, the crystalline methyl isobutyl ketone solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern F, exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 5.63 °2-theta, about 6.27 °2-theta, about 20.55 °2-theta, and about 22.33 °2-theta. In some embodiments, crystalline methyl isobutyl ketone solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, pattern F, exhibits a stable XRPD that switches to pattern I after drying under dynamic vacuum at 50° C. for 2 hours.

[0071] In some embodiments, the crystalline methyl isobutyl ketone solvate Pattern F of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.27°2-theta. In some embodiments, the crystalline tetrahydrofuran solvate Pattern E is further characterized by X-ray diffraction pattern reflections at about 5.63°2-theta, about 20.55°2-theta, and about 22.33°2-theta. In some embodiments, the crystalline methyl isobutyl ketone solvate Pattern F is further characterized by at least one X-ray diffraction pattern reflection at about 16.51°2-theta and about 27.25°2-theta.

[0072] Crystalline ethyl acetate solvate of compound A·2MSA, pattern G Also provided herein is a crystalline ethyl acetate solvate pattern G of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising a crystalline ethyl acetate solvate pattern G of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the crystalline ethyl acetate solvate pattern G of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 22; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.62°2-theta, about 13.21°2-theta, about 19.79°2-theta, and about 21.72°2-theta; (c) XRPD switching to pattern I after drying under dynamic vacuum at 50°C for 2 hours, or (d) a combination thereof.

[0073] In some embodiments, the crystalline ethyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern G, exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 22. In some embodiments, the crystalline ethyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern G, exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.62 °2-theta, about 13.21 °2-theta, about 19.79 °2-theta, and about 21.72 °2-theta. In some embodiments, the crystalline ethyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern G, exhibits a stable XRPD that switches to Pattern I after drying under dynamic vacuum at 50° C. for 2 hours.

[0074] In some embodiments, the crystalline ethyl acetate solvate pattern G of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.62°2-theta. In some embodiments, the crystalline ethyl acetate solvate pattern G is further characterized by X-ray diffraction pattern reflections at about 13.21°2-theta, about 19.79°2-theta, and about 21.72°2-theta.

[0075] Crystalline isopropyl acetate solvate of compound A·2MSA, pattern H Also provided herein is a crystalline isopropyl acetate solvate pattern H of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising a crystalline isopropyl acetate solvate pattern H of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the crystalline isopropyl acetate solvate pattern H of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 23; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.66°2-theta, about 16.77°2-theta, and about 22.78°2-theta; (c) XRPD switching to pattern I after drying under dynamic vacuum at 50°C for 2 hours, or (d) a combination thereof.

[0076] In some embodiments, the crystalline isopropyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern H, exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 23. In some embodiments, the crystalline isopropyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern H, exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 5.66 degrees two-theta, about 16.77 degrees two-theta, and about 22.78 degrees two-theta. In some embodiments, the crystalline isopropyl acetate solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern H, exhibits a stable XRPD that switches to Pattern I after drying under dynamic vacuum at 50° C. for 2 hours.

[0077] In some embodiments, the crystalline isopropyl acetate solvate Pattern H of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 5.66°2-theta. In some embodiments, the crystalline isopropyl acetate solvate Pattern H is further characterized by X-ray diffraction pattern reflections at about 16.77°2-theta and about 22.78°2-theta. In some embodiments, the crystalline methyl isobutyl ketone solvate Pattern F is further characterized by at least one X-ray diffraction pattern reflection at about 10.93°2-theta and about 20.83°2-theta.

[0078] Crystal pattern J of compound A·2MSA Also provided herein is crystalline pattern J of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising crystalline pattern J of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, crystalline pattern J of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 24; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.32°2-theta, about 6.72°2-theta, about 12.33°2-theta, and about 21.47°2-theta; or (c) a combination thereof.

[0079] In some embodiments, crystalline pattern J of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 24. In some embodiments, crystalline pattern J of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.32 degrees 2-theta, about 6.72 degrees 2-theta, about 12.33 degrees 2-theta, and about 21.47 degrees 2-theta.

[0080] In some embodiments, crystalline pattern J of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.72°2-theta. In some embodiments, crystalline pattern J is further characterized by X-ray diffraction pattern reflections at about 6.32°2-theta, about 12.33°2-theta, and about 21.47°2-theta. In some embodiments, crystalline pattern J is further characterized by at least one X-ray diffraction pattern reflection at about 14.07°2-theta, about 17.50°2-theta, and about 22.31°2-theta.

[0081] Crystal pattern K of compound A·2MSA Also provided herein is crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 25; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.42°2-theta, about 15.90°2-theta, about 19.59°2-theta, and about 21.52°2-theta; (c) A differential scanning calorimetry thermogram substantially the same as that shown in Figure 26b; (d) a differential scanning calorimetry thermogram with an endothermic event having an onset of about 254.1°C and a peak at about 271.9°C, and an endothermic event having an onset of about 294.5°C and a peak at about 297.7°C; (e) Thermogravimetric analysis pattern substantially the same as that shown in Figure 26a; (f) Thermogravimetric analysis pattern with a 0.1% w / w loss between 40°C and 190°C and a further 0.69% w / w loss between 190°C and 310°C; (g) XRPD that remains unchanged after drying under dynamic vacuum at 50°C for 2 hours, or (h) a combination thereof.

[0082] In some embodiments, crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 25. In some embodiments, crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 5.42 degrees 2-theta, about 15.90 degrees 2-theta, about 19.59 degrees 2-theta, and about 21.52 degrees 2-theta. In some embodiments, crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram substantially the same as that shown in Figure 26b. In some embodiments, crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram with an endothermic event having an onset at about 254.1°C and a peak at about 271.9°C, and an endothermic event having an onset at about 294.5°C and a peak at about 297.7°C. In some embodiments, crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric pattern substantially the same as that shown in Figure 26a. In some embodiments, crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric pattern with a 0.1% w / w loss from 40°C to 190°C and an additional 0.69% w / w loss from 190°C to 310°C.In some embodiments, crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a stable XRPD after drying under dynamic vacuum at 50° C. for 2 hours.

[0083] In some embodiments, crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 5.42°2-theta. In some embodiments, crystalline pattern K is further characterized by X-ray diffraction pattern reflections at about 15.90°2-theta, about 19.59°2-theta, and about 21.52°2-theta. In some embodiments, crystalline pattern K is further characterized by at least one X-ray diffraction pattern reflection selected from about 7.57°2-theta, about 8.05°2-theta, about 12.62°2-theta, about 15.09°2-theta, about 18.64°2-theta, 18.92°2-theta, about 20.82°2-theta, about 22.69°2-theta, and 29.48°2-theta.

[0084] Crystalline acetone solvate pattern M of compound A·2MSA Also provided herein is a crystalline acetone solvate pattern M of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising a crystalline acetone solvate pattern M of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the crystalline acetone solvate pattern M of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 27; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.67°2-theta, about 14.63°2-theta, about 22.14°2-theta, and about 24.91°2-theta; or (c) a combination thereof.

[0085] In some embodiments, the crystalline acetone solvate Pattern M of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 27. In some embodiments, the crystalline acetone solvate Pattern M of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 5.67 °2-theta, about 14.63 °2-theta, about 22.14 °2-theta, and about 24.91 °2-theta.

[0086] In some embodiments, the crystalline acetone solvate pattern M of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 5.67°2-theta. In some embodiments, the crystalline acetone solvate pattern M is further characterized by X-ray diffraction pattern reflections at about 14.63°2-theta, about 22.14°2-theta, and about 24.91°2-theta. In some embodiments, the crystalline acetone solvate pattern M is further characterized by at least one X-ray diffraction pattern reflection selected from about 11.94°2-theta, about 16.67°2-theta, about 19.70°2-theta, about 23.33°2-theta, about 24.46°2-theta, and 26.35°2-theta.

[0087] Crystalline acetonitrile solvate pattern N of compound A·2MSA Also provided herein is a crystalline acetonitrile solvate pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide a composition comprising a crystalline acetonitrile solvate pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, the crystalline acetonitrile solvate pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 28; (b) an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 5.18° 2-theta, and about 17.21° 2-theta; (c) A differential scanning calorimetry thermogram substantially the same as that shown in Figure 29b; (d) a differential scanning calorimetry thermogram with an endothermic event with an onset of about 132.6°C and a peak of about 144.0°C, an endothermic event with an onset of about 179.7°C and a peak of about 193.5°C, and an endothermic event with an onset of about 192.4°C and a peak of about 211.1°C; (e) Thermogravimetric analysis pattern substantially the same as that shown in Figure 29a; (f) Thermogravimetric analysis pattern with a 5.44% w / w loss between 40 and 220 °C; (g) XRPD that remains unchanged after drying under dynamic vacuum at 50°C for 2 hours, or (h) a combination thereof.

[0088] In some embodiments, the crystalline acetonitrile solvate Pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 28. In some embodiments, the crystalline acetonitrile solvate Pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 5.18 degrees two-theta, and about 17.21 degrees two-theta. In some embodiments, the crystalline acetonitrile solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern N, exhibits a differential scanning calorimetry thermogram substantially the same as that shown in Figure 29b. In some embodiments, the crystalline acetonitrile solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, Pattern N, exhibits a differential scanning calorimetry thermogram with an endothermic event with an onset at about 132.6°C and a peak at about 144.0°C, an endothermic event with an onset at about 179.7°C and a peak at about 193.5°C, and an endothermic event with an onset at about 192.4°C and a peak at about 211.1°C. In some embodiments, the crystalline acetonitrile solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, pattern N, exhibits a thermogravimetric analysis pattern substantially the same as that shown in Figure 29a. In some embodiments, the crystalline acetonitrile solvate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, pattern N, exhibits a thermogravimetric analysis pattern with a loss of 5.44% w / w between 40 and 220°C.In some embodiments, the crystalline acetonitrile solvate pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a stable XRPD after drying under dynamic vacuum at 50° C. for 2 hours.

[0089] In some embodiments, the crystalline acetonitrile solvate Pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 5.18 degrees 2-theta. In some embodiments, the crystalline acetonitrile solvate Pattern N is further characterized by an X-ray diffraction pattern reflection at about 17.21 degrees 2-theta. In some embodiments, the crystalline acetonitrile solvate Pattern N is further characterized by an X-ray diffraction pattern reflection at about 21.11 degrees 2-theta.

[0090] Crystalline hydrate pattern of compound A·2MSA Also provided herein is crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. Some embodiments provide compositions comprising crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate. In some embodiments, crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 30; (b) an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 5.56°2-theta, 15.87°2-theta, 18.43°2-theta, and about 24.80°2-theta; (c) A differential scanning calorimetry thermogram substantially the same as that shown in Figure 31b; (d) a differential scanning calorimetry thermogram with an endothermic event having an onset of about 206.9°C and a peak at about 217.6°C; (e) Thermogravimetric analysis pattern substantially the same as that shown in Figure 31a; (f) Thermogravimetric analysis pattern with a 4.54% w / w loss between 40 and 260 °C; (g) XRPD that remains unchanged after drying under dynamic vacuum at 50°C for 2 hours, or (h) a combination thereof.

[0091] In some embodiments, the crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 30. In some embodiments, the crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 5.56 °2-theta, 15.87 °2-theta, 18.43 °2-theta, and about 24.80 °2-theta. In some embodiments, the crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram substantially the same as that shown in Figure 31b. In some embodiments, the crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a differential scanning calorimetry thermogram with an endothermic event having an onset at about 206.9°C and a peak at about 217.6°C. In some embodiments, the crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern substantially the same as that shown in Figure 31a. In some embodiments, the crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a thermogravimetric analysis pattern with a loss of 4.54% w / w between 40 and 260 °C. In some embodiments, the crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an unchanged XRPD after drying under dynamic vacuum at 50 °C for 2 hours.

[0092] In some embodiments, the crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 15.87°2-theta. In some embodiments, the crystalline hydrate pattern O is further characterized by X-ray diffraction pattern reflections at about 5.56°2-theta, 18.43°2-theta, and about 24.80°2-theta. In some embodiments, the crystalline hydrate pattern O is further characterized by X-ray diffraction pattern reflections at about 7.43°2-theta, about 17.50°2-theta, about 20.22°2-theta, about 20.96°2-theta, and about 22.38°2-theta.

[0093] Crystal pattern P of compound A·2MSA Also provided herein is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline pattern P. Some embodiments provide a composition comprising 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline pattern P. In some embodiments, 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline pattern P is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 32; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.97°2-theta, about 17.26°2-theta, about 19.33°2-theta, and about 20.94°2-theta; (c) XRPD remains unchanged after drying under dynamic vacuum at 50°C for 2 hours, and switches to pattern B upon storage at 96% RH and 25°C for 3 days; or (d) a combination thereof.

[0094] In some embodiments, crystalline pattern P of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 32. In some embodiments, crystalline pattern P of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern with X-ray diffraction pattern reflections at about 6.97 degrees 2-theta, about 17.26 degrees 2-theta, about 19.33 degrees 2-theta, and about 20.94 degrees 2-theta. In some embodiments, crystalline pattern P of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a stable XRPD after drying under dynamic vacuum for 2 hours at 50° C. In some embodiments, crystalline pattern P of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that switches to pattern B upon storage at 96% RH and 25° C. for 3 days.

[0095] In some embodiments, crystalline pattern P of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.97°2-theta. In some embodiments, crystalline pattern P is further characterized by X-ray diffraction pattern reflections at about 17.26°2-theta, about 19.33°2-theta, and about 20.94°2-theta. In some embodiments, crystalline pattern P is further characterized by X-ray diffraction pattern reflections at about 10.97°2-theta, about 13.88°2-theta, about 17.67°2-theta, about 21.94°2-theta, and about 29.32°2-theta.

[0096] Synthesis of compound A·2MSA The compounds described herein are synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein. Unless otherwise specified, conventional methods of mass spectrometry, NMR, HPLC are employed.

[0097] The compounds are prepared using standard organic chemistry techniques, for example, as described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be used, such as variations in solvents, reaction temperatures, reaction times, and different chemical reagents or other reaction conditions.

[0098] In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxy or amino groups, if desired in the final product, to prevent their undesired participation in the reaction. A detailed description of techniques applicable to the creation and removal of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994 (incorporated herein by reference for the purposes of this disclosure).

[0099] Herein, a method for preparing compound A·2MSA is outlined in Scheme A.

[0100] [ka]

[0101] Briefly, in some embodiments, compound A·2HCl is obtained by deprotection of the Boc group of compound 13 and treatment with HCl. In some embodiments, compound A·2HCl is treated with a suitable base, such as sodium hydroxide, to obtain compound A (free base). In some embodiments, compound A (free base) is then treated with methanesulfonic acid (MSA) to obtain compound A·2MSA. In an alternative embodiment, compound 13 is treated with MSA to obtain compound A·2MSA directly.

[0102] In some embodiments, compound 13 is synthesized as previously disclosed in U.S. Pat. No. 9,896,432 and U.S. Patent Application No. 16 / 249,729. Briefly, compound 13 is synthesized from compound 11 by two sequential Suzuki reactions: first, reaction with boronic acid 7 or trifluoroborate 5; and then reaction with 3,5-difluorophenylboronic acid. In some embodiments, compound 12 is isolated before the second Suzuki reaction. In some embodiments, compound 12 is not isolated between the two Suzuki reactions. In some embodiments, the two Suzuki reactions are carried out in a single reaction vessel. In some embodiments, the two Suzuki reactions are carried out with the same catalyst system. In some embodiments, the two Suzuki reactions are carried out in a single reaction vessel and with the same catalyst system. In some embodiments, the two Suzuki reactions are carried out in a single reaction vessel and with the same catalyst system without adding additional catalyst between the Suzuki reactions.

[0103] [ka]

[0104] In some embodiments, residual palladium is removed from compound 13 by a palladium scavenger such as SiO2, charcoal, L-cysteine, N-acetyl-L-cysteine, SilicaBond cysteine, Si-thiol, SilicaBond DMT, and the like.

[0105] In some embodiments, compound 13 contains a detectable amount of unreacted starting material. In some embodiments, a sample of compound 13 contains a detectable amount of an impurity selected from the following:

[0106] [ka]

[0107] In some embodiments, a sample of Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA) is substantially free of structurally related impurities, including, but not limited to, compounds used in any step of the synthesis of Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA), as well as the compounds described in the previous section.

[0108] In some embodiments, compound 13 is purified by recrystallization. In some embodiments, compound 13 is heated in an appropriate solvent or solvent mixture for a suitable time. In some embodiments, the purity of compound 13 is improved by this process. In some embodiments, this recrystallization / slurrying process removes or reduces the amount of residual palladium in a sample of compound 13.

[0109] Purification steps are performed to reduce the amount of palladium in the product. Purification steps are performed to reduce the amount of palladium in the product so that the active pharmaceutical ingredient meets palladium specification guidelines. (“Guideline on the Specification Limits for Residues of Metal Catalysts,” European Medicines Agency Pre-authorization Evaluation of Medicines for Human Use, London, January 2007, Doc. Ref. CPMP / SWP / QWP / 4446 / 00 corr.). In some embodiments, purification steps to reduce the amount of palladium in the product include, but are not limited to, treatment with solid trimercaptotriazine (TMT), polystyrene-bound TMT, mercaptoporous polystyrene-bound TMT, polystyrene-bound ethylenediamine, activated carbon, glass bead sponge, Smopex™, silica-bound scavengers, thiol-derivatized silica gel, N-acetyl-L-cysteine, n-Bu3P, crystallization, extraction, L-cysteine, n-Bu3P / lactic acid (Garrett et al., Adv. Synth. Catal. 2004, 346, 889-900). In some embodiments, activated carbon includes, but is not limited to, DARCO® KB-G, DARCO® KB-WJ. In one aspect, silica-bound scavengers include, but are not limited to:

[0110] [ka] where:

[0111] [ka] indicates silica gel. In some embodiments, the purification step to reduce the amount of palladium comprises the use of activated carbon, derivatized silica gel (e.g., thiol-derivatized silica gel), or a combination thereof.

[0112] In some embodiments, 13 is further treated with a metal scavenger to remove residual palladium. In some embodiments, the metal scavenger comprises SiO, charcoal, an aqueous solution of L-cysteine, N-acetyl-L-cysteine, Silicycle metal scavenger, Si-thiol, SiliaBond DMT, or SiliaBond cysteine. In some embodiments, the scavenger loading (w / w) is 1:3, 1:2, or 1:1. In some embodiments, the metal scavenger is Si-thiol.

[0113] In some embodiments, crude 13 as isolated from the reaction is treated with a metal scavenger. In other embodiments, recrystallized 13 is treated with a metal scavenger. In some of these embodiments, palladium levels are reduced sufficiently to be undetectable.

[0114] In some embodiments, the presence of residual heavy metal (e.g., palladium) impurities is determined by utilizing methods known in the art. In some embodiments, the presence of residual heavy metal (e.g., palladium) impurities is determined by the use of inductively coupled plasma mass spectrometry (ICP-MS). ... <231> Determined by use of the techniques described in Heavy Metals.

[0115] Preparation of Compound A·2HCl from Compound 13

[0116] [ka]

[0117] In some embodiments, compound 13 is treated with hydrochloric acid in a suitable solvent to produce compound A·2HCl. In some embodiments, the suitable solvent is isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), toluene, ethyl acetate, isopropyl acetate, water, or a mixture thereof. In some embodiments, the suitable solvent is isopropyl alcohol, ethyl acetate, or isopropyl acetate. In some embodiments, the suitable solvent is IPA. In some embodiments, the suitable solvent is isopropyl acetate.

[0118] Preparation of Compound A (free base) from Compound A·2HCl

[0119] [ka]

[0120] In some embodiments, the free base of Compound A is made by treating Compound A·2HCl with a suitable base in a suitable solvent. In some embodiments, the suitable base is sodium hydroxide, sodium bicarbonate, etc. In some embodiments, the suitable base is sodium hydroxide. In some embodiments, the suitable solvent is water. In some embodiments, the solids are filtered from the mixture to isolate the free base of Compound A.

[0121] Preparation of Compound A-2MSA from Compound A (free base)

[0122] [ka]

[0123] In some embodiments, Compound A·2MSA is produced by treating the free base with methanesulfonic acid in a suitable solvent. In some embodiments, the suitable solvent is methanol, ethanol, isopropyl alcohol, acetone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, tetrahydropyran, water, or a combination thereof. In some embodiments, the suitable solvent is a mixture of acetone and water. In some embodiments, Compound A·2MSA is isolated from the reaction mixture by filtering the solids. In some embodiments, the isolated Compound A·2MSA exhibits an XRPD pattern consistent with Pattern B.

[0124] Preparation of compound A·2MSA directly from compound 13

[0125] [ka]

[0126] In some embodiments, compound A·2MSA is formed directly from 13. In some embodiments, 13 is treated with methanesulfonic acid in a suitable solvent to produce compound A·2MSA. In some embodiments, the suitable solvent is isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), tetrahydrofuran, toluene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, N-methyl-2-pyrrolidone (NMP), water, or a mixture thereof. In some embodiments, the suitable solvent is a mixture of acetone and water. In some embodiments, the suitable solvent is NMP. In some embodiments, the isolated compound A·2MSA exhibits an XRPD pattern consistent with pattern B. In some embodiments, the isolated compound A·2MSA is stored in a humid environment to form compound A·2MSA that exhibits an XRPD pattern consistent with pattern B.

[0127] Preparation of Compound A·2MSA In one aspect, disclosed herein is a method for preparing 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or a solvate thereof, the method comprising: (i) reacting hydrochloric acid with tert-butyl(1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamoyl in a suitable solvent; (ii) optionally adding additional solvent to the reaction mixture of step (i) and purging the reaction mixture with argon or nitrogen gas to remove excess hydrochloric acid; and (iii) dissolving the slurry of step (ii) to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile dihydrochloride. (iv) adding an appropriate amount of water to the solid of step (iii); (v) adding ammonium hydroxide solution, sodium bicarbonate solution, or sodium hydroxide solution to the slurry of step (iv) to achieve a pH of about 9-10; (vi) filtering the slurry of step (vi) to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (free base); (vii) contacting the solid of step (vi) with methanesulfonic acid in a suitable solvent at a suitable temperature; and (viii) cooling the suspension of step (vii) and filtering the solid to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile dimesylate or a solvate thereof.In some embodiments, the suitable solvent for step (i) is isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), toluene, ethyl acetate, isopropyl acetate, water, or a combination thereof; the additional solvent for step (ii) is isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), toluene, ethyl acetate, isopropyl acetate, water, or a combination thereof; and the suitable solvent for step (vii) is methanol, ethanol, isopropyl alcohol, acetone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, tetrahydropyran, water, or a combination thereof, or a combination thereof. In some embodiments, the suitable solvent in step (i) is isopropyl acetate, water, or a combination thereof, the additional solvent in step (ii) is isopropyl acetate, argon gas is used in step (ii), sodium hydroxide solution is used in step (v), the suitable solvent in step (vii) is acetone, water, or a mixture thereof, and the suitable temperature in step (vii) is about 50° C., or a combination thereof.

[0128] In one embodiment, disclosed herein is a method for preparing 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or a solvate thereof, comprising: (i) reacting tert-butyl (1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate with methanesulfonic acid in a suitable solvent at a suitable temperature; and (ii) optionally, adding additional solvent to the reaction mixture of step (i), cooling the suspension of step (i), and filtering the solids, thereby providing 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile dimesylate, or a solvate thereof. In some embodiments, the suitable solvent for step (i) is isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), tetrahydrofuran, toluene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, N-methyl-2-pyrrolidone (NMP), water, or a mixture thereof; the suitable temperature for step (ii) is about 40° C. to about 110° C.; and the additional solvent for step (ii) is isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), tetrahydrofuran, toluene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, N-methyl-2-pyrrolidone (NMP), water, or a mixture thereof, or a combination thereof. In some embodiments, the suitable solvent for step (i) is acetone, water, or a mixture thereof; the suitable temperature for step (ii) is about 45° C.; and the additional solvent for step (ii) is acetone, or a combination thereof. In some embodiments, the suitable solvent for step (i) is N-methyl-2-pyrrolidone (NMP), water, or a mixture thereof, the suitable temperature for step (ii) is about 100° C., no additional solvent is added in step (ii), or a combination thereof.

[0129] In one aspect, disclosed herein is a method for preparing 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate or a solvate thereof, the method comprising: (i) slurrying 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (free base) in a suitable solvent; (ii) heating the slurry of step (i) to about 50°C; (iii) adding methanesulfonic acid to the hot slurry of step (ii); (iv) cooling the hot slurry of step (iii); and (v) filtering the solids to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile dimesylate or a solvate thereof. In some embodiments, the suitable solvent for step (i) is isopropanol, acetone, water, or a mixture thereof. In some embodiments, the suitable solvent for step (I) is isopropanol. In some embodiments, the amount of isopropanol is 15 volumes. In some embodiments, the hot slurry of step (ii) is stirred for 30 minutes before the addition of methanesulfonic acid in step (iii). In some embodiments, the methanesulfonic acid in step (iii) is added as a solution in water. In some embodiments, the methanesulfonic acid in step (iii) is added neat, not as a solution. In some embodiments, the hot slurry in step (iii) is stirred for 10 minutes to 3 hours before cooling in step (iv). In some embodiments, the hot slurry in step (iii) is stirred for 30 minutes before cooling in step (iv). In some embodiments, the slurry in step (iv) is stirred at room temperature for about 10 hours before filtering in step (v). In some embodiments, the isolated solid in step (v) is washed with a suitable solvent after isolation. In some embodiments, the suitable solvent is acetone or isopropanol. In some embodiments, the suitable solvent is isopropanol. In some embodiments, the isolated solid in step (v) is vacuum dried.In some embodiments, the isolated solid from step (v) is dried under vacuum at about 50° C. for about 5 hours.

[0130] In some embodiments, the compounds described herein are synthesized as outlined in the Examples.

[0131] "Pharmaceutically acceptable," as used herein, refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., it may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0132] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than non-ionic species and dissolve rapidly in gastric and intestinal fluids, making them useful in solid dosage forms. Furthermore, their solubility is often pH-dependent, allowing for selective dissolution in one or another part of the gastrointestinal tract, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Furthermore, salt-forming molecules can be in equilibrium with neutral forms, allowing for controlled passage through biological membranes.

[0133] It should be understood that the reference to pharmaceutically acceptable salts includes solvent addition forms.In some embodiments, solvates contain either stoichiometric or non-stoichiometric solvents, and are formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol.Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.In addition, the compounds provided herein optionally exist in both solvated and non-solvated forms.

[0134] Therapeutic drugs that can be administered to mammals, including humans, must be prepared in accordance with regulatory guidelines. These government-regulated guidelines are called Good Manufacturing Practices (GMP) for drugs and quasi-drugs. GMP guidelines outline acceptable levels of contamination of active therapeutic agents, such as the amount of residual solvents in the final product. Preferred solvents are suitable for use in GMP facilities and consistent with industrial safety concerns. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005).

[0135] Solvents are classified into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents restricted for use during the manufacture of therapeutic drugs. Class 3 solvents are solvents with low potential toxicity and pose a low risk to human health. Data for Class 3 solvents indicates that they have low toxicity in acute or short-term studies and negative genotoxicity tests.

[0136] Class 1 solvents to be avoided include benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.

[0137] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0138] Class 3 solvents, which have low toxicity, include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0139] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacturing of the API. In some cases, the solvent is not completely removed by the actual manufacturing technique. The appropriate selection of solvents for the synthesis of APIs can enhance the yield and determine properties such as crystalline form, purity, and solubility. Therefore, solvents are a critical parameter in the synthesis process.

[0140] In some embodiments, a composition comprising Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA) comprises an organic solvent. In some embodiments, a composition comprising Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA) comprises a residual amount of an organic solvent. In some embodiments, a composition comprising Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA) comprises a residual amount of a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, Class 3 solvents are selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0141] In some embodiments, the composition comprising Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA) contains a detectable amount of organic solvent. In some embodiments, the pharmaceutically acceptable salt of Compound A is an MSA salt (i.e., Compound A·2MSA). In some embodiments, the organic solvent is a Class 3 solvent.

[0142] In another embodiment, there is a composition comprising Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA), wherein the composition contains less than about 1% detectable amount of solvent, wherein the solvent is selected from acetone, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, heptane, and 2-propanol. In a further embodiment, there is a composition comprising Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA), wherein the composition contains less than about 5000 ppm detectable amount of solvent. In a further embodiment, there is a composition comprising Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA), wherein the detectable amount of solvent is less than about 5000 ppm, less than about 4000 ppm, less than about 3000 ppm, less than about 2000 ppm, less than about 1000 ppm, less than about 500 ppm, or less than about 100 ppm.

[0143] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA) is free of impurities. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA) is free of structurally related impurities. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA) is substantially free of impurities. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA) is substantially free of structurally related impurities. In some embodiments, the amount of impurities is less than 1% (w / w). In some embodiments, the amount of impurities is less than 0.5% (w / w). In some embodiments, the amount of impurities is less than 0.4% (w / w). In some embodiments, the amount of impurities is less than 0.3% (w / w). In some embodiments, the amount of impurities is less than 0.25% (w / w). In some embodiments, the amount of impurities is less than 0.20% (w / w). In some embodiments, the amount of impurities is less than 0.15% (w / w). In some embodiments, the amount of impurities is less than 0.10% (w / w). In some embodiments, the amount of impurities is less than 0.08% (w / w). In some embodiments, the amount of impurities is less than 0.05% (w / w). In some embodiments, the amount of impurities is not detectable.

[0144] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA) is substantially free of impurities. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A·2MSA) is substantially free of structurally related impurities. In some embodiments, substantially free means less than about 5% (w / w), less than about 3% (w / w), less than about 1% (w / w), less than about 0.5% (w / w), or less than about 0.2% (w / w). In some embodiments, substantially free means less than about 1% (w / w), less than about 0.9% (w / w), less than about 0.8% (w / w), less than about 0.7% (w / w), less than about 0.6% (w / w), less than about 0.5% (w / w), less than about 0.4% (w / w), less than about 0.3% (w / w), less than about 0.25% (w / w), less than about 0.20% (w / w), less than about 0.15% (w / w), less than about 0.10% (w / w), less than about 0.08% (w / w), or less than about 0.05% (w / w). In some embodiments, substantially free means an undetectable amount.

[0145] The methods and formulations described herein also include the use of N-oxides (where appropriate) or pharmaceutically acceptable salts of compounds having the structures disclosed herein, as well as active metabolites of these compounds that possess the same type of activity.

[0146] In some embodiments, the organic radical (e.g., alkyl group, aromatic ring) moiety of the compounds disclosed herein is susceptible to various metabolic reactions. By incorporating appropriate substituents into the organic radical, this metabolic pathway can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions include, by way of example only, halogen, deuterium, alkyl group, haloalkyl group, or deuterated alkyl group.

[0147] In another embodiment, the compounds described herein are labeled with isotopes (e.g., with radioisotopes) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0148] The compounds described herein include isotopically labeled compounds, which are identical to the compounds detailed in the various formulas and structures presented herein except for the fact that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the present compounds include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P, and 33 and isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, etc., such as P. In one embodiment, the isotopically labeled compounds described herein, e.g., 3 H and 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with isotopes such as deuterium offers certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or altered metabolic pathways to reduce undesirable metabolites or reduced dosage requirements.

[0149] In some embodiments, one or more hydrogen atoms on Compound A are replaced with deuterium. In some embodiments, the substitution with deuterium provides certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0150] In one embodiment, a methanesulfonate salt of a compound having the structure:

[0151] [ka] wherein each R is independently selected from hydrogen or deuterium.

[0152] In some embodiments, the methanesulfonate salt is a dimethanesulfonate salt.

[0153] In some embodiments, the compounds disclosed herein have one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. For example, in some embodiments, when one stereocenter is present, the compounds disclosed herein exist in the R configuration. In other embodiments, when one stereocenter is present, the compounds disclosed herein exist in the S configuration. In some embodiments, when two stereocenters are present, the compounds disclosed herein exist in the RR configuration. In other embodiments, when two stereocenters are present, the compounds disclosed herein exist in the RS configuration. In other embodiments, when two stereocenters are present, the compounds disclosed herein exist in the SS configuration. In other embodiments, when two stereocenters are present, the compounds disclosed herein exist in the SR configuration.

[0154] The compounds presented herein include all diastereomeric, individual enantiomeric, atropisomeric, and epimeric forms, as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof.

[0155] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns, or separation of diastereomers by non-chiral or chiral chromatographic columns, or crystallization and recrystallization in an appropriate solvent or mixture of solvents. In certain embodiments, the compounds disclosed herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, resolution of the individual enantiomers of the compounds disclosed herein is carried out using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, diastereomers of the compounds disclosed herein are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of the stereoisomers disclosed herein is carried out by chromatography, or by forming diastereomeric salts and separating them by recrystallization or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0156] Separation of individual enantiomers from racemic mixtures can be achieved by the use of chiral supercritical fluid chromatography (SFC) or chiral high-performance liquid chromatography (HPLC). In some embodiments, enantiomers described herein are separated from each other by the use of chiral SFC or chiral HPLC. In some embodiments, compounds disclosed herein that contain one or more chiral centers (e.g., compounds disclosed herein that contain a trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl moiety) are separated into individual enantiomers using chiral SFC or chiral HPLC. A variety of conditions and suitable columns are available.

[0157] Daicel polysaccharide chiral stationary phase (CSP) is one of the columns used for chiral SFC separations. In some embodiments, Daicel analytical immobilized and coated CHIRALPAK and CHIRALCEL HPLC columns can be used for SFC analysis.

[0158] In some embodiments, screening for suitability for use with SFC columns is performed with various concentrations of organic modifier on four main stationary phases (CHIRALPAK IA, IB, IC, and ID) and four main coated columns (CHIRALPAK AD and AS, and CHIRALCEL OD and OJ). A variety of column phases are available, including, but not limited to, chlorinated phases OD and OJ, OX and OZ, and a series of complementary cellulose-based CHIRALCEL phases, including OA, OB, OC, OF, OG, and OK.

[0159] Non-limiting examples of chiral selectors contemplated for use in separating enantiomers include amylose tris(3,5-dimethylphenylcarbamate), cellulose tris(3,5-dimethylphenylcarbamate), cellulose tris(3,5-dichlorophenylcarbamate), amylose tris(3-chlorophenylcarbamate, amylose tris(3,5-dichlorophenylcarbamate), amylose tris(3-chloro,4-methylphenylcarbamate), amylose tris((S)-alpha-methylbenzylcarbamate), amylose tris(5-chloro-2-methylphenylcarbamate), cellulose tris(4-methylbenzoate), cellulose tris(4-chloro-3-methylphenylcarbamate), and cellulose tris(3-chloro-4-methylphenylcarbamate).

[0160] Non-limiting examples of chiral columns contemplated for use in separating enantiomers include CHIRALPAK IA SFC, CHIRALPAK AD-H SFC, CHIRALPAK IB SFC, CHIRALCEL OD-H SFC, CHIRALPAK IC SFC, CHIRALPAK ID SFC, CHIRALPAK IE SFC, CHIRALPAK IF SFC, CHIRALPAK AZ-H SFC, CHIRALPAK AS-H SFC, CHIRALPAK AY-H SFC, CHIRALCEL OJ-H SFC, CHIRALCEL OX-H SFC, and CHIRALCEL OZ-H SFC.

[0161] In some embodiments, the identity and arrangement of the substituents of the compounds described herein help minimize undesired activity. For example, in some embodiments, the undesired activity includes undesired hERG inhibition. In some embodiments, the presence of a cyano group adjacent to a hydroxyl group on the aromatic ring significantly reduces undesired hERG inhibition compared to the absence of both groups, the presence of a hydroxyl group without an adjacent cyano group, or the presence of a cyano group without an adjacent hydroxyl group. For example, in some embodiments, when R is substituted or unsubstituted 2-hydroxy-3-cyanophenyl, a significant reduction in undesired hERG inhibition is observed.

[0162] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism to produce metabolic products that are then used to provide a desired effect, including a desired therapeutic effect.

[0163] A "metabolite" of a compound disclosed herein is a derivative of the compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of the compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the entire process by which a particular substance is transformed by an organism, including, but not limited to, hydrolysis and enzyme-catalyzed reactions. Thus, enzymes can cause specific structural changes to a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0164] Unless otherwise specified, definitions of the following terms used in this application are provided below. The use of the term "including" and other forms such as "include," "includes," and "included" is non-limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0165] The term "halo," or alternatively "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0166] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms joined by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a single bond, the reference group is absent, thereby allowing for the formation of a single bond between the remaining specified groups.

[0167] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical substance embedded in or attached to a molecule.

[0168] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the health of the subject being treated.

[0169] As used herein, the term "modulate" means to interact with a target directly or indirectly so as to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0170] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0171] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0172] "Co-administration" and like terms, as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0173] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of an agent or compound being administered to relieve to some extent one or more of the symptoms of the disease or disorder being treated. The result includes a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic purposes is the quantity of a composition comprising a compound disclosed herein that is required to produce a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0174] The terms "enhance" or "enhancing," as used herein, means to increase or prolong, either in potency or duration, a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0175] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or co-administration of more than one active ingredient, and includes fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, for example, the compounds disclosed herein or pharmaceutically acceptable salts thereof, and the auxiliary agent are both administered to a patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, for example, the compounds disclosed herein or pharmaceutically acceptable salts thereof, and the auxiliary agent are administered to a patient as separate entities simultaneously, concurrently, or sequentially, without any specific intervening time limit, such that such administration provides the patient's body with effective levels of the two compounds. The latter term also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0176] The terms "article of manufacture" and "kit" are used synonymously.

[0177] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of the following classes of mammals: humans, non-human primates such as chimpanzees, and other apes and monkeys, livestock such as cows, horses, sheep, goats, and pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals including rodents, such as rats, mice, and guinea pigs. In one aspect, the mammal is a human.

[0178] The terms "treat," "treating," or "treatment," as used herein, include alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., suppressing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition prophylactically and / or therapeutically.

[0179] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Suitable formulations depend on the route of administration selected. Summary summaries of the pharmaceutical compositions described herein can be found in, for example, The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0180] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. Administration of the compounds and compositions described herein can be achieved by a method that allows delivery of the compound to the site of action. These methods include, but are not limited to, enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository, and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epidermal, dermal, enema, eye drops, ear drops, intranasal, and vaginal) administration, although the most appropriate route can depend, for example, on the disease or disorder of the recipient. By way of example only, the compounds described herein may be administered locally to the area in need of treatment, for example, by local infusion during surgery, topical application such as a cream or ointment, injection, catheter, or implantation. Administration may also be by direct injection at the site of the diseased tissue or organ.

[0181] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water emulsion or a water-in-oil emulsion in an oil liquid. In some embodiments, the active ingredient is provided as a bolus, electuary, or paste.

[0182] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersant. Molded tablets can be made by molding in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide delayed or controlled release of the active ingredient. All formulations for oral administration should be in a dosage suitable for such administration. Push-fit capsules can contain the active ingredient in combination with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize various combinations of active compound dosages.

[0183] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with added preservatives. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The compositions may be provided in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, e.g., saline or pyrogen-free distilled water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type described above.

[0184] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0185] Pharmaceutical compositions can also be formulated as depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0186] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0187] Pharmaceutical compositions can be administered topically, i.e., by non-systemic administration. This includes applying the compounds of the present invention to the epidermis or externally to the buccal cavity, and instilling the compounds into the ears, eyes, and nose so that the compounds do not enter the bloodstream in significant amounts. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0188] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise from 0.001% w / w to 10% w / w, for example 1% to 2% by weight, of the formulation for topical administration.

[0189] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, a nebulizer, a pressurized pack, or other convenient means for delivering an aerosol spray.Pressurized packs can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, the formulation can take the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch.The powder composition can be presented in a unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator.

[0190] For example, in addition to the ingredients specifically mentioned above, it will be understood that the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, formulations suitable for oral administration may include flavoring agents.

[0191] Dosage and treatment regimens In one embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are used in the preparation of a medicament for the treatment of a disease or disorder in a mammal that would benefit from modulation of somatostatin activity. A method for treating any of the diseases or disorders described herein in a mammal in need of such treatment comprises administering to the mammal a therapeutically effective amount of at least one compound disclosed herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0192] In some embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatment. In some therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0193] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dosage." For this application, the precise amount will vary depending on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom of the disease being treated and is now in remission, to prevent the recurrence of the disease or condition symptoms.

[0194] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the patient's lifetime, to ameliorate or otherwise suppress or limit the symptoms of the patient's disease or disorder.

[0195] Once the patient's condition has improved, a maintenance dose is administered as needed. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, are reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. In some embodiments, however, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0196] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), etc., but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0197] In general, however, dosages employed in adult human treatment are typically in the range of 0.01 mg to 2000 mg per day. In one embodiment, the desired dosage is suitably provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0198] In one embodiment, a suitable daily dosage for a compound disclosed herein or a pharmaceutically acceptable salt thereof described herein is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the daily dosage or effective amount of the active ingredient in a dosage form will be lower or higher than the ranges set forth herein, depending on many variables related to the particular treatment regimen. In various embodiments, the daily dosage amount and unit dose will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0199] The toxicity and therapeutic efficacy of such treatment regimens may include, but are not limited to, LD 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD 50 and ED 50 In some embodiments, the data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dosage range and / or therapeutically effective unit dose for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is the ED400 with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or unit dose varies within this range depending on the dosage form employed and the route of administration utilized.

[0200] In any of the foregoing aspects, in further embodiments, an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by injection to a mammal, and / or (e) administered topically to a mammal, and / or (f) administered non-systemically or topically to a mammal.

[0201] In any of the foregoing aspects, there are further embodiments comprising a single administration of an effective amount of the compound, including further embodiments where (i) the compound is administered once daily, or (ii) the compound is administered multiple times throughout the day to the mammal.

[0202] In any of the foregoing aspects, there are further embodiments comprising multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently, as in a single dose; (ii) the interval between multiple doses is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; or (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, in which administration of the compound is temporarily suspended or the amount of compound being administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. [Example]

[0203] Abbreviation: ACN: acetonitrile AcOH: acetic acid Amphos: Di-tert-butyl(4-dimethylaminophenyl)phosphine: Boc or BOC: tert-butyloxycarbonyl DCM: dichloromethane DI: deionized DIEA or DIPEA: Diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DSC: Differential scanning calorimetry DVS: Dynamic Vapor Sorption EtOAc: ethyl acetate EtOH: ethanol equiv: equivalent, typically molar equivalent HPLC: High-performance liquid chromatography hrs: hours h or hr: hours IPA: Isopropyl alcohol IPAc: Isopropyl acetate IPC: Ion-pair chromatography KF: Karl Fischer titration MeOAc: methyl acetate MeOH: Methanol MIBK: Methyl isobutyl ketone MOMCl: methoxymethyl chloride MSA: methanesulfonic acid MTBE: Methyl tert-butyl ether NCS: N-chlorosuccinimide NMP: N-methyl-2-pyrrolidone NMR: nuclear magnetic resonance Pd(dppf)Cl2: [1',1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (pinB)2: Bis(pinacolato)diboron PPh: Triphenylphosphine rt or RT: room temperature Rt: retention time SFC: Supercritical Fluid Chromatography SST: somatostatin SSTR: somatostatin receptor TEA: Trimethylamine TFA: Trifluoroacetic acid TGA: Thermogravimetric analysis THF: tetrahydrofuran TLC: Thin Layer Chromatography vol: volume typically used for reaction volumes or solvent ratios XRPD: X-ray powder diffraction.

[0204] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0205] Preparation of compounds Example 1: Synthesis of potassium (3-cyano-2-hydroxyphenyl)trifluoroborate (Compound 5)

[0206] [ka]

[0207] Step 1: 3-Bromo-2-fluorobenzonitrile (1.25 g, 1.0 equiv.) and potassium acetate (5 equiv.) were mixed in DMSO (7 vol.) and heated at 90-95 °C for 48 h. IPC showed 0.38% 1 and 96.5% compound 2. The reaction mixture was cooled to 25-30 °C and quenched with water (25 vol.). The pH was then adjusted to 3-4 using 6N HCl solution. The resulting mixture was diluted with MTBE (10 vol.). The organic layer was separated, and the aqueous layer was extracted with 10 vol. of MTBE. The combined organic layers were washed with water (10 vol. × 3), concentrated to a 2-vol. level, chased with DCM (3 vol.), concentrated again to 2 vol., and then diluted with DCM (8 vol.) to give a crude solution of compound 2. This solution was used in the subsequent process without further purification.

[0208] Step 2: The crude solution of compound 2 was mixed with acetic anhydride (1.3 equiv.) and DMAP (0.1 equiv.) at 25-30°C with stirring for 2 hours. IPC showed 0.8% compound 2 and 94.8% compound 3. The reaction mixture was diluted with purified water (10 vol.) and stirred for 30 minutes. The organic layer was separated. The aqueous layer was extracted with 2 volumes of DCM. The combined organic layers were washed with water (8 vol. × 2). Charcoal (10%) was added to the organic layer, stirred for 1 hour, and then filtered through a celite bed. The filtrate was then concentrated to a 2-vol. level and chased with 3 and 2 volumes of n-heptane before being cooled to room temperature and stirred at 5-10°C for 1 hour. The product was isolated as a solid by filtration (25.5 g, 85% yield over two steps, 96.8% HPLC purity).

[0209] Step 3: Compound 3 (20 g, 1.0 equiv.) was mixed with KOAc (3.0 equiv.) and bis(pinacolato)diboron (1.2 equiv.) in 2-methyl-THF. The mixture was stirred and degassed with N bubbling, and then Pd(dppf)Cl·DCM (0.025 equiv.) was added. The resulting mixture was heated at 80–85 °C for 16 h. IPC showed 0.3% starting material and 92% compound 4. The reaction mixture was cooled to 25–30 °C and filtered through a Celite pad. The Celite pad was washed with MTBE (5 vol.). The combined filtrate was concentrated to 2 vol. and chased with MTBE to 2 vol. The resulting solution was diluted with MTBE (10 vol.) and stirred at ambient temperature for 1 h. The suspension was filtered again through a Celite pad, and the Celite pad was rinsed with MTBE. The combined filtrate was washed with water (500 ml, 5 volumes). The aqueous layer was extracted with MTBE. The combined organic layers were washed twice with 5% N-acetyl-L-cysteine ​​solution (300 mL, 3 volumes each) and water (300 mL, 3 volumes). The organic layer was then separated, treated with 10% activated carbon, and filtered through a Celite pad. The Celite pad was rinsed with MTBE. The combined filtrate was concentrated to a 2-volume level, chased twice with methanol to 3 volumes (2 × 4 volumes), and cooled to ambient temperature before use in the next step.

[0210] Step 4: To a solution of compound 4, KHF (5.0 equiv.), purified water (2.6 vol.), and MeOH (1 vol.) were added and heated to 65°C for 1 hour. The reaction mixture was diluted with MTBE (15 vol.) and cooled to 10±5°C. The resulting suspension was stirred for 1 hour and then filtered. The solid was transferred to a reaction flask, 20 vol. of acetone was added, stirred at 25±5°C for 1 hour, treated with 10% charcoal, and stirred for an additional hour. The resulting reaction mixture was then filtered through a Celite pad. The filtrate was concentrated to a 2-vol. level, chased with MTBE (3 vol. × 2), concentrated to a 2-vol. level, and diluted with MTBE (4 vol.). The suspension was stirred at 25±5°C for 1 hour and then filtered to give the desired product, compound 5, as an off-white solid (11.5 g, 49.5%, HPLC purity 97.8%). 1 H NMR (400 MHz, DMSO-d6): δ8.2(s,1H),7.41(m,1H),7.34(m,1H),6.80(m,1H); 13 C NMR(100 MHz,DMSO-d6):161.8,138.0,138.0,130.8,119.4,118.0,96.6.

[0211] Example 2: Synthesis of (3-cyano-2-hydroxyphenyl)boronic acid (compound 7)

[0212] [ka]

[0213] Step 1: Diisopropylethylamine (114 mL, 1.3 equiv.) was slowly added to a solution of 3-bromo-2-hydroxybenzonitrile (compound 2, 100 g, 1 equiv.) in CHCl (1 L, 10 vol.) at 0 °C and stirred for 30 min. Chloromethyl methyl ether (MOMCl) (46 mL, 1.2 equiv.) was then slowly added, maintaining an internal temperature of 0–5 °C. The reaction was then warmed to room temperature and stirred for 4 h until TLC indicated complete reaction. The reaction was cooled to 0 °C, quenched with deionized water (300 mL, 3 vol.), and the layers were separated. The aqueous layer was extracted with CHCl (300 mL, 3 vol.), and the combined organic layers were washed with water and brine and concentrated on a rotavap to give 115 g of crude product as a brown oil. The crude product was purified on a plug of SiO2 and eluted with 10% ethyl acetate and pet-ether (20 vol.). Only one fraction was collected, evaporated under vacuum, and dried under high vacuum to give 86 g (70%) of compound 6 as a colorless oil, which was 99.96% pure (HPLC-AUC).

[0214] Step 2: in THF (2M in THF, 340 mL, 2.2 eq.) iThe solution of PrMgCl was slowly added to a solution of compound 6 (75 g, 1 equiv.) in THF (1.12 L, 15 vol.) while maintaining an internal temperature of -5 to 5 °C and stirred for 10 min. Then, triisopropyl borate (180 mL, 2.5 equiv.) was added while maintaining an internal temperature of -5 to 3 °C. The reaction was then warmed to room temperature and stirred for 18 h until TLC indicated complete reaction. The reaction was then cooled to -10 °C and quenched by the slow addition of 3 N HCl (620 mL, 6 equiv.) at -10 °C. The mixture was stirred at room temperature for 3 h, extracted with ethyl acetate (525 mL, 5 vol.), and the aqueous layer was extracted with ethyl acetate (225 mL, 3 vol.). The combined organic layers were washed successively with deionized water (3 × 3 vol.), brine (525 mL, 3 vol.), and concentrated under vacuum to give the crude material as a sticky solid. The crude material was stirred in pet-ether (525 mL, 5 volumes) for 30 min, and the resulting solid was filtered, washed with pet-ether (150 mL, 2 volumes), and dried under vacuum to give 35 g (70%) of boronic acid compound 7 as an off-white solid, which was 97.91% pure (HPLC-AUC).

[0215] Example 3: Synthesis of tert-butyl (1-(6-bromo-3-chloroquinolin-4-yl)piperidin-4-yl)carbamate (11)

[0216] [ka]

[0217] Step 1: N-Chlorosuccinimide (377 g, 1.05 equiv.) was added to a suspension of 6-bromoquinolin-4(1H)-one (8, 600 g, 1 equiv.) in acetic acid (12 L, 20 vol.) at room temperature. The reaction was then heated to 50° C. and stirred for 8 h. The reaction was cooled to 20° C., filtered, washed successively with AcOH (1.8 L, 3 vol.), water (2.4 L, 4 vol.), and MTBE (1.2 L, 2 vol.), and dried under vacuum on the filter to give crude 9. The crude material was stirred in MTBE (7.2 L, 12 vol.) for 2 h, filtered, washed with MTBE (0.6 L, 1 vol.), and dried under vacuum to give 541 g (78%) of 9 as an off-white solid, which was found to be 97.35% pure (HPLC-AUC).

[0218] Step 2: Phosphorus tribromide (317 mL, 1.6 equiv) was added slowly to a solution of 9 (540 g, 1 equiv) in DMF (7 L, 13 vol) at 0-5 °C. The reaction was warmed to room temperature and stirred for 4 h. The reaction was cooled to 0 °C, quenched with a saturated aqueous solution of NaHCO to pH 8 (10.8 L, 20 vol), and diluted with water (5.4 L, 10 vol). The mixture was stirred at room temperature for 2 h, and the solid was filtered, washed with water (2.7 L, 5 vol), and dried on the filter under vacuum. The wet cake was slurried in water (5.4 L, 10 vol) for 2 h, filtered, washed with water (980 mL, 2 vol), and dried on the filter under vacuum to give crude 10 as a solid. The crude material was stirred in MTBE (2.7 L, 5 vol) for 2 h, filtered, washed with MTBE (980 mL, 2 vol) and dried under vacuum to give 434 g (65%) of 10 as an off-white solid, which was found to be 97.95% pure (HPLC-AUC).

[0219] Step 3: Diisopropylethylamine (932 mL, 4 equiv.) and 4-(N-Boc-amino)piperidine (430 g, 1.6 equiv.) were added sequentially to a solution of 10 (430 g, 1 equiv.) in DMSO (4.3 L, 10 vol.) at room temperature. The suspension was then heated to 140° C. and stirred for 3 h. The reaction was cooled to room temperature, diluted with water (12.9 L, 30 vol.), and stirred for 2 h. The resulting solid was filtered and dried on the filter. The wet cake was dissolved in DCM (3 L, 7 vol.), and the aqueous layer was extracted with DCM (860 mL, 2 vol.). The combined organic layers were washed with water (2×2.1 L, 5 vol. each), brine (2.1 L, 5 vol.), and dried under vacuum to give crude 11 as a solid. The crude material was stirred in MTBE (2.21 L, 5 vol) for 1 h, filtered, washed with MTBE (860 mL, 2 vol) and dried under vacuum to give 412 g (70%) of 11 as an off-white solid, which was found to be 98.26% pure (HPLC-AUC).

[0220] Example 4: Alternative synthesis of tert-butyl (1-(6-bromo-3-chloroquinolin-4-yl)piperidin-4-yl)carbamate (11)

[0221] [ka]

[0222] A mixture of 6-bromo-4-chloroquinoline (14, 25 g, 1.0 equiv.), DMF (6.0 vol.), 4-(tert-butoxycarbonylamino)piperidine (2.0 equiv.), and K2CO3 (2.5 equiv.) was stirred and heated to 105 °C for 16 h. The reaction was monitored by IPC-HPLC, showing 93.5% 15 and 0.12% 14. The reaction mixture was cooled to 25-30 °C, diluted with purified water (30 vol.), and stirred for 2 h. The solid was filtered and washed with purified water. The crude solid was slurried with n-heptane (5 vol.), filtered, and washed with n-heptane (2 vol.). The solid was dried at 55 °C to give 15 (35.3 g, 84% yield). 1H NMR(400 MHz,DMSO-d6):δ8.69(d,1H),8.02(d,1H),7.88(m,1H),7.80(m,1H),7.02(d,1H) ),6.97(d,1H),3.44(m,3H),2.87(m,2H),1.94(d,2H),1.68(m,2H),1.38(s,9H).

[0223] Compound 15 (25 g, 1 equiv.), DIPEA (0.078 equiv.), NCS (1.5 equiv.), and toluene (10 vol.) were mixed and heated at 70° C. for 4 hours. The reaction mixture was concentrated to 3 volumes at 45±5° C., cooled to room temperature, diluted with MTBE (10 vol.), and washed with purified water (10 vol.). After layer separation, the aqueous layer was extracted with MTBE (5.0 vol.). The combined organic layers were washed twice with purified water (2×5 vol.) and then with brine. The organic layers were dried over sodium sulfate, concentrated to 2 levels, and the aqueous layer was washed twice with MTBE (2×2 vol.). The combined organic layers were cooled, and MTBE (1 vol.) was added before warming to 50±5° C. and stirring for 1 hour. The resulting suspension was cooled to 5±5° C. and stirred for 1 hour. The solid was collected by filtration and washed with pre-cooled MTBE (1 vol.). The solid was taken up in MTBE (2 volumes), reheated to 55 ± 5 °C, stirred for 1 h, cooled to 5 ± 5 °C, and stirred for an additional 1 h. The solid was collected by filtration and washed with pre-chilled MTBE (1 volume). The collected solid was dried under reduced pressure at 45 ± 5 °C for 8 h to give 11 in 66% isolated yield (18 g) with an HPLC purity of 98.9%. 1 H NMR(400 MHz,DMSO-d6):δ8.65(s,1H),8.25(d,1H),7.92(m,1H),7.73(m,1H),3.76 (s,1H),3.51(m,2H),3.37(d,2H),2.14(d,2H),1.69(m,2H),1.46(s,9H).

[0224] Example 5: Synthesis of tert-butyl (1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate (13)

[0225]

change

[0226] Quinoline 11 (350 g, 1 equiv.), (3-cyano-2-hydroxyphenyl)boronic acid (compound 7) (155 g, 1.2 equiv.), and K2CO3 (438 g, 4 equiv.) were charged to a round-bottom flask. 1,4-Dioxane (3.5 L, 10 vol.) and deionized water (350 mL, 1 vol.) were added to the flask, and the resulting reaction mixture was degassed with argon for 30 min. PdCl2(dppf)·CHCl2 (32.5 g, 0.05 equiv.) was added to the reaction under argon, and the mixture was degassed for an additional 10 min. The reaction was stirred at 80–85 °C and monitored by TLC and HPLC. After the reaction was complete (6 h), it was cooled to 25-30 °C, and 3,5-difluorophenylboronic acid (346 g, 3 equiv.) was added to the reaction mixture, which was then degassed with argon for 10 min. PdCl(amphos) (25.9 g, 0.05 equiv.) was added to the flask under an argon atmosphere, and the reaction mixture was degassed for another 10 min. The reaction was then heated to 90-100 °C and stirred for 19 h (monitored by TLC and HPLC). HPLC showed 82.04% of 13 at 8.2 min, along with 1.95% of unreacted 12 and 0.94% of other impurities. The reaction was cooled to 25-30 °C, filtered through a pad of Celite, and washed with ethyl acetate (1350 mL, 3 volumes). The filtrate was concentrated under vacuum until ∼10% solvent remained, and the resulting residue was diluted with ethyl acetate (6.3 L, 18 vol), washed with water (2 × 3.5 L, 10 vol each), brine (3.5 L, 10 vol), and dried over anhydrous NaSO. The organic layer was concentrated under vacuum to dryness and then slurried in ethyl acetate (2.1 L, 6 vol) at room temperature for 4 h (free solid formation was observed after 2.5 h of stirring at room temperature). The resulting free solid was filtered, washed with ethyl acetate (700 mL, 2 vol), and dried under vacuum to constant weight to afford 200 g (45%) of 13 as an off-white solid, which was 98.4% pure (HPLC-AUC) and contained approximately 3500 ppm of trace palladium.

[0227] Example 6: Further purification of compound 13

[0228] Compound 13 (200 g, 98.40% pure) was taken up in IPAc (1 L, 5 volumes) and refluxed for 1 h. The mixture was then cooled to room temperature, then cooled to 15° C., filtered, washed with IPAc (600 mL, 3 volumes), and dried to give 170 g of 13 as an off-white solid that was 98.71% pure (HPLC-AUC) and contained a trace of approximately 50 ppm palladium.

[0229] Example 7: Removal of residual palladium from 13

[0230] Compound 13 (150 g, 98.71% pure) was dissolved in THF (3.4 L, 20 vol). Si-thiol (240 g) was added, and the solution was stirred at room temperature overnight. The mixture was filtered through a celite bed, washed with THF (510 mL, 3 vol), and concentrated in vacuo to give a solid. The crude solid was then diluted with IPAc (1 L, 5 vol), and the slurry was refluxed for 2 h. The mixture was then cooled to room temperature, then cooled to 15 °C, filtered, washed with IPAc (510 mL, 3 vol), and dried to give 150 g of 13 as an off-white solid, which was 100% pure (HPLC-AUC) and contained no detectable residual palladium.

[0231] Example 8: Alternative synthesis of tert-butyl (1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate (13)

[0232] [ka]

[0233] Compound 11 (25.0 g, 1 equiv.), compound 5 (1.2 equiv.), K2CO3 (3.0 equiv.), 1,4-dioxane (9 vol.), and purified water (0.75 vol.) were added to a reaction flask. The mixture was degassed with N2 bubbling, and then Pd(PPh3)4 (0.017 equiv.) was added. The reaction mixture was then heated to 80-85 °C for 12 h. IPC at 12 h indicated <1% compound 11. 3,5-difluorophenylboronic acid (2.0 equiv.), Pd(amphos)Cl2 (0.03 equiv.) were then added, and the reaction mixture was again degassed and then heated up to 90-95 °C for 6 h. IPC indicated <2% remaining compound 11. A sample of pure compound 13 was isolated. 1 Characterized by H NMR (400 MHz, DMSO-d): δ 8.63 (s, 1H), 8.27 (bs, 1H), 7.94 (m, 2H), 7.53 (d, 1H, J = 7.2 Hz), 7.47 (d, 1H, J = 6.0 Hz), 6.99 (d, 1H, J = 7.6 Hz), 6.77 (bs, 1H), 3.50 (m, 1H), 3.41 (m, 2H), 3.34 (m, 2H), 1.87 (m, 2H), 1.65 (m, 2H), 1.39 (s, 9H).

[0234] Workup and Pd Removal: The reaction mixture was cooled to 25-30°C and filtered through a Celite pad. The Celite pad was washed with IPAc (2.0 vol). The filtrates were combined, concentrated to 3 vol, and chased twice with IPAc (5 vol) to 4 vol. The resulting solution was diluted with IPAc (8 vol) and washed with water (2 x 10 vol). The organic layer was separated, washed with 1% N-acetyl L-cysteine ​​(2 x 10 vol), and then concentrated to 6 vol. The resulting suspension was stirred at reflux for 2 h and cooled to ambient temperature. The suspension was further cooled to 10 ± 5°C, stirred for 2 h, and filtered. The filter cake was washed with 1 vol of IPAc and dried to give the desired crude product as a pale yellow solid.

[0235] The isolated crude solid of compound 13 was dissolved in 2-methyl-THF (15 volumes), Si-thiol (0.25% w / w) was added, and the mixture was stirred at ambient temperature for 3 hours. The suspension was filtered through a Celite bed and washed with 2-methyl-THF (2 volumes). The above process was repeated again. The final filtrate was concentrated to 2 volumes and chased twice with n-heptane (2 x 3 volumes). The resulting suspension was filtered. The solid was dried under vacuum at 45 ± 5 °C to give purified compound 13 as a solid (HPLC purity 96% with a Pd level of 13 ppm).

[0236] Example 9a: Alternative synthesis of tert-butyl (1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate (13)

[0237] [ka]

[0238] To a suspension of 11 (1.0 equiv.), 5 (1.1 equiv.), and amphos (0.051 equiv.) in 1,4-dioxane (9 vol.), a clear solution of K2CO3 (3.0 equiv.) in water (3.0 vol.) was added and degassed with argon at ambient temperature for 30 min. Pd(OAc)2 (0.017 equiv.) was added to the reaction under argon and degassed for an additional 10 min. The reaction mass was stirred at 60-85 °C for 40 min to 6 h while being monitored by TLC and HPLC. After the reaction was complete as detected by HPLC, it was cooled to ambient temperature. 3,5-Difluorophenylboronic acid (2.0 equiv.) was charged to the light brown, clear solution of the reaction mixture at ambient temperature and degassed with argon for 30 min. The reaction was then heated to 85-95 °C and stirred for 6-20 h while being monitored by TLC and HPLC.

[0239] The reaction mass was cooled to 25±5° C. and transferred to a separatory funnel (the reaction flask was rinsed with 1 volume of isopropyl acetate to ensure complete transfer). The layers were separated and the organic layer (1,4-dioxane) was concentrated to approximately 3.0 volumes and chased with isopropyl acetate in two approximately 4 volume steps (5 volumes each).

[0240] The resulting solution was diluted with IPAc (10.0 vol) and washed twice with water (2 x 10 vol). 1% N-acetyl-L-cysteine ​​in water (10 vol) was added to the organic layer and stirred for 15 minutes before separating. The 1% N-acetyl-L-cysteine ​​treatment was repeated again. The layers were filtered through a celite bed and separated. The organic layer was washed with purified water (10 vol). Activated carbon (10% w / w) was added to the organic layer at 25 ± 5 °C, stirred for 1 hour, filtered through a celite bed, and washed with isopropyl acetate (2.0 vol). The filtrate was concentrated to 6 volumes, and the resulting yellow suspension was heated to 80 ± 5 °C for 1 hour. The suspension was cooled to 25 ± 5 °C and stirred for 1 hour, then cooled to 10 ± 5 °C and stirred for 1 hour. The suspension was collected by filtration and washed with pre-cooled (5 ± 5 °C) isopropyl acetate (1.0 vol). The solid was dried under reduced pressure at 50±5° C. for 4 h to give crude 13 as a pale yellow solid (55-56%, ∼98.0% HPLC purity).

[0241] Pd Mitigation: Crude 13 was dissolved in 2-Me-THF (30.0 vol), Si-thiol (1:0.25 with respect to starting 11) was added, stirred at ambient temperature for 3 h, filtered on a Celite bed, and washed with 2.0 vol of 2-Me-THF. The filtrate was concentrated to approximately 2 vol steps and charged with 2 vol of ethanol and 2 vol of IPAc. The resulting suspension was refluxed for 6 h, cooled to 25 ± 5 °C, stirred for 1 h, and further cooled to 10 ± 5 °C and stirred for 1 h. The suspension was collected by filtration and washed with pre-cooled (5 ± 5 °C) isopropyl acetate (1.0 vol). The solid was dried under reduced pressure at 50 ± 5 °C for 4 h to give crude 13 as a pale yellow solid (45–48%, ∼99.0% HPLC purity).

[0242] Example 9b: Alternative synthesis of tert-butyl (1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate (13)

[0243] [ka]

[0244] A clean, dry 400 mL reaction vessel was charged with 11 (9.96 g, 22.6 mmol, 1 equiv.), 5 (5.34 g, 23.75 mmol, 1.05 equiv.), and amphos (0.307 g, 0.051 equiv.). After capping and purging with nitrogen, K2CO3 solution (23.7% w / w K2CO3 in water, 39.407 g, 3 equiv.) and 1,4-dioxane (92.3 g, 9 vol.) were added under an inert atmosphere. The nitrogen line was lowered and the biphasic solution was sparged with nitrogen for 15 minutes while mixing with an overhead stirrer. While sparging, Pd(OAc)2 (0.087 g, 1.7 mol%) was added. The reaction mixture was stirred at room temperature for 10 minutes while sparging. A nitrogen line was transferred to the top of a reflux condenser (cooled by a condenser set at 10 °C) and the reaction vessel was heated to 60 °C and refluxed (85-90 °C). Conversion was determined to be >95% within 30 min of reaching reflux, and the reaction mixture was allowed to cool to RT with stirring, maintaining the nitrogen flow throughout.

[0245] Under a stream of nitrogen, 3,5-difluorophenylboronic acid (7.195 g, 2 equiv.) was added, and the reaction mixture was sparged for 10 min and then heated to reflux (90-95 °C). The biphasic reaction mixture was monitored by HPLC over a 10-h reaction time, and reaction conversion reached approximately 98%.

[0246] The biphasic reaction mixture was cooled to RT, transferred to a separatory funnel, and rinsed with IPAc (50 g). The organic layer was concentrated in vacuo to 3 volumes (40 g) and chased with IPAc (3 × 5 volumes). The thick slurry was diluted with IPAc (300 g total mass) and extracted with 100 mL of HO. The cloudy organic layer was treated with 1% N-acetyl-L-cysteine ​​(10 volumes) for 15 minutes and filtered through Celite. Prior to separation, the Celite bed was rinsed with IPAc (20 mL). The cloudy orange organic layer was treated with an additional 100 mL (10 volumes) of the 1% N-acetyl-L-cysteine ​​solution. The solid crashed out of solution on top of the Celite bed. The Celite was rinsed with IPAc (50 mL) and 2-Me-THF (50 mL). The solution was decanted and the solid was rinsed with IPAc to obtain the first crop of product. The remaining solution was concentrated in vacuo, chased with IPAc (3 × 5 volumes), refluxed for 2 hours, cooled to RT, and stirred overnight. The slurry was stirred at 10–15°C for 2 hours and filtered to give an off-white solid. The cake was rinsed with 15 mL of cold IPAc (approximately 0°C) and dried in vacuo at 50°C overnight to give a second crop of product. The combined final mass of the two crops of product was 7.1 g (58% isolated yield) of an off-white solid with an HPLC purity of 99.5%.

[0247] Example 10: Synthesis of Crystal Pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate (Compound A·2MSA)

[0248] [ka]

[0249] To a suspension of 13 (1.8 kg, 3.23 mol) in isopropyl acetate (9.0 L, 5 vol) was added 6 N HCl solution (9.0 L, 5 vol) over 30 min at 25 ± 5 °C. To the suspension, isopropyl acetate (14.4 L, 8 vol) was added at 25 ± 5 °C and stirred at 25 ± 5 °C for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, isopropyl acetate (5.4 L, 3 vol) was added to the reaction mixture, which was then purged with argon gas for approximately 15 min to remove excess HCl gas from the reaction mixture. After purging, the reaction mixture was stirred at 25 ± 5 °C for 1 h. The solid was collected by filtration, washed with isopropyl acetate (5.4 L, 3 vol), and dried under reduced pressure at 45 ± 5 °C for 12 h to give 1.8 kg of compound A·2HCl as a pale yellow solid with a purity of 99.18% by HPLC. The solid was taken up in purified water (108 L, 60 volumes) and the pH was adjusted to 9-10 using sodium hydroxide solution (3N) at 25±5°C. After pH adjustment, the mixture was stirred at 25±5°C for 1 hour, filtered, and washed with purified water (18 L, 10 volumes) until the pH of the last drop was 7-8. The solid was dried under reduced pressure at 55±5°C for 12 hours to give 1.5 kg of Compound A (free base) as a pale yellow solid with a purity of 99.37%.

[0250] To a suspension of Compound A (free base) (1.5 kg, 3.28 mol) in acetone (9.0 L, 6 vol) at 25±5°C, seeds (Pattern B, 6.6 g, 0.0044 w / w) were added and the suspension was heated to 50±5°C for 5 min. A solution of methanesulfonic acid in water (1.35 L, 0.9 vol; 0.6 kg MSA in 1.2 L water) was added to the single-lot suspension at 50±5°C, and the resulting solution was stirred for 10 min. The reaction mixture was then diluted with acetone (9.0 L, 6 vol) and stirred at 50±5°C for 3 h. The resulting suspension was cooled to 25±5°C and stirred for 15 min. The solid was collected by filtration and washed with acetone (3.0 L, 2 vol). The wet solid was dried under reduced pressure at 30 ± 5 °C for 8 h to give compound A 2MSA (1.57 kg, 73% yield) as a pale yellow solid with an HPLC purity of 99.5%. XRPD was consistent with pattern B.

[0251] Example 11: Alternative synthesis of crystalline pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate (Compound A·2MSA)

[0252] [ka]

[0253] A suspension of 13 (1 g, 1.79 mmol) in acetone (6 mL, 6 vol) was stirred for 5 min and heated to 45–50 °C. A solution of MSA (0.58 mL, 5 eq) in water (0.58 mL, 18 eq) was added to the slurry at 45–50 °C. The mixture was then seeded with 50 mg of Pattern B and stirred at 50 °C for 1.5 h. TLC and HPLC indicated a complete reaction. Acetone (6 mL, 6 vol) was slowly added to the mixture at the same temperature, followed by cooling to 25–30 °C. The pale yellow slurry was then filtered, washed with a 1:10 mixture of acetone (2 mL, 2 vol), and dried in a vacuum oven at 50 °C for 3.5 h to give 1 g of compound A 2MSA as a pale yellow solid (HPLC purity 99.73%).

[0254] Synthesis of clean Pattern B by humidification: In a sealed container, 1 g of the above material was placed in a Petri dish along with a beaker (250 mL) containing water (~200 mL, initial water temperature approximately 30 °C, no further temperature control required) to create a humid environment. Leaving the setup for 24 h to expose the sample to humidity yielded 1 g of compound A·2MSA as a pale yellow solid. XRPD of the resulting solid was consistent with Pattern B.

[0255] Example 12: Alternative synthesis of crystalline pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate (Compound A·2MSA)

[0256] [ka]

[0257] To a solution of 13 (2 g, 3.59 mmol) in NMP (6 mL, 3 volumes), MSA (1.16 mL, 5 equiv.) was added and heated at 100 °C for 2 h. TLC and HPLC indicated a complete reaction. The reaction was cooled to room temperature and stirred for an additional 10 h. The solid was filtered, washed with EtOAc, and dried under vacuum. The wet cake was slurried in EtOAc under reflux for 1 h to remove residual NMP. The mixture was cooled to RT, filtered, washed with EtOAc, and dried under vacuum to give 2 g of compound A·2MSA as a pale yellow solid with an unknown XRPD pattern. The solid was then hydrated according to the procedure described above to give 2 g of compound A·2MSA (HPLC purity: 99.62%) as a pale yellow solid with an XRPD pattern consistent with pattern B.

[0258] Example 13: Synthesis of Crystal Pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate (Compound A·2MSA)

[0259] [ka]

[0260] A slurry of compound A (free base) (5 g) in isopropanol (75 mL, 15 volumes) was heated to 50–55 °C for 30 min. MSA (1.7 mL, 2.4 equiv.) was added to the hot slurry and stirred for 30 min. The reaction was allowed to cool to room temperature and stirred for an additional 10 h. The solid was filtered, washed with isopropanol (2 × 2 volumes), and dried under vacuum at 50 °C for 5 h to yield 7 g (98%) of compound A·2MSA as a pale yellow solid with an XRPD pattern consistent with Pattern A (HPLC purity: 99.68%). Karl Fischer titration determined a water content of 1.38 wt%.

[0261] Polymorphism Screening Method Example A-1: ​​Short-Term Gravimetric Solubility Slurries Short-term slurries were performed in 14 solvents at two temperatures. Approximately 25 mg of solid was added to a 2 mL vial, followed by 0.70 mL of solvent. Once all the solid dissolved, more solid was added until a slurry formed within reasonable limits. The slurry was stirred at a constant temperature for 4 days (ambient, 21-23 °C; or elevated, 50 °C). After stirring for 4 days, the solid was allowed to settle and then collected for XRPD analysis. XRPD analysis was performed on the wet cake, and if a new pattern was observed, the sample was dried in a vacuum oven at 50 °C for a minimum of 4 hours, after which the dried sample was analyzed by XRPD.

[0262] Nine unique patterns and one pattern that was a combination of unique and unknown patterns were recovered from the slurry. The patterns that remained stable upon drying were patterns A, B, C, and I. Pattern C was recovered from EtOH, patterns D and E switched to pattern A upon drying, and patterns F, G, and H switched to pattern I upon drying. Some pattern B samples showed minor peak shifts at high 2θ values.

[0263] [Table 1]

[0264] Example A-2: Evaporative Crystallization The supernatant from the gravimetric soluble slurry was collected for evaporative crystallization. The solution was evaporated to dryness in air at 50°C overnight and then left under vacuum at 50°C overnight (approximately 16 hours). Most vials did not contain sufficient solids for analysis. For those that did, the collected solids showed pattern B except for EtOH, from which a new, unique pattern, K, was observed. A summary of the results is shown in Table 2.

[0265] [Table 2]

[0266] A further set of evaporative crystallization experiments was performed at 50 °C with stirring. Approximately 10 mg of compound A·2MSA was added to a vial, and the selected solvent was added. The mixture was stirred at 50 °C. In THF, acetone, and IPAc dissolution did not occur after approximately 1900 volumes of solvent were added. Water was added to dissolve the solid in THF and acetone. MeOH was used to aid dissolution in IPAc, but this was unsuccessful. The solution was left uncapped, and the solvent was evaporated at 50 °C with continuous stirring. Patterns indicating low-crystalline solids were obtained from the evaporated solution. THF / water (final composition 97:3 by volume) and ACN:water (9:1 by volume) produced pattern B, while water-saturated MeOAc and acetone / water (final composition 95:5 by volume) produced patterns that were primarily amorphous with some unidentifiable minor features. Table 3 shows a summary of the data.

[0267] [Table 3]

[0268] Example A-3: Formation of amorphous material Approximately 100 mg of compound A·2MSA was dissolved in 1 mL of ACN:water (8:2 by volume) and flash-frozen in an IPA / dry ice bath (-78 °C). The frozen solution was lyophilized overnight (~16 h). The resulting fluffy yellow solid was characterized by XRPD, simultaneous TGA / DSC, modulated DSC, solution 1H NMR, and microscopy. The XRPD pattern indicated a lack of crystallinity. The TGA pattern showed a mass loss of 3.85% between 40 and 170 °C (Figure 2a). Modulated DSC of the sample was performed. Reversible heat flow analysis indicated a glass transition temperature with an onset at 166.6 °C (Figure 1). Solution (DMSO-d6) 1 The H-NMR spectrum is consistent with the structure of compound A·2MSA.

[0269] A second batch of amorphous material was produced. Approximately 350 mg of compound A·2MSA was dissolved in 2 mL of ACN:water (8:2 by volume) and flash-frozen in liquid nitrogen (-196 °C). The frozen sample was connected to a freeze dryer and maintained under dynamic vacuum over the weekend (3 days). The resulting fluffy yellow solid exhibited a characteristic amorphous pattern by XRPD.

[0270] Example A-4: Slurry of amorphous material Approximately 22 mg of amorphous material was dispensed into a vial, 0.5 mL of the selected solvent (approximately 23 volumes) was added, and the mixture was stirred at room temperature (20-23°C). Solutions formed in water and water-saturated MeOAc. Additional solids were added to these solutions, but if a solution remained after approximately doubling the original solid amount (approximately 90 mg / mL), further addition was stopped. All other samples remained as slurries. After 4 hours of slurrying, aliquots were taken for XRPD analysis of the slurry solids from all samples except the water and water-saturated MeOAc samples, which remained in solution. The mixture was continued to stir at room temperature overnight, after which the remaining slurry solids were collected (approximately 24 hours total slurry time).

[0271] Amorphous material was recovered from heptane at both time points. At 4 h, the solid recovered from the EtOH slurry was consistent with pattern K, and pattern C was recovered after 24 h. Pattern D was recovered from the IPA slurry. Pattern I was recovered from slurries in THF (24 h), MIBK (4 and 24 h), and EtOAc (4 and 24 h). Pattern F was recovered from IPAc after 24 h. The acetone slurry produced a new pattern M, which lost crystallinity upon drying. The ACN slurry produced a new pattern N, which remained stable upon drying. The results are summarized in Table 4.

[0272] [Table 4]

[0273] Example A-5: Cooling Crystallization Approximately 30 mg of amorphous material was loaded into a vial equipped with a stir bar. The selected solvent was added to dissolve the solid at 50°C. THF and IPAc failed to dissolve the solid in 20 mL, even when heated to 60°C. In THF:water (9:1 by volume), the solution separated into an oily orange layer and a yellow solution. The quenched samples were removed with stirring at 50°C and placed in an ice bath without stirring. After 3 hours, with no precipitate present, the vials were transferred to a -20°C freezer. The next day, no precipitation was observed, and the vials are being monitored daily. The slowly cooled samples continued to stir, and the heating block temperature was reduced to room temperature at a rate of 5°C / hour. The solid that precipitated from the EtOH was collected within one day and analyzed by XRPD, showing pattern K. The other samples remained in solution and are being monitored daily, with stirring at room temperature. Table 5 summarizes the results.

[0274] [Table 5]

[0275] Example A-6: Antisolvent Crystallization Approximately 25 mg of amorphous material dissolved in 5 volumes of solvent at room temperature (20-23° C.) was filled into vials. Two antisolvent addition regimes were used.

[0276] For direct antisolvent addition, a double volume of antisolvent was used, which was added dropwise in four portions over 40 minutes. For example, if a solid was dissolved in 0.5 mL of solvent, 1.0 mL of antisolvent was added over 40 minutes.

[0277] In the case of anti-solvent addition, the solution was transferred to four times the volume of anti-solvent in one go while stirring rapidly. For example, if a solid was dissolved in 0.5 mL of solvent,

[0278] The solution was added rapidly to 2.0 mL of antisolvent while stirring. In the reverse addition experiment, a yellow slurry developed immediately upon addition of the solution to the antisolvent. Pattern K was recovered from both reverse addition experiments.

[0279] A new pattern O was recovered from the direct addition experiment and was stable when dried. A summary of the data is shown in Table 6.

[0280] [Table 6]

[0281] Example A-7: Crushing Experiment Dry and solvent drop milling as the grinding media 1 / 4 inch ( 1 This was done using a small Wig-L-Bug ball mill with 1 / 4" stainless steel balls. Approximately 30 mg of amorphous material was weighed into a grinding capsule and 1 volume of the selected solvent was added. Grinding was carried out at 3500 rpm in 3 x 30 second increments, with solids being scraped off the capsule wall to minimize caking between grinds. The ground samples were analyzed by XRPD as wet cakes. The recovered patterns generally showed low crystallinity, with dry-ground samples appearing amorphous.

[0282] Patterns recovered from solvent drop milling generally paired with patterns recovered from slurries in that solvent. From ACN, a combination of patterns I and N was observed, one recovered from a slurry of pattern A in ACN and the other recovered from an amorphous slurry in ACN. The exception was pattern K, recovered from acetone:water (9:1 by volume), a solvent system that produced pattern B in the slurry. Table 7 shows a summary of the data.

[0283] [Table 7]

[0284] Generation of selected crystal patterns of compound A·2MSA

[0285] Example B-1: Preparation of crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Compound A·2MSA (Pattern A, 0.2649 g) was added to a 20 mL vial equipped with a stir bar. 10 volumes (2.65 mL) of acetone:water (9:1 by volume) was added, and the slurry was stirred at room temperature. After approximately 5 minutes, the slurry froze, and an additional 5 volumes (3.98 mL total volume) were added to form a mixable slurry. The slurry was stirred overnight (~20 hours), sampled to confirm proper pattern formation, and then the solid was collected by filtration. The resulting pale yellow solid was dried in a vacuum oven under dynamic vacuum at 50 °C for 2 hours, then under static vacuum overnight (~16 hours). Pattern B (0.1174 g, 44% yield) was identified by XRPD, solution. 1 The solution was characterized by H-NMR, simultaneous TGA / DSC, and stand-alone DSC. 1 The H-NMR spectrum was consistent with the dimesylate structure and showed 0.47 wt% residual acetone. TGA showed a 2.9% mass loss between 40 and 205 °C. A simultaneous endotherm of 64 J / g (onset 86.3 °C) was observed by DSC, suggesting that the mass loss was due to water. A melting endotherm with an onset of 213.2 °C was also observed by DSC. DVS was performed on Pattern B, showing a total mass difference of 3.2 wt% over the RH range of 2 to 95%. Over the RH range of 10 to 80%, the mass change was 1.3 wt%. There was no change in morphology after the experiment, and the XRPD pattern remained Pattern B.

[0286] Crystalline pattern B is assigned as the crystalline hydrate of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

[0287] Characterization after storage under ambient conditions: Pattern B was left at ambient conditions (21–22 °C, 10–40% RH) for one week and then characterized by water content measured by XRPD, TGA / DSC, and Karl Fischer titration. The XRPD pattern is identical to Pattern B. The TGA shows a mass loss of 4.23%, with an additional approximately 1.4% water content from the TGA recorded immediately after removing the sample from the oven. The water content was confirmed by KF titration, yielding a value of 4.20 wt%. After the melting endotherm of Pattern B (onset 205.6 °C), an additional exotherm (onset 243.0 °C) and endotherm (onset 278.0 °C) were observed in the DSC thermogram (Figure 10b). It may be coincidental that these phase transitions did not occur in the previous thermal analysis of Pattern B (Figure 9b).

[0288] Stability when dry: A sample of Pattern B was prepared on an XRPD sample holder and analyzed by XRPD to create a baseline. The disk was then placed in a vacuum oven under static vacuum at 50°C for 3 days. After 3 days, the sample was removed from the oven and the "dry" pattern was immediately recorded. The dry pattern was consistent with Pattern B.

[0289] Example B-2: Alternative formation of crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate An additional lot of Pattern B was generated by exposing Pattern A to a 90%+ RH environment at room temperature (20-23°C) for 5 days. The humid environment was created by placing a beaker of saturated K2SO4(aq) in a sealed container. A noticeable color change from bright yellow to a pale off-white / yellow was evident. The sample was allowed to dry for 1 hour, after which the solution 1 The product was analyzed by H-NMR. Residual IPA was below the detectable limit by proton NMR. XRPD was consistent with pattern B.

[0290] Example B-3: Alternative formation of crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Compound A (free base) (25.6 mg) was slurried in 0.153 mL of acetone (6 volumes). The dark yellow slurry was seeded with approximately 1 mg of Pattern B. A 0.518 mg / mL solution of MSA in water was prepared, and 0.023 mL (2.2 equivalents) was added to the yellow slurry to make the solvent composition acetone:water (85:15 volumes). The slurry became significantly thinner and was stirred at 50°C for 1 hour, after which it was transferred to a room temperature stir plate and allowed to cool. Over the next 30 minutes, the slurry thickened, and an additional 0.153 mL (6 volumes) of acetone was added to make the solvent composition acetone:water (92.5:7.5 volumes), producing a medium-thick, pale yellow slurry that was stirred for an additional 15 minutes. The solids were collected by filtration, and the wet cake was washed once with 2 volumes of acetone before being dried in a vacuum oven at 50°C for 3.5 hours. The dried solid was weighed (25 mg, 57% yield) and XRPD analysis showed pattern B.

[0291] Example B-4: Production of Crystal Pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Compound A·2MSA (Pattern A, 0.2622 g) was added to a 20 mL vial equipped with a stir bar. 15 volumes (3.93 mL) of EtOH was added, and the slurry was stirred overnight (~20 h). The slurry was sampled to confirm proper pattern formation, after which the solid was collected by filtration. The resulting yellow solid was dried in a vacuum oven under dynamic vacuum at 50 °C for 2 h, then under static vacuum overnight (~16 h) to yield 0.2015 g (77% yield). The collected in situ sample was dried for 3 h, after which the solid was dissolved in water. 1The bulk was used for characterization by H-NMR spectroscopy and simultaneous TGA / DSC. The bulk was dried overnight and used for stand-alone DSC and thermal treatment. To generate a higher quality pattern after 6 days at ambient conditions, the bulk was analyzed by XRPD, which generated a pattern similar to Pattern I.

[0292] XRPD analysis of the initial sample was consistent with pattern C. Solution 1 The H-NMR spectrum was consistent with the dimesylate structure. TGA showed a mass loss of 0.12% between 40 and 140 °C and a mass loss of 0.62% between 140 and 290 °C, with a step of 260 °C. DSC showed an exotherm with an onset of 192.7 °C, a broad endotherm with an onset of 252.2 °C, and a melting endotherm with an onset of 296.6 °C.

[0293] Pattern C was assigned as an anhydrous crystalline solid of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

[0294] Example B-5: Alternative formation of crystal pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Compound A·2MSA (Pattern A) was slurried in EtOH at room temperature overnight (approximately 16 hours). A sample of the slurry solids showed Pattern C by XRPD. The remainder of the solids was collected, and a sample of the bulk wet cake was analyzed by XRPD, which also showed Pattern C. The bulk was dried in a vacuum oven at 50°C under dynamic vacuum for 4.5 hours. The dried solids were removed from the oven, and a "dry" XRPD analysis was collected. The dried solids showed a pattern that was a combination of Pattern C and Pattern I. A wet sample left at ambient conditions was left unchanged over 24 hours. Pattern C was observed to switch to I.

[0295] Example B-6: Formation of Crystal Pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Compound A·2MSA (Pattern A, 0.2659 g) was added to a 20 mL vial equipped with a stir bar. 25 volumes (6.65 mL) of ACN was added, and the slurry was stirred overnight (~20 h). The slurry was sampled to confirm that the appropriate pattern had been produced, after which the solid was collected by filtration. The resulting yellow solid was dried in a vacuum oven under dynamic vacuum at 50 °C for 2 h, then under static vacuum overnight (~16 h) to yield 0.2255 g (85% yield). The collected sample was dried for 3 h, after which the solid was dissolved in water. 1 The bulk was used for characterization by H-NMR spectroscopy and simultaneous TGA / DSC. The bulk was dried overnight and used for stand-alone DSC. To generate a higher quality pattern after 6 days at ambient conditions, the bulk was analyzed by XRPD, which produced a pattern with additional peaks.

[0296] XRPD analysis of the in situ sample was consistent with Pattern I. Solution 1 The H-NMR spectrum was consistent with the dimesylate structure. TGA showed a 0.19% mass loss between 40 and 185 °C and a 0.67% mass loss between 185 and 290 °C, with a step of 255 °C. A few adjacent thermal events were observed in the DSC. A broad endotherm with an onset of 260.9 °C overlapped with a shoulder feature of the sharpest endotherm with an onset of 292.6 °C. Karl Fischer titration determined a water content of 0.29 wt%. DVS was performed (see Figure 18). The solid switched to Pattern B during the experiment. At the end of the experiment, the solid was pale off-white / yellow, in contrast to the input Pattern I, which was bright yellow. Over the 2-95% RH range, there was a 9.1% total mass difference in the sorption segment and a 4.6% total mass difference in the desorption segment. Over the 15-75% RH range, the mass change was 2.5 wt%.

[0297] Pattern I was assigned as an anhydrous crystalline solid of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

[0298] Analysis and characterization methods

[0299] Example C-1: X-ray powder diffraction (XRPD) X-ray powder diffraction was performed using a Rigaku MiniFlex 600. Samples were prepared on Si zero-return wafers. A typical scan is from 4 to 30° 2θ with a step size of 0.05 degrees over 5 minutes at 40 kV and 15 mA. A high-resolution scan is from 4 to 40° 2θ with a step size of 0.05 degrees over 30 minutes at 40 kV and 15 mA. Typical parameters for XRPD are shown below.

[0300] [Table 8]

[0301] XRPD characterization of the solid form of compound A·2MSA The X-ray powder diffraction pattern of the amorphous form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate showed a lack of crystallinity.

[0302] The X-ray powder diffraction pattern of crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 3. The peaks include those shown in the following table:

[0303] [Table 9]

[0304] The X-ray powder diffraction pattern of crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 7. The peaks include those shown in the following table:

[0305] [Table 10]

[0306] The X-ray powder diffraction pattern of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline pattern C, is shown in Figure 12. The peaks include those shown in the following table:

[0307] [Table 11]

[0308] The X-ray powder diffraction pattern of crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 15. The peaks include those shown in the following table:

[0309] [Table 12]

[0310] The X-ray powder diffraction pattern of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline isopropanol solvate pattern D is shown in Figure 19. Peaks include those shown in the following table:

[0311] [Table 13]

[0312] The X-ray powder diffraction pattern of crystalline tetrahydrofuran solvate pattern E of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 20. The peaks include those shown in the following table:

[0313] [Table 14]

[0314] The X-ray powder diffraction pattern of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline methyl isobutyl ketone solvate pattern F is shown in Figure 21. Peaks include those shown in the following table:

[0315] [Table 15]

[0316] The X-ray powder diffraction pattern of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline ethyl acetate solvate pattern G is shown in Figure 22. Peaks include those shown in the following table:

[0317] [Table 16]

[0318] The X-ray powder diffraction pattern of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline isopropyl acetate solvate pattern H is shown in Figure 23. Peaks include those shown in the following table:

[0319] [Table 17]

[0320] The X-ray powder diffraction pattern of crystalline pattern J of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 24. The peaks include those shown in the following table:

[0321] [Table 18]

[0322] The X-ray powder diffraction pattern of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline pattern K, is shown in Figure 25. The peaks include those shown in the following table:

[0323] [Table 19]

[0324] The X-ray powder diffraction pattern of the crystalline acetone solvate pattern M of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 27. The peaks include those shown in the following table:

[0325] [Table 20]

[0326] The X-ray powder diffraction pattern of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate crystalline acetonitrile solvate pattern N is shown in Figure 28. Peaks include those shown in the following table:

[0327] [Table 21]

[0328] The X-ray powder diffraction pattern of crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 30. The peaks include those shown in the following table:

[0329] [Table 22]

[0330] The X-ray powder diffraction pattern of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, crystalline pattern P, is shown in Figure 32. The peaks include those shown in the following table:

[0331] [Table 23]

[0332] Example C-2: Differential Scanning Calorimetry (DSC) Differential scanning calorimetry was performed using a Mettler Toledo DSC3+. The desired amount of sample is weighed directly into a sealed aluminum pan with a pinhole. Typical sample mass is 3-5 mg. Typical temperature range is 30°C to 300°C at a heating rate of 10°C per minute (total time of 27 minutes). Typical parameters for the DSC are given below:

[0333] [Table 24]

[0334] Standalone DSC thermogram of the solid form of compound A·2MSA The modulated DSC thermogram of the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 1. The modulated DSC thermogram has a glass transition temperature with an onset at about 166.6°C and a midpoint at about 169.3°C.

[0335] The standalone DSC thermogram of crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 4. The standalone DSC thermogram has four endothermic events: an onset at about 78.4°C and a peak at about 81.8°C; an onset at about 266.1°C and a peak at about 270.1°C; an onset at about 281.1°C and a peak at about 286.1°C; and an onset at about 294.6°C and a peak at about 297.7°C.

[0336] The standalone DSC thermogram of crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 8. The standalone DSC thermogram has a broad endothermic event with an onset at about 86.3°C and a peak at about 115.1°C, and an endothermic event with an onset at about 213.2°C and a peak at about 221.8°C.

[0337] The standalone DSC thermogram of crystalline pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 13. The standalone DSC thermogram has an exothermic event with an onset at about 192.8°C and a peak at about 213.3°C, an endothermic event with an onset at about 252.2°C and a peak at about 272.3°C, and an endothermic event with an onset at about 296.6°C and a peak at about 298.9°C.

[0338] The standalone DSC thermogram of crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 16. The standalone DSC thermogram has an endothermic event with an onset at about 260.9°C and a peak at about 274.8°C, and an endothermic event with an onset at about 292.7°C and a peak at about 296.0°C.

[0339] Characterization of the solid state morphology of compound A·2MSA upon thermal treatment Pattern A Pattern A was heated to 277°C and monitored by DSC. The contents of the pan were collected and analyzed by XRPD, revealing a new pattern, P. Pattern P was then produced separately by heating Pattern A to 255°C. This material was exposed to ~90% RH at room temperature, slurried in ACN, and after 4 hours, patterns B and I were collected, respectively.

[0340] Pattern B Pattern B was heated beyond moisture loss and monitored by DSC. The pan was allowed to cool to room temperature, after which the contents were collected and analyzed by XRPD. The collected pattern is consistent with Pattern B. Another sample was heated to 270 °C, then allowed to cool naturally to room temperature, and the contents of the pan were analyzed by XRPD to determine the form that crystallized at 250 °C. The pattern appears to be a good match for Pattern I, although it is less crystalline and has a few broad peaks. The XRPD sample was placed in an atmosphere at ~88% RH overnight (16 hours) and then analyzed again. The post-humidity pattern appeared to be in the process of reverting to Pattern B.

[0341] Pattern C Pattern C was heated to 240°C (just above the exothermic event) and monitored by DSC. The pan was allowed to cool to room temperature, after which the contents were collected and analyzed by XRPD, which showed the formation of Pattern I. Another experiment was performed in which the sample was heated to 280°C beyond the first endotherm. The pan was then allowed to cool to room temperature, and the contents were collected and analyzed by XRPD. Compared to the pattern collected when heated just beyond the exotherm, there are some differences in the intensities of many of the peaks, but the pattern still resembles Pattern I.

[0342] Example C-3: Simultaneous Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) Thermogravimetric analysis and differential scanning calorimetry were performed using a Mettler Toledo TGA / DSC3+. The desired amount of sample was weighed directly into a sealed aluminum pan with a pinhole. Typical sample masses for the measurements were 5-10 mg. Typical temperature ranges were 30-300 °C with a heating rate of 10 °C per minute (total time of 27 min). Protective and purge gases were nitrogen (20-30 mL / min and 50-100 mL / min).

[0343] Typical parameters for DSC / TGA are shown below.

[0344] [Table 25]

[0345] Simultaneous TGA / DSC thermogram of the solid form of compound A·2MSA The TGA pattern of the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 2a. The thermogravimetric analysis pattern has a loss of 3.85% w / w between 40 and 170 °C. The DSC thermogram of the amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 2b.

[0346] The TGA pattern of crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 5a. The thermogravimetric analysis pattern has a loss of 2.28% w / w from 60 to 180°C. The DSC thermogram of crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 5b. The DSC thermogram has an endothermic event with an onset at about 293.8°C and a peak at about 297.6°C.

[0347] The TGA pattern of crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 9a. The thermogravimetric analysis pattern has a loss of 2.9% w / w from 40 to 205 °C. The DSC thermogram of crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 9b. The DSC thermogram has an endothermic event with an onset at approximately 212.4 °C and a peak at approximately 220.6 °C.

[0348] The TGA pattern of crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate after standing at ambient conditions is displayed in Figure 10a. The thermogravimetric analysis pattern has a loss of 4.23% w / w from 45 to 175 °C. The DSC thermogram of crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate after standing at ambient conditions is shown in Figure 10b. The DSC thermogram has an endothermic event with an onset at about 205.6°C and a peak at about 221.8°C, an exothermic event with an onset at about 243.0°C and a peak at about 254.2°C, and an endothermic event with an onset at about 278.0°C and a peak at about 288.2°C.

[0349] The TGA pattern of crystalline pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 14a. The thermogravimetric analysis pattern has a loss of 0.12% w / w from 40 to 140°C and an additional loss of 0.62% w / w from 140 to 290°C. The DSC thermogram of crystalline pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 14b. The DSC thermogram has an endothermic event with an onset at about 258.0°C and a peak at about 272.7°C, and an endothermic event with an onset at about 293.5°C and a peak at about 297.3°C.

[0350] The TGA pattern of crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 17a. The thermogravimetric analysis pattern has a loss of 0.19% w / w from 40 to 185°C and an additional loss of 0.67% w / w from 185 to 290°C. The DSC thermogram of crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 17b. The DSC thermogram has an endothermic event with an onset at about 262.1°C and a peak at about 272.6°C, and an endothermic event with an onset at about 290.0°C and a peak at about 294.2°C.

[0351] The TGA pattern of crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 26a. The thermogravimetric analysis pattern has a loss of 0.1% w / w from 40 to 190°C and an additional loss of 0.69% w / w from 190 to 310°C. The DSC thermogram of crystalline pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 26b. The DSC thermogram has an endothermic event with an onset at about 254.1°C and a peak at about 271.9°C, and an endothermic event with an onset at about 294.5°C and a peak at about 297.7°C.

[0352] The TGA pattern of the crystalline acetonitrile solvate pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 29a. The thermogravimetric analysis pattern has a loss of 5.44% w / w from 40 to 220°C. The DSC thermogram of the crystalline acetonitrile solvate pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 29b. The DSC thermogram has an endothermic event with an onset at about 132.6°C and a peak at about 144.0°C, an endothermic event with an onset at about 179.7°C and a peak at about 193.5°C, and an endothermic event with an onset at about 192.4°C and a peak at about 211.1°C.

[0353] The TGA pattern of crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 31a. The thermogravimetric analysis pattern has a loss of 4.54% w / w from 40 to 260°C. The DSC thermogram of crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 31b. The DSC thermogram has an endothermic event with an onset at about 206.9°C and a peak at about 217.6°C.

[0354] Example C-4: Dynamic Vapor Sorption (DVS) Dynamic vapor sorption (DVS) was performed using a DVS Intrinsic 1. The sample is loaded into a sample pan and suspended on a microbalance. A typical sample mass for DVS measurements is 25 mg. Nitrogen gas bubbled through distilled water provides the desired relative humidity.

[0355] A typical measurement involves the following steps: 1- Equilibrate at 50% RH 2- 50%~2%. (50%, 40%, 30%, 20%, 10%, and 2%) Hold at each humidity for a minimum of 5 minutes and a maximum of 240 minutes. The pass criterion is a change of less than 0.002%. 3- 2%~95% (2%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%) Hold at each humidity for a minimum of 5 minutes and a maximum of 240 minutes. The pass criterion is a change of less than 0.002%. 4- 95%~2% (95%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 2%) Hold at each humidity for a minimum of 5 minutes and a maximum of 240 minutes. The pass criterion is a change of less than 0.002%. 5- 2%~50% (2%, 10%, 20%, 30%, 40%, 50%) Hold at each humidity for a minimum of 5 minutes and a maximum of 240 minutes. The pass criterion is a change of less than 0.002%.

[0356] Dynamic vapor sorption isotherm plot of the solid form of compound A·2MSA The DVS isotherm plot of crystalline pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 6. The DVS isotherm plot shows reversible water uptake (9.8% w / w) between 2% and 95% relative humidity (RH).

[0357] A DVS isotherm plot of crystalline hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 11. The DVS isotherm plot shows reversible water uptake (3.2% w / w) between 2% and 95% relative humidity (RH).

[0358] The DVS isotherm plot of crystalline pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is shown in Figure 18. The DVS isotherm plot shows reversible water uptake (9.1% w / w) between 2% and 95% relative humidity (RH) and 2.5% w / w between 15 and 75% RH. Pattern I switched to pattern B after DVS analysis between 2% and 95% RH and at 25 °C, as determined by XRPD.

[0359] Example C-5: Karl Fischer titration Karl Fischer titration for water determination was performed using a Mettler Toledo C20S Coulometric KF Titrato equipped with a diaphragm-equipped current generator cell and double platinum-pin electrodes. (商標) CombiCoulomat fritless was used in both the anodic and cathodic compartments. Approximately 0.03–0.10 g of sample was dissolved in the anodic compartment and titrated until the solution potential was below 100 mV. A 1 wt% Hydranal water standard was used for sample verification prior to analysis.

[0360] The results of the selected patterns are shown in the table below.

[0361] [Table 26]

[0362] Example C-6: Humidity Stress Test Approximately 15 mg of compound A·2MSA (pattern A) was loaded into a 4 mL vial and the opening was covered with a Kimwipe. This was placed in a 20 mL vial containing saturated aqueous KSO solution and sealed, creating an environment of 94-96% relative humidity (RH) at room temperature (RT). After 3 days, the solid was analyzed by XRPD, which showed pattern B. The sample was dried overnight in a vacuum oven and the dry XRPD pattern was collected, but no change in the pattern was observed.

[0363] Approximately 10 mg of Compound A·2MSA Pattern A and Pattern B were loaded into separate 4 mL vials. These were placed in 20 mL vials containing saturated aqueous NaCl, sealed, and placed at 40 °C and 75% RH. After one week, Pattern A switched to Pattern B, which remained the same. The same one-week test was performed on Pattern C(+I) and Pattern I, and both remained stable by XRPD. Samples were also collected for chemical purity analysis by HPLC and showed no decomposition compared to the as-received material.

[0364] A summary of the humidity stress test data is shown in the table below.

[0365] [Table 27]

[0366] Example C-7: Solubility of simulated fluids and water The solubility of Compound A·2MSA, Patterns A, B, and I was measured in water, fasted-state simulated gastric fluid (FaSSGF), and fed-state simulated intestinal fluid (FaSSIF) at 37°C by slurrying in each medium for 24 hours. 1.5 mL of fluid was stirred at 37°C. Approximately 5 mg of the designated solid was added to FaSSIF, immediately forming a thin slurry. As a test, approximately 80 and 60 mg of Pattern A were added to 1.5 mL of water and FaSSGF, respectively, but no slurry formed. Therefore, approximately 10 mg of the desired pattern was added to the water and FaSSGF solution. The sample was stirred at 37°C for 24 hours. The stir bar was removed from the FaSSIF vial, and the solid was allowed to settle at 37°C for 0.5 hours. The supernatant / solution was syringe filtered and collected for analysis by HPLC and pH measurement. Table 8 shows a summary of the results.

[0367] [Table 28]

[0368] Example C-8: Comparison of Compound A mono-HCl and 2MSA in simulated fluid generation of Compound A mono-HCl salt Compound A (free base, 58.9 mg) was added to 0.59 mL (10 volumes) of IPA:water (95:5) to give a yellow slurry. Concentrated HCl (12.1 M, 10.7 μL, 1 equiv.) was added. The mixture turned orange in color and the slurry thinned (potential for dissolution). The slurry was stirred at 150°C for 5 minutes, then transferred to a room temperature (20-23°C) stir plate and allowed to cool for 15 minutes, during which time a dark orange slurry developed. The orange solid was collected by filtration and washed twice with 1 volume of IPA:water (95:5 volumes). The solid was dried overnight (~16 hours) in a vacuum oven at 50°C under static vacuum. Solution 1 1H-NMR analysis detected 3.68 wt% IPA.

[0369] Alternatively, compound A·2HCl (102.6 mg) was added to 0.51 mL (5 vol) of IPA:water (1:1 vol) at 45 °C to give a thick yellow slurry. Concentrated (~28 wt%) NH3(aq.) (11 μL, 0.8 equiv.) was added, causing the slurry on the vial walls to turn orange. The mixture was vortexed to ensure good mixing, and the slurry returned to a yellow color. Stirring was then continued at 45 °C for 10 min. The vial was transferred to a room-temperature stir plate and allowed to cool to room temperature (20–23 °C). Water (1.0 mL, 10 vol) was added dropwise over 2 min to form a medium-thick slurry, which was stirred overnight (~16 h) at room temperature. The bulk was collected by filtration and washed with 3 × 3 volumes of IPA:water (15:85 vol). The wet cake crust turned orange after the second wash. The wet solid was loaded into a vial and dried in a vacuum oven at 50°C under dynamic vacuum for 4 hours, and the dried clumps were broken down after about 1.5 hours of drying. 1 H-NMR analysis detected 0.65 wt% IPA.

[0370] Kinetic solubility tests in FaSSIF and FeSSIF The solubility of the dimesylate (pattern B) and mono-HCl salt of Compound A was determined in FaSSIF (pH 6.5) at 37°C after 5, 20, and 40 minutes of slurry time. FaSSIF was warmed to 37°C and approximately 9 mg of salt was added to the vial, marking t = 0. The mixture was kept stirring at 37°C, and samples were taken with a syringe at t + 5, 20, and 40 minutes. The samples were syringe filtered, and the filtrate was diluted 2-fold to prevent precipitation while waiting for HPLC analysis. The pH of the solution collected at 40 minutes was measured. The next day, the slurry was sampled again, and the supernatant from the syringe filtration was directly analyzed by HPLC without dilution. The same experiment was performed using FeSSIF (pH 5.0).

[0371] A summary of the data is shown in Table 9. The HCl salt exhibited approximately 6 times the solubility of the 2MSA salt in FaSSIF; and the 2MSA salt exhibited 12 times the solubility of the HCl salt in FeSSIF.

[0372] [Table 29]

[0373] Example C-9: High-Performance Liquid Chromatography (HPLC) High-performance liquid chromatography (HPLC) was performed using an Agilent 1220 Infinity LC with a flow rate range of 0.2–5.0 mL / min, an operating pressure range of 0–600 bar, a temperature range of 5°C above ambient temperature to 60°C, and a wavelength range of 190–600 nm.

[0374] Typical parameters for DSC / TGA are shown below.

[0375] [Table 30]

[0376] Gradient method:

[0377] [Table 31]

[0378] Example C-10: Nuclear magnetic resonance (NMR) Proton NMR was performed on a Bruker Avance 300 MHz spectrometer. Solids were dissolved in 0.75 mL of deuterated solvent in 4 mL vials and transferred to NMR tubes (Wilmad 5 mm thin film 8" 200 MHz, 506-PP-8). A typical run is generally 16 scans.

[0379] Pharmaceutical preparations

[0380] Example D-1: Parenteral Pharmaceutical Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-100 mg of a water-soluble salt of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. An appropriate buffer, along with any acid or base, is optionally added to adjust the pH. The mixture is incorporated into a dosage unit form suitable for administration by injection.

[0381] Example D-2: Oral Solution To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is added to water (along with any solubilizing agents, any buffers, and taste-masking excipients) to obtain a 20 mg / mL solution.

[0382] Example D-3: Oral Tablet Tablets are prepared by mixing 20-50% by weight of a compound disclosed herein or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate, or other suitable excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100-500 mg.

[0383] Example D-4: Oral Capsules To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend, and the mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, suitable for oral administration.

[0384] In another embodiment, 10-500 mg of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is placed into a size 4 capsule, or a size 1 capsule (hypromellose or hard gelatin), and the capsule is closed.

[0385] The examples and embodiments described herein are for illustrative purposes only, and various modifications and changes suggested to those skilled in the art are intended to be included within the spirit and scope of this specification and the scope of the appended claims.

Claims

1. Mesylate salt of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile or a solvate thereof.

2. The mesylate salt or solvate thereof according to claim 1, which is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile monomesylate or a solvate thereof, or 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate or a solvate thereof.

3. The mesylate salt or solvate thereof according to claim 1, which is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile monomesylate or a solvate thereof.

4. The mesylate salt or solvate thereof according to claim 1, which is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile monomesylate.

5. The mesylate salt or solvate thereof according to claim 1, which is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate or a solvate thereof.

6. The mesylate salt or solvate thereof according to claim 1, which is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

7. 7. The mesylate salt or solvate thereof according to any one of claims 1 to 6, in amorphous form.

8. 7. The mesylate salt or solvate thereof according to any one of claims 1 to 6, in crystalline form.

9. 2. The mesylate salt or solvate thereof according to claim 1, wherein the mesylate salt is an amorphous form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

10. The amorphous form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) X-ray powder diffraction (XRPD) pattern showing lack of crystallinity; (b) a modulated differential scanning calorimetry thermogram substantially the same as that shown in Figure 1; (c) a modulated differential scanning calorimetry thermogram having a glass transition temperature with an onset of about 166.6°C and a midpoint of about 169.3°C; (d) a thermogravimetric analysis pattern substantially the same as that shown in Figure 2a; (e) a thermogravimetric analysis pattern with a loss of 3.85% w / w between 40 and 170°C; or (f) characterized as having any combination thereof; The mesylate salt or solvate thereof according to claim 9.

11. 10. The mesylate salt or solvate thereof of claim 9, wherein the amorphous form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having an X-ray powder diffraction (XRPD) pattern that exhibits a lack of crystallinity.

12. The amorphous form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a modulated differential scanning calorimetry thermogram substantially the same as that shown in FIG. 1; or 10. The mesylate salt or solvate thereof of claim 9, characterized as having a modulated differential scanning calorimetry thermogram having a glass transition temperature with an onset of about 166.6°C and a midpoint of about 169.3°C.

13. The amorphous solid form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a thermogravimetric analysis pattern substantially the same as that shown in FIG. 2a; or 10. The mesylate salt or solvate thereof of claim 9, characterized as having a thermogravimetric analysis pattern with a loss of 3.85% w / w between 40 and 170°C.

14. 2. The mesylate salt or solvate thereof according to claim 1, wherein the mesylate salt is a crystalline form of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate or a solvate thereof.

15. The mesylate salt or solvate thereof according to claim 14, wherein the mesylate salt is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate in crystal pattern A.

16. Crystal pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 3; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.20° 2-theta, about 6.76° 2-theta, about 17.14° 2-theta, and about 21.70° 2-theta; (c) a differential scanning calorimetry thermogram substantially the same as that shown in Figure 4; (d) a differential scanning calorimetry thermogram with four endothermic events, having an onset of about 78.4°C and a peak at about 81.8°C, an onset of about 266.1°C and a peak at about 270.1°C, an onset of about 281.1°C and a peak at about 286.1°C, and an onset of about 294.6°C and a peak at about 297.7°C; (e) a thermogravimetric analysis pattern substantially the same as that shown in Figure 5a; (f) Thermogravimetric analysis pattern with a 2.28% w / w loss between 60 and 180°C; (g) a dynamic water vapor sorption isotherm plot substantially the same as that shown in Figure 6; (h) reversible water uptake (9.8% w / w) at relative humidity (RH) between 2% and 95%; (i) XRPD switching to pattern B upon storage at 75% RH and 40°C for 7 days; (j) XRPD switching to pattern B upon storage at 96% RH and 25°C for 3 days; (k) Stable XRPD after drying under dynamic vacuum at 50° C. for 2 hours. (l) XRPD switching to pattern P after heating to 255°C; (m) a water content of 1.5% w / w, or (n) a combination thereof.

17. Crystal pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is an X-ray powder diffraction pattern substantially the same as that shown in FIG. 3; or 16. The mesylate salt or solvate thereof of claim 15, characterized as having an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.20°2-theta, about 6.76°2-theta, about 17.14°2-theta, and about 21.70°2-theta.

18. Crystal pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a differential scanning calorimetry thermogram substantially the same as that shown in FIG. 4; or 16. The mesylate salt or solvate thereof of claim 15, characterized as having a differential scanning calorimetry thermogram with four endothermic events, having an onset of about 78.4°C and a peak at about 81.8°C, an onset of about 266.1°C and a peak at about 270.1°C, an onset of about 281.1°C and a peak at about 286.1°C, and an onset of about 294.6°C and a peak at about 297.7°C.

19. Crystal pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a thermogravimetric analysis pattern substantially the same as that shown in FIG. 5a; or 16. The mesylate salt or solvate thereof of claim 15, characterized as having a thermogravimetric analysis pattern with a loss of 2.28% w / w between 60 and 180°C.

20. Crystal pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a dynamic water vapor sorption isotherm plot substantially the same as that shown in FIG. 6; or 16. The mesylate salt or solvate thereof of claim 15, characterized as having a reversible water uptake (9.8% w / w) at a relative humidity (RH) of 2% to 95%.

21. Crystal pattern A of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is XRPD switches to pattern B upon storage at 75% RH and 40°C for 7 days. XRPD switches to pattern B upon storage at 96% RH and 25°C for 3 days. XRPD that remains unchanged after drying under dynamic vacuum at 50° C. for 2 hours, or 16. The mesylate salt or solvate thereof of claim 15, characterized as having an XRPD that switches to pattern P after heating to 255°C.

22. 15. The mesylate salt or solvate thereof of claim 14, wherein the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

23. The crystal hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 7; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.58° 2-theta, about 7.48° 2-theta, about 15.94° 2-theta, and about 25.13° 2-theta; (c) a differential scanning calorimetry thermogram substantially the same as that shown in Figure 8 or Figure 10b; (d)—A broad endothermic event with an onset of about 86.3° C. and a peak at about 115.1° C., and an endothermic event with an onset of about 213.2° C. and a peak at about 221.8° C.; or an endothermic event with an onset of about 205.6°C and a peak of about 221.8°C, an exothermic event with an onset of about 243.0°C and a peak of about 254.2°C, and an endothermic event with an onset of about 278.0°C and a peak of about 288.2°C; a differential scanning calorimetry thermogram with (e) a thermogravimetric analysis pattern substantially the same as that shown in Figure 9a or Figure 10a; (f) a thermogravimetric analysis pattern with a 2.9% w / w loss from 40°C to 205°C or a 4.23% w / w loss from 45°C to 175°C; (g) A dynamic water vapor sorption isotherm plot substantially the same as that shown in FIG. 11; (h) reversible water uptake (3.2% w / w) at relative humidity (RH) between 2% and 95%; (i) XRPD unchanged after DVS analysis at 95% RH and 25°C; (j) XRPD unchanged after storage at 75% RH and 40° C. for 7 days; (k) Stable XRPD after drying under dynamic vacuum at 50° C. for 2 hours. (l) XRPD unchanged after storage under static vacuum at 50°C for 3 hours; (m) XRPD switching to pattern I after heating to 270°C; (n) a water content of 4.2% w / w; or (o) a combination thereof.

24. The crystal hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7; or 23. The mesylate salt or solvate thereof of claim 22, characterized as having an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.58°2-theta, about 7.48°2-theta, about 15.94°2-theta, and about 25.13°2-theta.

25. The crystal hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a differential scanning calorimetry thermogram substantially the same as that shown in FIG. 8; or 23. The mesylate salt or solvate thereof of claim 22, characterized as having a differential scanning calorimetry thermogram with a broad endothermic event having an onset of about 86.3°C and a peak at about 115.1°C, and an endothermic event having an onset of about 213.2°C and a peak at about 221.8°C.

26. The crystal hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a differential scanning calorimetry thermogram substantially the same as that shown in FIG. 10b; or 16. The mesylate salt or solvate thereof of claim 15, characterized as having a differential scanning calorimetry thermogram with an endothermic event with an onset of about 205.6°C and a peak of about 221.8°C, an exothermic event with an onset of about 243.0°C and a peak of about 254.2°C, and an endothermic event with an onset of about 278.0°C and a peak of about 288.2°C.

27. The crystal hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a thermogravimetric analysis pattern substantially the same as that shown in FIG. 9a; or 23. The mesylate salt or solvate thereof of claim 22, characterized as having a thermogravimetric analysis pattern with a 2.9% w / w loss between 40°C and 205°C.

28. The crystal hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a thermogravimetric analysis pattern substantially the same as that shown in FIG. 10a; or 23. The mesylate salt or solvate thereof of claim 22, characterized as having a thermogravimetric analysis pattern with a 4.23% w / w loss between 45 and 175°C.

29. The crystal hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a dynamic water vapor sorption isotherm plot substantially the same as that shown in FIG. 11; or 23. The mesylate salt or solvate thereof of claim 22, characterized as having a reversible water uptake (3.2% w / w) at a relative humidity (RH) of 2% to 95%.

30. The crystal hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is XRPD unchanged after DVS analysis at 95% RH and 25°C; XRPD unchanged after storage at 75% RH and 40°C for 7 days; XRPD unchanged after drying under dynamic vacuum at 50° C. for 2 hours. XRPD that does not change after storage under static vacuum at 50°C for 3 hours, or 23. The mesylate salt or solvate thereof of claim 22, characterized as having an XRPD that switches to pattern I after heating to 270°C.

31. The mesylate salt or solvate thereof according to claim 14, wherein the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate in crystal pattern C.

32. The crystalline hydrate pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 12; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 7.10° 2-theta, about 17.44° 2-theta, about 22.18° 2-theta, and about 25.20° 2-theta; (c) a differential scanning calorimetry thermogram substantially the same as that shown in Figure 13; (d) a differential scanning calorimetry thermogram with an exothermic event having an onset of about 192.8°C and a peak of about 213.3°C, an endothermic event having an onset of about 252.2°C and a peak of about 272.3°C, and an endothermic event having an onset of about 296.6°C and a peak of about 298.9°C; (e) a thermogravimetric analysis pattern substantially the same as that shown in Figure 14a; (f) Thermogravimetric analysis pattern with a 0.12% w / w loss from 40°C to 140°C and a further 0.62% w / w loss from 140°C to 290°C; (g) XRPD unchanged after storage at 75% RH and 40° C. for 7 days; (h) Stable XRPD after drying under dynamic vacuum at 50° C. for 2 hours. (i) XRPD that switches to pattern I after heating to 240°C, or (j) a combination thereof.

33. The crystalline hydrate pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is an X-ray powder diffraction pattern substantially the same as that shown in FIG. 12; or 32. The mesylate salt or solvate thereof of claim 31 , characterized as having an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 7.10°2-theta, about 17.44°2-theta, about 22.18°2-theta, and about 25.20°2-theta.

34. The crystalline hydrate pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a differential scanning calorimetry thermogram substantially the same as that shown in FIG. 13; or 32. The mesylate salt or solvate thereof of claim 31 , characterized as having a differential scanning calorimetry thermogram with an exothermic event with an onset of about 192.8° C. and a peak at about 213.3° C., an endothermic event with an onset of about 252.2° C. and a peak at about 272.3° C., and an endothermic event with an onset of about 296.6° C. and a peak at about 298.9° C.

35. The crystalline hydrate pattern C of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a thermogravimetric analysis pattern substantially the same as that shown in FIG. 4; or 32. The mesylate salt or solvate thereof of claim 31 , characterized as having a thermogravimetric analysis pattern with a 0.12% w / w loss from 40° C. to 140° C. and a further 0.62% w / w loss from 140° C. to 290° C.

36. The crystal hydrate pattern B of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is XRPD unchanged after storage at 75% RH and 40°C for 7 days; XRPD that remains unchanged after drying under dynamic vacuum at 50° C. for 2 hours, or 32. The mesylate salt or solvate thereof of claim 31 , characterized as having an XRPD that switches to pattern I after heating to 240° C.

37. 15. The mesylate salt or solvate thereof according to claim 14, wherein the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate in crystalline pattern I.

38. Crystal pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 15; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.74° 2-theta, about 11.17° 2-theta, about 20.83° 2-theta, and about 21.65° 2-theta; (c) a differential scanning calorimetry thermogram substantially the same as that shown in Figure 16; (d) a differential scanning calorimetry thermogram with an endothermic event having an onset of about 260.9°C and a peak at about 274.8°C, and an endothermic event having an onset of about 292.7°C and a peak at about 296.0°C; (e) a thermogravimetric analysis pattern substantially the same as that shown in Figure 17a; (f) Thermogravimetric analysis pattern with a 0.19% w / w loss from 40°C to 185°C and a further 0.67% w / w loss from 185°C to 290°C; (g) A dynamic water vapor sorption isotherm plot substantially the same as that shown in Figure 18; (h) reversible water uptake (9.1% w / w) from 2% to 95% relative humidity (RH) with 2.5% w / w water uptake from 15 to 75% RH; (i) XRPD switching to pattern B after DVS analysis from 2% to 95% RH and 25°C; (j) XRPD unchanged after storage at 75% RH and 40° C. for 7 days; (k) Stable XRPD after drying under dynamic vacuum at 50° C. for 2 hours. (l) a water content of 0.29% w / w, or (m) a combination thereof.

39. Crystal pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is an X-ray powder diffraction pattern substantially the same as that shown in FIG. 15; or 38. The mesylate salt or solvate thereof of claim 37, characterized as having an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.74°2-theta, about 11.51°2-theta, about 20.83°2-theta, and about 21.65°2-theta.

40. Crystal pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a differential scanning calorimetry thermogram substantially the same as that shown in FIG. 16; or 38. The mesylate salt or solvate thereof of claim 37, characterized as having a differential scanning calorimetry thermogram with an endothermic event having an onset of about 260.9°C and a peak at about 274.8°C, and an endothermic event having an onset of about 292.7°C and a peak at about 296.0°C.

41. Crystal pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a thermogravimetric analysis pattern substantially the same as that shown in FIG. 17a; or 38. The mesylate salt or solvate thereof of claim 37, characterized as having a thermogravimetric analysis pattern with a 0.19% w / w loss from 40°C to 185°C and a further 0.67% w / w loss from 185°C to 290°C.

42. Crystal pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is a dynamic water vapor sorption isotherm plot substantially the same as that shown in FIG. 18; or 38. The mesylate salt or solvate thereof of claim 37, characterized as having a reversible water uptake (9.1% w / w) at 2% to 95% relative humidity (RH), with a water uptake of 2.5% w / w at 15 to 75% RH.

43. Crystal pattern I of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is XRPD switching to pattern B after DVS analysis from 2% to 95% RH and 25°C; XRPD that remains unchanged after storage at 75% RH and 40° C. for 7 days; or 38. The mesylate salt or solvate thereof of claim 37, characterized as having an XRPD that does not vary after drying under dynamic vacuum at 50°C for 2 hours.

44. 15. The mesylate salt or solvate thereof of claim 14, wherein the compound is a crystalline isopropanol solvate pattern D of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

45. The crystalline isopropanol solvate pattern D of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 19; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.10° 2-theta, about 6.70° 2-theta, about 17.75° 2-theta, and about 22.22° 2-theta; (c) XRPD switching to pattern A after drying under dynamic vacuum at 50° C. for 2 hours, or (d) a combination thereof.

46. 15. The mesylate salt or solvate thereof of claim 14, wherein the compound is crystalline tetrahydrofuran solvate pattern E of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

47. The crystalline tetrahydrofuran solvate pattern E of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 20; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.42° 2-theta, about 19.99° 2-theta, and about 21.12° 2-theta; (c) XRPD switching to pattern A after drying under dynamic vacuum at 50° C. for 2 hours, or (d) a combination thereof.

48. 15. The mesylate salt or solvate thereof of claim 14, wherein the compound is a crystalline methyl isobutyl ketone solvate pattern F of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

49. The crystalline methyl isobutyl ketone solvate pattern F of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 21; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.63° 2-theta, about 6.27° 2-theta, about 20.55° 2-theta, and about 22.33° 2-theta; (c) XRPD switching to pattern I after drying under dynamic vacuum at 50° C. for 2 hours, or (d) a combination thereof.

50. 15. The mesylate salt or solvate thereof of claim 14, wherein the compound is crystalline ethyl acetate solvate pattern G of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

51. The crystalline ethyl acetate solvate pattern G of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 22; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.62° 2-theta, about 13.21° 2-theta, about 19.79° 2-theta, and about 21.72° 2-theta; (c) XRPD switching to pattern I after drying under dynamic vacuum at 50° C. for 2 hours, or (d) a combination thereof.

52. 15. The mesylate salt or solvate thereof of claim 14, wherein the compound is crystalline isopropyl acetate solvate pattern H of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

53. The crystalline isopropyl acetate solvate pattern H of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 23; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.66° 2-theta, about 16.77° 2-theta, and about 22.78° 2-theta; (c) XRPD switching to pattern I after drying under dynamic vacuum at 50° C. for 2 hours, or (d) a combination thereof.

54. The mesylate salt or solvate thereof according to claim 14, wherein the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate in crystal pattern J.

55. Crystal pattern J of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 24; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.32° 2-theta, about 6.72° 2-theta, about 12.33° 2-theta, and about 21.47° 2-theta; or (c) a combination thereof.

56. The mesylate salt or solvate thereof according to claim 14, wherein the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate in crystal pattern K.

57. The crystal pattern K of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 25; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.42° 2-theta, about 15.90° 2-theta, about 19.59° 2-theta, and about 21.52° 2-theta; (c) A differential scanning calorimetry thermogram substantially the same as that shown in Figure 26b; (d) a differential scanning calorimetry thermogram with an endothermic event having an onset of about 254.1°C and a peak at about 271.9°C, and an endothermic event having an onset of about 294.5°C and a peak at about 297.7°C; (e) Thermogravimetric analysis pattern substantially the same as that shown in Figure 26a; (f) a thermogravimetric analysis pattern with a 0.1% w / w loss from 40°C to 190°C and a further 0.69% w / w loss from 190°C to 310°C; (g) XRPD that remains unchanged after drying under dynamic vacuum at 50° C. for 2 hours; or (h) a combination thereof.

58. 15. The mesylate salt or solvate thereof of claim 14, wherein the compound is crystalline acetone solvate pattern M of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

59. The crystalline acetone solvate pattern M of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 27; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.67° 2-theta, about 14.63° 2-theta, about 22.14° 2-theta, and about 24.91° 2-theta; or (c) a combination thereof.

60. 15. The mesylate salt or solvate thereof of claim 14, wherein the compound is crystalline acetonitrile solvate pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

61. The crystalline acetonitrile solvate pattern N of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 28; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.18° 2-theta, and about 17.21° 2-theta; (c) A differential scanning calorimetry thermogram substantially the same as that shown in Figure 29b; (d) a differential scanning calorimetry thermogram with an endothermic event having an onset of about 132.6°C and a peak at about 144.0°C, an endothermic event having an onset of about 179.7°C and a peak at about 193.5°C, and an endothermic event having an onset of about 192.4°C and a peak at about 211.1°C; (e) a thermogravimetric analysis pattern substantially the same as that shown in Figure 29; (f) Thermogravimetric analysis pattern with a 5.44% w / w loss between 40 and 220°C; (g) XRPD that remains unchanged after drying under dynamic vacuum at 50° C. for 2 hours; or (h) a combination thereof.

62. 15. The mesylate salt or solvate thereof of claim 14, wherein the compound is crystalline hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.

63. The crystal hydrate pattern O of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 30; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 5.56° 2-theta, 15.87° 2-theta, 18.43° 2-theta, and about 24.80° 2-theta; (c) a differential scanning calorimetry thermogram substantially the same as that shown in Figure 31b; (d) a differential scanning calorimetry thermogram with an endothermic event having an onset of about 206.9°C and a peak at about 217.6°C; (e) a thermogravimetric analysis pattern substantially the same as that shown in Figure 31a; (f) Thermogravimetric analysis pattern with a loss of 4.54% w / w between 40 and 260°C; (g) XRPD that remains unchanged after drying under dynamic vacuum at 50° C. for 2 hours; or (h) a combination thereof.

64. The mesylate salt or solvate thereof according to claim 14, wherein the compound is 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate in crystal pattern P.

65. The crystal pattern P of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is (a) An X-ray powder diffraction pattern substantially the same as that shown in Figure 32; (b) an X-ray powder diffraction pattern having X-ray diffraction pattern reflections at about 6.97° 2-theta, about 17.26° 2-theta, about 19.33° 2-theta, and about 20.94° 2-theta; (c) Stable XRPD after drying under dynamic vacuum at 50° C. for 2 hours. (d) XRPD switching to pattern B upon storage at 96% RH and 25°C for 3 days, or (e) a combination thereof.

66. 66. The mesylate salt or solvate thereof of any one of claims 1-65, which is substantially free of impurities.

67. 66. The mesylate salt or solvate thereof of any one of claims 1-65, which is substantially free of structurally related impurities.

68. 68. The mesylate salt or solvate thereof of claim 66 or 67, wherein substantially free means less than about 5% (w / w), less than about 3% (w / w), less than about 1% (w / w), less than about 0.5% (w / w), or less than about 0.2% (w / w).

69. 66. A pharmaceutical composition comprising the mesylate salt or a pharmaceutically acceptable solvate thereof of any one of claims 1-65, and at least one pharmaceutically acceptable excipient.

70. A pharmaceutical composition comprising the amorphous 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate or a solvate thereof according to any one of claims 9 to 13, and at least one pharmaceutically acceptable excipient.

71. 66. A pharmaceutical composition comprising crystalline 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile dimesylate or a solvate thereof according to any one of claims 14 to 65, and at least one pharmaceutically acceptable excipient.

72. 69. The pharmaceutical composition of any one of claims 66-68, wherein the pharmaceutical composition is formulated for administration to a mammal by oral administration.

73. 70. The pharmaceutical composition of any one of claims 66-69, wherein the pharmaceutical composition is in the form of a solid pharmaceutical composition.

74. 71. The pharmaceutical composition of any one of claims 66-70, wherein the pharmaceutical composition is in the form of a tablet, pill, or capsule.

75. 66. A pharmaceutical composition comprising 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile dimesylate or a solvate thereof according to any one of claims 1-65, and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition comprises from about 1 mg to about 200 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile dimesylate or a solvate thereof.

76. 73. The pharmaceutical composition of claim 72, wherein the pharmaceutical composition is in the form of a tablet, pill, or capsule.

77. 73. The pharmaceutical composition of claim 72, wherein the pharmaceutical composition is in the form of a tablet and contains from about 1 mg to about 100 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile dimesylate or a solvate thereof per tablet.

78. 73. The pharmaceutical composition of claim 72, wherein the pharmaceutical composition is in the form of a pill and comprises from about 1 mg to about 100 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile dimesylate or a solvate thereof per pill.

79. 73. The pharmaceutical composition of claim 72, wherein the pharmaceutical composition is in the form of a capsule and contains from about 1 mg to about 100 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile dimesylate or a solvate thereof per capsule.

80. 77. A pharmaceutical composition according to any one of claims 66-76 for use in treating a disease or disorder in a mammal that would benefit from modulation of somatostatin receptor subtype 2 (SSTR2) activity.

81. 78. The pharmaceutical composition of claim 77, wherein the disease or condition is acromegaly, neuroendocrine tumors, eye diseases or conditions, neurological disorders, nephropathy, respiratory diseases or conditions, cancer, pain, neurodegenerative diseases or conditions, inflammatory diseases or conditions, psychiatric diseases or conditions, or a combination thereof.

82. 66. A method of treating a disease or disorder in a mammal that would benefit from modulation of somatostatin receptor subtype 2 (SSTR2) activity, comprising administering to said mammal a mesylate salt or solvate thereof according to any one of claims 1-65.

83. 77. A method of treating a disease or disorder in a mammal that would benefit from modulation of somatostatin receptor subtype 2 (SSTR2) activity, comprising administering to said mammal a pharmaceutical composition according to any one of claims 66-76.

84. 81. The method of claim 79 or 80, wherein the disease or condition is acromegaly, neuroendocrine tumor, eye disease or condition, neurological disorder, nephropathy, respiratory disease or condition, cancer, pain, neurodegenerative disease or condition, inflammatory disease or condition, psychiatric disease or condition, or a combination thereof.

85. 81. The method of claim 79 or 80, wherein the disease or condition is acromegaly, neuroendocrine tumors, pain, or a combination thereof.

86. 1. A process for preparing 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate or a solvate thereof, the process comprising: (i) reacting tert-butyl (1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate with hydrochloric acid in a suitable solvent; (ii) optionally, adding additional solvent to the reaction mixture of step (i) and purging the reaction mixture with argon or nitrogen gas, thereby removing excess hydrochloric acid; (iii) filtering the slurry of step (ii) to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile dihydrochloride; (iv) adding an appropriate amount of water to the solid material of step (iii); (v) adding ammonium hydroxide solution, sodium bicarbonate solution, or sodium hydroxide solution to the slurry of step (iv) to achieve a pH of about 9-10; (vi) filtering the slurry of step (vi) to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (free base); (vii) contacting the solid of step (vi) with methanesulfonic acid in a suitable solvent at a suitable temperature; (viii) cooling the suspension of step (vii) and filtering the solid to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile dimesylate or a solvate thereof.

87. Suitable solvents for step (i) are isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), toluene, ethyl acetate, isopropyl acetate, water, or combinations thereof; the additional solvent in step (ii) is isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), toluene, ethyl acetate, isopropyl acetate, water, or a combination thereof; Suitable solvents for step (vii) are methanol, ethanol, isopropyl alcohol, acetone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, tetrahydropyran, water, or combinations thereof; The method of claim 86, which is a combination thereof.

88. Suitable solvents for step (i) are isopropyl acetate, water, or a combination thereof; The additional solvent in step (ii) is isopropyl acetate; Argon gas is used in step (ii), Sodium hydroxide solution is used in step (v), Suitable solvents for step (vii) are acetone, water, or mixtures thereof; A suitable temperature for step (vii) is about 50°C; The method of claim 86 or 87, which is a combination thereof.

89. 1. A process for preparing 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate or a solvate thereof, the process comprising: (i) reacting tert-butyl (1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate with methanesulfonic acid in a suitable solvent at a suitable temperature; (ii) optionally, adding additional solvent to the reaction mixture of step (i), cooling the suspension of step (i), and filtering the solid, thereby providing 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile dimesylate or a solvate thereof.

90. Suitable solvents for step (i) are isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), tetrahydrofuran, toluene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, N-methyl-2-pyrrolidone (NMP), water, or mixtures thereof; A suitable temperature for step (ii) is from about 40°C to about 110°C; the additional solvent in step (ii) is isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), tetrahydrofuran, toluene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, N-methyl-2-pyrrolidone (NMP), water, or a mixture thereof; or The method of claim 89, which is a combination thereof.

91. Suitable solvents for step (i) are acetone, water, or mixtures thereof; A suitable temperature for step (ii) is about 45°C; the additional solvent in step (ii) is acetone, or 91. The method of claim 89 or 90, which is a combination thereof.

92. Suitable solvents for step (i) are N-methyl-2-pyrrolidone (NMP), water, or mixtures thereof; A suitable temperature for step (ii) is about 100°C; No additional solvent is added in step (ii), or 91. The method of claim 89 or 90, which is a combination thereof.

93. 1. A process for preparing 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate or a solvate thereof, the process comprising: (i) slurrying 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (free base) in a suitable solvent; (ii) heating the slurry of step (i) to about 50°C; (iii) adding methanesulfonic acid to the hot slurry of step (ii); (iv) cooling the hot slurry of step (iii); (v) filtering the solid to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile dimesylate or a solvate thereof.

94. 94. The method of claim 93, wherein the suitable solvent in step (i) is isopropanol, acetone, water, or a mixture thereof.

95. 95. The method of claim 93 or 94, wherein the suitable solvent in step (i) is isopropanol.

96. 96. The method of claim 95, wherein the amount of isopropanol is 15 volumes.

97. 97. The method of any one of claims 93-96, wherein the hot slurry of step (ii) is stirred for 30 minutes prior to the addition of methanesulfonic acid in step (iii).

98. 98. The method of any one of claims 93-97, wherein the methanesulfonic acid in step (iii) is added as a solution in water.

99. 98. The method of any one of claims 93-97, wherein the methanesulfonic acid in step (iii) is added neat and not as a solution.

100. 100. The method of any one of claims 93-99, wherein the hot slurry of step (iii) is stirred for 10 minutes to 3 hours before cooling in step (iv).

101. 101. The method of any one of claims 93-100, wherein the hot slurry of step (iii) is stirred for 30 minutes before cooling in step (iv).

102. 102. The method of any one of claims 93-101, wherein the slurry of step (iv) is stirred at room temperature for about 10 hours before filtering in step (v).

103. 103. The method of any one of claims 93-102, wherein the isolated solid of step (v) is washed with a suitable solvent after isolation.

104. 104. The method of claim 103, wherein the suitable solvent is acetone or isopropanol.

105. 105. The method of claim 103 or 104, wherein the suitable solvent is isopropanol.

106. 106. The method of any one of claims 93-105, wherein the isolated solid of step (v) is vacuum dried.

107. 107. The method of claim 106, wherein the isolated solid of step (v) is dried under vacuum at about 50° C. for about 5 hours; 1. A method for preparing tert-butyl (1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate (compound 13), comprising the steps of: 【Chemical 1】 (i) tert-butyl (1-(3-chloro-6-(3-cyano-2-hydroxyphenyl)quinolin-4-yl)piperidin-4-yl)carbamate (Compound 12) 【Chemistry 2】 tert-butyl (1-(6-bromo-3-chloroquinolin-4-yl)piperidin-4-yl)carbamate (compound 11) in the presence of a palladium catalyst system and a suitable base in a suitable solvent to give 【Chemistry 3】 with potassium (3-cyano-2-hydroxyphenyl)trifluoroborate (compound 5). 【Chemistry 4】 and reacting the compound with (ii) contacting the reaction mixture of step (i) with 3,5-difluorophenylboronic acid to provide tert-butyl (1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate (compound 13).

108. 108. The method of claim 107, wherein the palladium catalyst system comprises a ligand.

109. 109. The method of claim 108, wherein the palladium catalyst system comprises a pre-coordinated palladium-ligand complex.

110. 109. The method of claim 108, wherein the palladium catalyst system comprises a palladium catalyst and an exogenous ligand.

111. The palladium catalyst is Pd(OAc) ２ , PdCl ２ , Pd(PPh) ３ Cl ２ , or Pd(PPh) ４ The method according to any one of claims 107 to 110, wherein

112. 112. The method of any one of claims 108-111, wherein the ligand is trimethylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, XPhos, SPhos, JohnPhos, Amphos, triphenylphosphine, methyldiphenylphosphine, diphenylphosphinomethane (dppm), diphenylphosphinoethane (dppe), or 1,1'-bis(diphenylphosphino)ferrocene (dppf).

113. Suitable bases include triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), NaOAc, KOAc, Ba(OH). ２ , Li ２ CO ３ , Na ２ CO ３ , K. ２ CO ３ , Cs ２ CO ３ , Na ３ P.O. ４ , K. ３ P.O. ４ , or CsF.

114. 114. The method of any one of claims 107-113, wherein the suitable solvent is acetonitrile, dimethylformamide, dimethoxyethane, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, diisopropyl ether, 1,4-dioxane, toluene, water, or a combination thereof.

115. The palladium catalyst system includes Pd(OAc)2 and amphos; A suitable base is KCO, and The method of any one of claims 107-114, wherein the suitable solvent is a mixture of 1,4-dioxane and water.

116. 116. The method of any one of claims 107-115, wherein step (i) is carried out at about 85-90°C.

117. 117. The method of any one of claims 107-116, wherein step (ii) is carried out at about 90-95°C.

Images