Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity.
• Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.
• somatostatin receptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) and are encoded by five different somatostatin receptor genes. Modulation of a particular subtype somatostatin receptor, or combination thereof, is attractive for the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity.
• the compound is the amorphous solid form of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• the amorphous solid form of 3-(4-(4-aminopiperidin-l-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 shown in Figure 1; a modulated Differential Scanning Calorimetry thermogram with a glass transition temperature having an onset at about 166.6 °C and a midpoint at about 169.3 °C; a Thermogravimetric Analysis pattern substantially the same as shown in Figure 12; a Thermogravimetric Analysis pattern with a 3.85% w/w loss between 40 and 170 °C; or a combination thereof.
• XRPD X- ray powder diffraction
• the compound is a crystalline form of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• the compound is the crystalline Pattern A of 3- (4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 3; an X-ray powder diffraction pattern with 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 shown in Figure 4; 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
• the compound is the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 7; an X- ray powder diffraction pattern with 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; a Differential Scanning Calorimetry thermogram substantially the same as shown in: Figure 8; or Figure 10b; a
• Differential Scanning Calorimetry thermogram with: a broad endothermic event having an onset at about 86.3 °C and a peak at about 115.1 °C; and an endothermic event having an onset at about
• a Thermogravimetric Analysis pattern substantially the same as shown in: Figure 9a; or Figure 10a; a Thermogravimetric Analysis pattern with: a 2.9% w/w loss from 40 to 205 °C; or a 4.23% w/w loss from 45 to 175 °C; a Dynamic Vapour Sorption isotherm plot substantially the same as shown in Figure 11; a reversible water uptake (3.2 % w/w) between 2% and 95% Relative Humidity (RH); an unchanged XRPD after DVS analysis at 95% RH
• the compound is the crystalline Pattern C of 3- (4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 12; an X- ray powder diffraction pattern with 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 shown in Figure 13; a Differential Scanning Calorimetry thermogram with an exothermic event having an onset at about 192.8 °C and a peak at about 213.3 °C; an endothermic event having an onset at about 252.2 °C and a peak at about 272.3 °C; and an end
• the compound is the crystalline Pattern I of 3- (4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 15; 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; a Differential Scanning Calorimetry thermogram substantially the same as shown in Figure 16; 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; a Thermogr
• FIG. 17a a Thermogravimetric Analysis pattern with a 0.19% w/w loss from 40 to 185 °C and a further 0.67% w/w loss from 185 to 290 °C; a Dynamic Vapour Sorption isotherm plot substantially the same as shown in Figure 18; a reversible water uptake (9.1 % w/w) between 2% and 95% Relative Humidity (RH); with a 2.5% w/w water uptake between 15 and 75% RH; an XRPD that converts to Pattern B after DVS analysis between 2% and 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; a 0.29 % w/w water content; or a
• the compound is the crystalline isopropanol solvate Pattern D of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate.
• the crystalline isopropyl solvate Pattern D of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 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 converts to Pattern A after drying under dynamic vacuum at 50 °C for 2 hours; or a combination thereof.
• the compound is the crystalline tetrahydrofuran solvate Pattern E of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate.
• the crystalline tetrahydrofuran solvate Pattern E of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 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 converts to Pattern A after drying under dynamic vacuum at 50 °C for 2 hours; or a combination thereof.
• the compound is the crystalline methyl isobutyl ketone solvate Pattern F of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate.
• the crystalline methyl isobutyl ketone solvate Pattern F of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 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 converts to Pattern I after drying under dynamic vacuum at 50 °C for 2 hours; or a combination thereof.
• the compound is the crystalline ethyl acetate solvate Pattern G of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate.
• the crystalline ethyl acetate solvate Pattern G of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 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 converts to Pattern I after drying under dynamic vacuum at 50 °C for 2 hours; or a combination thereof.
• the compound is the crystalline isopropyl acetate solvate Pattern H of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate.
• the crystalline isopropyl acetate solvate Pattern H of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 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 converts to Pattern I after drying under dynamic vacuum at 50 °C for 2 hours; or a combination thereof.
• the compound is the crystalline Pattern J of 3- (4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• the crystalline Pattern J of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 24; an X-ray powder diffraction pattern with 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.
• the compound is the crystalline Pattern K of 3- (4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• the crystalline Pattern K of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 25; an X-ray powder diffraction pattern with 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 shown in Figure 26b; 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; a Ther
• Figure 26a a Thermogravimetric Analysis pattern with a 0.1% w/w loss from 40 to 190 °C and a further 0.69% w/w loss from 190 to 310 °C; an unchanged XRPD after drying under dynamic vacuum at 50 °C for 2 hours; or a combination thereof.
• the compound is the crystalline acetone solvate Pattern M of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate.
• the crystalline acetone solvate Pattern M of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 27; 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; or a combination thereof.
• the compound is the crystalline acetonitrile solvate Pattern N of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate.
• the crystalline acetonitrile solvate Pattern N of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 28; an X-ray powder diffraction pattern with 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 shown in Figure 29b; a Differential Scanning Calorimetry thermogram with an endothermic event having an onset at about 132.6 °C and a peak at about 144.0 °C; an endothermic event having an onset at about 179.7 °C and a peak at about 193.5 °C; and an endothermic event having an onset at about 192.4 °
• the compound is the crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• the crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin- l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as shown in Figure 30; 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; a Differential Scanning Calorimetry thermogram substantially the same as shown in Figure 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 substantially the same as shown in Figure 31a; a Thermogravimetric Analysis
• the compound is the crystalline Pattern P of 3- (4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• the crystalline Pattern P of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having: an X-ray powder diffraction pattern substantially the same as 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 unchanged XRPD after drying under dynamic vacuum at 50 °C for 2 hours; an XRPD that converts to Pattern B on storage at 96% RH and 25 °C for 3 days; or a combination thereof.
• a pharmaceutical composition comprising 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or a solvate thereof, and at least one pharmaceutically acceptable excipient.
• the pharmaceutical composition comprises amorphous 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or a solvate thereof, and at least one pharmaceutically acceptable excipient.
• the pharmaceutical composition comprises crystalline 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)- quinolin-6-yl] -2-hydroxy -benzonitrile dimesylate, or solvate thereof, and at least one
• the pharmaceutical composition is formulated for administration to a mammal by oral administration.
• the pharmaceutical composition is in the form of a solid form pharmaceutical composition.
• the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
• the pharmaceutical composition is a composition for use for the treatment of a disease or condition in a mammal that would benefit from the modulation of the somatostatin receptor subtype 2 (SSTR2) activity.
• SSTR2 somatostatin receptor subtype 2
• the disease or condition is acromegaly, a neuroendocrine tumor, an ophthalmic disease or condition, neuropathy, nephropathy, a respiratory disease or condition, cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or combinations thereof.
• a method of treating a disease or condition in a mammal that would benefit from the modulation of the somatostatin receptor subtype 2 (SSTR2) activity comprising administering 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin- 6-yl)-2-hydroxybenzonitrile dimesylate, or a solvate thereof, to the mammal in need thereof.
• SSTR2 somatostatin receptor subtype 2
• the disease or condition is acromegaly, a neuroendocrine tumor, an ophthalmic disease or condition, neuropathy, nephropathy, a respiratory disease or condition, cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or combinations thereof.
• a method of treating a disease or condition in a mammal that would benefit from the modulation of the somatostatin receptor subtype 2 (SSTR2) activity comprising administering a pharmaceutical composition comprising 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or a solvate thereof, and at least one pharmaceutically acceptable excipient, to the mammal in need thereof.
• SSTR2 somatostatin receptor subtype 2
• the disease or condition is acromegaly, a neuroendocrine tumor, an ophthalmic disease or condition, neuropathy, nephropathy, a respiratory disease or condition, cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or combinations thereof.
• the mammal is a human.
• Articles of manufacture which include packaging material, the somatostatin receptor modulator 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate, or a solvate thereof, within the packaging material, and a label that indicates that the somatostatin receptor modulator is used for modulating the activity of somatostatin receptor(s), or for the treatment, prevention or amelioration of one or more symptoms of a disease of condition described herein are provided.
• Figure 1 shows the modulated reversible and non-reversible heat flow DSC
• thermograms of amorphous Compound A-2MSA thermograms of amorphous Compound A-2MSA.
• Figure 2a shows the TGA pattern of amorphous Compound A-2MSA.
• Figure 2b shows the DSC thermogram of amorphous Compound A-2MSA.
• Figure 3 shows the XRPD pattern of Compound A-2MSA Pattern A.
• Figure 4 shows the stand-alone DSC thermogram of Compound A-2MSA Pattern A.
• Figure 5a shows the TGA pattern of Compound A-2MSA Pattern A.
• Figure 5b shows the DSC thermogram of Compound A-2MSA Pattern A.
• Figure 6 shows the DVS isotherm plot of Compound A-2MSA Pattern A.
• Figure 7 shows the XRPD pattern of Compound A-2MSA Pattern B.
• Figure 8 shows the stand-alone DSC thermogram of Compound A-2MSA Pattern B.
• Figure 9a shows the TGA pattern of Compound A-2MSA Pattern B.
• Figure 9b shows the DSC thermogram of Compound A-2MSA Pattern B.
• Figure 10a shows the TGA pattern of Compound A-2MSA Pattern B after storage at ambient conditions for one week.
• Figure 10b shows the DSC thermogram of Compound A-2MSA Pattern B after storage at ambient conditions for one week.
• Figure 11 shows the DVS isotherm plot of Compound A-2MSA Pattern B.
• Figure 12 shows the XRPD pattern of Compound A-2MSA Pattern C.
• Figure 13 shows the stand-alone DSC thermogram of Compound A-2MSA Pattern C.
• Figure 14a shows the TGA pattern of Compound A-2MSA Pattern C.
• Figure 14b shows the DSC thermogram of Compound A-2MSA Pattern C.
• Figure 15 shows the XRPD pattern of Compound A-2MSA Pattern I.
• Figure 16 shows the stand-alone DSC thermogram of Compound A-2MSA Pattern I.
• Figure 17a shows the TGA pattern of Compound A-2MSA Pattern I.
• Figure 17b shows the DSC thermogram of Compound A-2MSA Pattern I.
• Figure 18 shows the DVS isotherm plot of Compound A-2MSA Pattern I.
• Figure 19 shows the XRPD pattern of Compound A-2MSA Pattern D.
• Figure 20 shows the XRPD pattern of Compound A-2MSA Pattern E.
• Figure 21 shows the XRPD pattern of Compound A-2MSA Pattern F.
• Figure 22 shows the XRPD pattern of Compound A-2MSA Pattern G.
• Figure 23 shows the XRPD pattern of Compound A-2MSA Pattern H.
• Figure 24 shows the XRPD pattern of Compound A-2MSA Pattern J.
• Figure 25 shows the XRPD pattern of Compound A-2MSA Pattern K.
• Figure 26a shows the TGA pattern of Compound A-2MSA Pattern K.
• Figure 26b shows the DSC thermogram of Compound A-2MSA Pattern K.
• Figure 27 shows the XRPD pattern of Compound A-2MSA Pattern M.
• Figure 28 shows the XRPD pattern of Compound A-2MSA Pattern N.
• Figure 29a shows the TGA pattern of Compound A-2MSA Pattern N.
• Figure 29b shows the DSC thermogram of Compound A-2MSA Pattern N.
• Figure 30 shows the XRPD pattern of Compound A-2MSA Pattern O.
• Figure 31a shows the TGA pattern of Compound A-2MSA Pattern O.
• Figure 31b shows the DSC thermogram of Compound A-2MSA Pattern O.
• Figure 32 shows the XRPD pattern of Compound A-2MSA Pattern P.
• Somatostatin also known as somatotropin release inhibiting factor (SRTF) was initially isolated as a 14-amino acid peptide from ovine hypothalamii (Brazeau et al ., Science 179, 77-79, 1973). An V-terminal extended 28-amino acid peptide with similar biological activity to 14-amino acid somatostatin was subsequently isolated (Pradayrol et, al ., FEB S Letters,
• SST is a regulatory peptide produced by several cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SST acts through 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).
• GH growth hormone
• GH growth hormone
• SSTR1 SSTR2a
• SSTR2b SSTR3, SSTR4, and SSTR5
• any one of the somatostatin receptor subtypes is possible to selectively modulate any one of the somatostatin receptor subtypes, or combination thereof. In some embodiments, selectively modulating any one of the somatostatin receptor subtypes relative to the other somatostatin receptor subtypes, or combination thereof, is useful in a variety of clinical applications. In some embodiments, selectively modulating any one of the somatostatin receptor subtypes relative to the other somatostatin receptor subtypes reduces unwanted side effects in a variety of clinical applications.
• SSTR2 modulation of SSTR2 activity mediates the inhibition of growth hormone (GH) release from the anterior pituitary and glucagon release from pancreas.
• GH growth hormone
• SSTR2 is also implicated in many other biological functions such as, but not limited to, cell proliferation, nociception, inflammation, and angiogenesis.
• a selective SSTR2 modulator is used in the treatment of acromegaly, gut neuroendocrine tumors, pain, neuropathies, nephropathies, and inflammation, as well as retinopathies resulting from aberrant blood vessel growth.
• a selective SSTR2 modulator is 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 ophthalmic disorders such as age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, and Graves ophthalmology, among others.
• AMD age-related macular degeneration
• diabetic retinopathy diabetic macular edema
• Graves ophthalmology among others.
• SSTR4 agonists exhibit anti-inflammatory and anti -nociceptive effects.
• SSTR3 agonists inhibit insulin secretion.
• SSTR5 agonists inhibit insulin secretion.
• SSTR5 has also been implicated to modulate the release of growth hormone.
• Somatostatin peptide and its receptor subtypes are also widely expressed in the brain and disruption or diminishment of their activity is potentially involved in several psychiatric and neurodegenerative diseases. For example, concentrations of somatostatin in the cerebral cortex and hippocampus are reduced in schizophrenics and one of the most consistent neuropathologic findings in this patient group is a deficit in cortical inhibitory intemeurons expressing
• Somatostatin is also highly expressed in brain regions associated with seizures and has also been implicated as having an important role in epilepsy. Somatostatin levels are diminished in the hippocampi of Alzheimer’s and Parkinson’s patients, suggesting that restoration of its signaling as a potential drug target for neurodegeneration.
• compounds described herein are modulators of SSTR2. In some embodiments, compounds described herein selectively modulate the activity of SSTR2 relative to the other somatostatin receptors.
• compounds described here are amenable to oral administration to a mammal in need of treatment with a somatostatin modulator.
• somatostatin receptor modulators described herein have utility over a wide range of therapeutic applications.
• somatostatin receptor modulators described herein are used in the treatment of a variety of diseases or conditions such as, but not limited to acromegaly, neuroendocrine tumors, retinopathies and other ophthalmic disorders, neuropathy, nephropathy, respiratory diseases, cancers, pain, neurodegenerative diseases, inflammatory diseases, as well as psychiatric and neurodegenerative disorders.
• somatostatin receptor modulators described herein are used in the treatment of acromegaly in a mammal.
• somatostatin receptor modulators described herein inhibit the secretion of various hormones and trophic factors in mammals.
• the compounds are used to suppress certain endocrine secretions, such as, but not limited to GH, insulin, glucagon and prolactin.
• the suppression of certain endocrine secretions is useful in the treatment of disorders such as acromegaly; endocrine tumors such as carcinoids, VIPomas, insulinomas and glucagonomas; or diabetes and diabetes-related pathologies, including retinopathy, neuropathy and nephropathy.
• somatostatin receptor modulators described herein are used to suppress exocrine secretions in the pancreas, stomach and intestines, for the treatment of disorders such as pancreatitis, fistulas, bleeding ulcers and diarrhea associated with such diseases as AIDS or cholera.
• disorders involving autocrine or paracrine secretions of trophic factors such as IGF-1 which may be treated by administration of the compounds described herein include cancers of the breast, prostate, and lung (both small cell and non-small cell epidermoids), as well as hepatomas, neuroblastomas, colon and pancreatic adenocarcinomas (ductal type), chondrosarcomas, and melanomas, diabetic retinopathy, and atherosclerosis associated with vascular grafts and restenosis following angioplasty.
• somatostatin receptor modulators described herein are used to suppress the mediators of neurogenic inflammation (e.g. substance P or the tachykinins), and may be used in the treatment of rheumatoid arthritis; psoriasis; topical inflammation such as is associated with sunburn, eczema, or other sources of itching; inflammatory bowel disease;
• neurogenic inflammation e.g. substance P or the tachykinins
• the somatostatin receptor modulators described herein function as neuromodulators in the central nervous system and are useful in the treatment of Alzheimer's disease and other forms of dementia, pain, and headaches.
• somatostatin receptor modulators described herein provide cytoprotection in disorders involving the splanchnic blood flow, including cirrhosis and oesophagal varices.
• Compound A is a somatostatin modulator that is useful in the methods of treatment described herein.
• Compound A refers to 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile, which has the chemical structure shown below.
• mesylate salt of Compound A. Unless indicated otherwise, “mesylate salt” encompasses both“mono mesylate salt” and“dimesylate salt.”
• the dimesylate salt of Compound A is referred to as“3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate”,“3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin- 6-yl)-2-hydroxybenzonitrile dimethanesulfonic acid”, or“3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimethanesulfonic acid salt”.
• Compound A-2MSA is amorphous.
• Compound A-2MSA is crystalline.
• amorphous solid form of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Some embodiments provide a composition comprising the amorphous solid form of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• the amorphous solid form of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate has one of the following properties:
• the amorphous solid form of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction (XRPD) pattern showing a lack of crystallinity.
• XRPD X-ray powder diffraction
• the amorphous solid form of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits a modulated Differential Scanning Calorimetry thermogram substantially the same as shown in Figure 1.
• the amorphous solid form of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits a modulated Differential Scanning Calorimetry thermogram with a glass transition temperature having an onset at about 166.6 °C and a midpoint at about 169.3 °C.
• the amorphous solid form of 3-(4-(4-aminopiperidin- l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a modulated Differential Scanning Calorimetry thermogram with a glass transition temperature having an onset at about 166.6 °C and a midpoint at about 169.3 °C.
• Thermogravimetric Analysis pattern substantially the same as shown in Figure 2a.
• the amorphous solid form of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern with a 3.85% w/w loss between 40 and 170 °C
• crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Some embodiments provide a composition comprising the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 3.
• the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-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, about 6.76 ° 2-Theta, about 17.14 ° 2- Theta, and about 21.70 ° 2-Theta.
• the crystalline Pattern A of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Differential Scanning Calorimetry thermogram substantially the same as shown in Figure 4.
• the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-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.
• the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)- 3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a
• Thermogravimetric Analysis pattern substantially the same as shown in Figure 5a.
• the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern with a 2.28% w/w loss from 60 to 180 °C.
• the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits a Dynamic Vapour Sorption isotherm plot substantially the same as shown in Figure 6.
• the crystalline Pattern A of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a reversible water uptake (9.8 % w/w) between 2% and 95% Relative Humidity (RH).
• the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern B on storage at 75% RH and 40 °C for 7 days.
• the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern B on storage at 96% RH and 25 °C for 3 days.
• the crystalline Pattern A of 3-(4-(4- aminopiperidin-l-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.
• the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern P after heating to 255 °C.
• the crystalline Pattern A of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a 1.5 % w/w water content.
• the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.76 ° 2-Theta.
• 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.
• crystalline Pattern A is further characterized by at least one X-ray diffraction pattern reflection selected from about 13.51 ° 2- Theta, about 18.21 ° 2-Theta, about 19.73 ° 2-Theta, about 22.02 ° 2-Theta, and about 26.77 ° 2- Theta.
• crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• Some embodiments provide a composition comprising the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 7.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-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 5.58 ° 2-Theta, about 7.48 ° 2-Theta, about 15.94 ° 2- Theta, and about 25.13 ° 2-Theta.
• the crystalline hydrate Pattern B of 3- (4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Differential Scanning Calorimetry thermogram substantially the same as shown in Figure 8.
• the crystalline hydrate Pattern B of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Differential Scanning Calorimetry thermogram with a broad endothermic event having an onset at about 86.3 °C and a peak at about 115.1 °C; and an endothermic event having an onset at about 213.2 °C and a peak at about 221.8 °C.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits a Differential Scanning Calorimetry thermogram substantially the same as shown in Figure 10b.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-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 205.6 °C and a peak at about 221.8 °C; an exothermic event having an onset at about 243.0 °C and a peak at about 254.2 °C; and an endothermic event having an onset at about 278.0 °C and a peak at about 288.2 °C.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern substantially the same as shown in Figure 9a.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6- yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern with a 2.9% w/w loss from 40 to 205 °C.
• the crystalline hydrate Pattern B of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern substantially the same as shown in Figure 10a.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern with a 4.23% w/w loss from 45 to 175 °C.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6- yl)-2-hydroxybenzonitrile dimesylate exhibits a Dynamic Vapour Sorption isotherm plot substantially the same as shown in Figure 11.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits a reversible water uptake (3.2 % w/w) between 2% and 95% Relative Humidity (RH).
• the crystalline hydrate Pattern B of 3-(4- (4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an unchanged XRPD after DVS analysis at 95% RH and 25 °C.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin- 6-yl)-2-hydroxybenzonitrile dimesylate exhibits an unchanged XRPD after storage at 75% RH and 40 °C for 7 days.
• the crystalline hydrate Pattern B of 3-(4-(4- aminopiperidin-l-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.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an unchanged XRPD after storage under static vacuum at 50 °C for 3 days.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern I after heating to 270 °C.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a 4.2 % w/w water content.
• the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 15.94 ° 2-Theta.
• 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.
• 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, about 15.51 ° 2-Theta, about 18.48 ° 2-Theta, about 20.91 ° 2-Theta, and about 28.26 ° 2-Theta.
• crystalline Pattern C of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• Some embodiments provide a composition comprising the crystalline Pattern C of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• crystalline Pattern C of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline Pattern C of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 12.
• the crystalline Pattern C of 3-(4-(4-aminopiperidin-l-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, about 17.44 ° 2-Theta, about 22.18 ° 2- Theta, and about 25.20 ° 2-Theta.
• the crystalline Pattern C of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Differential Scanning Calorimetry thermogram substantially the same as shown in Figure 13.
• the crystalline Pattern C of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Differential Scanning Calorimetry thermogram with an exothermic event having an onset at about 192.8 °C and a peak at about 213.3 °C; an endothermic event having an onset at about 252.2 °C and a peak at about 272.3 °C; and an endothermic event having an onset at about 296.6 °C and a peak at about 298.9 °C.
• the crystalline Pattern C of 3-(4-(4-aminopiperidin-l-yl)- 3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thennogravimetric Analysis pattern substantially the same as shown in Figure 14a.
• the crystalline Pattern C of 3-(4-(4-aminopiperidin-l-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 to 140 °C and a further 0.62% w/w loss from 140 to 290 °C.
• the crystalline Pattern C of 3-(4-(4-aminopiperidin-l-yl)- 3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an unchanged XRPD after storage at 75% RH and 40 °C for 7 days.
• the crystalline Pattern C of 3-(4-(4-aminopiperidin-l-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.
• the crystalline Pattern C of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern I after heating to 240 °C.
• the crystalline Pattern C of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 17.44 ° 2-Theta.
• 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.
• 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 about 27.58 ° 2-Theta.
• crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• Some embodiments provide a composition comprising the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 15.
• the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-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.
• the crystalline Pattern I of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Differential Scanning Calorimetry thermogram substantially the same as shown in Figure 16.
• the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-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.
• the crystalline Pattern I of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern substantially the same as shown in Figure 17a.
• the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern with a 0.19% w/w loss from 40 to 185 °C and a further 0.67% w/w loss from 185 to 290 °C.
• the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Dynamic Vapour Sorption isotherm plot substantially the same as shown in Figure 18.
• the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits a reversible water uptake (9.1 % w/w) between 2% and 95% Relative Humidity (RH); with a 2.5% w/w water uptake between 15 and 75% RH.
• the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern B after DVS analysis between 2% and 95% RH and 25 °C.
• the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits an unchanged XRPD after storage at 75% RH and 40 °C for 7 days.
• the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-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. In some embodiments, the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits a 0.29 % w/w water content.
• the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.74 ° 2-Theta.
• 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.
• 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.
• Some embodiments provide a composition comprising the crystalline isopropanol solvate Pattern D of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• crystalline isopropanol solvate Pattern D of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline isopropanol solvate Pattern D of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 19.
• the crystalline isopropanol solvate Pattern D of 3-(4-(4-aminopiperidin-l- 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 6.10 ° 2-Theta, about 6.70 ° 2-Theta, about 17.75 ° 2-Theta, and about 22.22 ° 2-Theta.
• the crystalline isopropanol solvate Pattern D of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern A after drying under dynamic vacuum at 50 °C for 2 hours.
• the crystalline isopropanol solvate Pattern D of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.10 ° 2-Theta.
• 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.
• crystalline isopropanol solvate Pattern D is further characterized by at least one X-ray diffraction pattern reflection selected from about 13.31 ° 2-Theta, about 19.17 ° 2-Theta, and about 20.21 ° 2-Theta.
• Some embodiments provide a composition comprising the crystalline tetrahydrofuran solvate Pattern E of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate.
• crystalline tetrahydrofuran solvate Pattern E of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline tetrahydrofuran solvate Pattern E of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 20.
• the crystalline tetrahydrofuran solvate Pattern E of 3-(4-(4-aminopiperidin- l-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 6.42 ° 2-Theta, about 19.99 ° 2-Theta, and about 21.12 ° 2-Theta.
• the crystalline tetrahydrofuran solvate Pattern E of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern A after drying under dynamic vacuum at 50 °C for 2 hours.
• the crystalline tetrahydrofuran solvate Pattern E of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.42 ° 2-Theta.
• crystalline tetrahydrofuran solvate Pattern E is further characterized by X-ray diffraction pattern reflections at about 19.99 ° 2-Theta, and about 21.12 ° 2-Theta.
• crystalline tetrahydrofuran solvate Pattern E is further characterized by an X-ray diffraction pattern reflection at about 17.76 ° 2-Theta.
• Some embodiments provide a composition comprising the crystalline methyl isobutyl ketone solvate Pattern F of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate.
• crystalline methyl isobutyl ketone solvate Pattern F of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline methyl isobutyl ketone solvate Pattern F of 3-(4- (4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 21.
• the crystalline methyl isobutyl ketone solvate Pattern F of 3-(4-(4- aminopiperidin-l-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 5.63 ° 2-Theta, about 6.27 ° 2-Theta, about 20.55 ° 2-Theta, and about 22.33 ° 2-Theta.
• the crystalline methyl isobutyl ketone solvate Pattern F of 3-(4-(4-aminopiperidin- l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern I after drying under dynamic vacuum at 50 °C for 2 hours.
• the crystalline methyl isobutyl ketone solvate Pattern F of 3-(4- (4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.27 ° 2-Theta.
• 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.
• crystalline methyl isobutyl ketone solvate Pattern F is further characterized by at least one X-ray diffraction pattern reflection selected from about 16.51 ° 2-Theta, and about 27.25 ° 2-Theta.
• Some embodiments provide a composition comprising the crystalline ethyl acetate solvate Pattern G of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate.
• crystalline ethyl acetate solvate Pattern G of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline ethyl acetate solvate Pattern G of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 22.
• the crystalline ethyl acetate solvate Pattern G of 3-(4-(4-aminopiperidin-l- 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 6.62 ° 2-Theta, about 13.21 ° 2-Theta, about 19.79 ° 2-Theta, and about 21.72 ° 2-Theta.
• the crystalline ethyl acetate solvate Pattern G of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern I after drying under dynamic vacuum at 50 °C for 2 hours.
• the crystalline ethyl acetate solvate Pattern G of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.62 ° 2-Theta.
• 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.
• Some embodiments provide a composition comprising the crystalline isopropyl acetate solvate Pattern H of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate.
• crystalline isopropyl acetate solvate Pattern H of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline isopropyl acetate solvate Pattern H of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 23.
• the crystalline isopropyl acetate solvate Pattern H of 3-(4-(4-aminopiperidin- l-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 5.66 ° 2-Theta, about 16.77 ° 2-Theta, and about 22.78 ° 2-Theta.
• the crystalline isopropyl acetate solvate Pattern H of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern I after drying under dynamic vacuum at 50 °C for 2 hours.
• the crystalline isopropyl acetate solvate Pattern H of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 5.66 ° 2-Theta.
• 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.
• crystalline methyl isobutyl ketone solvate Pattern F is further characterized by at least one X-ray diffraction pattern reflection selected from about 10.93 ° 2-Theta, and about 20.83 ° 2-Theta.
• crystalline Pattern J of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Some embodiments provide a composition comprising the crystalline Pattern J of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• crystalline Pattern J of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline Pattern J of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 24.
• the crystalline Pattern J of 3-(4-(4-aminopiperidin-l-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 ° 2-Theta, about 6.72 ° 2-Theta, about 12.33 ° 2- Theta, and about 21.47 ° 2-Theta.
• the crystalline Pattern J of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.72 ° 2-Theta.
• 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.
• crystalline Pattern J is further characterized by at least one X-ray diffraction pattern reflection selected from about 14.07 ° 2- Theta, about 17.50 ° 2-Theta, and about 22.31 ° 2-Theta.
• crystalline Pattern K of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• Some embodiments provide a composition comprising the crystalline Pattern K of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• crystalline Pattern K of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline Pattern K of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 25.
• the crystalline Pattern K of 3-(4-(4-aminopiperidin-l-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 ° 2-Theta, about 15.90 ° 2-Theta, about 19.59 ° 2- Theta, and about 21.52 ° 2-Theta.
• the crystalline Pattern K of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Differential Scanning Calorimetry thermogram substantially the same as shown in Figure 26b.
• the crystalline Pattern K of 3-(4-(4-aminopiperidin-l-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.
• the crystalline Pattern K of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern substantially the same as shown in Figure 26a.
• the crystalline Pattern K of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern with a 0.1% w/w loss from 40 to 190 °C and a further 0.69% w/w loss from 190 to 310 °C.
• the crystalline Pattern K of 3-(4-(4-aminopiperidin-l-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.
• the crystalline Pattern K of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 5.42 ° 2-Theta.
• 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, about 18.92 ° 2-Theta, about 20.82 ° 2-Theta, about 22.69 ° 2-Theta, and about 29.48 ° 2-Theta. Crystalline Acetone Solvate Pattern M of Compound A-2MSA
• crystalline acetone solvate Pattern M of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• Some embodiments provide a composition comprising the crystalline acetone solvate Pattern M of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• crystalline acetone solvate Pattern M of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline acetone solvate Pattern M of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 27.
• the crystalline acetone solvate Pattern M of 3-(4-(4-aminopiperidin-l-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.
• the crystalline acetone solvate Pattern M of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 5.67 ° 2-Theta.
• 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.
• 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 about 26.35 ° 2-Theta.
• crystalline acetonitrile solvate Pattern N of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Some embodiments provide a composition comprising the crystalline acetonitrile solvate Pattern N of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• crystalline acetonitrile solvate Pattern N of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline acetonitrile solvate Pattern N of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 28.
• the crystalline acetonitrile solvate Pattern N of 3-(4-(4-aminopiperidin-l-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 ° 2-Theta, and about 17.21 ° 2-Theta.
• the crystalline acetonitrile solvate Pattern N of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Differential Scanning Calorimetry thermogram substantially the same as shown in Figure 29b.
• the crystalline acetonitrile solvate Pattern N of 3-(4-(4- aminopiperidin-l-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 132.6 °C and a peak at about 144.0 °C; an endothermic event having an onset at about 179.7 °C and a peak at about 193.5 °C; and an endothermic event having an onset at about 192.4 °C and a peak at about 211.1 °C.
• the crystalline acetonitrile solvate Pattern N of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern substantially the same as shown in Figure 29a.
• the crystalline acetonitrile solvate Pattern N of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern with a 5.44% w/w loss from 40 to 220 °C.
• the crystalline acetonitrile solvate Pattern N of 3-(4-(4- aminopiperidin-l-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.
• the crystalline acetonitrile solvate Pattern N of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 5.18 ° 2-Theta.
• crystalline acetonitrile solvate Pattern N is further characterized by an X-ray diffraction pattern reflection at about 17.21 ° 2-Theta.
• crystalline acetonitrile solvate Pattern N is further characterized by an X-ray diffraction pattern reflection at about 21.11 ° 2-Theta.
• crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Some embodiments provide a composition comprising the crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is characterized as having:
• the crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 30.
• the crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin-l-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.
• the crystalline hydrate Pattern O of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Differential Scanning Calorimetry thermogram substantially the same as shown in Figure 31b.
• the crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin- l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a
• the crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern substantially the same as shown in Figure 31a.
• the crystalline hydrate Pattern O of 3-(4- (4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits a Thermogravimetric Analysis pattern with a 4.54% w/w loss from 40 to 260 °C.
• the crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin-l-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.
• the crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 15.87 ° 2-Theta.
• 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.
• crystalline hydrate Pattern O is further characterized by an X-ray diffraction pattern reflection 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.
• crystalline Pattern P of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate Some embodiments provide a composition comprising the crystalline Pattern P of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• crystalline Pattern P of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2- hydroxybenzonitrile dimesylate is characterized as having: (a) an X-ray powder diffraction pattern substantially the same as shown in Figure 32;
• the crystalline Pattern P of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an X-ray powder diffraction pattern substantially the same as shown in Figure 32.
• the crystalline Pattern P of 3-(4-(4-aminopiperidin-l-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 ° 2-Theta, about 17.26 ° 2-Theta, about 19.33 ° 2- Theta, and about 20.94 ° 2-Theta.
• the crystalline Pattern P of 3-(4-(4- aminopiperidin-l-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.
• the crystalline Pattern P of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate exhibits an XRPD that converts to Pattern B on storage at 96% RH and 25 °C for 3 days.
• the crystalline Pattern P of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate has an X-ray diffraction pattern reflection at about 6.97 ° 2-Theta.
• 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.
• crystalline Pattern P is further characterized by an X-ray diffraction pattern reflection 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.
• deprotection of the Boc group of compound 13 and treatment with HC1 yields Compound A-2HC1.
• Compound A-2HC1 is treated with an appropriate base, such as sodium hydroxide, in order to yield Compound A (free base).
• Compound A (free base) is then treated with methanesulfonic acid (MSA) to yield Compound A-2MSA.
• MSA methanesulfonic acid
• compound 13 treated with MSA to directly yield Compound A-2MSA.
• compound 13 is synthesized as previously disclosed in US Patent No. 9,896,432, and in US Patent Application No. 16/249,729. Briefly, compound 13 is synthesized from compound 11 by two successive Suzuki reactions: first with boronic acid 7 or trifluoroborate 5; then 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 performed in a single reaction vessel. In some embodiments, the two Suzuki reactions are performed with the same catalyst system. In some embodiments, the two Suzuki reactions are performed in a single reaction vessel and with the same catalyst system. In some embodiments, the two Suzuki reactions are performed in a single reaction vessel and with the same catalyst system without additional catalyst being added between the Suzuki reactions.
• residual Palladium is removed from compound 13 via a palladium scavenger, such as SiC , charcoal, L-cysteine, N-acetyl-L-cysteine, SilicaBond Cysteine, Si-Thiol, SilicaBond DMT, or the like.
• a palladium scavenger such as SiC , charcoal, L-cysteine, N-acetyl-L-cysteine, SilicaBond Cysteine, Si-Thiol, SilicaBond DMT, or the like.
• compound 13 contains a detectable amount of unreacted starting materials.
• a sample of compound 13 contains a detectable amount of an impurity selected from:
• samples of Compound A, or a pharmaceutically acceptable salt thereof are substantially free of structurally related impurities.
• Structurally related impurities include, but are not limited to, those compounds that are used at any step of the synthesis of Compound A, or a pharmaceutically acceptable salt thereof (i.e., Compound A-2MSA), as well as those compounds described in the preceding paragraph.
• compound 13 is purified by recrystallization. In some embodiments, compound 13 is heated in a suitable solvent or solvent mixture for an appropriate amount of time. In some embodiments, the purity of compound 13 is improved by this process.
• this process of recry stallization/slurrying removes or reduces the amount of residual palladium in samples of Compound 13.
• Purification steps are performed to reduce the amount of palladium in the product. Purification steps to reduce the amount of palladium in a product are conducted so that active pharmaceutical ingredients meet palladium specification guidelines. (“Guideline on the
• purification steps to reduce the amount of palladium in a product includes, but is not limited to, treatment with solid trimercaptotriazine (TMT), polystyrene-bound TMT, mercapto-porous polystyrene-bound TMT, polystyrene-bound ethylenediamine, activated carbon, glass bead sponges, SmopexTM, silica bound scavengers, thiol-derivatized silica gel, N-acetyl-L-cysteine, n-BmP, crystallization, extraction, L-cysteine, n- Bu3P/lactic acid (Garrett el al., Adv.
• TMT solid trimercaptotriazine
• polystyrene-bound TMT polystyrene-bound TMT
• mercapto-porous polystyrene-bound TMT polystyrene-bound ethylenediamine
• activated carbon includes but is not limited to DARCO ® KB-G, DARCO ® KB-WJ.
• silica bound scavengers include but are not limited to
• the purification steps to reduce the amount of palladium include the use of activated carbon, derivatized silica gel (e.g., thiol derivatized silica gel), or combinations thereof.
• 13 is further treated with a metal scavenger to remove residual palladium.
• the metal scavenger comprises Si02, charcoal, aqueous solution of L-cysteine, N-acetyl-L-cysteine, a Silicycle metal scavenger, Si-thiol, SiliaBond DMT or SiliaBond Cysteine.
• the scavenger loading (w/w) is 1 :3, 1 :2, or 1 : 1.
• the metal scavenger is Si-thiol.
• crude 13 as isolated from the reaction is treated with a metal scavenger.
• recrystallized 13 is treated with a metal scavenger.
• palladium levels are reduced sufficiently to be undetectable.
• 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). In some embodiments, the presence of residual heavy metal (e.g. palladium) impurities is determined by the use of techniques described in U.S.
• 13 is treated with hydrochloric acid in a suitable solvent to yield Compound A-2HC1.
• the suitable solvent is isopropyl alcohol (IP A), methyl /er/-butyl ether (MTBE), toluene, ethyl acetate, isopropyl acetate, water, or mixtures thereof.
• the suitable solvent is isopropyl alcohol, ethyl acetate, or isopropyl acetate.
• the suitable solvent is IPA.
• the suitable solvent is isopropyl acetate.
• the free base of Compound A is made by treating Compound A-2HC1 with a suitable base in a suitable solvent.
• the suitable base is sodium hydroxide, sodium bicarbonate, or the like.
• the suitable base is sodium hydroxide.
• the suitable solvent is water.
• the solid is filtered from the mixture to isolate the free base of Compound A.
• Compound A-2MSA is generated by treating the free base with methanesulfonic acid in a suitable solvent.
• the suitable solvent is methanol, ethanol, isopropyl alcohol, acetone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, tetrahydropyran, water, or combinations thereof.
• the suitable solvent is a mixture of acetone and water.
• Compound A-2MSA is isolated by filtering the solids from the reaction mixture. In some embodiments, the isolated Compound A-2MSA exhibits an XRPD pattern consistent with Pattern B.
• Compound A-2MSA is formed directly from 13.
• 13 is treated with methanesulfonic acid in a suitable solvent to yield Compound A-2MSA.
• the suitable solvent is isopropyl alcohol (IP A), methyl tert- butyl ether (MTBE), tetrahydrofuran, toluene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, N-methyl-2-pyrrolidone (NMP), water, or mixtures thereof.
• the suitable solvent is a mixture of acetone and water.
• the suitable solvent is NMP.
• 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.
• a method of making 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or solvate thereof comprising the steps of: (i) reacting /cvV-butyl (l-(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 to remove excess hydrochloric acid; (iii) filtering the slurry of step (ii) to provide 3-[4-(4-amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)
• the suitable solvent in step (i) is the suitable solvent is isopropyl alcohol (IP A), methyl tert-butyl ether (MTBE), toluene, ethyl acetate, isopropyl acetate, water, or a combination thereof;
• the additional solvent in step (ii) is isopropyl alcohol (IP A), methyl tert-butyl ether (MTBE), toluene, ethyl acetate, isopropyl acetate, water, or a combination thereof;
• the suitable solvent in 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.
• the suitable solvent in step (i) is isopropyl acetate, water, or a combination thereof
• step (v) sodium hydroxide solution is used in step (v); the suitable solvent in step (vii) is acetone, water, or a mixture thereof; the suitable temperature in step (vii) is about 50 °C; or a combination thereof.
• a method of making 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or solvate thereof comprising the steps of: (i) reacting /cvV-butyl (l-(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 to provide 3-[4-(4- amino-piperidin-l-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile di
• the suitable solvent in step (i) is isopropyl alcohol (IP A), methyl tert-butyl ether (MTBE), tetrahydrofuran, toluene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, N-methyl-2-pyrrolidone (NMP), water, or mixtures thereof;
• the suitable temperature in step (ii) is about 40 °C to about 110 °C;
• the additional solvent in step (ii) is isopropyl alcohol (IP A), methyl /cvV-butyl ether (MTBE), tetrahydrofuran, toluene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, N-methyl-2-pyrrolidone (NMP), water, or mixtures thereof; or a combination thereof.
• the suitable solvent in step (i) is acetone, water, or mixtures thereof; the suitable temperature in step (ii) is about 45 °C; the additional solvent in step (ii) acetone; or a combination thereof.
• the suitable solvent in step (i) is N-methyl-2-pyrrolidone (NMP), water, or mixtures thereof; the suitable temperature in step (ii) is about 100 °C; no additional solvent is added in step (ii); or a combination thereof.
• a method of making 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate, or solvate thereof comprising the steps of: (i) slurrying 3-[4-(4-amino-piperidin-l-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-l-yl)-3- (3,5-
• the suitable solvent of step (i) is isopropanol, acetone, water, or a mixture thereof. In some embodiments, the suitable solvent of 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 prior to the addition of methanesulfonic acid in step (iii). In some embodiments, the methanesulfonic acid of step (iii) is added as a solution in water. In some embodiments, the methanesulfonic acid of step (iii) is added neat and not as a solution.
• hot slurry of step (iii) is stirred for 10 minutes to 3 hours before cooling in step (iv). In some embodiments, the hot slurry of step (iii) is stirred for 30 minutes before cooling in step (iv). In some embodiments, the slurry of step (iv) is stirred at room temperature for about 10 hours before filtering in step (v). In some embodiments, the isolated solids step (v) are 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 of step (v) is vacuum dried. In some embodiments, the isolated solid of step (v) is vacuum dried at about 50 °C for about 5 h.
• “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
• the term“pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an 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 ,
• salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviours. Also, because the salt- forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
• solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.
• Solvents are categorized into three classes. Class 1 solvents are toxic and are to be avoided. Class 2 solvents are solvents to be limited in use during the manufacture of the therapeutic agent. Class 3 solvents are solvents with low toxic potential and of lower risk to human health. Data for Class 3 solvents indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies.
• Class 1 solvents which are to be avoided, include: benzene; carbon tetrachloride; 1,2- dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.
• 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-ethoxy ethanol, ethyleneglycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidine, nitrom ethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene and xylene.
• Class 3 solvents which possess low toxicity, include: acetic acid, acetone, anisole, 1- butanol, 2-butanol, butyl acetate, /cvV-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, methylisobutyl ketone, 2- m ethyl- 1 -propanol, pentane, 1-pentanol, 1 -propanol, 2-propanol, propyl acetate, and tetrahydrofuran.
• acetic acid acetone
• anisole 1- butanol
• 2-butanol
• Residual solvents in active pharmaceutical ingredients originate from the manufacture of API. In some cases, the solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of APIs may enhance the yield, or determine characteristics such as crystal form, purity, and solubility.
• the solvent is a critical parameter in the synthetic process.
• compositions comprising Compound A, or a pharmaceutically acceptable salt thereof comprise an organic solvent(s).
• compositions comprising Compound A, or a pharmaceutically acceptable salt thereof include a residual amount of an organic solvent(s).
• compositions comprising Compound A, or a pharmaceutically acceptable salt thereof comprise a residual amount of a Class 3 solvent.
• the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, /cvV-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, methylisobutyl ketone, 2- m ethyl- 1 -propanol, pentane, 1-pentanol, 1 -propanol, 2-propanol, propyl acetate, and
• the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, /er/-butylmethyl ether, heptane, isopropanol, and ethanol.
• compositions comprising Compound A, or a
• the pharmaceutically acceptable salt thereof include a detectable amount of an organic solvent.
• the pharmaceutically acceptable salt of Compound A is an MSA salt (i.e., Compound A-2MSA).
• the organic solvent is a Class 3 solvent.
• compositions comprising Compound A, or a
• compositions comprising Compound A, or a pharmaceutically acceptable salt thereof (i.e., Compound A-2MSA), wherein the composition comprises a detectable amount of solvent that is less than about 1%, wherein the solvent is selected from acetone, 1,2-dimethoxy ethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, heptane, and 2-propanol.
• the composition comprises a detectable amount of solvent which is less than about 5000 ppm.
• compositions 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.
• Compound A, or a pharmaceutically acceptable salt thereof is free of impurities.
• Compound A, or a pharmaceutically acceptable salt thereof is free of structurally related impurities.
• Compound A, or a pharmaceutically acceptable salt thereof is essentially free of impurities.
• Compound A, or a pharmaceutically acceptable salt thereof is essentially free of structurally related impurities.
• the amount of impurities is less than 1 % (w/w).
• 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.
• Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A-2MSA), is substantially free of impurities.
• Compound A-2MSA a pharmaceutically acceptable salt thereof
• Compound A or a pharmaceutically acceptable salt thereof (i.e., Compound A-2MSA), is substantially free of structurally related impurities.
• 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).
• 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.
• sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds disclosed herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway.
• the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
• the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
• Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2 H, 3 ⁇ 4, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 C1, 123 I, 124 I, 125 I, 131 1, 32 P and 33 P.
• isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
• substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or altered metabolic pathways to reduce undesirable metabolites or reduced dosage requirements.
• one or more hydrogen atoms on Compound A are replaced with deuterium.
• substitution with deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
• each R is independently selected from hydrogen or deuterium.
• the methanesulfonic salt is a dimethanesulfonic acid salt.
• the compounds disclosed herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
• the compound disclosed herein exists in the R configuration when one stereocenter is present.
• the compound disclosed herein exists in the S configuration when one stereocenter is present.
• the compound disclosed herein exists in the RR configuration when two stereocenters are present.
• the compound disclosed herein exists in the RS configuration when two stereocenters are present.
• the compound disclosed herein exists in the SS configuration when two stereocenters are present.
• the compound disclosed herein exists in the SR configuration when two stereocenters are present.
• the compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
• the compounds and methods provided herein include all cis, trans, syn, anti,
• E
• Z
• isomers as well as the appropriate mixtures thereof.
• stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents.
• 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.
• resolution of individual enantiomers of compounds disclosed herein is carried out using covalent diastereomeric derivatives of the compounds described herein.
• diastereomers of compounds disclosed herein are separated by separation/resolution techniques based upon differences in solubility.
• separation of stereoisomers of compounds disclosed herein is performed by chromatography or by the forming diastereomeric salts and separation 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.
• stereoisomers are obtained by stereoselective synthesis.
• enantiomers described herein are separated from each other by the use of chiral SFC or chiral HPLC.
• compounds disclosed herein that include one or more chiral centers e.g. compounds disclosed herein that include the moiety trans-octahydro-lH-pyrido[3,4-b]morpholin-6-yl
• chiral SFC or chiral HPLC e.g. compounds disclosed herein that include the moiety trans-octahydro-lH-pyrido[3,4-b]morpholin-6-yl
• Daicel polysaccharide chiral stationary phases are among the columns used for chiral SFC separations.
• Daicel analytical immobilised and coated are among the columns used for chiral SFC separations.
• CHIRALPAK and CHIRALCEL HPLC columns can be used for SFC analysis.
• screening for the suitability of using a SFC column is performed on the four main immobilised phases (CHIRALPAK IA, IB, IC and ID) and the four main coated columns (CHIRALPAK AD and AS and CHIRALCEL OD and OJ), with varying concentrations of organic modifier.
• CHIRALPAK IA, IB, IC and ID the four main immobilised phases
• CHIRALPAK AD and AS and CHIRALCEL OD and OJ varying concentrations of organic modifier.
• a variety of column phases are available, including but not limited to OD and OJ, OX and OZ chlorinated phases, and a range of complementary cellulose based
• CHIRALCEL phases including OA, OB, OC, OF, OG and OK.
• Non-limiting examples of chiral selectors contemplated for use in the separation of enantiomers include amylose tris (3, 5-dimethylphenylcarbamate), cellulose tris (3, 5- dimethylphenylcarbamate), cellulose tris (3, 5-dichlorophenyl carbamate), 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).
• Non-limiting examples of chiral columns contemplated for use in the separation of 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,
• the identity of and placement of substituents on the compounds described herein help to minimize undesired activity.
• undesired activity includes undesired hERG inhibition.
• the presence of a hydroxyl group and an adjacent cyano group on an aromatic ring reduces undesired hERG inhibition significantly as compared to the lack 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.
• significant reduction of undesired hERG inhibition is observed when R B is a substituted or unsubstituted 2-hydroxy-3-cyanophenyl.
• the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
• A“metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
• the term“active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
• the term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
• cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups.
• Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
• halo or, alternatively,“halogen” or“halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
• 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 larger substructure.
• bond when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
• moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
• modulate means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
• modulator refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.
• administer refers to the methods that may be used to enable delivery of compounds or compositions to the 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 and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
• co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
• an“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
• an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
• An appropriate“effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
• the terms“enhance” or“enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
• 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.
• An“enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
• the term“pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
• the term“fixed combination” means that the active ingredients, e.g. a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
• the term“non-fixed combination” means that the active ingredients, e.g.
• a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
• cocktail therapy e.g. the administration of three or more active ingredients.
• the term“subject” or“patient” encompasses mammals.
• mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
• the mammal is a human.
• the terms“treat,”“treating” or“treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
• the compounds described herein are formulated into
• compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
• a summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;
• the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a
• Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via 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), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
• compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant.
• topical application such as creams or ointments, injection, catheter, or implant.
• the administration can also be by direct injection at the site of a diseased tissue or organ.
• 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 a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient is presented as a bolus, electuary or paste.
• compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed 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 may 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 binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
• the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings.
• concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
• compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
• Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• compositions may be presented in unit-dose or multi dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
• sterile liquid carrier for example, saline or sterile pyrogen-free water
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• compositions for parenteral administration include aqueous and non- aqueous (oily) sterile injection solutions of the active compounds which may contain
• aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
• Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
• the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
• Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
• compositions may be administered topically, that is by non-systemic administration.
• non-systemic administration includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
• systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
• compositions suitable for topical administration include liquid or semi liquid preparations 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, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation.
• compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
• Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• pharmaceutical preparations may 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 may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
• compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
• the compounds disclosed herein, or a pharmaceutically acceptable salt thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from modulation of somatostatin activity.
• Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of pharmaceutical compositions that include at least one compound disclosed herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
• compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
• therapeutic agents in certain embodiments, are administered for prophylactic and/or therapeutic treatments.
• compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition.
• Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, 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, a dose escalation and/or dose ranging clinical trial.
• compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
• prophylactically effective amount or dose the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
• prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
• the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
• a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
• the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g ., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
• doses employed for adult human treatment are typically in the range of 0.01 mg-2000 mg per day.
• the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
• the daily dosages appropriate for the compound disclosed herein, or a pharmaceutically acceptable salt thereof, described herein are from about 0.01 to about 50 mg/kg per body weight.
• the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime.
• the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be 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 practitioner.
• Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50.
• the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50.
• the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
• the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity.
• the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
• the effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal.
• any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
• any of the aforementioned aspects are further embodiments comprising multiple administrations of the 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 time between multiple administrations 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; (v) the compound is administered to the mammal every 24 hours.
• the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations 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; (v) the compound is administered to the mammal every 24 hours.
• the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
• the length of the drug holiday varies from 2 days to 1 year.
• ACN acetonitrile
• Boc or BOC tert-butyloxy carbonyl
• DIEA or DIPEA diisopropylethylamine
• DMSO dimethyl sulfoxide
• DSC differential scanning calorimetry
• DVS dynamic vapour sorption
• IP Ac isopropyl acetate
• MTBK methyl isobutyl ketone
• MTBE methyl tert-butyl ether
• NCS N-chlorosuccinimide
• NMP N-methyl-2-pyrrolidone
• Pd(dppf)Ch [1, r-bis(diphenylphosphino)ferrocene]dichloropalladium(II);
• SSTR somatostatin receptor
• TFA trifluoroacetic acid
• vol volume, typically used for reaction volume or ratio of solvents
• XRPD x-ray powder diffraction
• Step 1 3-Bromo-2-fluro-benzonitrile (1, 25 g, 1.0 equiv), potassium acetate (5 equiv) was mixed in DMSO (7 vol) and heated to 90-95 °C for 48 h. IPC showed 0.38% of 1 and 96.5% of compound 2. Reaction mixture was cooled to 25-30 °C and quenched with purified water (25 vol water). Then pH was adjusted pH to 3-4 using 6N HC1 solution. The obtained resulting mixture was diluted with MTBE (10 vol). The organic layer was separated, and aqueous layer was extracted with 10 vol MTBE.
• Step 2 Crude solution of compound 2 was mixed with acetic anhydride (1.3 equiv), DMAP (0.1 equiv) at 25-30 C for 2h with stirring. IPC showed 0.8% compound 2 and 94.8% compound 3. Reaction mass was diluted with purified water (10 vol), stirred for 30 mins. Organic layer was separated. Aqueous layer was extracted with 2 vol DCM. The combined organic layer was washed with water (8 vol> ⁇ 2). Charcoal (10%) was added to organic layer and stirred for 1 h before filtered through celite bed. The filtrate was then concentrated to 2 vol level, chased with 3 vol and 2 vol of «-heptane subsequently before cooled to RT and stirred for lhr at 5-10 °C. The product was isolated via filtration as solid (25.5g, 85% yield over two steps, HPLC purity 96.8%).
• Step 3 Compound 3 (20 g, 1.0 equiv) was mixed with KOAc (3.0 equiv),
• Reaction mixture was cooled to 25-30 °C and filtered through 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 for lh at ambient temperature.
• the suspension was again filtered through celite pad and the celite pad was rinsed with MTBE.
• the combined filtrate was washed with water (500 mL, 5 vol).
• the aqueous layer was extracted with MTBE.
• Combined organic layers were washed with 5% A -A cetyl -L- cysteine solution twice (each time 300 mL, 3 vol) and water (300 mL, 3 vol).
• Step 4 Compound 4 solution was added with KHF2 (5.0 equiv), purified water (2.6 vol), and MeOH (1 vol) before heated to 65 °C for lh.
• the reaction mixture was diluted with MTBE (15 vol) before cooled to 10 ⁇ 5 °C.
• the resulting suspension was stirred for lh before filtration.
• the solid was transferred to reaction flask, added with 20 vol acetone, stirred at 25 ⁇ 5 °C for lh, treated with 10% charcoal, and stirred for another 1 h.
• the resulting reaction mixture was then filtered through celite pad. Filtrate was concentrated to 2vol level, chased with MTBE (3 volx2), concentrate to 2 vol level, and diluted with MTBE (4 vol).
• Step 1 Diisoproylethylamine (114 mL, 1.3 equiv) was slowly added to a solution of 3- bromo-2-hydroxybenzonitrile (Compound 2, 100 g, 1 equiv) in CH2CI2 (1 L, 10 vol) at 0 °C and stirred for 30 min. Chloromethyl methyl ether (MOMCI) (46 mL, 1.2 equiv) was then added slowly while maintaining the internal temperature at 0 to 5 °C. The reaction was then allowed to warm to RT and stirred for 4 h, until TLC showed complete reaction. The reaction was cooled to 0 °C and quenched with DI- water (300 mL, 3 vol) and the layers were separated.
• MOMCI chloromethyl methyl ether
• Step 2 A solution of 'PrMgCI in THF (2 M in THF, 340 mL, 2.2 equiv) was added slowly to a solution of compound 6 (75 g, 1 equiv) in THF (1.12 L, 15 vol) while maintaining the internal temperature at -5 to 5 °C and stirred for 10 min. Triisopropyl borate (180 mL, 2.5 equiv) was then added while maintaining the internal temperature at -5 to 3 °C. The reaction was then allowed to warm to room temperature and stirred for 18 h until TLC showed complete reaction.
• Step 1 /V-Chlorosuccinimide (377 g, 1.05 equiv) was added to a suspension of 6- bromoquinolin-4(lH)-one (8, 600 g, 1 equiv) in acetic acid (12 L, 20 vol) at RT. The reaction was then heated to 50 °C and stirred for 8 h. The reaction was cooled to 20 °C, filtered, successively washed 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 a filter to afford crude 9.
• Step 2 Phosphorus tribromide (317 mL, 1.6 equiv) was slowly added to a solution of 9 (540 g, 1 equiv) in DMF (7 L, 13 vol) at 0-5 °C. The reaction was allowed to warm to RT and stirred for 4 h. The reaction was cooled to 0 °C and quenched by sat. aqueous solution of NaHCCh to pH ⁇ 8 (10.8 L, 20 vol) and diluted with water (5.4 L, 10 vol). The mixture was stirred for 2 h at RT and the solids were 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 and filtered, washed with water (980 mL, 2 vol) and dried on the filter under vacuum to afford crude 10 as a solid.
• Step 3 Diisopropylethylamine (932 mL, 4 equiv) and 4-(A f -Boc-amino)pi peri dine (430 g, 1.6 equiv) were successively added to a solution of 10 (430 g, 1 equiv) in DMSO (4.3 L, 10 vol) at RT. The suspension was then heated to 140 °C and stirred for 3 h. The reaction was allowed to cool to RT, diluted with water (12.9 L, 30 vol), and stirred for 2 h. The resulting solids were filtered and dried on a filter.
• reaction was stirred at 80-85 °C and monitored by TLC and HPLC. After complete reaction (6 h), it was allowed to cool 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. PdCb(amphos) (25.9 g, 0.05 equiv) was added to the flask under argon atmosphere and the reaction mixture was degassed further for 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 along with 1.95% of un-reacted 12 and 0.94% of another impurity at 8.2 min.
• the reaction was allowed to cool to 25-30 °C and filtered through a pad of Celite and washed with ethyl acetate (1350 mL, 3 vol). 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 x 3.5 L, 10 vol each), brine (3.5 L, 10 vol), and dried over anhydrous NaiSCL.
• the celite pad was washed with IP Ac (2.0 vol). The filtrate was combined, concentrated to 3 vol, chased with IP Ac (5 vol) twice to 4 vol. The resulting solution was diluted with IP Ac (8 vol) and washed with water (2x10 vol). Organic layer was separated and washed with 1% A- Acetyl L-cysteine (2x10 vol) before concentrated to 6 vol. The resulting suspension was stirred at reflux for 2h and cooled to ambient temperature. The suspension is further cooled to 10 ⁇ 5 °C, stirred for 2h, and filtered. The filter cake was washed with lvol IP Ac and dried to provide the desired crude product as pale-yellow solid.
• Isolated compound 13 crude solid was dissolved in 2-methyl-THF (15 vol), added with Si-Thiol (0.25%w/w), and stirred at ambient temperature for 3h. The suspension was filtered through celite bed, washed with 2-methyl-THF (2 vol). The above process was repeated again. The final filtrate was concentrated to 2 vol, chased with «-heptane twice (2x3 vol). The resultant suspension was filtered. The solid was dried under vacuum at 45 ⁇ 5 °C to afford the purified compound 13 as solid (HPLC purity 96% with Pd level of 13ppm).
• Example 9a Alternative Svnthesis of tert- Butyl (l-(6-(3-cvano-2-hvdroxyphenyl)-3-(3,5- difluorophenvl)auinolin-4-vl)Diperidin-4-vl)carbamate (13)
• 3,5-Difluorophenylboronic acid (2.0 equiv) was charged to the pale brown clear solution of 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 to 20 h while monitoring by TLC and HPLC.
• reaction mass was allowed to cool to 25 ⁇ 5 °C and transferred to the separating funnel (the reaction flask was rinsed with 1 vol of isopropyl acetate for complete transfer).
• the layers were separated and organic layer (1,4-dioxane) was concentrated to about 3.0 vol and chased with isopropyl acetate twice (5 vol each) to about 4 vol stage.
• the filtrate was concentrated to 6 vol and the resultant yellow suspension heated to 80 ⁇ 5 °C for 1 hour.
• the suspension was cooled to 25 ⁇ 5 °C and stirred for 1 hour and further cooled to 10 ⁇ 5 °C, 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 hours to get crude 13 as pale yellow solid (55-56%, -98.0% HPLC purity).
• Example 9b Alternative Synthesis of fert-Butyl (l-(6-(3-cvano-2-hvdroxyphenv0-3-(3.,5- difluorophenvPquinolin-4-vPpiperidin-4-vPcarbamate 113)
• the biphasic reaction mixture was cooled to RT, transferred to a separatory funnel, and rinsed with IPAc (50g).
• the organic layer was concentrated in vacuo to 3 volumes (40g) and chased with IPAc (3 x 5 volumes).
• the thick slurry was diluted with IPAc (300 g total mass) and extracted with 100 mL ThO.
• the hazy organic phase was treated with 1% A-acetyl-L-cysteine (10 vol) for 15 minutes and filtered through celite.
• the celite bed was rinsed with IPAc (20 mL) prior to separation.
• the hazy orange organic phase was treated with another 100 mL (10 vol) of 1% A-acetyl-L-cysteine solution.
• the solid was collected by filtration and washed with isopropyl acetate (5.4 L, 3.0 vol) and dried under reduced pressure at 45 ⁇ 5 °C for 12 hours to get 1.8 kg of Compound A-2HC1 as a pale yellow solid with 99.18% purity by HPLC.
• the above solid was taken in purified water (108 L, 60 vol) and adjusted the pH to 9-10 using sodium hydroxide solution (3N) at 25 ⁇ 5 °C. After pH adjustment, the mixture was stirred for 1 hour at 25 ⁇ 5 °C and filtered and washed with purified water (18 L, 10 vol) until the pH of last drop became 7 to 8. The solid was dried under reduced pressure at 55 ⁇ 5 °C for 12 hours to get 1.5 kg of Compound A (free base) as a pale yellow solid with 99.37 % purity.
• Patterns A, B, C and I were recovered from EtOH, Patterns D and E converted to Pattern A upon drying, and Patterns F, G and H converted to Pattern I upon drying. Some Pattern B samples exhibited minor peak shifts at high values of 20. Table 1. XRPD patterns of solids obtained from short term slurry experiments
• a second batch of amorphous material was generated. About 350 mg of Compound A-2MSA was dissolved in 2 mL of ACN:water (8:2 vol.) and flash-frozen in liquid nitrogen (- 196 °C). The frozen sample was connected to the freeze drier and kept under dynamic vacuum over the weekend (3 days). The resultant fluffy yellow solid exhibited a characteristically amorphous pattern by XRPD.
• Example A-4 Slurries of Amorphous Material
• Amorphous material was recovered from heptane at both time points. At 4 hours, the solids recovered from EtOH slurry matched Pattern K, after 24 hours Pattern C was recovered. Pattern D was recovered from IPA slurry. Pattern I was recovered from THF (24 hours), MIBK (4 and 24 hours) and EtOAc (4 and 24 hours) slurries. Pattern F was recovered from IP Ac after
• Vials were loaded with about 25 mg of amorphous material which was dissolved in 5 volumes of solvent at room temperature (20-23 °C). Two antisolvent addition regimes were employed.
• Dry and solvent drop milling was done using a small Wig-L-Bug ball mill with 1 ⁇ 4” stainless steel ball as milling media. About 30 mg of amorphous material was weighed into a milling capsule and one volume of the chosen solvent was added. The milling was carried out in 3 x 30 second increments at 3500 rpm, scraping solids off the capsule walls to minimize caking between millings. The milled samples were analyzed by XRPD as a wet cake. The patterns recovered were generally of low crystallinity, the dry milled sample became amorphous.
• Example B-l Generation of crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-vP- 3-t3,5-difluorophenyDquinolin-6-yD-2-hydroxybenzonitrile dimesylate
• Compound A-2MSA (Pattern A, 0.2649 g) was added to a 20 mL vial with a stir bar. Ten volumes (2.65 mL) of acetone:water (9: 1 vol.) was added and the slurry was stirred at room temperature. After about 5 minutes, the slurry had frozen and an additional 5 volumes (3.98 mL total volume) was added to form a mixable slurry. The slurry was stirred overnight ( ⁇ 20 hours), sampled to confirm the correct pattern was generated, then the solids were collected by filtration. The resultant pale-yellow solid was dried in a vacuum oven at 50 °C under dynamic vacuum for 2 hours, then under static vacuum overnight ( ⁇ 16 hours).
• Pattern B (0.1174 g, 44% yield) was characterized by XRPD, solution 1 H-NMR, simultaneous TGA/DSC, and stand-alone DSC.
• the solution 1 H-NMR spectrum conformed with the structure of the dimesylate and showed 0.47 wt. % residual acetone.
• TGA showed a mass loss of 2.9% between 40 and 205 °C.
• a coincident endotherm of 64 J/g (onset 86.3 °C) is observed in DSC, implying that the mass loss is water.
• a melting endotherm was also observed in DSC with an onset of 213.2 °C.
• DVS was performed on Pattern B and showed a total mass difference of 3.2 wt. % over the 2-95% RH range. In the range of 10-80% RH, the mass change was 1.3 wt. %. There was no change in form after the experiment, the XRPD pattern remained Pattern B.
• Crystalline Pattern B is assigned as a crystalline hydrate of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• Pattern B was left at ambient conditions (21 - 22 °C, 10 - 40% RH) for a week then characterized by XRPD, TGA/DSC, and water content measured by Karl-Fischer titration.
• the XRPD pattern is identical to Pattern B.
• TGA showed a mass loss of 4.23%, about an additional 1.4% water from the TGA recorded soon after removing the sample from the oven.
• the water content was confirmed by KF titration which yielded a value of 4.20 wt. %.
• Pattern B was prepared on an XRPD sample holder and analysed by XRPD to create a baseline. The disk was then left in a vacuum oven at 50 °C under static vacuum for 3 days. On the third day, the sample was removed from the oven and the “dry” pattern was recorded immediately. The dry pattern matched Pattern B.
• Example B-2 Alternative Generation of crystalline hydrate Pattern B of 3-14-14- aminopiperidin-l-vP-3-(3.,5-difluorophenvPquinolin-6-vP-2-hvdroxybenzonitrile dimesylate
• Pattern B An additional lot of Pattern B was generated by exposing Pattern A to an environment of 90%+ RH 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 colour change from bright yellow to a pale, off-white/yellow was apparent.
• a sample was dried for an hour and then analyzed by solution 1 H-NMR. Residual IPA was below the detectable limit by proton NMR.
• Example B-3 Alternative Generation of crystalline hydrate Pattern B of 3-(4-(4- aminopiperidin-l-vB-3-(3.,5-difluorophenvBquinolin-6-vB-2-hvdroxybenzonitrile dimesylate
• Example B-4 Generation of crystalline Pattern C of 3-(4-(4-aminopiperidin-l-vB-3-(3.,5- difluorophenvBquinolin-6-vB-2-hvdroxybenzonitrile dimesylate
• Pattern C is designated as an anhydrous crystalline solid of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• Example B-5 Alternative Generation of crystalline Pattern C of 3-(4-(4-aminopiperidin-l- vD-3-(3.,5-difluorophenvDquinolin-6-vD-2-hvdroxybenzonitrile dimesylate
• Compound A-2MSA (Pattern A) was slurried in EtOH overnight at room temperature (ca. 16 hours). A sample of the slurry solids exhibited Pattern C by XRPD. The remainder of the solids were collected, and a sample of the bulk wet-cake was analyzed by XRPD and 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 dry solids exhibited a pattern that was a combination of Patterns C and I. The wet sample left at ambient conditions did not change over 24 hours. Pattern C was observed to convert to I.
• Example B-6 Generation of crystalline Pattern of 3-(4-(4-aminopiperidin-l-vD-3-(3,5-)
• Compound A-2MSA (Pattern A, 0.2659 g) was added to a 20 mL vial with a stir bar. Twenty-five volumes (6.65 mL) of ACN was added and the slurry was stirred overnight ( ⁇ 20 hours). The slurry was sampled to confirm the correct pattern was generated, then the solids were collected by filtration. The resultant yellow solid was dried in a vacuum oven at 50 °C under dynamic vacuum for 2 hours, then under static vacuum overnight ( ⁇ 16 hours) to yield 0.2255 g (85% yield). The sample drawn was dried for 3 hours then the solid was used for characterization by solution 1 H-NMR spectroscopy and simultaneous TGA/DSC. The bulk was dried overnight and used for stand-alone DSC. The bulk was analyzed by XRPD to generate a higher quality pattern after 6 days at ambient conditions, but this yielded a pattern with additional peaks.
• Pattern I was designated as an anhydrous crystalline solid of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate.
• Example C-l X-Ray Powder Diffraction (XRPD)
• X-ray powder diffraction was done using a Rigaku MiniFlex 600. Samples were prepared on Si zero-return wafers. A typical scan is from 20 of 4 to 30 degrees, with step size 0.05 degrees over five minutes with 40 kV and 15 mA. A high-resolution scan is from 20 of 4 to 40 degrees, with step size 0.05 degrees over thirty minutes with 40 kV and 15 mA. Typical parameters for XRPD are listed below.
• Example C-2 Differential Scanning Calorimetry (DSC)
• the modulated DSC thermogram of the amorphous solid form of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is display ed in Figure 1.
• the modulated DSC thermogram has a glass transition temperature having an onset at about 166.6 °C and a midpoint at about 169.3 °C.
• the stand-alone DSC thermogram for the crystalline Pattern A of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 4.
• the stand-alone DSC thermogram has 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
• the stand-alone DSC thermogram for the crystalline hydrate Pattern B of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 8.
• the stand-alone DSC thermogram has a broad endothermic event having an onset at about 86.3 °C and a peak at about 115.1 °C; and an endothermic event having an onset at about 213.2 °C and a peak at about 221.8 °C.
• the stand-alone DSC thermogram for the crystalline Pattern C of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 13.
• the stand-alone DSC thermogram has an exothermic event having an onset at about 192.8 °C and a peak at about 213.3 °C; an endothermic event having an onset at about 252.2 °C and a peak at about 272.3 °C; and an endothermic event having an onset at about
• the stand-alone DSC thermogram for the crystalline Pattern I of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 16.
• the stand-alone DSC thermogram has 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.
• Pattern A was heated to 277 °C, monitored by DSC. The pan contents were recovered and analyzed by XRPD, exhibiting a new pattern, P. Pattern P was subsequently independently made by heating Pattern A to 255 °C. This material was exposed to -90% RH at room temperature and slurried in ACN and after 4 hours the Patterns B and I were recovered, respectively.
• Pattern B was heated beyond the water loss and monitored by DSC. The pan was allowed to cool to room temperature then the contents were recovered and analyzed by XRPD. The pattern recovered matches Pattern B. Another sample was heated to 270 °C followed by cooling naturally to room temperature and the pan contents were analyzed by XRPD to determine what form crystallized at 250 °C. The pattern is low crystalline with a few broad peaks, but seems to conform well to Pattern I. The XRPD sample was put in an atmosphere of - 88% RH overnight (16 hrs) and then analyzed again. The pattern after humidity seemed to be in the process of reverting back to Pattern B.
• Pattern C was heated to 240 °C (just beyond the exothermic event) and monitored by DSC.
• the pan was allowed to cool to room temperature then the contents recovered and analyzed by XRPD, indicating formation of Pattern I.
• Another experiment was performed where a sample was heated to 280 °C, beyond the first endotherm. The pan was then allowed to cool to room temperature and the contents recovered and analyzed by XRPD. There are some differences in the intensity of a number of peaks when comparing to the pattern recovered when heating just beyond the exotherm, but the pattern still resembles pattern I.
• Example C-3 Simultaneous Thermogravimetric Analysis 1TGA1 and Differential Scanning Calorimetry 1DSC1
• Thermogravimetric analysis and differential scanning calorimetry was done using a Mettler Toledo TGA/DSC3+. The desired amount of sample is weighed directly in a hermetic aluminum pan with pin-hole. A typical sample mass for the measurement is 5-10 mg. A typical temperature range is 30 °C to 300 °C at a heating rate of 10 °C per minute (total time of 27 minutes). Protective and purge gasses are nitrogen (20 - 30 mL/min and 50 - 100 mL/min).
• the TGA pattern of the amorphous solid form of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 2a.
• the thermogravimetric analysis pattern has a 3.85% w/w loss between 40 and 170 °C.
• the DSC thermogram of the amorphous solid form of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 2b.
• the TGA patern of the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 5a.
• the thermogravimetric analysis pattern has a 2.28% w/w loss from 60 to 180 °C.
• the DSC thermogram of the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 5b.
• the DSC thermogram has an endothermic event having an onset at about 293.8 °C and a peak at about 297.6 °C.
• the TGA patern of the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 9a.
• the thermogravimetric analysis pattern has a 2.9% w/w loss from 40 to 205 °C.
• the DSC thermogram of the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 9b.
• the DSC thermogram has an endothermic event having an onset at about 212.4 °C and a peak at about 220.6 °C.
• the thermogravimetric analysis pattern has a 4.23% w/w loss from 45 to 175 °C.
• the DSC thermogram has an endothermic event having an onset at about 205.6 °C and a peak at about 221.8 °C; an exothermic event having an onset at about 243.0 °C and a peak at about 254.2 °C; and an endothermic event having an onset at about 278.0 °C and a peak at about 288.2 °C.
• the TGA patern of the crystalline Pattern C of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 14a.
• the thermogravimetric analysis pattern has a 0.12% w/w loss from 40 to 140 °C and a further 0.62% w/w loss from 140 to 290 °C.
• the DSC thermogram of the crystalline Pattern C of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 14b.
• the DSC thermogram has an endothermic event having an onset at about 258.0 °C and a peak at about 272.7 °C; and an endothermic event having an onset at about 293.5 °C and a peak at about 297.3 °C.
• thermogravimetric analysis pattern has a 0.19% w/w loss from 40 to 185 °C and a further 0.67% w/w loss from 185 to 290 °C.
• the DSC thermogram of the crystalline Pattern I of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 17b.
• the DSC thermogram has an endothermic event having an onset at about 262.1 °C and a peak at about 272.6 °C; and an endothermic event having an onset at about 290.0 °C and a peak at about 294.2 °C.
• the TGA pattern of the crystalline Pattern K of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 26a.
• the thermogravimetric analysis pattern has a 0.1% w/w loss from 40 to 190 °C and a further 0.69% w/w loss from 190 to 310 °C.
• the DSC thermogram of the crystalline Pattern K of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 26b.
• the DSC thermogram has 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.
• the TGA pattern of the crystalline acetonitrile solvate Pattern N of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 29a.
• the thermogravimetric analysis pattern has a 5.44% w/w loss from 40 to 220 °C.
• the DSC thermogram of the crystalline acetonitrile solvate Pattern N of 3-(4-(4- aminopiperidin-l-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 29b.
• the DSC thermogram has an endothermic event having an onset at about 132.6 °C and a peak at about 144.0 °C; an endothermic event having an onset at about 179.7 °C and a peak at about 193.5 °C; and an endothermic event having an onset at about 192.4 °C and a peak at about 211.1 °C.
• the TGA pattern of the crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 31a.
• the thermogravimetric analysis pattern has a 4.54% w/w loss from 40 to 260 °C.
• the DSC thermogram of the crystalline hydrate Pattern O of 3-(4-(4-aminopiperidin-l-yl)-3-(3,5- difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 31b.
• the DSC thermogram has an endothermic event having an onset at about 206.9 °C and a peak at about 217.6 °C.
• Example C-4 Dynamic Vapor Sorption 1DVS1
• Dynamic Vapor Sorption was done using a DVS Intrinsic 1. The sample is loaded into a sample pan and suspended from a microbalance. A typical sample mass for DVS measurement is 25 mg. Nitrogen gas bubbled through distilled water provides the desired relative humidity.
• a typical measurement comprises the steps: 1- Equilibrate at 50% RH
• the DVS isotherm plot of the crystalline Pattern A of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 6.
• the DVS isotherm plot shows a reversible water uptake (9.8 % w/w) between 2% and 95% Relative Humidity (RH).
• the DVS isotherm plot of the crystalline hydrate Pattern B of 3-(4-(4-aminopiperidin-l- yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 11.
• the DVS isotherm plot shows a reversible water uptake (3.2 % w/w) between 2% and 95% Relative Humidity (RH).
• the DVS isotherm plot of the crystalline Pattern I of 3-(4-(4-aminopiperidin-l-yl)-3- (3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile dimesylate is displayed in Figure 18.
• the DVS isotherm plot shows a reversible water uptake (9.1 % w/w) between 2% and 95% Relative Humidity (RH); with a 2.5% w/w water uptake between 15 and 75% RH.
• Pattern I converts to Pattern B after DVS analysis between 2% and 95% RH and 25 °C, as determined by XRPD.
• Karl-Fischer titration for water determination was done using a Mettler Toledo C20S Coulometric KF Titrator equipped with a current generator cell with a diaphragm, and a doubleplatinum-pin electrode.
• AquastarTM CombiCoulomat fritless reagent was used in both the anode and cathode compartments. Samples of approximately 0.03 - 0.10 g were dissolved in the anode compartment and titrated until the solution potential dropped below 100 mV. Hydranal 1 wt. % water standard is used for validation prior to sample analysis.
• Results for select patterns are in the following table.
• Pattern A and Pattern B were loaded into separate 4 mL vials. These were placed in 20 mL vials with saturated aqueous NaCl and sealed to provide an environment of 75% RH at 40 °C. After one week, Pattern A had converted to Pattern B, and Pattern B remained the same. The same 1 week study was done with Pattern C(+I) and Pattern I, both remained stable by XRPD. The samples were also collected for chemical purity analysis by HPLC and did not degrade relative to the as-received material.
• Example C-8 Comparison of Compound A mono-HCl and 2MSA in Simulated Fluids Generation of Compound A mono-HCl salt
• HPLC High performance liquid chromatography
• Proton NMR was done on a Bruker Avance 300 MHz spectrometer. Solids are dissolved in 0.75 mL deuterated solvent in a 4 mL vial and transferred to an NMR tube (Wilmad 5mm thin wall 8” 200MHz, 506-PP-8). A typical measurement is usually 16 scans.
• 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.
• a suitable buffer is optionally added as well as optional acid or base to adjust the pH.
• the mixture is incorporated into a dosage unit form suitable for administration by injection
• a sufficient amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof is added to water (with optional solubilizer(s), optional buffer(s) and taste masking excipients) to provide a 20 mg/mL solution.
• a tablet is 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 appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg.
• a pharmaceutical composition for oral delivery 10-500 mg of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is optionally mixed with starch or other suitable powder blends.
• the mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

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