WO2023241551A1 - Sel et/ou forme cristalline de composés en tant qu'inhibiteurs de caséine kinase - Google Patents

Sel et/ou forme cristalline de composés en tant qu'inhibiteurs de caséine kinase Download PDF

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Publication number
WO2023241551A1
WO2023241551A1 PCT/CN2023/099850 CN2023099850W WO2023241551A1 WO 2023241551 A1 WO2023241551 A1 WO 2023241551A1 CN 2023099850 W CN2023099850 W CN 2023099850W WO 2023241551 A1 WO2023241551 A1 WO 2023241551A1
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degrees
type
endotherm
freebase
crystalline form
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PCT/CN2023/099850
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English (en)
Inventor
Guanglong WU
Yuan Liu
Hanping Wang
Qing Ma
Enxing ZHOU
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Gritscience Biopharmaceuticals Co., Ltd
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Publication of WO2023241551A1 publication Critical patent/WO2023241551A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application relates to salt and/or crystal form for compounds as casein kinase inhibitors, a pharmaceutical composition comprising said salt and/or crystal form, uses of said salt and/or crystal form and pharmaceutical compositions, and methods for preparing said salt and/or crystal form.
  • the compound HY-A is 2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -5- (methylsulfonyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine, which is a potent inhibitor of the casein kinase.
  • 2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -5- (methylsulfonyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine which is a potent inhibitor of the casein kinase.
  • no crystalline form of it has been reported yet.
  • the present application includes the unexpected discovery of novel solid forms of HY-A.
  • the novel salt and/or crystal form of HY-A disclosed herein have surprising and useful properties.
  • the present disclosure provides salt and/or crystal form for compounds as casein kinase inhibitors.
  • the present disclosure also provides a process for preparing the salt and/or crystal form for compounds as casein kinase inhibitors.
  • the present disclosure also provides a pharmaceutical composition contains the salt and/or crystal form for compounds as casein kinase inhibitors and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure also provides a method for inhibiting casein kinase includes a step of administering to a subject in need thereof an effective amount of the salt and/or crystal form for compounds as casein kinase inhibitors.
  • Figure 1-1 shows Inter-conversion diagram of HY-A freebase polymorphs
  • Figure 2-1 shows XRPD pattern of freebase Type A (823121-01-A) ;
  • Figure 2-2 shows TGA/DSC curves of freebase Type A (823121-01-A) ;
  • Figure 2-3 shows 1H NMR spectrum of freebase Type A (823121-01-A) ;
  • Figure 2-4 shows HPLC chromatogram of freebase Type A (823121-01-A) ;
  • Figure 2-5 shows VT-XRPD overlay of freebase Type A (823121-01-A) ;
  • Figure 2-6 shows XRPD pattern of freebase Type C (823121-16-A) ;
  • Figure 2-7 shows TGA/DSC curves of freebase Type C (823121-16-A) ;
  • Figure 2-8 shows 1H NMR spectrum of freebase Type C (823121-16-A) ;
  • Figure 2-9 shows UPLC chromatogram of freebase Type C (823121-16-A) ;
  • Figure 2-10 shows XRPD overlay of residual solids after equilibrium solubility test
  • Figure 3-1 shows XRPD overlay of HY-A freebase (I/IV) ;
  • Figure 3-2 shows XRPD overlay of HY-A freebase (II/IV) ;
  • Figure 3-3 shows XRPD overlay of HY-A freebase (III/IV) ;
  • Figure 3-4 shows XRPD overlay of HY-A freebase (IV/IV) ;
  • Figure 3-5 shows XRPD pattern of freebase Type P (823121-36-A2-TO 150C) ;
  • Figure 3-6 shows TGA/DSC curves of freebase Type P (823121-36-A2-TO 150C) ;
  • Figure 3-7 shows 1H NMR spectrum of freebase Type P (823121-36-A2-TO 150C) ;
  • Figure 3-8 shows VT-XRPD overlay of freebase Type P (823121-36-A2-TO 150C) ;
  • Figure 3-9 shows XRPD pattern of freebase Type N (823121-20-A10-DRY) ;
  • Figure 3-10 shows TGA/DSC curves of freebase Type N (823121-20-A10-DRY) ;
  • Figure 3-11 shows 1H NMR spectrum of freebase Type N (823121-20-A10-DRY) ;
  • Figure 3-12 shows XRPD overlay of re-preparation samples for freebase Type N
  • Figure 3-13 shows XRPD pattern of freebase Type Q (823121-45-A1_AFT 90C) ;
  • Figure 3-14 shows TGA/DSC curves of freebase Type Q (823121-45-A1_AFT 90C) ;
  • Figure 3-15 shows 1H NMR spectrum of freebase Type Q (823121-45-A1_AFT 90C) ;
  • Figure 3-16 shows XRPD overlay of freebase Type B samples
  • Figure 3-17 shows TGA/DSC curves of freebase Type B (823121-43-A2) ;
  • Figure 3-18 shows 1H NMR spectrum of freebase Type B (823121-43-A2) ;
  • Figure 3-19 shows VT-XRPD overlay of freebase Type B (823121-43-A2) (I/II) ;
  • Figure 3-20 shows VT-XRPD overlay of freebase Type B (823121-43-A2) (II/II) ;
  • Figure 3-21 shows XRPD overlay of freebase Type I samples
  • Figure 3-22 shows TGA/DSC curves of freebase Type I (823121-45-A1) ;
  • Figure 3-23 shows 1H NMR spectrum of freebase Type I (823121-45-A1) ;
  • Figure 3-24 shows XRPD overlay of freebase Type I (823121-45-A1) before and after heating;
  • Figure 3-25 shows VT-XRPD overlay of freebase Type I (823121-45-A1) ;
  • Figure 3-26 shows XRPD overlay of freebase Type L samples
  • Figure 3-27 shows TGA/DSC curves of freebase Type L (823121-36-A3) ;
  • Figure 3-28 shows 1H NMR spectrum of freebase Type L (823121-36-A3) ;
  • Figure 3-29 shows VT-XRPD overlay of freebase Type L (823121-36-A3) ;
  • Figure 3-30 shows XRPD pattern of freebase Type D (823121-20-A6-DRY) ;
  • Figure 3-31 shows TGA/DSC curves of freebase Type D (823121-20-A6-DRY) ;
  • Figure 3-32 shows 1H NMR spectrum of freebase Type D (823121-20-A6-DRY) ;
  • Figure 3-33 shows XRPD overlay of freebase Type D (823121-20-A6-DRY) before and after heating;
  • Figure 3-34 shows XRPD overlay of freebase Type F samples
  • Figure 3-35 shows TGA/DSC curves of freebase Type F (823121-17-A8-DRY) ;
  • Figure 3-36 shows 1H NMR spectrum of freebase Type F (823121-17-A8-DRY) ;
  • Figure 3-37 shows XRPD overlay of freebase Type F (823121-17-A8-DRY) before and after heating;
  • Figure 3-38 shows TGA curves of freebase Type F (823121-39-A1-1210) ;
  • Figure 3-39 shows 1H NMR spectrum of freebase Type F (823121-39-A1-1210) ;
  • Figure 3-40 shows XRPD pattern of freebase Type G (823121-18-A8-DRY) ;
  • Figure 3-41 shows TGA/DSC curves of freebase Type G (823121-18-A8-DRY) ;
  • Figure 3-42 shows 1H NMR spectrum of freebase Type G (823121-18-A8-DRY) ;
  • Figure 3-43 shows XRPD overlay of freebase Type G (823121-18-A8-DRY) before and after heating;
  • Figure 3-44 shows XRPD overlay of freebase Type H samples
  • Figure 3-45 shows TGA/DSC curves of freebase Type H (823121-37-A3) ;
  • Figure 3-46 shows 1H NMR spectrum of freebase Type H (823121-37-A3) ;
  • Figure 3-47 shows XRPD overlay of freebase Type H (823121-20-A16-DRY) before and after heating;
  • Figure 3-48 shows XRPD pattern of freebase Type J (823121-19-A5-DRY) ;
  • Figure 3-49 shows TGA/DSC curves of freebase Type J (823121-19-A5-DRY) ;
  • Figure 3-50 shows 1H NMR spectrum of freebase Type J (823121-19-A5-DRY) ;
  • Figure 3-51 shows XRPD overlay of freebase Type J (823121-19-A5-DRY) before and after heating;
  • Figure 3-52 shows XRPD pattern of freebase Type K (823121-19-A8-DRY) ;
  • Figure 3-53 shows TGA/DSC curves of freebase Type K (823121-19-A8-DRY) ;
  • Figure 3-54 shows 1H NMR spectrum of freebase Type K (823121-19-A8-DRY) ;
  • Figure 3-55 shows XRPD overlay of freebase Type K (823121-19-A8-DRY) before and after heating;
  • Figure 3-56 shows XRPD pattern of freebase Type M (823121-23-A4-DRY) ;
  • Figure 3-57 shows TGA/DSC curves of freebase Type M (823121-23-A4-DRY) ;
  • Figure 3-58 shows 1H NMR spectrum of freebase Type M (823121-23-A4-DRY) ;
  • Figure 3-59 shows XRPD overlay of freebase Type M (823121-23-A4-DRY) before and after heating;
  • Figure 3-60 shows XRPD pattern of freebase Type O (823121-18-A9-DRY) ;
  • Figure 3-61 shows TGA/DSC curves of freebase Type O (823121-18-A9-DRY) ;
  • Figure 3-62 shows 1H NMR spectrum of freebase Type O (823121-18-A9-DRY) ;
  • Figure 3-63 shows XRPD overlay of freebase Type O (823121-18-A9-DRY) before and after heating;
  • Figure 3-64 shows XRPD overlay of freebase Type C (823121-16-A) after/before soaking in MeOH and after drying;
  • Figure 3-65 shows XRPD overlay of freebase Type N (823121-45-A1-check) after/before soaking in MeOH and after drying;
  • Figure 3-66 shows XRPD pattern of freebase Type E (823121-23-A4) ;
  • Figure 3-67 shows XRPD pattern of freebase Type R (823121-43-A2-N2_30.0°C) ;
  • Figure 4-1 shows XRPD overlay of the solids from competitive slurry for 3 days
  • Figure 4-2 shows XRPD overlay of the solids from competitive slurry for 5 days
  • Figure 4-3 shows XRPD overlay of the solids from competitive slurry among Type C, B, I and L (I/II) ;
  • Figure 4-4 shows XRPD overlay of the solids from competitive slurry among Type C, B, I and L (II/II) ;
  • Figure 5-1 shows XRPD pattern of HCl salt Type A (823121-28-A1) ;
  • Figure 5-2 shows TGA/DSC curves of HCl salt Type A (823121-28-A1) ;
  • Figure 5-3 shows 1H NMR spectrum of HCl salt Type A (823121-28-A1) ;
  • Figure 5-4 shows XRPD pattern of citrate Type A (823121-28-A3) ;
  • Figure 5-5 shows TGA/DSC curves of citrate Type A (823121-28-A3) ;
  • Figure 5-6 shows 1H NMR spectrum of citrate Type A (823121-28-A3) ;
  • Figure 5-7 shows XRPD pattern of phosphate Type A (823121-32-A) ;
  • Figure 5-8 shows TGA/DSC curves of phosphate Type A (823121-32-A) ;
  • Figure 5-9 shows 1H NMR spectrum of phosphate Type A (823121-32-A) ;
  • Figure 6-1 shows Plots of kinetic solubility
  • Figure 6-2 shows XRPD overlay of residual solids from solubility test of HCl salt Type A in FaSSIF;
  • Figure 6-3 shows XRPD overlay of residual solids from solubility test of HCl salt Type A in FeSSIF;
  • Figure 6-4 shows XRPD overlay of residual solids from solubility test of citrate Type A in FaSSIF;
  • Figure 6-5 shows XRPD overlay of residual solids from solubility test of citrate Type A in FeSSIF;
  • Figure 6-6 shows XRPD overlay of residual solids from solubility test of phosphate Type A in FeSSIF
  • Figure 6-7 shows XRPD overlay of residual solids from solubility test of freebase Type A in H2O;
  • Figure 6-8 shows XRPD overlay of residual solids from solubility test of freebase Type A in FaSSIF;
  • Figure 6-9 shows XRPD overlay of residual solids from solubility test of freebase Type A in FeSSIF;
  • Figure 6-10 shows DVS plot of freebase Type C (823121-16-A) ;
  • Figure 6-11 shows XRPD overlay of freebase Type C (823121-16-A) before and after DVS;
  • Figure 6-12 shows DVS plot of HCl salt Type A (823121-28-A1) ;
  • Figure 6-13 shows XRPD overlay of HCl salt Type A (823121-28-A1) before and after DVS;
  • Figure 6-14 shows DVS plot of citrate Type A (823121-28-A3) ;
  • Figure 6-15 shows XRPD overlay of citrate Type A (823121-28-A3) before and after DVS;
  • Figure 6-16 shows DVS plot of phosphate Type A (823121-32-A) ;
  • Figure 6-17 shows XRPD overlay of phosphate Type A (823121-32-A) before and after DVS;
  • Figure 6-18 shows XRPD overlay of freebase Type A (823121-01-A) before and after stability evaluation
  • Figure 6-19 shows XRPD overlay of freebase Type C (823121-16-A) before and after stability evaluation
  • Figure 6-20 shows XRPD overlay of HCl salt Type A (823121-28-A1) before and after stability evaluation;
  • Figure 6-21 shows XRPD overlay of citrate Type A (823121-28-A3) before and after stability evaluation;
  • Figure 6-22 shows XRPD overlay of phosphate Type A (823121-32-A) before and after stability evaluation
  • Figure 6-23 shows UPLC chromatogram of freebase Type A (823121-01-A) after stability evaluation at 25 °C /60%RH for one week;
  • Figure 6-24 shows UPLC chromatogram of freebase Type A (823121-01-A) after stability evaluation at 40 °C /75%RH for one week;
  • Figure 6-25 shows UPLC chromatogram of freebase Type C (823121-16-A) after stability evaluation at 25 °C /60%RH for one week;
  • Figure 6-26 shows UPLC chromatogram of freebase Type C (823121-16-A) after stability evaluation at 40 °C /75%RH for one week;
  • Figure 6-27 shows UPLC chromatogram of HCl salt Type A (823121-28-A1) after stability evaluation at 25 °C /60%RH for one week;
  • Figure 6-28 shows UPLC chromatogram of HCl salt Type A (823121-28-A1) after stability evaluation at 40 °C /75%RH for one week;
  • Figure 6-29 shows UPLC chromatogram of citrate Type A (823121-28-A3) after stability evaluation at 25 °C /60%RH for one week;
  • Figure 6-30 shows UPLC chromatogram of citrate Type A (823121-28-A3) after stability evaluation at 40 °C /75%RH for one week;
  • Figure 6-31 shows UPLC chromatogram of phosphate Type A (823121-32-A) after stability evaluation at 25 °C /60%RH for one week;
  • Figure 6-32 shows UPLC chromatogram of phosphate Type A (823121-32-A) after stability evaluation at 40 °C /75%RH for one week;
  • Figure 7-1 shows XRPD pattern of freebase Type T (823121-63-A) ;
  • Figure 7-2 shows XRPD overlay of Type T (823121-63-A) before and after heating;
  • Figure 7-3 shows 1H NMR spectrum of freebase Type T (823121-63-A) after heating;
  • Figure 7-4 shows XRPD overlay of HCl salt Type A/B (823121-06-D1/D2) ;
  • Figure 7-5 shows TGA/DSC curves of HCl salt Type A (823121-06-D1) ;
  • Figure 7-6 shows 1H NMR spectrum of HCl salt Type A (823121-06-D1) ;
  • Figure 7-7 shows VT-XRPD overlay of HCl salt Type A (823121-06-D1) ;
  • Figure 7-8 shows TGA/DSC curves of HCl salt Type B (823121-06-D2) ;
  • Figure 7-9 shows 1H NMR spectrum of HCl salt Type B (823121-06-D2) ;
  • Figure 7-10 shows XRPD pattern of sulfate Type A (823121-06-C3) ;
  • Figure 7-11 shows TGA/DSC curves of sulfate Type A (823121-06-C3) ;
  • Figure 7-12 shows 1H NMR spectrum of sulfate Type A (823121-06-C3) ;
  • Figure 7-13 shows XRPD overlay of maleate Type A/B/C (823121-06-A4/D4/C4) ;
  • Figure 7-14 shows TGA/DSC curves of maleate Type A (823121-06-A4) ;
  • Figure 7-15 shows 1H NMR spectrum of maleate Type A (823121-06-A4) ;
  • Figure 7-16 shows TGA/DSC curves of maleate Type B (823121-06-D4) ;
  • Figure 7-17 shows 1H NMR spectrum of maleate Type B (823121-06-D4) ;
  • Figure 7-18 shows TGA/DSC curves of maleate Type C (823121-06-C4) ;
  • Figure 7-19 shows 1H NMR spectrum of maleate Type C (823121-06-C4) ;
  • Figure 7-20 shows XRPD pattern of phosphate Type A (823121-06-A6) ;
  • Figure 7-21 shows TGA/DSC curves of phosphate Type A (823121-06-A6) ;
  • Figure 7-22 shows 1H NMR spectrum of phosphate Type A (823121-06-A6) ;
  • Figure 7-23 shows XRPD overlay of L-tartrate Type A/B (823121-06-A7/C7) ;
  • Figure 7-24 shows TGA/DSC curves of L-tartrate Type A (823121-06-A7) ;
  • Figure 7-25 shows 1H NMR spectrum of L-tartrate Type A (823121-06-A7) ;
  • Figure 7-26 shows TGA/DSC curves of L-tartrate Type B (823121-06-C7) ;
  • Figure 7-27 shows 1H NMR spectrum of L-tartrate Type B (823121-06-C7) ;
  • Figure 7-28 shows XRPD pattern of fumarate Type A (823121-06-A8) ;
  • Figure 7-29 shows TGA/DSC curves of fumarate Type A (823121-06-A8) ;
  • Figure 7-30 shows 1H NMR spectrum of fumarate Type A (823121-06-A8) ;
  • Figure 7-31 shows XRPD pattern of citrate Type A (823121-06-C9) ;
  • Figure 7-32 shows TGA/DSC curves of citrate Type A (823121-06-C9) ;
  • Figure 7-33 shows 1H NMR spectrum of citrate Type A (823121-06-C9) ;
  • Figure 7-34 shows XRPD pattern of tosylate Type A (823121-06-A10) ;
  • Figure 7-35 shows TGA/DSC curves of tosylate Type A (823121-06-A10) ;
  • Figure 7-36 shows 1H NMR spectrum of tosylate Type A (823121-06-A10) ;
  • Figure 7-37 shows XRPD overlay of mesylate A/B (823121-06-C11/D11) ;
  • Figure 7-38 shows TGA/DSC curves of mesylate Type B (823121-06-D11) ;
  • Figure 7-39 shows 1H NMR spectrum of mesylate Type B (823121-06-D11) ;
  • Figure 7-40 shows XRPD overlay of besylate Type A/B/C (823121-06-A12/B12/C12) ;
  • Figure 7-41 shows TGA/DSC curves of besylate Type A (823121-06-A12) ;
  • Figure 7-42 shows 1H NMR spectrum of besylate Type A (823121-06-A12) ;
  • Figure 7-43 shows TGA/DSC curves of besylate Type B (823121-06-B12) ;
  • Figure 7-44 shows 1H NMR spectrum of besylate Type B (823121-06-B12) ;
  • Figure 7-45 shows TGA/DSC curves of besylate Type C (823121-06-C12) ;
  • Figure 7-46 shows 1H NMR spectrum of besylate Type C (823121-06-C12) ;
  • Figure 7-47 shows XRPD pattern of gentisate Type A (823121-06-C13) ;
  • Figure 7-48 shows TGA/DSC curves of gentisate Type A (823121-06-C13) ;
  • Figure 7-49 shows 1H NMR spectrum of gentisate Type A (823121-06-C13) ;
  • Figure 7-50 shows UPLC overlay of supernatants from the equilibrium solubility experiments in water and pH buffers
  • Figure 7-51 shows LC-MS results of the supernatant from the equilibrium solubility experiment in pH 6.0 buffer
  • Figure 7-52 shows LC-MS results of the supernatant from the equilibrium solubility experiment in pH 8.0 buffer
  • Figure 7-53 shows LC-MS results of the supernatant from the equilibrium solubility experiment in water.
  • Figure 7-54 shows UPLC overlay of supernatants from the kinetic solubility experiments in water for 1 hr. ;
  • Figure 7-55 shows UPLC overlay of supernatants from the kinetic solubility experiments in FaSSIF for 1 hr. ;
  • Figure 7-56 shows XRPD overlay of residual solids after slurry in water for 24 hrs or 6 days;
  • Figure 7-57 shows UPLC overlay of supernatants after slurry in water for 24 hrs or 6 days. ;
  • Figure 7-58 shows UPLC chromatogram of residual solids after slurry of freebase Type C in water for 24 hrs;
  • Figure 7-59 shows UPLC chromatogram of residual solids after slurry freebase Type C in water for 6 days.
  • treating generally refers to reversing, alleviating the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment generally refers to the act of treating as “treating” is defined immediately above.
  • treating may also include adjuvant and neo-adjuvant treatment of a subject.
  • the term “preventing” unless otherwise indicated, generally refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It may be understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words may be also expressly disclosed.
  • the term “pharmaceutically acceptable salt” generally refers to a salt that may be pharmaceutically acceptable and that may possess the desired pharmacological activity of the parent compound.
  • Such salts may include: acid addition salts, formed with inorganic acids or formed with organic acids or basic addition salts formed with the conjugate bases of any of the inorganic acids wherein the conjugate bases comprise a cationic component.
  • aqueous or nonaqueous solutions generally refers to aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles may include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) , carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
  • Injectable depot forms may be made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly (orthoesters) and poly (anhydrides) . Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release may be controlled. Depot injectable formulations may be also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers may include sugars such as lactose. Desirably, at least 95%by weight of the particles of the active ingredient may have an effective particle size in the range of 0.01 to 10 micrometers.
  • prodrug generally refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention.
  • Typical examples of prodrugs may include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs may include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, dedcylated, phosphorylated, dephosphorylated to produce the active compound.
  • casein kinase generally refers to a protein having an activity of catalyzing the serine/threonine-selective phosphorylation of proteins. This activity may be referred to as “casein kinase activity” .
  • the Gene ID for gene encoding casein kinase may be 1453 or 1454.
  • the term “subject” generally refers to an animal, which may include, but not limited to, cattle, pigs, sheep, chicken, turkey, buffalo, llama, ostrich, dogs, cats, and humans, and the subject may be a human. It may be contemplated that in the method of treating a subject thereof of the sixth embodiment can be any of the compounds either alone or in combination with another compound of the present invention.
  • an “effective amount” generally refers to an amount of an agent or a compound being administered which will treat a disease or disorder, or some or all of the symptom. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in a disease or disorder symptoms without undue adverse side effects.
  • administering generally refers to the compound may be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form.
  • the term “formula” may be hereinafter referred to as a “compound (s) of the invention” . Such terms are also defined to include all forms of the compound of formula, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof.
  • the compounds of formula, or pharmaceutically acceptable salts thereof may exist in unsolvated and solvated forms.
  • the complex When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity.
  • the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • the compounds of “formula” may have asymmetric carbon atoms.
  • the carbon-carbon bonds of the compounds of formula may be depicted herein using a solid line, a solid wedge, or a dotted wedge.
  • the use of a solid line to depict bonds to asymmetric carbon atoms may be meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc. ) at that carbon atom are included.
  • the use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms may be meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the present application may contain more than one asymmetric carbon atom.
  • a solid line to depict bonds to asymmetric carbon atoms may be meant to indicate that all possible stereoisomers are meant to be included.
  • the compounds of formula can exist as enantiomers and diastereomers or as racemates and mixtures thereof.
  • the use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of formula and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound may be meant to indicate that a mixture of diastereomers is present.
  • the compounds of the present application may exist as clathrates or other complexes. Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host may be present in stoichiometric or non-stoichiometric amounts. Also included may be complexes of formula containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. Pharm. Sci., 64 (8) , 1269-1288 by Haleblian (August 1975) .
  • Stereoisomers of formula may include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of formula, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs) . Also included may be acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • the compounds of formula may exhibit the phenomena of tautomerism and structural isomerism.
  • the compounds of formula may exist in several tautomeric forms, including the enol and imine forms, and the keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms may be included within the scope of compounds of formula.
  • Tautomers may exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of formula.
  • the present invention also includes isotopically-labeled compounds, which are identical to those recited in formula above, but for the fact that one or more atoms may be 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 may be incorporated into compounds of formula include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • isotopically-labeled compounds of formula for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, may be useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes may be particularly used for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be used in some circumstances.
  • Isotopically-labeled compounds of formula may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
  • the compounds of the present application may be used in the form of salts derived from inorganic or organic acids.
  • a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidity, or a desirable solubility in water or oil.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • the present application provides crystalline form of compound HY-A, 2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -5- (methylsulfonyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine, wherein said crystalline form exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta selected from the group consisting of:
  • said crystalline form further exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta selected from the group consisting of:
  • said crystalline form exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta selected from the group consisting of:
  • said crystalline form exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta selected from the group consisting of:
  • said crystalline form exhibits mass loss in the TGA (thermogravimetric) analysis selected from the group consisting of:
  • said crystalline form exhibits endotherm and/or exotherm peak in the DSC (differential scanning calorimetry) analysis selected from the group consisting of:
  • crystalline form exhibits salt stoichiometry in the UPLC-IC (ultra-performance liquid chromatography-ion chromatography) analysis selected from the group consisting of (molar rate of acid and freebase) :
  • said crystalline form comprises no residual solvent or comprises residual solvent selected from the group consisting of: 0.2 weight%of EtOAc; 6.3 weight%of 2-MeTHF; 9.3 weight%of 1, 4-Dioxane; 7.2 weight%of CHCl 3 ; 9.0 weight%of Toluene, 0.7 weight%of 2-MeTHF; 11.9 weight%of Anisole; 6.6 weight%of Toluene; 5.3 weight%of n-Hexane; and 12.3 weight%of DMSO.
  • residual solvent selected from the group consisting of: 0.2 weight%of EtOAc; 6.3 weight%of 2-MeTHF; 9.3 weight%of 1, 4-Dioxane; 7.2 weight%of CHCl 3 ; 9.0 weight%of Toluene, 0.7 weight%of 2-MeTHF; 11.9 weight%of Anisole; 6.6 weight%of Toluene; 5.3 weight%of n-Hexane; and 12.3 weight%of DMSO.
  • said crystalline form exhibits purity rate in the LC-MS (liquid chromatography–mass spectrometry) analysis selected from the group consisting of: (1) 99.8 area%; (2) 99.7 area%; (3) 100.0 area%; (4) 99.80 area%; and (5) 99.7 area%.
  • LC-MS liquid chromatography–mass spectrometry
  • said crystalline form has solubility selected from the group consisting of:
  • said crystalline form exhibits hygroscopicity in the DVS (Dynamic vapor sorption) analysis at 25 °C and 80%RH (room humidity) selected from the group consisting of: 4.12%, 0.38%, 0.97%, and 0.50%.
  • DVS Dynamic vapor sorption
  • room humidity room humidity
  • the present application provides an acid addition salt of crystalline form of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing.
  • the present application provides a process of preparing crystalline form of the present application, the process is selected from the group consisting of:
  • compound HY-A is heated to 130 °C and cooled to 30 °C under N 2 atmosphere;
  • compound HY-A is added in IPA/MIBK (1: 1, v/v) at 50 °C for 5 days followed by vacuum drying;
  • compound HY-A is heated to 90 °C under N 2 atmosphere followed by cooling to RT;
  • compound HY-A is added in ACN/H 2 O (v/v, 1: 4) for 5 days followed by drying at RT;
  • compound HY-A is added in 2-MeTHF at 50 °C for 5 days followed by slurrying at 5 °Cfor 1 day and drying at RT;
  • compound HY-A is added in 2-MeTHF/toluene (v/v, 1: 1) at 50 °C for 5 days followed by drying at RT;
  • the present application provides a pharmaceutical composition
  • the pharmaceutical composition comprises crystalline form of the present application and/or acid addition salt of crystalline form of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, and a pharmaceutically acceptable carrier.
  • the present application provides a kit, the kit comprises crystalline form of the present application, acid addition salt of crystalline form of the present application and/or pharmaceutical composition of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, and a pharmaceutically acceptable carrier.
  • the present application provides a method for inhibiting casein kinase (CK) activity, said method comprising administering to a subject in need thereof an effective amount of crystalline form of the present application, acid addition salt of crystalline form of the present application and/or pharmaceutical composition of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing and/or kit of the present application.
  • the casein kinase (CK) may be selected from the group consisting of casein kinase I alpha (CK1 ⁇ ) , casein kinase I delta (CK1 ⁇ ) and casein kinase I epsilon (CK1 ⁇ ) .
  • the method may be selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.
  • the present application provides use crystalline form of the present application, acid addition salt of crystalline form of the present application and/or pharmaceutical composition of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing and/or kit of the present application in the preparation of a drug and/or a kit for use in inhibiting casein kinase (CK) activity.
  • the casein kinase (CK) may be selected from the group consisting of casein kinase I alpha (CK1 ⁇ ) , casein kinase I delta (CK1 ⁇ ) and casein kinase I epsilon (CK1 ⁇ ) .
  • the method may be selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.
  • the present application provides crystalline form of the present application, acid addition salt of crystalline form of the present application and/or pharmaceutical composition of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing and/or kit of the present application for use in inhibiting casein kinase (CK) activity.
  • the casein kinase (CK) may be selected from the group consisting of casein kinase I alpha (CK1 ⁇ ) , casein kinase I delta (CK1 ⁇ ) and casein kinase I epsilon (CK1 ⁇ ) .
  • the method may be selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.
  • the present application provides a method for preventing and/or treating a disease or disorder, said method comprising administering to a subject in need thereof an effective amount of the compound of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing.
  • the disease or disorder may be selected from the group consisting of neurological disease and psychiatric disease.
  • the disease or disorder may be selected from the group consisting of mood disorder, sleep disorder, and circadian disorder.
  • the disease or disorder may be selected from the group consisting of depressive disorder and bipolar disorder.
  • the present application provides use crystalline form of the present application, acid addition salt of crystalline form of the present application and/or pharmaceutical composition of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing and/or kit of the present application in the preparation of a drug and/or a kit for use in preventing and/or treating a disease or disorder.
  • the disease or disorder may be selected from the group consisting of neurological disease and psychiatric disease.
  • the disease or disorder may be selected from the group consisting of mood disorder, sleep disorder, and circadian disorder.
  • the disease or disorder may be selected from the group consisting of depressive disorder and bipolar disorder.
  • the present application provides crystalline form of the present application, acid addition salt of crystalline form of the present application and/or pharmaceutical composition of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing and/or kit of the present application for use in preventing and/or treating a disease or disorder.
  • the disease or disorder may be selected from the group consisting of neurological disease and psychiatric disease.
  • the disease or disorder may be selected from the group consisting of mood disorder, sleep disorder, and circadian disorder.
  • the disease or disorder may be selected from the group consisting of depressive disorder and bipolar disorder.
  • the present application provides compositions comprising a compound of the present application or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, and optionally a pharmaceutically acceptable carrier.
  • the compounds of the application may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • the compounds of the present application may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration may include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration may include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • the compounds of the present application may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In some cases, the compounds of the present application may also be administered intranasally or by inhalation. In some cases, the compounds of the present application may be administered rectally or vaginally. In another embodiment, the compounds of the present application may also be administered directly to the eye or ear.
  • the dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day may be useful in the treatment of the above-indicated conditions.
  • Suitable subjects according to the present invention include mammalian subjects. Mammals according to the present invention may include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
  • the present application provides use of one or more compounds of the present application for the preparation of a medicament for the treatment of the conditions recited herein.
  • the compounds of the present application may be administered as compound per se.
  • pharmaceutically acceptable salts may be suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
  • compositions may comprise a compound of the present application presented with a pharmaceutically acceptable carrier.
  • the carrier may be a solid product, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05%to 95%by weight of the active compounds.
  • a compound of the present application may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances may also be present.
  • the compounds of the present invention may be administered by any suitable route, maybe in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the active compounds and compositions for example, may be administered orally, rectally, parenterally, or topically.
  • the compounds of the present application may be used, alone or in combination with other therapeutic agents, in the treatment of various conditions or disease states.
  • the compound (s) of the present application and other therapeutic agent (s) may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially.
  • the administration of two or more compounds “in combination” may mean that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other.
  • the two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.
  • Standard abbreviations may be used, e.g., bp, base pair (s) ; kb, kilobase (s) ; pl, picoliter (s) ; s or sec, second (s) ; min, minute (s) ; h or hr, hour (s) ; aa, amino acid (s) ; nt, nucleotide (s) ; i.m., intramuscular (ly) ; i.p., intraperitoneal (ly) ; s.c., subcutaneous (ly) ; and the like.
  • the CK1 ⁇ kinase assay was performed with a buffer (40 ⁇ L, pH 7.5) containing 50 mM Tris, 10 mM MgCl 2 , 1 mM dithiothreitol, 100 ⁇ g/mL BSA with 10 ⁇ M ATP, 2nM wild type CK1 ⁇ , and 42 ⁇ M peptide substrate PLSRTLpSVASLPGL (Flotow et al., 1990) in the presence of 1 ⁇ L of a CK1 ⁇ inhibitor (e.g., a compound of the present application) or 4%DMSO (e.g., as control) .
  • a CK1 ⁇ inhibitor e.g., a compound of the present application
  • 4%DMSO e.g., as control
  • reaction mixture was incubated for 85 min at 25 °C; detection was carried out as described for the Kinase-Glo Assay (Promega) .
  • Luminescent output was measured on the Perkin Elmer Envision plate reader (PerkinElmer, Waltham, MA) .
  • Bmal1-dLuc or Per2-dLuc U2OS cells were suspended in the culture medium (DMEM supplemented with 10%fetal bovine serum, 0.29 mg/mL L-glutamine, 100 units/mL penicillin, and 100 mg/mL streptomycin) and plated onto 96-well white solid-bottom plates at 200 ⁇ L (10,000 cells) per well.
  • DMEM fetal bovine serum
  • 0.29 mg/mL L-glutamine 100 units/mL penicillin
  • streptomycin 100 mg/mL
  • the CK1 ⁇ inhibition results (IC50) of HY-A is 369.4 nM.
  • the CK1 ⁇ inhibition results (EC50) of HY-A is 2.2 ⁇ M.
  • the present disclosure provides HY-A as potent inhibitor of casein kinase.
  • Caco-2 cells were diluted to 6.86 ⁇ 10 5 cells/mL with culture medium and 50 ⁇ L of cell suspension were dispensed into the filter well of the 96-well HTS Transwell plate. Cells were cultivated for 14-18 days in a cell culture incubator at 37 °C, 5%CO 2 , 95%relative humidity. Cell culture medium was replaced every other day, beginning no later than 24 hours after initial plating.
  • TEER Transepithelial electrical resistance
  • the TEER value was calculated according to the following equation:
  • TEER measurement (ohms) *Area of membrane (cm 2 ) TEER value (ohm ⁇ cm 2 )
  • TEER value should be greater than 230 ohm ⁇ cm 2 , which indicates the well-qualified Caco-2 monolayer.
  • Lucifer Yellow leakage after 2 hour transport period stock solution of Lucifer yellow was prepared in water and diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 ⁇ M. 100 ⁇ L of the Lucifer yellow solution was added to each Transwell insert (apical compartment) , followed by filling the wells in the receiver plate (basolateral compartment) with 300 ⁇ L of HBSS (10 mM HEPES, pH 7.4) . The plates were Incubated at 37 °C for 30 mins. 80 ⁇ L samples were removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates. The Lucifer Yellow fluorescence (to monitor monolayer integrity) signal was measured in a fluorescence plate reader at 485 nM excitation and 530 nM emission.
  • V A is the volume (in mL) in the acceptor well
  • Area is the surface area of the membrane (0.143 cm 2 for Transwell-96 Well Permeable Supports)
  • time is the total transport time in seconds.
  • P app (B-A) indicates the apparent permeability coefficient in basolateral to apical direction
  • P app (A-B) indicates the apparent permeability coefficient in apical to basolateral direction
  • V A is the volume (in mL) in the acceptor well (0.235 mL for Ap ⁇ Bl flux, and 0.075 mL for Bl ⁇ Ap)
  • V D is the volume (in mL) in the donor well (0.075 mL for Ap ⁇ Bl flux, and 0.235 mL for Bl ⁇ Ap)
  • the master solution was prepared according to below.
  • reaction was started with the addition of 4 ⁇ L of 200 ⁇ M test compound solution or control compound solution at the final concentration of 2 ⁇ M and carried out at 37 °C.
  • Peak areas were determined from extracted ion chromatograms.
  • the slope value, k was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs.incubation time curve.
  • in vitro half-life (in vitro t 1/2 ) was determined from the slope value:
  • the HY-A has a desirable intrinsic clearance property.
  • the purpose of this application is to perform a salt screening for compound HY-A and a polymorph screening for a selected salt or freebase to identify solid forms for toxicology study and further development.
  • freebase Type C as material, 100 polymorph screening experiments were performed, using methods of anti-solvent addition, solid vapor diffusion, slurry at room temperature (RT) and 50 °C, slow evaporation, slow cooling, liquid vapor diffusion, polymer induced crystallization and grinding. A total of 20 polymorphs were obtained from screening and further experiments, named as freebase Type A ⁇ T, which were characterized using X-ray powder diffraction (XRPD) , thermogravimetric analysis (TGA) , differential scanning calorimeter (DSC) and proton nuclear magnetic resonance ( 1 H NMR) .
  • XRPD X-ray powder diffraction
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimeter
  • 1 H NMR proton nuclear magnetic resonance
  • Type A, C, P, N and Q were anhydrates
  • Type B, I and L were hydrates
  • Type D, F, G, H, J, K, M, O, S and T were solvates
  • Type E converted to Type M after drying at 20 ⁇ 22 °C/44 ⁇ 77%RH
  • Type R may be converted to Type B after exposing to air for 10 min
  • freebase Type C was obtained when a w ⁇ 0.6; freebase Type L was obtained when a w was 0.8, while freebase Type B was obtained in pure water (a w ⁇ 1) .
  • the inter-conversion diagram was shown in Figure 1-1, and the conversion methods were summarized in Table 1-2. Based on the inter-conversion results, freebase Type C showed: good properties in solid state; the most stable at RT and 50 °C among anhydrates; stable in a relative wide range of water activity (0 ⁇ 0.6) .
  • a salt screening was performed under 52 different conditions using 12 acids (different molar ratios of HCl was applied) in 4 solvent systems.
  • a total of 11 crystalline salt hits (19 crystal forms) were obtained during screening, which were characterized by XRPD, TGA and DSC.
  • the salt stoichiometry was determined using 1 H NMR or ultra performance liquid chromatography (UPLC) combined with ion chromatography (IC) .
  • HCl salt Type A citrate Type A and phosphate Type A were selected for re-preparation, and the results showed HCl salt Type A, citrate Type A and phosphate Type A were obtained successfully.
  • the three re-prepared salt forms and freebase were used for evaluation, including kinetic solubility, hygroscopicity (DVS) and solid stability.
  • the results of salt evaluation were summarized in Table 1-3. The evaluation results were summarized as following.
  • Hygroscopicity results water update of freebase Type C, citrate Type A and phosphate Type A were 0.50%, 0.38%and 0.97%, respectively, at 25 °C/80%RH (slightly hygroscopic) .
  • HCl salt Type A showed water uptake of 2.95%at 25 °C/30%RH and 4.07%at 25 °C/80%RH.
  • freebase Type C may be proper for further development and toxicology study. If salts are considered for development as backup of freebase Type C, the salt candidate could be selected based on the kinetic solubility evaluation and PK results.
  • batch one (200754-075-P3, which was employed for approximate solubility test, salt screening experiment, equilibrium solubility, kinetic solubility and solid stability evaluations)
  • batch two (200754-075-P5, which was employed for the freebase polymorph screening experiment, hygroscopicity and solid stability evaluations) . Both of these two batches were characterized by XRPD, TGA, DSC, 1 H NMR and purity tests.
  • the material (200754-075-P3; 823121-01-A) was tested.
  • XRPD result was displayed in Figure 2-1, named as freebase Type A.
  • TGA/DSC curves were displayed in Figure 2-2.
  • TGA result showed a weight loss of 2.2%up to 150 °C.
  • DSC result showed one endotherm at 175.6 °C (peak) and one exotherm at 121.5 °C (peak) .
  • 1 H NMR result was displayed in Figure 2-3. Due to the small TGA weight loss, the freebase Type A was postulated to be an anhydrate.
  • the HPLC result was displayed in Figure 2-4 and Table 2-1, which showed the purity of this freebase Type A material was 99.8 area%.
  • VT-XRPD Variable-temperature XRPD
  • the material (200754-075-P5; 823121-16-A) was tested.
  • XRPD result was displayed in Figure 2-6, named as freebase Type C.
  • TGA/DSC curves were displayed in Figure 2-7.
  • TGA result showed a weight loss of 0.6%up to 120 °C.
  • DSC result showed one endotherm at 176.2 °C (peak) .
  • 1 H NMR result was displayed in Figure 2-8. Due to the small TGA weight loss, the freebase Type A was postulated to be an anhydrate.
  • the UPLC result was displayed in Figure 2-9 and Table 2-2, which showed the purity of this freebase Type C material was 99.70 area%.
  • freebase Type B After slurry of the freebase Type A material (823121-01-A) in pH 2.0, 4.0, 6.0, 8.0 buffers for 24 hrs, a new form was obtained, named as freebase Type B.
  • the solubility in pH 2.0 and 4.0 was 2.36 and 1.47 mg/mL, respectively, relatively higher comparing to the solubility in other medias (0.023 ⁇ 0.046 mg/mL) .
  • Freebase Type P (823121-36-A2-TO 150C) was obtained via heating freebase Type K (823121-36-A2) to 120 °C under N 2 atmosphere followed by cooling to RT in air.
  • XRPD pattern was shown in Figure 3-5.
  • TGA/DSC curves were displayed in Figure 3-6.
  • TGA result showed a weight loss of 7.0%up to 120 °C.
  • DSC result showed one endotherm at 176.1 °C.
  • 1 H NMR result Figure 3-7) showed no detectable solvent residue was found.
  • VT-XRPD was performed for freebase Type P.
  • Freebase Type N (823121-20-A10-DRY) was obtained via slurry of the freebase Type C material (823121-16-A) in IPA/MIBK (1: 1, v/v) at 50 °C for 5 days followed by vacuum drying. XRPD pattern was shown in Figure 3-9. TGA/DSC curves were displayed in Figure 3-10. TGA result showed a weight loss of 3.5%up to 120 °C. DSC result showed two endotherms at 170.4 °C and 176.1 °C. 1 H NMR result ( Figure 3-11) showed no detectable IPA or MIBK solvent residue was found.
  • freebase Type N was also obtained from the VT-XRPD experiments of freebase Type I, obtaining a mixture of freebase Type N and C by heating the sample to 130 °C under N 2 atmosphere (Example) . Therefore, freebase Type N was postulated to be an anhydrate. Re-preparation of freebase Type N by using freebase Type A (823121-01-A) as the material was attempted, and the result was summarized in Table 3-1. The XRPD result was displayed in Figure 3-12 showing all of the re-preparation samples were freebase Type C.
  • Freebase Type Q (823121-45-A1_AFT 90C) was obtained via heating freebase Type I (823121-45-A1) to 90 °C under N 2 atmosphere followed by cooling to RT (Example) .
  • XRPD pattern was shown in Figure 3-13.
  • TGA/DSC curves were displayed in Figure 3-14.
  • TGA result showed a weight loss of 1.1%up to 120 °C.
  • DSC result showed three endotherms at 115.9 °C, 170.3 °C and 176.1 °C (peak) and one exotherm at 120.0 °C (peak) .
  • 1 H NMR result ( Figure 3-15) showed no detectable solvent residue was found. Since freebase Type Q was obtained under heating condition and N 2 atmosphere, combined with its small TGA weight loss, freebase Type Q was postulated to be an anhydrate.
  • Freebase Type B (823121-24-A5-DRY) obtained in the polymorph screening experiments was via slow evaporating the solution of material (823121-16-A) along with polymer mixture B at RT.
  • the re-prepared freebase Type B was obtained via slurry of the freebase Type C material (823121-16-A) in H 2 O for one day followed by drying at RT.
  • XRPD pattern was shown in Figure 3-16.
  • the TGA/DSC curves were displayed in Figure 3-17.
  • TGA result showed a weight loss of 13.6%up to 120 °C (the weight loss for monohydrate was about 4.3%) .
  • DSC result showed two endotherms at 91.5 °C and 175.8 °C (peak) .
  • the 1 H NMR result showed in Figure 3-18.
  • VT-XRPD results of freebase Type B (823121-43-A2) , displayed in Figure 3-19 and Figure 3-20, showed peak shift after purging N 2 for 20 min, and the form, after N 2 purging, was named as freebase Type R.
  • freebase Type R After exposing to air for 10 min, freebase Type R was converted back to freebase Type B.
  • Freebase Type C was obtained after heating freebase Type B to 100 °C under N 2 atmosphere. No further form change was observed after cooling to 30 °C under N 2 atmosphere and exposing to air for 10 min. Combined with the form change after heating and large TGA weight loss, freeform Type B was postulated as a hydrate.
  • Freebase Type I (823121-19-A1-DRY) was obtained via slurry of the freebase Type C material (823121-16-A) in MeOH for 5 days followed by drying at RT. Re-prepared freebase Type I sample (823121-45-A1) was obtained under the same procedure. XRPD pattern was shown in Figure 3-21. The TGA/DSC curves were displayed in Figure 3-22. TGA result showed a weight loss of 7.6%up to 120 °C. DSC result showed four endotherms at 89.0 °C, 116.2 °C, 170.5 °C and 176.9 °C (peak) and one exotherm at 122.5 °C (peak) .
  • Freebase Type L (823121-19-A1-DRY) was obtained via slurry of the freebase Type C material (823121-16-A) in ACN/H 2 O (v/v, 1: 4) for 5 days followed by drying at RT.
  • Re-prepared freebase Type L sample (823121-36-A3) was obtained under the same procedure.
  • XRPD pattern was shown in Figure 3-26.
  • the TGA/DSC curves were displayed in Figure 3-27. TGA result showed a weight loss of 13.9%up to 120 °C.
  • DSC result showed four endotherms at 66.2 °C, 70.8 °C, 79.1 °C and 176.0 °C (peak) .
  • the 1 H NMR ( Figure 3-28) result showed no detectable ACN residue was found.
  • VT-XRPD results of freebase Type L (823121-36-A3) , displayed in Figure 3-29, showed the form was converted to freebase Type A after purging N 2 for 20 min. After heating to 120 °C under N 2 atmosphere, cooling to 30 °C under N 2 atmosphere and exposing to air for 10 min, no form change was observed. Combined with the endotherm signal and large TGA weight loss, freeform Type L was postulated as a hydrate.
  • Freebase Type D (823121-20-A6-DRY) was obtained via slurry of the freebase Type C material (823121-16-A) in 2-MeTHF at 50 °C for 5 days followed by slurrying at 5 °C for 1 day and drying at RT.
  • XRPD pattern was shown in Figure 3-30.
  • the TGA/DSC curves were displayed in Figure 3-31.
  • TGA result showed a weight loss of 8.9%up to 120 °C.
  • DSC result showed two endotherms at 99.9 °C and 175.7 °C (peak) .
  • the 1 H NMR ( Figure 3-32) result showed the molar ratio of residual 2-MeTHF/API was 0.3 (6.3 wt%) .
  • Freebase Type F (823121-17-A8-DRY) was obtained via adding anti-solvent of MTBE into the 1, 4-dioxane solution of the material (823121-16-A) , followed by drying at RT. XRPD pattern was shown in Figure 3-34.
  • the TGA/DSC curves were displayed in Figure 3-35.
  • TGA result showed a weight loss of 24.5%up to 150 °C.
  • DSC result showed two endotherms at 126.3 °C and 175.3 °C (peak) .
  • the 1 H NMR ( Figure 3-36) result showed the molar ratio of residual 1, 4-dioxane/API was 0.5 (9.3 wt%) and no detectable MTBE residue was found.
  • Freebase Type G (823121-18-A8-DRY) was obtained via exposing the freebase Type C material (823121-16-A) under the atmosphere of CHCl 3 for one day followed by drying at RT. XRPD pattern was shown in Figure 3-40.
  • the TGA/DSC curves were displayed in Figure 3-41.
  • TGA result showed a weight loss of 10.7%up to 120 °C.
  • DSC result showed two endotherms at 72.5 °C and 176.0 °C (peak) .
  • the 1 H NMR ( Figure 3-42) result showed the molar ratio of residual CHCl 3 /API was 0.25 (7.2 wt%) .
  • Freebase Type H (823121-20-A16-DRY) was obtained via slurry of the freebase Type C material (823121-16-A) in 2-MeTHF/toluene (v/v, 1: 1) at 50 °C for 5 days followed by drying at RT.
  • the re-prepared freebase Type H (823121-37-A3) was obtained via the same method.
  • XRPD pattern was shown in Figure 3-44.
  • the TGA/DSC curves were displayed in Figure 3-45. TGA result showed a weight loss of 11.2%up to 120 °C.
  • DSC result showed two endotherms at 116.4 °C and 175.9 °C (peak) .
  • Freebase Type J (823121-19-A5-DRY) was obtained via slurry of the freebase Type C material (823121-16-A) in anisole at RT for 5 days followed by drying at RT.
  • XRPD pattern was shown in Figure 3-48.
  • the TGA/DSC curves were displayed in Figure 3-49.
  • TGA result showed a weight loss of 13.9%up to 120 °C.
  • DSC result showed two endotherms at 102.1 °C and 176.3 °C (peak) .
  • the 1 H NMR ( Figure 3-50) result showed the molar ratio of residual anisole/API was 0.5 (11.9 wt%) .
  • Freebase Type K (823121-19-A8-DRY) was obtained via slurry of the freebase Type C material (823121-16-A) in toluene at RT for 5 days followed by drying at RT.
  • XRPD pattern was shown in Figure 3-52.
  • the TGA/DSC curves were displayed in Figure 3-53.
  • TGA result showed a weight loss of 7.1%up to 150 °C.
  • DSC result showed two endotherms at 115.9 °C and 176.1 °C (peak) .
  • the 1 H NMR ( Figure 3-54) result showed the molar ratio of residual toluene/API was 0.3 (6.6 wt%) .
  • Freebase Type M (823121-23-A4-DRY) was obtained via drying freebase Type E (823121-23-A4) at RT (temperature range: 20 ⁇ 22 °C; humidity range: 44 ⁇ 77%RH) .
  • XRPD pattern was shown in Figure 3-56.
  • the TGA/DSC curves were displayed in Figure 3-57.
  • TGA result showed weight losses of 2.5%up to 61 °C and 8.8%from 61 °C to 90 °C.
  • DSC result showed two endotherms at 83.6 °C and 176.0 °C (peak) .
  • the 1 H NMR ( Figure 3-58) result showed the molar ratio of residual n-hexane/API was 0.3 (5.3 wt%) .
  • Freebase Type O (823121-18-A9-DRY) was obtained via exposing the freebase Type C material (823121-16-A) under DMSO atmosphere for 7 days followed by drying at RT. XRPD pattern was shown in Figure 3-60.
  • the TGA/DSC curves were displayed in Figure 3-61.
  • TGA result showed a weight loss of 11.1%up to 120 °C.
  • DSC result showed two endotherms at 118.4 °C and 175.2 °C (peak) .
  • the 1 H NMR ( Figure 3-62) result showed the molar ratio of residual DMSO/API was 0.7 (12.3 wt%) .
  • Freebase Type E (823121-23-A4) was obtained by liquid vapor diffusion via exposing the THF solution of the material (823121-16-A) under n-hexane atmosphere. XRPD pattern was shown in Figure 3-66. After drying at RT (temperature range: 20 ⁇ 22 °C; humidity range: 44 ⁇ 77%RH) , the form was converted to freebase Type M (referred to Example) . Thus, TGA, DSC and 1 H NMR characterizations were not conducted for freebase Type E.
  • Freebase Type R (823121-43-A2-N2_30.0°C) was obtained via purging N 2 on freebase Type B (823121-43-A2) for 20 min (referred to Example) .
  • XRPD pattern was shown in Figure 3-67. After exposing to air for 10 min, the form was converted back to freebase Type B. Thus, TGA, DSC and 1 H NMR characterizations were not conducted for freebase Type R.
  • Freebase Type A, C, P, N and Q was added into 1 mL of saturated solution (slurry under the desired temperature for 2 hrs followed by filtration) of freebase Type A material (823121-01-A) in EtOH and IPAc. After slurry at RT or 50 °C for 3 or 5 days, the solid was tested by XRPD. The results were summarized in Table 4-1 and the XRPD results were shown in Figure 4-1 and Figure 4-2. Freebase Type C was obtained in all experiments, which indicated that Type C was the most stable anhydrate from RT to 50 °C.
  • Freebase Type C was obtained when a w ⁇ 0.6.
  • Freebase Type L was obtained when the a w was 0.8, while freebase Type B was obtained in pure water (a w ⁇ 1) . Based on the results above, anhydrate Type C could convert to hydrate Type L with a w of 0.6 ⁇ 0.8 and Type L could convert to hydrate Type B with a w of 0.8 ⁇ 1.0 at RT.
  • HCl salt Type A (823121-28-A1) preparation procedure: 300.8 mg of the freebase Type A material (823121-01-A) and 10 mL of EtOAc were added into a 20-mL glass vial. 68 ⁇ L of 12 M HCl (1.05 molar ratio) were slowly added into the solution with magnetic stirring. After stirring for 3 days, the solid (275.0 mg, yield ⁇ 83.8%) was obtained by vacuum drying at RT after centrifugation. XRPD result was displayed in Figure 5-1, which showed HCl salt Type A was successfully obtained.
  • Citrate Type A (823121-28-A3) preparation procedure Adding 299.8 mg of the freebase Type A material (823121-01-A) and 162.9 mg citric acid into a 20-mL glass vial. Then, 10 mL of EtOH was added. After stirring (1000 rpm) for 3 days at RT, the solid was obtained by vacuum drying at RT after centrifugation (320 mg, yield ⁇ 69.1%) . The XRPD pattern was displayed in Figure 5-4, which showed citrate Type A was successfully obtained. The TGA/DSC curves of citrate Type A were displayed in Figure 5-5, which showed a weight loss of 2.0%up to 120 °C and one endotherm at 164.2 °C (peak) . The 1 H NMR result in Figure 5-6 showed the molar ratio of acid/FB was 1.0 and no detectable EtOH residue was found.
  • Phosphate Type A (823121-32-A) preparation procedure 300.0 mg of the freebase Type A material (823121-01-A) and 10 mL of EtOH were added into a 20-mL glass vial. 95.4 ⁇ L of 85% (2.05 molar ratio) H 3 PO 4 was slowly added into the solution with magnetic stirring. After stirring for 3 days, the solid was isolated by centrifuged and continued to slurry in EtOAc. After slurry for 2 hrs, the solid (297.0 mg, yield ⁇ 66.3%) was obtained by vacuum drying at RT after centrifugation. XRPD result was displayed in Figure 5-7, which showed phosphate Type A was successfully obtained.
  • HCl salt Type A (823121-28-A1) , citrate Type A (823121-28-A3) and phosphate Type A (823121-32-A) were used for evaluation to compare with the freebase, including kinetic solubility, hygroscopicity and solid stability.
  • Freebase Type A (200754-075-P3; 823121-01-A) was employed in the kinetic solubility evaluation.
  • Freebase Type C (200754-075-P5; 823121-16-A) was employed in the hygroscopicity evaluation. Both freebase batches were employed in the solid stability evaluation.
  • Kinetic solubility was measured for re-prepared HCl salt Type A (823121-28-A1) , citrate Type A (823121-28-A3) , phosphate Type A (823121-32-A) and freebase Type A (823121-01-A) in water and three bio-relevant medias.
  • the material was added into H 2 O, SGF, FaSSIF or FeSSIF (solid loading: 5 mg/mL, based on freebase) followed by rolling at 37 °C at 25 rpm for 1, 2, 4 and 24 hrs. For each time point, centrifugation and filtration (0.45 ⁇ m PTFE filter) were performed. Solubility by UPLC and pH were tested for supernatants. Solids were tested by XRPD. The results were summarized in Table 6-1. The solubility plots were displayed in Figure 6-1 and the XRPD results were shown from Figure 6-2 to Figure 6-9. Based on the results, all of the three salts showed higher solubility in water comparing with the freebase. Both of salts and freebase were completely dissolved in SGF.
  • FaSSIF FaSSIF
  • phosphate Type A showed higher solubility than other salts and freebase
  • HCl salt Type A, citrate Type A and freebase Type A were converted to other crystal forms of the freebase after rolling for 1 hr.
  • FeSSIF the solubility of these three salts were higher than the freebase, while the solubility of salts and freebase became comparable after 24 hrs; These three salts were disproportionated to other crystal forms of the freebase after rolling for 1 hr.
  • freebase Type C In order to evaluate the hygroscopicity, freebase Type C, HCl salt Type A, citrate Type A and phosphate Type A were characterized by DVS. DVS isotherm plots were collected at 25 °C between 0%RH and 95%RH. The initial RH%for freebase Type C was started from 0 RH%, since it was postulated as an anhydrate, while the initial RH%for salts were started from 50 RH% (room humidity) . XRPD characterization was performed for the samples after DVS test. The DVS plots and XRPD results were shown from Figure 6-10 to Figure 6-17.
  • Freebase Type A/C, re-prepared HCl salt Type A, citrate Type A and phosphate Type A were placed under the conditions of 25 °C/60%RH and 40 °C/75%RH for one week for solid stability evaluation.
  • the physical and chemical stability were evaluated by XRPD and purity, respectively.
  • the results were summarized in Table 6-2 and the XRPD results were shown from Figure 6-18 to Figure 6-22, which indicated freebase Type A was converted to Type C after storing at 40 °C/75%RH for one week, and no form conversion was observed for other samples.
  • the UPLC results and impurity summary were shown from Figure 6-23 to Figure 6-32 and from Table 6-3 to Table 6-12, which showed no obvious purity decrease was observed for all samples after stored under two conditions for one week.
  • Type C As the material, 100 polymorph screening experiments were performed. A total of 20 polymorphs were obtained from screening and further experiments, named as freebase Type A ⁇ T, which were characterized using XRPD, TGA, DSC and 1 H NMR. Based on the characterization results, Type A, C, P, N and Q were anhydrates; Type B, I and L were hydrates; Type D, F, G, H, J, K, M, O, S and T were solvates; Type E (converted to Type M after drying at 20 ⁇ 22 °C/44 ⁇ 77%RH) and Type R (may be converted to Type B after exposing to air) and thus was not tested.
  • freebase Type C was obtained when a w was ⁇ 0.6; freebase Type L was obtained when a w ⁇ 0.8, while freebase Type B was obtained in pure water (a w ⁇ 1) .
  • freebase Type C showed: good properties in solid state; more stable at RT and 50 °C than other anhydrates; stable in a relative wide range of water activity (0 ⁇ 0.6) . Therefore, freebase Type C was proper for further development and toxicology study.
  • HCl salt Type A citrate Type A and phosphate Type A were selected for re-preparation, and the results showed HCl salt Type A, citrate Type A and phosphate Type A were obtained successfully.
  • the three re-prepared salt forms and freebase were used for evaluation, including kinetic solubility, hygroscopicity and solid stability.
  • Hygroscopicity results showed water update of freebase Type C, citrate Type A and phosphate Type A were 0.50%, 0.38%and 0.97%, respectively, at 25 °C/80%RH (slightly hygroscopic) .
  • HCl salt Type A showed water uptake of 2.95%at 25 °C/30%RH and 4.07%at 25 °C/80%RH.
  • Solid stability evaluation results showed freebase Type A was converted to Type C after storing at 40 °C/75%RH for one week. No form change was observed for other samples. No obvious purity decrease was observed for all samples after storing under 25 °C/60%RH or 40 °C/75%RH for one week.
  • salt candidate could be selected based on the kinetic solubility evaluation and PK results.
  • Polymer mixture A polyvinyl pyrrolidone (PVP) , polyvinyl alcohol (PVA) , polyvinylchloride (PVC) , polyvinyl acetate (PVAC) , hypromellose (HPMC) , methyl cellulose (MC) (mass ratio of 1: 1: 1: 1: 1: 1) .
  • PVP polyvinyl pyrrolidone
  • PVA polyvinyl alcohol
  • PVC polyvinylchloride
  • HPMC hypromellose
  • MC methyl cellulose
  • Polymer mixture B polycaprolactone (PCL) , polyethylene glycol (PEG) , polymethyl methacrylate (PMMA) sodium alginate (SA) , and hydroxyethyl cellulose (HEC) (mass ratio of 1: 1: 1: 1: 1) .
  • PCL polycaprolactone
  • PEG polyethylene glycol
  • PMMA polymethyl methacrylate
  • SA polymethyl methacrylate
  • HEC hydroxyethyl cellulose
  • HCl salt Type A/B (823121-06-D1/D2) were obtained via dissolving 20 mg freebase Type A (823121-01-A) in 2-MeTHF, followed by addition of HCl (molar ratio of 1: 1 and 1: 2 acid/FB, respectively) for slurry at RT for 3 days and drying under vacuum.
  • the XRPD overlay were displayed in Figure 7-4.
  • Sulfate Type A (823121-06-C3) were obtained via dissolving 20 mg freebase Type A (823121-01-A) in EtOAc, followed by addition of H 2 SO 4 (molar ratio of 1: 1, acid/FB) for slurry for 3 days at RT, and drying under vacuum.
  • the XRPD overlay were displayed in Figure 7-10.
  • the TGA/DSC curves of sulfate Type A (823121-06-C3) were displayed in Figure 7-11, which showed a weight loss of 6.5%up to 120 °C and three endotherms at 92.2 °C and 145.0 °C (peak) .
  • 1 H NMR result ( Figure 7-12) showed no detectable EtOAc residue.
  • UPLC/IC results showed the molar ratio was 1.0: 1.0 (acid/FB) .
  • Maleate Type A/B/C (823121-06-A4/D4/C4) was obtained via dissolving 20 mg freebase Type A (823121-01-A) and maleic acid (molar ratio of 1: 1, acid/FB) in EtOH, 2-MeTHF and EtOAc, respectively, for slurry for 3 days at RT and drying under vacuum.
  • the XRPD overlay were displayed in Figure 7-13.
  • Phosphate Type A (823121-06-A6) were obtained via dissolving 20 mg freebase Type A (823121-01-A) in EtOH, followed by addition of H 3 PO 4 (molar ratio of 1: 1, acid/FB) for slurry for 3 days at RT, and drying under vacuum.
  • the XRPD overlay were displayed in Figure 7-20.
  • the TGA/DSC curves of phosphate Type A (823121-06-A6) were displayed in Figure 7-21.
  • TGA result showed a weight loss of 2.6%up to 120 °C.
  • DSC result showed one endotherm at 214.8 °C (peak) .
  • 1 H NMR result ( Figure 7-22) showed no detectable EtOH residue.
  • UPLC/IC results showed the molar ratio was 2.0: 1.0 (acid/FB) .
  • L-Tartrate Type A/B (823121-06-A7/C7) was obtained via dissolving 20 mg freebase Type A (823121-01-A) and L-tartaric acid (molar ratio of 1: 1, acid/FB) in EtOH and EtOAc, respectively, for slurry for 3 days at RT and drying under vacuum.
  • the XRPD overlay were displayed in Figure 7-23.
  • Fumarate Type A (823121-06-A8) was obtained via dissolving 20 mg freebase Type A (823121-01-A) and fumaric acid (molar ratio of 1: 1, acid/FB) in EtOH for slurry for 3 days at RT and drying under vacuum.
  • the XRPD overlay were displayed in Figure 7-28.
  • the TGA/DSC curves of fumarate Type A (823121-06-A8) were displayed in Figure 7-29, which showed a weight loss of 4.8%up to 120 °C and an endotherms at 120.7 °C and 201.5 °C (peak) .
  • the 1 H NMR result in Figure 7-30 showed the molar ratio of acid/FB was 0.9: 1.0 and the molar ratio of EtOH/API was 0.03: 1 (0.3 wt%) .
  • Citrate Type A (823121-06-C9) was obtained via dissolving 20 mg freebase Type A (823121-01-A) and citric acid (molar ratio of 1: 1, acid/FB) in EtOAc for slurry for 3 days at RT and drying under vacuum.
  • the XRPD overlay were displayed in Figure 7-31.
  • the TGA/DSC curves of citrate Type A (823121-06-C9) were displayed in Figure 7-32, which showed a weight loss of 2.3%up to 120 °C and an endotherms at 167.4 °C and 181.0 °C (peak) .
  • the 1 H NMR result in Figure 7-33 showed the molar ratio of acid/FB was 1.0: 1.0 and no detectable EtOAc residue was found.
  • Tosylate Type A (823121-06-A10) was obtained via dissolving 20 mg freebase Type A (823121-01-A) and p-toluenesulfonic acid (molar ratio of 1: 1, acid/FB) in EtOH for slurry for 3 days at RT and drying under vacuum.
  • the XRPD overlay were displayed in Figure 7-34.
  • the TGA/DSC curves of tosylate Type A (823121-06-A10) were displayed in Figure 7-35, which showed a weight loss of 2.5%up to 120 °C and two endotherms at 81.2 °C and 242.9 °C (peak) .
  • the 1 H NMR result in Figure 7-36 showed the molar ratio of acid/FB was 1.0: 1.0, and no detectable EtOH residue was found.
  • Besylate Type A/B/C (823121-06-A12/B12/C12) was obtained via dissolving 20 mg freebase Type A (823121-01-A) and benzenesulfonic acid (molar ratio of 1: 1, acid/FB) in EtOH, acetone/H 2 O (19: 1, v/v) and EtOAc, respectively, for slurry for 3 days at RT and drying under vacuum.
  • the XRPD overlay were displayed in Figure 7-40.
  • Gentisate Type A (823121-06-C13) was obtained via dissolving 20 mg freebase Type A (823121-01-A) and gentistic acid (molar ratio of 1: 1, acid/FB) in EtOAc for slurry for 3 days at RT and drying under vacuum.
  • the XRPD overlay were displayed in Figure 7-47.
  • the TGA/DSC curves of Gentisate Type A (823121-06-C13) were displayed in Figure 7-48, which showed a weight loss of 2.3%up to 120 °C and one endotherm at 214.6 °C (peak) .
  • the 1 H NMR result in Figure 7-49 showed the molar ratio of acid/FB was 1.0: 1.0, and no detectable EtOAc residue was found.
  • Fasted-State Simulated Intestinal Fluid FaSSIF
  • pH 2.0 buffer 149.1 mg KCl and 0.5 mol 1M HCl solution were added into a 50-mL volumetric flask. Purified water was then added to the volume. The pH was 2.04.
  • pH 4.0 buffer 283.4 mg anhydrous citric acid and 301.5 mg trisodium citrate dihydrate were added into a 50-mL volumetric flask. Purified water was then added to the volume. The pH was 4.00.
  • pH 6.0 buffer 55.2 mg anhydrous citric acid and 650.7 mg trisodium citrate dihydrate were added into a 50-mL volumetric flask. Purified water was then added to the volume. The pH was 5.95.
  • pH 8.0 buffer 336.1 mg Na 2 HPO 4 and 15.9 mg NaH 2 PO 4 were added into a 50-mL volumetric flask. Purified water was then added to the volume. The pH was 8.01.
  • TGA data were collected using a TA Q5000/Discovery 5500 TGA from TA Instruments.
  • DSC was performed using a TA Discovery 2500 DSC from TA Instruments. Detailed parameters used are listed in Table 8-18.
  • DVS was measured via a SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25 °C were calibrated against deliquescence point of LiCl, Mg (NO 3 ) 2 and KCl. Parameters for DVS test are listed in Table 8-19.

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Abstract

La présente invention concerne un sel et/ou une forme cristalline de composés, en particulier de composés en tant qu'inhibiteurs de caséine kinase.
PCT/CN2023/099850 2022-06-14 2023-06-13 Sel et/ou forme cristalline de composés en tant qu'inhibiteurs de caséine kinase WO2023241551A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005061506A1 (fr) * 2003-12-16 2005-07-07 Pfizer Products Inc. Composes bicycliques de pyrazolyle et d'imidazolyle en tant que ligands des recepteurs cannabinoides et leurs utilisations
CN106661056A (zh) * 2014-06-19 2017-05-10 百时美施贵宝公司 作为酪蛋白激酶1δ/ε抑制剂的咪唑并哒嗪衍生物
WO2021190615A1 (fr) * 2020-03-27 2021-09-30 Gritscience Biopharmaceuticals Co., Ltd. Composés utilisés en tant qu'inhibiteurs de la caséine kinase
WO2021190616A1 (fr) * 2020-03-27 2021-09-30 Gritscience Biopharmaceuticals Co., Ltd. Procédés d'inhibition de caséine kinases
WO2022127756A1 (fr) * 2020-12-15 2022-06-23 Gritscience Biopharmaceuticals Co., Ltd. Composés utilisés en tant qu'inhibiteurs de la caséine kinase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005061506A1 (fr) * 2003-12-16 2005-07-07 Pfizer Products Inc. Composes bicycliques de pyrazolyle et d'imidazolyle en tant que ligands des recepteurs cannabinoides et leurs utilisations
CN106661056A (zh) * 2014-06-19 2017-05-10 百时美施贵宝公司 作为酪蛋白激酶1δ/ε抑制剂的咪唑并哒嗪衍生物
WO2021190615A1 (fr) * 2020-03-27 2021-09-30 Gritscience Biopharmaceuticals Co., Ltd. Composés utilisés en tant qu'inhibiteurs de la caséine kinase
WO2021190616A1 (fr) * 2020-03-27 2021-09-30 Gritscience Biopharmaceuticals Co., Ltd. Procédés d'inhibition de caséine kinases
WO2022127756A1 (fr) * 2020-12-15 2022-06-23 Gritscience Biopharmaceuticals Co., Ltd. Composés utilisés en tant qu'inhibiteurs de la caséine kinase

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