WO2023241552A1 - Sel et/ou forme cristalline pour des composés utilisés en tant qu'inhibiteurs de caséine kinase - Google Patents

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

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WO2023241552A1
WO2023241552A1 PCT/CN2023/099851 CN2023099851W WO2023241552A1 WO 2023241552 A1 WO2023241552 A1 WO 2023241552A1 CN 2023099851 W CN2023099851 W CN 2023099851W WO 2023241552 A1 WO2023241552 A1 WO 2023241552A1
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degrees
crystalline form
type
freebase
acid
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PCT/CN2023/099851
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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 WO2023241552A1 publication Critical patent/WO2023241552A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/06—Oxalic acid
    • C07C55/07—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid

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-B is 2- (8- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) imidazo [1, 2-b] pyridazin-2-yl) propan-2-ol, which is a potent inhibitor of the casein kinase.
  • 2- (8- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) imidazo [1, 2-b] pyridazin-2-yl) propan-2-ol 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-B.
  • the novel salt and/or crystal form of HY-B 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 structure of HY-B.
  • Figure 2-1 shows XRPD patterns of starting materials (823129-01-A/B) ;
  • Figure 2-2 shows TGA/DSC curves of starting material (823129-01-A) ;
  • Figure 2-3 shows 1H NMR spectrum of starting material (823129-01-A) ;
  • Figure 2-4 shows UPLC chromatogram of starting material (823129-01-A) ;
  • Figure 2-5 shows TGA/DSC curves of starting material (823129-01-B) ;
  • Figure 2-6 shows 1H NMR spectrum of starting material (823129-01-B) ;
  • Figure 2-7 shows UPLC chromatogram of starting material (823129-01-B) ;
  • Figure 3-1 shows XRPD pattern of re-prepared sulfate Type A (823129-12-A) ;
  • Figure 3-2 shows TGA/DSC curves of re-prepared sulfate Type A (823129-12-A) ;
  • Figure 3-3 shows 1H NMR spectrum of re-prepared sulfate Type A (823129-12-A) ;
  • Figure 3-4 shows UPLC chromatogram of re-prepared sulfate Type A (823129-12-A) ;
  • Figure 3-5 shows XRPD pattern of re-prepared maleate Type B (823129-13-A) ;
  • Figure 3-6 shows TGA/DSC curves of re-prepared maleate Type B (823129-13-A) ;
  • Figure 3-7 shows 1H NMR spectrum of re-prepared maleate Type B (823129-13-A) ;
  • Figure 3-8 shows UPLC chromatogram of re-prepared maleate Type B (823129-13-A) ;
  • Figure 3-9 shows XRPD pattern of re-prepared tosylate Type A (823129-14-A) ;
  • Figure 3-10 shows TGA/DSC curves of re-prepared tosylate Type A (823129-14-A) ;
  • Figure 3-11 shows 1H NMR spectrum of re-prepared tosylate Type A (823129-14-A) ;
  • Figure 3-12 shows UPLC chromatogram of re-prepared tosylate Type A (823129-14-A) ;
  • Figure 4-1 shows DVS plot of freebase Type A (823129-01-A) ;
  • Figure 4-2 shows XRPD overlay of freebase Type A (823129-01-A) before and after DVS;
  • Figure 4-3 shows DVS plot of sulfate Type A (823129-12-A) ;
  • Figure 4-4 shows XRPD overlay of sulfate Type A (823129-12-A) before and after DVS;
  • Figure 4-5 shows DVS plot of maleate Type B (823129-13-A) ;
  • Figure 4-6 shows XRPD overlay of maleate Type B (823129-13-A) before and after DVS;
  • Figure 4-7 shows DVS plot of tosylate Type A (823129-14-A) ;
  • Figure 4-8 shows XRPD overlay of tosylate Type A (823129-14-A) before and after DVS;
  • Figure 4-9 shows Plots of kinetic solubility
  • Figure 4-10 shows XRPD overlay of freebase Type A (823129-01-A) after stability evaluation
  • Figure 4-11 shows XRPD overlay of sulfate Type A (823129-12-A) after stability evaluation
  • Figure 4-12 shows XRPD overlay of maleate Type B (823129-13-A) after stability evaluation
  • Figure 4-13 shows XRPD overlay of tosylate Type A (823129-14-A) after stability evaluation
  • Figure 5-1 shows XRPD overlay of HY-B maleate polymorphs
  • Figure 5-2 shows VT-XRPD patterns of maleate Type B (823129-13-A) ;
  • Figure 5-3 shows XRPD pattern of maleate Type C (823129-27-A) ;
  • Figure 5-4 shows TGA/DSC curves of maleate Type C (823129-27-A) ;
  • Figure 5-5 shows 1H NMR spectrum of maleate Type C (823129-27-A) ;
  • Figure 5-6 shows UPLC chromatogram of maleate Type C (823129-27-A) ;
  • Figure 5-7 shows XRPD pattern of maleate Type D (823129-35-A9) ;
  • Figure 5-8 shows TGA/DSC curves of maleate Type D (823129-35-A9) ;
  • Figure 5-9 shows 1H NMR spectrum of maleate Type D (823129-35-A9) ;
  • Figure 6-1 shows XRPD overlay of the solids from competitive slurry for 3 days (I/II) ;
  • Figure 6-2 shows XRPD overlay of the solids from competitive slurry for 3 days (II/II) ;
  • Figure 6-3 shows XRPD overlay of the solids from competitive slurry for another 1 day (I/II) ;
  • Figure 6-4 shows XRPD overlay of the solids from competitive slurry for another 1 day (I/II) ;
  • Figure 7-1 shows XRPD overlay of maleate Type B (823129-13-A) after stability evaluation
  • Figure 9-1 shows XRPD patterns of HCl salt Type A/B/C (823129-03-B1/D1/A2) ;
  • Figure 9-2 shows TGA/DSC curves of HCl salt Type A (823129-03-B1) ;
  • Figure 9-3 shows 1H NMR spectrum of HCl salt Type A (823129-03-B1) ;
  • Figure 9-4 shows TGA/DSC curves of HCl salt Type B (823129-03-D1) ;
  • Figure 9-5 shows 1H NMR spectrum of HCl salt Type B (823129-03-D1) ;
  • Figure 9-6 shows TGA/DSC curves of HCl salt Type C (823129-03-A2) ;
  • Figure 9-7 shows 1H NMR spectrum of HCl salt Type C (823129-03-A2) ;
  • Figure 9-8 shows XRPD pattern of sulfate Type A (823129-03-B3) ;
  • Figure 9-9 shows TGA/DSC curves of sulfate Type A (823129-03-B3) ;
  • Figure 9-10 shows 1H NMR spectrum of sulfate Type A (823129-03-B3) ;
  • Figure 9-11 shows XRPD patterns of maleate Type A/B (823129-03-A4/B4) ;
  • Figure 9-12 shows TGA/DSC curves of maleate Type A (823129-03-A4) ;
  • Figure 9-13 shows 1H NMR spectrum of maleate Type A (823129-03-A4) ;
  • Figure 9-14 shows TGA/DSC curves of maleate Type B (823129-03-B4) ;
  • Figure 9-15 shows 1H NMR spectrum of maleate Type B (823129-03-B4) ;
  • Figure 9-16 shows XRPD pattern of tosylate Type A (823129-03-B9) ;
  • Figure 9-17 shows TGA/DSC curves of tosylate Type A (823129-03-B9) ;
  • Figure 9-18 shows 1H NMR spectrum of tosylate Type A (823129-03-B9) ;
  • Figure 9-19 shows XRPD pattern of mesylate A (823129-03-A11) ;
  • Figure 9-20 shows TGA/DSC curves of mesylate Type A (823129-03-A11) ;
  • Figure 9-21 shows 1H NMR spectrum of mesylate Type A (823129-03-A11) ;
  • Figure 9-22 shows XRPD patterns of oxalate Type A/B (823129-03-B12/C12) ;
  • Figure 9-23 shows TGA/DSC curves of oxalate Type A (823129-03-B12) ;
  • Figure 9-24 shows 1H NMR spectrum of oxalate Type A (823129-03-B12) ;
  • Figure 9-25 shows TGA/DSC curves of oxalate Type B (823129-03-C12) ;
  • Figure 9-26 shows 1H NMR spectrum of oxalate Type B (823129-03-C12) ;
  • Figure 9-27 shows XRPD patterns of HBr salt Type A/B (823129-03-A13/B13) ;
  • Figure 9-28 shows TGA/DSC curves of HBr salt Type A (823129-03-A12) ;
  • Figure 9-29 shows 1H NMR spectrum of HBr salt Type A (823129-03-A13) ;
  • Figure 9-30 shows TGA/DSC curves of HBr salt Type B (823129-03-B13) ;
  • Figure 9-31 shows 1H NMR spectrum of HBr salt Type B (823129-03-B13) ;
  • Figure 9-32 shows XRPD overlay of residual solids from solubility test of freebase Type A in SGF
  • Figure 9-33 shows XRPD overlay of residual solids from solubility test of freebase Type A in FaSSIF;
  • Figure 9-34 shows XRPD overlay of residual solids from solubility test of freebase Type A in FeSSIF;
  • Figure 9-35 shows XRPD overlay of residual solids from solubility test of freebase Type A in water
  • Figure 9-36 shows XRPD overlay of residual solids from solubility test of sulfate Type A in SGF
  • Figure 9-37 shows XRPD overlay of residual solids from solubility test of sulfate Type A in FaSSIF;
  • Figure 9-38 shows XRPD overlay of residual solids from solubility test of sulfate Type A in FeSSIF;
  • Figure 9-39 shows XRPD overlay of residual solids from solubility test of sulfate Type A in water
  • Figure 9-40 shows XRPD overlay of residual solids from solubility test of maleate Type B in SGF
  • Figure 9-41 shows XRPD overlay of residual solids from solubility test of maleate Type B in FaSSIF;
  • Figure 9-42 shows XRPD overlay of residual solids from solubility test of maleate Type B in FeSSIF;
  • Figure 9-43 shows XRPD overlay of residual solids from solubility test of maleate Type B in water
  • Figure 9-44 shows XRPD overlay of residual solids from solubility test of tosylate Type A in SGF
  • Figure 9-45 shows XRPD overlay of residual solids from solubility test of tosylate Type A in FaSSIF;
  • Figure 9-46 shows XRPD overlay of residual solids from solubility test of maleate Type B in FeSSIF
  • Figure 9-47 shows XRPD overlay of residual solids from solubility test of tosylate Type A in water
  • Figure 9-48 shows XRPD pattern of re-prepared maleate Type B (823129-24-A) ;
  • Figure 9-49 shows TGA/DSC curves of re-prepared maleate Type B (823129-24-A) ;
  • Figure 9-50 shows 1H NMR spectrum of re-prepared maleate Type B (823129-24-A) ;
  • Figure 9-51 shows UPLC chromatogram of re-prepared maleate Type B (823129-24-A) ;
  • Figure 9-52 shows XRPD pattern of re-prepared tosylate Type A (823129-25-A) ;
  • Figure 9-53 shows TGA/DSC curves of re-prepared tosylate Type A (823129-25-A) ;
  • Figure 9-54 shows 1H NMR spectrum of re-prepared tosylate Type A (823129-25-A) ;
  • Figure 9-55 shows UPLC chromatogram of re-prepared tosylate Type A (823129-25-A) .
  • 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 a crystalline form of compound HY-B, 2- (8-(3-(4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) imidazo [1, 2-b] pyridazin-2-yl) propan-2-ol, 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 (weight%) selected from the group consisting of: 2.9 weight%of ACN; and 0.5 weight%of IPA.
  • said crystalline form exhibits purity rate in the LC-MS (liquid chromatography–mass spectrometry) analysis selected from the group consisting of: 99.50 area%; and 98.37 area%.
  • LC-MS liquid chromatography–mass spectrometry
  • said crystalline form has solubility selected from the group consisting of: 2.8 mg/mL for SGF, 0.17 mg/mL for FaSSIF, 0.11 mg/mL for FeSSIF, 0.77 mg/mL for H 2 O; 5.0 mg/mL for SGF, 0.68 mg/mL for FaSSIF, 0.12 mg/mL for FeSSIF, 3.1 mg/mL for H 2 O; and 2.4 mg/mL for SGF, 0.21 mg/mL for FaSSIF, 0.12 mg/mL for FeSSIF, 1.3 mg/mL for H 2 O.
  • 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: 0.03%, 9.1%, and 1.2%.
  • 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:
  • 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.
  • Step 1 methyl 8-bromo-6-chloroimidazo [1, 2-b] pyridazine-2-carboxylate
  • Step 2 6-chloro-8- [3- (4-fluorophenyl) -1-methylpyrazol-4-yl] imidazo [1, 2-b] pyridazine-2-carboxylate
  • 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 (EC50) of HY-B is 0.4 ⁇ M.
  • the present disclosure provides HY-B 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)
  • %LY leakage 100 ⁇ [LY] acceptor / ( [LY] donor + [LY] acceptor )
  • 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-B has a desirable intrinsic clearance property.
  • the purpose of this application was to perform a salt screening for compound HY-B and a polymorph screening for a selected salt to identify a proper form for further development.
  • HY-B freebase Type A as material (201328-029-P1, 823129-01-A) , a salt screening was performed under 52 different conditions using 11 acids in 4 solvent systems (Two molar ratios were used for two acids) .
  • a total of 12 crystalline salt hits were obtained during screening, which were characterized by X-ray powder diffraction (XRPD) , thermo gravimetric analysis (TGA) and differential scanning calorimetry (DSC) .
  • the salt stoichiometry was determined using ultra performance liquid chromatography (UPLC) combined with ion chromatography (IC) or 1 H solution nuclear magnetic resonance ( 1 H NMR) . Approximate solubility was tested for the salt hits in water at RT. Based on the approximate solubility and characterization results (small TGA weight loss and neat endothermic signal on DSC curve) , sulfate Type A, maleate Type B and tosylate Type A were selected for re-preparation.
  • UPLC ultra
  • Hygroscopicity evaluated using dynamic vapor sorption (DVS) indicated that the water uptake of freebase Type A, sulfate Type A, maleate Type B and tosylate Type A at 25 °C/80%RH was 0.02%, 9.1%, 0.03%and 1.2%, respectively. After DVS test, no form change was observed for all samples.
  • maleate was selected as the proper salt for further polymorph screening study.
  • HY-B maleate material as material (N210824-073-01, 823129-27-A. ) Based on XRPD result, the sample was crystalline, and thus named as maleate Type C.
  • 106 polymorph screening experiments were performed, using methods of anti-solvent addition, slow evaporation, slow cooling, slurry (RT and 50 °C) , temperature cycling, solid vapor diffusion, solution vapor diffusion, polymer induced crystallization and grinding. Based on the XRPD characterization results, a total of four polymorphs were obtained, including hemi-maleate Type A (anhydrate) , mono-maleate Type B and C (anhydrates) , and sesquialter-maleate Type D (anhydrate or hydrate) . The characterization results were summarized in Table 1-2.
  • Type B The inter-conversion relationship between mono-maleate anhydrates Type B and Type C was investigated via competitive slurry in different solvents at RT and 50 °C.
  • Maleate Type B was obtained in all experiments, which indicated that Type B was more thermodynamically stable than Type C from RT to 50 °C and thus maleate Type B was selected for polymorph evaluation. Since hygroscopicity, kinetic solubility and solid stability under conditions of 25 °C/60%RH and 40 °C/75%RH were performed during salt evaluation, solid stability at 80 °C for 24 hrs was performed in polymorph evaluation. The results showed no form change or obvious purity decrease for maleate Type B after stored at 80 °C for 24 hrs.
  • Approximate solubility of material (823129-01-A) was determined in 21 solvents/co-solvents at RT. Approximately 2 mg of sample was added into a 3-mL glass vial. Solvents in Table 2-3 were then added stepwise into the vials until the solids were dissolved visibly or a total volume of 2 mL was reached. Solubility results summarized in Table 2-3 were used to guide the solvent selection in salt screening experiment design.
  • Table 3-1 Summary of salt screening a : The clear samples were transferred to stir at 5 °C for 3 hrs; b : The clear samples were transferred to stir at 5 °C for 3 hrs, and stir at -20 °C for 6 hrs; c : The clear samples were transferred to stir at 5 °C for 3 hrs, stir at -20 °C for 6 hrs followed by addition of anti-solvent (MTBE) ; d : The clear samples were transferred to stir at 5 °C for 3 hrs, stir at -20 °C for 6 hrs followed by addition of anti-solvent (MTBE) and evaporation at RT under vacuum; e : The gel samples were transferred to stir with temperature cycling (50 °C ⁇ 5 °C, 0.01 °C/min, 2 cycles) .
  • MTBE anti-solvent
  • the solid was obtained via centrifugation and vacuum drying at RT.
  • the XRPD pattern was displayed in Figure 3-1.
  • the TGA/DSC curves were displayed in Figure 3-2, which showed a weight loss of 7.7%up to 120 °C and an endotherm at 121.8 °C (peak) .
  • the 1 H NMR result in Figure 3-3 showed no residual IPAc was detected.
  • UPLC results (Table 3-4 and Figure 3-4) showed the purity was 99.56 area%.
  • UPLC/IC results showed the molar ratio of acid/FB was 1.1.
  • Maleate Type B (823129-13-A) was obtained via adding 350.1 mg freebase Type A (823129-01-A) and 115.9 mg maleic acid in 5 mL IPAc at RT for 3 days (1000 rpm) .
  • the solid was obtained via vacuum drying at RT after centrifugation.
  • the XRPD pattern was displayed in Figure 3-5.
  • the TGA/DSC curves were displayed in Figure 3-6, which showed a weight loss of 0.4%up to 120 °C and an endotherm at 134.6 °C (peak) .
  • the 1 H NMR result in Figure 3-7 showed the molar ratio of acid/FB was 1.0 and no residual IPAc was detected.
  • UPLC results (Table 3-5 and Figure 3-8) showed the purity was 99.51 area%.
  • Tosylate Type A (823129-14-A) was re-prepared via adding 350.0 mg freebase Type A (823129-01-A) and 189.6 mg p-toluenesulfonic acid in 5 mL IPAc followed by slurry at RT for 3 days (1000 rpm) . The solid was obtained via vacuum drying at RT after centrifugation. The XRPD pattern was displayed in Figure 3-9. The TGA/DSC curves were displayed in Figure 3-10, which showed a weight loss of 0.4%up to 120 °C and an endotherm at 150.0 °C (peak) .
  • DVS test was performed for freebase Type A and 3 salt hits to evaluate the hygroscopicity.
  • DVS test started from ambient humidity ( ⁇ 40 %RH) and it started from 0%RH for other samples.
  • DVS isotherm plots were collected at 25 °C between 0%RH and 95%RH.
  • XRPD characterization was performed for the samples after DVS test.
  • the DVS evaluation results were summarized in Table 4-1. The DVS plots and XRPD results were shown from Figure 4-1 to Figure 4-8.
  • the material was added into H 2 O, SGF, FaSSIF or FeSSIF with solid loading of 5 mg/mL (10 mg/mL in SGF, and 12 mg/L for sulfate in water) 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 4-2 and the solubility plots were displayed in Figure 4-9.
  • freebase Type A and 3 salt showed similar solubility in FeSSIF ( ⁇ 0.12 mg/mL at 24 hrs) .
  • solubility of all 3 salts was higher than that of freebase Type A, and sulfate Type A exhibited the highest solubility (The 24-h solubility was 5.0 mg/mL, 0.68 mg/mL and 3.1 mg/mL, respectively) .
  • Maleate Type B and tosylate Type A showed similar solubility. Form change was observed for all forms after solubility test.
  • Freebase Type A and 3 re-prepared salt hits were stored under the conditions of 25 °C/60%RH and 40 °C/75%RH for 12 days for solid stability evaluation.
  • the physical and chemical stability were evaluated by XRPD and UPLC purity, respectively.
  • the results were summarized in Table 4-3 and the XRPD results were shown from Figure 4-10 to Figure 4-13. The results showed no form change or obvious purity decrease after stored under two conditions for 12 days.
  • maleate was selected as the lead salt for further polymorph screening study.
  • Maleate Type A (823129-03-A4) was obtained from salt screening. The preparation and characterization results referred to appendix 9.2.3. Due to the small TGA weight loss, maleate Type A was postulated to be an anhydrate.
  • Maleate Type B (823129-13-A) was obtained via mixing 350.1 mg freebase Type A (823129-01-A) and 115.9 mg maleic acid in 5 mL IPAc followed by slurry at RT for 3 days (1000 rpm) .
  • the characterization results referred to Example.
  • the VT-XRPD (variable-temperature XRPD) results ( Figure 5-2) showed no form change was observed for maleate Type B after N 2 purge for 20 min, heated to 100 °C under N 2 purge (The peak shifts were postulated to be due to the swell of lattice) , cooled to 30 °C under N 2 purge or exposed to air. Due to the small TGA weight loss and VT-XRPD results, maleate Type B was postulated to be an anhydrate.
  • Maleate Type D (823129-35-A9) was obtained via solution vapor diffusion in CH 2 Br 2 /n-Hexane at RT for 4 days using material (823129-27-A) .
  • the XRPD pattern was displayed in Figure 5-7.
  • the TGA/DSC curves were displayed in Figure 5-8, which showed a weight loss of 5.7%up to 120 °C, and an endotherm at 127.7 °C (peak) .
  • the 1 H NMR result in Figure 5-5 showed the molar ratio of acid/FB was 1.5 and no residual CH 2 Br 2 or n-Hexane was detected. Therefore, maleate Type D was postulated to be an anhydrate or hydrate. Due to the limited amount, no further study was performed.
  • Mono-maleate Type C (823129-27-A) was added into IPAc, Anisole and MEK. After slurry at RT and 50 °C for 2 hrs (1000 rpm) for filtration. Around 6 mg of maleate Type B and C were added into the saturated solution for slurry at RT and 50 °C for 3 days (1000 rpm) . And then around 0.5 mg hemi-maleate Type A was added for slurry at RT and 50 °C for 1 day (1000 rpm) . The solid was tested by XRPD.
  • N/A Clear and yellow solution was obtained after slurry for 1 day. Yellow gel sample was obtained after vacuum drying at RT, and thus XRPD test was not performed.
  • Mono-maleate Type B was more stable anhydrous form from RT to 50 °C than Type C, which was selected for evaluation.
  • evaluation including hygroscopicity, kinetic solubility, solid stability at 25 °C/60%RH and 40 °C/75%RH were performed for maleate Type B (Refer to Example) , and thus only the solid stability at 80 °C for 24 hrs was performed for maleate Type B in this Example.
  • the results were summarized in Table 7-1 and the XRPD results were displayed in Figure 7-1. The results showed no form change or obvious purity change was observed for maleate Type B after stored at 80 °C for 24 hrs.
  • HY-B freebase Type A as material, a salt screening was performed under 52 different conditions using 11 acids in 4 solvent systems (Two molar ratios were used for two acids) . A total of 12 crystalline salt hits were obtained during screening. Based on the approximate solubility and characterization results, sulfate Type A, maleate Type B and tosylate Type A were selected for re-preparation. The three re-prepared salt forms and freebase Type A were used for salt evaluation, including hygroscopicity, kinetic solubility and solid stability.
  • HY-B maleate Type C 106 polymorph screening experiments were performed. Based on the XRPD characterization results, a total of four polymorphs were obtained, including hemi-maleate Type A (anhydrate) , mono-maleate Type B and C (anhydrates) , and sesquialter-maleate Type D (anhydrate or hydrate) .
  • the inter-conversion relationship between mono-anhydrate anhydrates Type B and Type C was investigated via competitive slurry in different solvents at RT and 50 °C.
  • Maleate Type B was obtained in all experiments, which indicated that Type B was more thermodynamically stable than Type C from RT to 50 °C. The stability results showed no form change or obvious purity decrease for maleate Type B after stored at 80 °C for 24 hrs.
  • HCl salt Type A/B (823129-03-B1/D1) were obtained via mixing freebase Type A (823129-01-A) and equimolar HCl in IPAc and ACN/H 2 O (19: 1, v/v) , respectively, followed by slurry at RT for 3 days.
  • HCl salt Type C (823129-03-A2) was obtained via mixing freebase Type A (823129-01-A) and HCl (molar ratio of 1: 2, FB/acid) in IPA for slurry at RT for 3 days followed by evaporation at RT.
  • the XRPD patterns were displayed in Figure 9-1.
  • Sulfate Type A (823129-03-B3) were obtained via mixing freebase Type A (823129-01-A) equimolar H 2 SO 4 in IPAc followed by slurry at RT for 3 days.
  • the XRPD pattern was displayed in Figure 9-8.
  • the TGA/DSC curves of sulfate Type A (823129-03-B3) were displayed in Figure 9-9, which showed a weight loss of 8.7%up to 120 °C, and an endotherm at 121.9 °C (peak) .
  • 1 H NMR result ( Figure 9-10) showed no residual IPAc was detected.
  • UPLC/IC results showed the molar ratio was 1.1 (acid/FB) .
  • Maleate Type A/B (823129-03-A4/B4) was obtained via mixing freebase Type A (823129-01-A) and equimolar maleic acid in IPA and IPAc, respectively, followed by slurry at RT for 3 days.
  • the XRPD patterns were displayed in Figure 9-11.
  • Tosylate Type A (823129-03-B9) was obtained via mixing freebase Type A (823129-01-A) and equimolar p-toluenesulfonic acid in IPAc followed by slurry at RT for 3 days.
  • the XRPD pattern was displayed in Figure 9-16.
  • the TGA/DSC curves of tosylate Type A (823129-03-B9) were displayed in Figure 9-17, which showed a weight loss of 1.8%up to 120 °C and an endotherm at 151.8 °C (peak) .
  • the 1 H NMR result in Figure 9-18 showed the molar ratio of acid/FB was 1.0 and no residual IPAc was detected.
  • Mesylate Type A (823129-03-A11) was obtained via mixing freebase Type A (823129-01-A) and methanesulfonic acid (molar ratio of 1: 2, FB/acid) in IPA followed by slurry at RT for 3 days.
  • the XRPD pattern was displayed in Figure 9-19.
  • the TGA/DSC curves of mesylate Type A (823129-03-A11) were displayed in Figure 9-20, which showed a weight loss of 6.8%up to 120 °C and two endotherms at 91.8 and 122.4 °C (peak) .
  • the 1 H NMR result in Figure 9-21 showed the molar ratio of acid/FB was 1.0 and no residual IPA was detected.
  • Oxalate Type A/B (823129-03-B12/C12) were obtained via mixing freebase Type A (823129-01-A) and equimolar oxalic acid in IPAc and MIBK, respectively, followed by slurry at RT for 3 days.
  • the XRPD patterns were displayed in Figure 9-22.
  • HBr salt Type A/B (823129-03-A13/B13) were obtained via mixing freebase Type A (823129-01-A) and equimolar HBr in IPA and IPAc, respectively, followed by slurry at RT for 3 days.
  • the XRPD patterns were displayed in Figure 9-27.
  • Fasted-State Simulated Intestinal Fluid FaSSIF
  • 0.17 g of anhydrous NaH 2 PO 4 , 0.021 g of NaOH and 0.31 g of NaCl were weighed into a 50-mL volumetric flask. ⁇ 48 mL purified water was added to dissolve the solid. The pH was adjusted to 6.5 using 1 M HCl or 1 M NaOH. Purified water was then added to the volume. 22 mg of SIF powder was added into a 10-mL volumetric flask followed by addition of the prepared buffer to the volume.
  • Maleate Type B (823129-24-A) was re-prepared via adding 370.0 mg freebase Type A (823129-01-A) and 122.5 mg maleic acid in 6 mL IPAc followed by addition of seed (823129-13-A) and slurry at RT for 27 hrs (1000 rpm) . The solid was obtained via centrifugation and vacuum drying overnight at RT. The XRPD pattern was displayed in Figure 9-48. The TGA/DSC curves were displayed in Figure 9-49, which showed a weight loss of 0.4%up to 120 °C and an endotherm at 133.6 °C (peak) . The 1 H NMR result in Figure 9-50 showed the molar ratio of acid/FB was 1.0 and no residual IPAc was observed. UPLC results (Table 9-3 and Figure 9-51) showed the purity was 99.46 area%.
  • Tosylate Type A (823129-14-A) was re-prepared via adding 370.1 mg freebase Type A (823129-01-A) and 200.6 mg p-toluenesulfonic acid in 6 mL IPAc followed by addition of seed (823129-14-A) and slurry at RT for 27 hrs (1000 rpm) . The solid was obtained via centrifugation and vacuum drying overnight at RT. The XRPD pattern was displayed in Figure 9-52. The TGA/DSC curves were displayed in Figure 9-53, which showed a weight loss of 2.5%up to 120 °C and an endotherm at 150.6 °C (peak) .
  • maleate Type C (823129-27-A) was suspended in 0.5 mL of solvent in an HPLC glass vial. After the suspension was stirred magnetically (1000 rpm) for 5 days at RT, the remaining solids were centrifuged for XRPD analysis. Results summarized in Table 9-10 indicated that maleate Type A/B/C/A+C/A+freebase Type A were generated.
  • maleate Type C (823129-27-A) was suspended in 0.5 mL of solvent in an HPLC glass vial. After the suspension was stirred (1000 rpm) for about 5 days at 50 °C, the remaining solids were centrifuged for XRPD analysis. Results summarized in Table 9-11 indicated that maleate Type A/B/B/freebase Type A were generated.
  • maleate Type C (823129-27-A) was suspended in 0.5 mL of solvent in an HPLC glass vial. After slurry (1000 rpm) with temperature cycling (50 °C ⁇ 5 °C, 0.1 °C/min, 2 cycles) , the remaining solids were centrifuged for XRPD analysis. Results summarized in Table 9-12 indicated that maleate Type B/C/B+freebase Type A were obtained.
  • 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
  • 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 9-18.
  • 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 9-19.

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Abstract

La présente invention concerne un sel et/ou une forme cristalline pour des composés, en particulier pour des composés utilisés en tant qu'inhibiteurs de caséine kinase.
PCT/CN2023/099851 2022-06-14 2023-06-13 Sel et/ou forme cristalline pour des composés utilisés en tant qu'inhibiteurs de caséine kinase WO2023241552A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103260622A (zh) * 2010-12-20 2013-08-21 辉瑞大药厂 作为酪蛋白激酶抑制剂的新型稠合吡啶化合物
CN111479570A (zh) * 2017-12-13 2020-07-31 Facio知识产权有限公司 用于治疗与dux4表达相关的疾病的化合物
WO2020249717A1 (fr) * 2019-06-13 2020-12-17 Facio Intellectual Property B.V. Inhibiteurs de la caséine kinase 1 destinés à être utilisés dans le traitement de maladies liées à l'expression de dux4 telles que la dystrophie musculaire et le cancer
WO2021190616A1 (fr) * 2020-03-27 2021-09-30 Gritscience Biopharmaceuticals Co., Ltd. Procédés d'inhibition de caséine kinases
WO2021190615A1 (fr) * 2020-03-27 2021-09-30 Gritscience Biopharmaceuticals Co., Ltd. Composés utilisés en tant qu'inhibiteurs de la caséine kinase
WO2022127755A1 (fr) * 2020-12-15 2022-06-23 Gritscience Biopharmaceuticals Co., Ltd. Composés utilisés en tant qu'inhibiteurs de la caséine kinase

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103260622A (zh) * 2010-12-20 2013-08-21 辉瑞大药厂 作为酪蛋白激酶抑制剂的新型稠合吡啶化合物
CN111479570A (zh) * 2017-12-13 2020-07-31 Facio知识产权有限公司 用于治疗与dux4表达相关的疾病的化合物
WO2020249717A1 (fr) * 2019-06-13 2020-12-17 Facio Intellectual Property B.V. Inhibiteurs de la caséine kinase 1 destinés à être utilisés dans le traitement de maladies liées à l'expression de dux4 telles que la dystrophie musculaire et le cancer
WO2021190616A1 (fr) * 2020-03-27 2021-09-30 Gritscience Biopharmaceuticals Co., Ltd. Procédés d'inhibition de caséine kinases
WO2021190615A1 (fr) * 2020-03-27 2021-09-30 Gritscience Biopharmaceuticals Co., Ltd. Composés utilisés en tant qu'inhibiteurs de la caséine kinase
WO2022127755A1 (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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