WO2020151756A1 - Stable solid dispersions of b-raf kinase dimer inhibitor, methods of preparation, and uses therefor - Google Patents

Stable solid dispersions of b-raf kinase dimer inhibitor, methods of preparation, and uses therefor Download PDF

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Publication number
WO2020151756A1
WO2020151756A1 PCT/CN2020/073944 CN2020073944W WO2020151756A1 WO 2020151756 A1 WO2020151756 A1 WO 2020151756A1 CN 2020073944 W CN2020073944 W CN 2020073944W WO 2020151756 A1 WO2020151756 A1 WO 2020151756A1
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Prior art keywords
compound
hpmcas
freebase
weight ratio
solid dispersion
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PCT/CN2020/073944
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English (en)
French (fr)
Inventor
Guoliang Zhang
Changyou Zhou
Huangbin SUN
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BeOne Medicines Ltd
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Beigene Ltd
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Priority to EP20744694.9A priority Critical patent/EP3914591A4/en
Priority to AU2020211000A priority patent/AU2020211000B2/en
Priority to JP2021542104A priority patent/JP7591504B2/ja
Priority to SG11202107849RA priority patent/SG11202107849RA/en
Priority to US17/423,600 priority patent/US12582604B2/en
Priority to BR112021014563-0A priority patent/BR112021014563A2/pt
Priority to MX2021008884A priority patent/MX2021008884A/es
Priority to CA3123476A priority patent/CA3123476A1/en
Priority to KR1020217026908A priority patent/KR20210120039A/ko
Application filed by Beigene Ltd filed Critical Beigene Ltd
Priority to EA202192052A priority patent/EA202192052A1/ru
Priority to CN202080010548.8A priority patent/CN113330011A/zh
Publication of WO2020151756A1 publication Critical patent/WO2020151756A1/en
Priority to ZA2021/04032A priority patent/ZA202104032B/en
Priority to IL284636A priority patent/IL284636A/en
Anticipated expiration legal-status Critical
Priority to JP2024200421A priority patent/JP2025017374A/ja
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • a physically stable solid dispersion comprising Compound 1, i.e., the B-RAF kinase dimer inhibitor 1- ( (1S, 1aS, 6bS) -5- ( (7-oxo-5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-4-yl) oxy) -1a, 6b-dihydro-1H-cyclopropa [b] benzofuran-1-yl) -3- (2, 4, 5-trifluorophenyl) urea and a specific stabilizing polymer, the method for preparing the same, and the uses of the solid dispersion.
  • Compound 1 i.e., the B-RAF kinase dimer inhibitor 1- ( (1S, 1aS, 6bS) -5- ( (7-oxo-5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-4-yl) oxy) -1a, 6b-dihydro-1H-cyclopropa [
  • Also disclosed herein is a stable crystalline form of Compound 1, i.e., Form A, and a neat amorphous form of Compound 1, the methods of preparing the same. Also disclosed herein is a method of mass production of the B-RAF kinase dimer inhibitors disclosed herein.
  • the B-RAF inhibitor of WO 2014/206343 A1 was prepared from the reaction of the 1a, 6b-dihydro-1H-cyclopropa [b] benzofuran-1-carbonyl azide (Intermediate I) and substituted aniline.
  • a dimer impurity i.e., Impurity-1
  • Impurity-1 was always produced with quantity ranging from a few percent to even 50%and could not completely removed by common recrystallization process.
  • Impurity-1 The major cause of Impurity-1 formation was found to be attributed to the moisture existed in the reaction system. Even the moisture content in the reaction system was strictly controlled, the amount of Impurity-1 was found to be significant (>>1%) . In addition, Impurity-1 has very low solubilities in water and other common recrystallization solvents so that it cannot be controlled to be below 0.5% (a minimum requirement of good API quality) by recrystallization procedures. A repetitive column chromatography procedure had to be utilized to completely remove Impurity-1 from Compound 1 due to the polarity similarity of Compound 1 and Impurity-1. This costly and laborious chromatography process can only produce the pure Compound 1 in a small scale (milligrams or grams) . To manufacture Compound 1 in large industrial scale with high quality, a new process without utilizing column chromatography is highly desired.
  • Compound 1 per se either in a crystalline form or in a neat amorphous form, has shown to have poor solubility in water or in various solutions including 0.1 HCl, and buffer solutions of different pH values.
  • Compound 1 in a crystalline form also shows moderate hygroscopicity, as evidenced in a DVS test showing that Compound 1 in a crystalline form of hydrate is moderately hygroscopic with a sample weight gain of 4.96%at 80%relative humidity.
  • crystalline nanoparticles of such compounds upon storage, can act as seeds that induce crystallization resulting in an increase in the structural order over time and decrease in solubility.
  • the amorphous form thereof may have high crystallization tendency so that they easily crystallize in miniaturized experiments, for example, at large-scale manufacturing.
  • an amorphous form of solid dispersion comprising a poorly soluble compound dispersed in a polymer matrix has been reported to provide a stable amorphous formulation, e.g., U.S. Patent No. 6,350,786; or to provide improved solubility and better bioavailability, e.g., U.S. Patent No. 6,548,555.
  • the stabilizing polymer e.g. ionic nature, Tg, molecular weight, hydrogen bond donors/acceptors and potential for interaction;
  • US20080293787A1 discloses a pharmaceutical composition the poorly soluble drug, i.e., (2S, 3S) -2- ⁇ (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2, 5-dioxo-imidazolidin-1-yl ⁇ -3-phenyl-N- (4-propionyl-thiazol-2-yl) -butyramide (HEP) dispersed in a polymeric matrix.
  • US20080293787A1 discloses that the solid dispersion prepared by different processes may have different properties. For example, the solid dispersion prepared by spray drying did not provide the amorphous form of the drug.
  • the solid dispersion comprising the API and HPMCAS prepared by hot-melt extrusion showed higher bioavailability, superior dose proportionality and physical stability as compared to solid dispersions containing the same components prepared by co-precipitation.
  • the API started to crystallize in the co-precipitation product in aqueous suspension (2%hydroxypropyl cellulose) .
  • WO2010114928A3 also published as EP 2955180A1, disclosed solid dispersions comprising the API, propane-1-sulfonic acid ⁇ 3- [5- (4-chloro-phenyl) -lH-pyrrolo [2, 3-b] pyridinc- 3-carbonylJ-2, 4-difluoro-phenyl ⁇ -amide and different polymers at different ratios may form stable amorphous solid dispersions.
  • Compound 1 which shows better bioavailability and has chemical and physical stability during formulation and storage of this drug.
  • Compound 1 e.g., a crystalline form or an amorphous form
  • Compound 1 which has a stable physicochemical properties and is suitable for pharmaceutical manufacture, and a need for a method of mass production of the B-RAF kinase dimer inhibitors disclosed herein.
  • the inventors of the present application have found that the amorphous solid dispersion comprising Compound 1 as a poorly water-soluble drug and a stabilizing polymer prepared by microprecipitation bulk powder (MBP) technology shows excellent oral bioavailability (above 90%) compared with the crystalline form of Compound 1 or the neat amorphous form of Compound 1.
  • the amorphous solid dispersion of the present application also possesses unexpected and extraordinary long-term physicochemical stability (e.g., almost up to 2 years at RT) and pharmaceutical processability (e.g., high Tg and good flowability) .
  • the high bioavailability, long-time stability, and extraordinary pharmaceutical processability of the amorphous solid dispersion prepared by MBP of the present application suggests that the amorphous solid dispersion as MBP are suitable for manufacturing drug products in clinical studies and commercial uses of large scale.
  • a stable amorphous solid dispersion comprising Compound 1 and a stabilizing polymer, wherein Compound 1 is molecularly dispersed within a polymer matrix formed by the stabilizing polymer in its solid state.
  • HPMCAs is hydroxypropyl methylcellulose acetate succinate
  • Compound 1 is and m is a number so that the weight ratio of Compound 1 in the form of freebase and HPMCAS within the complex is between about 1: 9 and about 9: 1.
  • a method for preparing the stable amorphous solid dispersion or the complex disclosed herein comprising step co-precipitating Compound 1 and HPMCAS.
  • Figure 4 shows a Crystal Packing of single crystalline of Compound 1 (Form A**) .
  • Figure 8 shows an XRPD pattern of amorphous solid dispersion of Compound 1 as MBP (Form C) from 3: 7 ratio of Compound 1: HPMCAS-MF.
  • Figure 9 shows an XRPD pattern of amorphous solid dispersion of Compound 1 as MBP (Form D) from 2: 3 ratio of Compound 1: HPMCAS-MF.
  • Figure 11 shows an XRPD pattern of amorphous solid dispersion of Compound 1 as MBP (Form F) from 1: 4 ratio of Compound 1: HPMCAS-LF.
  • Figure 12 shows an XRPD pattern of amorphous solid dispersion of Compound 1 as MBP (Form G) from 3: 7 ratio of Compound 1: HPMCAS-LF.
  • Figure 14 shows an XRPD pattern of amorphous solid dispersion of Compound 1 as MBP (Form I) from 1: 4 ratio of Compound 1: HPMCAS-HF.
  • Figure 15 shows an XRPD pattern of amorphous solid dispersion of Compound 1 as MBP (Form J) from 1: 4 ratio of Compound 1: HPMCAS-MF.
  • Figure 16 shows a 1 H-NMR spectrum of crystalline form of Compound 1 (Form A) .
  • Figure 19 shows hygroscopicity (i.e., moisture sorption) of crystalline form of Compound 1 (Form A) by DVS.
  • Figure 21 shows a 1 H-NMR spectrum of neat amorphous form of Compound 1 (Form B)
  • Figure 29 shows XRPD overlay of neat amorphous form of Compound 1 (Form B)
  • Figure 30 shows XRPD overlay of amorphous solid dispersion of Compound 1 as MBP (Form C) from 3: 7 ratio of Compound 1: HPMCAS-MF.
  • Figure 31 shows XRPD overlay of amorphous solid dispersion of Compound 1 as MBP (Form D) from 2: 3 ratio of Compound 1: HPMCAS-MF.
  • Figure 32 shows XRPD overlay of amorphous solid dispersion of Compound 1 as MBP (Form E) from 1: 9 ratio of Compound 1: HPMCAS-LF.
  • a stable amorphous solid dispersion comprising Compound 1 and a stabilizing polymer, wherein Compound 1 is molecularly dispersed within a polymer matrix formed by the stabilizing polymer in its solid state.
  • polymers have been reported as stabilizing polymeric excipients for pharmaceutical formulation. See, US20080293787A1, U.S. Patent No. 6,350,786, and U.S. Patent No. 6,548,555.
  • Those polymers for this purpose are either cationic or anionic polymers, have a molecular weight of above about 80,000 D, a glass transition temperature equal to or greater than about 50°C., are relatively insoluble in water and preferably have pH-dependent solubility.
  • polymers include polyacrylates (e.g.
  • HPMCAS Hydromellose acetate succinate or hydroxypropyl methylcellulose acetate succinate
  • MBP hydroxypropyl methylcellulose acetate succinate
  • HPMCAS HPMCAS
  • HPMCAS With various contents of acetyl and succinoyl groups in the polymer, there are several types of HPMCAS, which dissolve at different pH levels.
  • Type LF has a high ratio of succinoyl substitution to acetyl substitution (S/Aratio)
  • type HF has a low S/Aratio
  • type MF has a medium S/Aratio.
  • S/Aratio succinoyl substitution to acetyl substitution
  • HPMCAS-LF dissolves at a lower pH ( ⁇ 5.5) , compared with pH ⁇ 6.0 for type MF and pH ⁇ 6.8 for type HF.
  • Type LF usually has 5.0-9.0%of acetyl group and 14.0-18.0%of succinoyl group
  • Type MF usually has 7.0-11.0%%of acetyl group and 10.0-14.0%of succinoyl group
  • Type HF usually has 10.0-14.0%of acetyl group and 4.0-8.0%of succinoyl group.
  • the stabilizing polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) , preferably HPMCAS with a high ratio of succinoyl substitution to acetyl substitution (S/Aratio) .
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • S/Aratio succinoyl substitution to acetyl substitution
  • the stabilizing polymer is any one of HPMCAS-LF, HPMCAS-MF, or HPMCAS-HF, or a mixture of two or more of the above substances.
  • the weight ratio of Compound 1 in the form of freebase and the polymer is between about 1: 9 and about 9: 1; preferably between about 1: 4 to about 2: 3; preferably about 3: 7 or about 1: 4; more preferably about 1: 4.
  • the ratio of Compound 1: HPMCAS is weight/weight (w/w) .
  • the stable amorphous solid dispersion has a drug-loading content of about 10%to 40%.
  • the weight ratio of Compound 1 and the polymer is about 1: 4 and the drug loading of the resulting dispersion is about 20%.
  • the stable amorphous solid dispersion is prepared by microprecipitated bulk powder (MBP) technology.
  • MBP microprecipitated bulk powder
  • the stable amorphous solid dispersion has a glass transition temperature of about 110-115°C, preferably about 111 °C.
  • the stable amorphous solid dispersion is formulated into an orally administrated formulation, e.g., tablet or capsule.
  • HPMCAs is hydroxypropyl methylcellulose acetate succinate
  • Compound 1 is and m is a number so that the weight ratio of Compound 1 in the form of freebase and HPMCAS within the complex is between about 1: 9 and about 9: 1.
  • the complex is prepared by microprecipitated bulk powder (MBP) technology.
  • MBP microprecipitated bulk powder
  • the present invention provides a Crystalline Form of Compound 1 (Form A) prepared or purified according to the procedures depicted in the Scheme 1.
  • Form A a Crystalline Form of Compound 1
  • the methods disclosed herein are especially suitable for reproducible, commercial-scale manufacture of Compound 1 in high quality and good yields.
  • the freebase of Compound 1 was obtained in the Crystalline Form A during synthetic process, which is moderately hygroscopic with 4.96%water gain from 0 to 80%RH.
  • the Crystalline Form A was changed to the Crystalline Form A*after dynamic vapor sorption (DVS) .
  • the crystallization of the crystalline forms of the present invention can also be conducted in an appropriate solvent system containing at least one solvent by evaporation of solvent, cooling and/or by addition of anti-solvents (solvents that are less able to solubilize the Compound 1, including but not limited to those described herein) to achieve super-saturation in the solvent system.
  • anti-solvents solvents that are less able to solubilize the Compound 1, including but not limited to those described herein
  • Crystallization may be done with or without seed crystals, which is described in the present invention.
  • a method for preparing the stable amorphous solid dispersion or the complex disclosed herein comprising step co-precipitating Compound 1 and HPMCAS.
  • Compound 1 and HPMCAS simultaneously precipitate out to form a molecular dispersion of Compound 1 in the matrix formed by HPMCAS.
  • the method comprises the step of a solvent controlled precipitation. In a preferred embodiment, the method comprises the step of microprecipitated bulk powder (MBP) technology.
  • MBP microprecipitated bulk powder
  • HPMCAS has a high ratio of succinoyl substitution to acetyl substitution (S/Aratio) .
  • HPMCAS is HPMCAS-LF, HPMCAS-MF, or HPMCAS-HF, or a mixture of two or more of the above substances.
  • Compound 1 is in a crystalline form or amorphous form. In a preferred embodiment, Compound 1 is Form A as disclosed herein.
  • HPMCAS is HPMCAS-LF, or HPMCAS-MF, or HPMCAS-HF; and Compound 1 in the form of freebase and HPMCAS-MF is in a weight ratio of 3: 7; or Compound 1 in the form of freebase and HPMCAS-MF is in a weight ratio of 2: 3; Compound 1 in the form of freebase and HPMCAS-MF is in a weight ratio of 1: 4; Compound 1 in the form of freebase and HPMCAS-LF is in a weight ratio of 1: 9; Compound 1 in the form of freebase and HPMCAS-LF is in a weight ratio of 1: 4; Compound 1 in the form of freebase and HPMCAS-LF is in weight ratio of 3: 7; Compound 1 in the form of freebase and HPMCAS-LF is in a weight ratio of 2: 3; or Compound 1 in the form of freebase and HPMCAS-HF in a weight ratio of 1: 4.
  • the method comprises dissolving Compound 1 and HPMCAS in an organic solvent.
  • the organic solvent is N, N-dimethylformamide (DMF) , N, N-dimethylacetamide (DMAc) , dimethyl sulfoxide (DMSO) or N-methyl-2-pyrrolidone (NMP) .
  • the resulting solid is further optionally micronized by, e.g., jet-milling to give a powder with a particle size suitable for drug formulation, e.g., of D 90 less than 150 ⁇ m or 200 ⁇ m.
  • the solid dispersion or the complex has a glass transition temperature of about 110-115°C, preferably about 111 °C.
  • the method disclosed herein comprises:
  • the neat amorphous form of Compound 1 disclosed herein is substantially characterized by an XRPD pattern as shown in Figure 7 having no peak diffraction angels.
  • the neat amorphous form of Compound 1 disclosed herein is substantially characterized by 1 H-NMR pattern as shown in Figure 21.
  • the neat amorphous form of Compound 1 disclosed herein has a glass transition temperature of between about 135 to 143°C, preferably about 138.3°C.
  • the neat amorphous form of Compound 1 disclosed herein has a particle size distribution of D 90 within about 60 to about 80 ⁇ m, a particle size distribution of D 50 within about 2 to about 6 ⁇ m, a particle size distribution of D 10 within about 1 to about 2 ⁇ m; preferably a particle size distribution of D 90 of about 69.9 ⁇ m, a particle size distribution of D 50 of 3.5 ⁇ m, a particle size distribution of D 10 of 1.4 ⁇ m.
  • the polar solvent comprises an ether, a carboxylic acid ester, a nitrile, a ketone, an amide, a sulfone, a sulfoxide or a halogenated hydrocarbon.
  • the polar solvent comprises , but not limited to, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, uncle Butanol, N, N-dimethylacetamide, N, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, etc.
  • the polar solvent is a mixture of halogenated hydrocarbons/amides, such as a mixture
  • the method comprise: an amine of Formula Ia and a protected carbamoyl compound of Formula Ib are subjected to a condensation reaction to obtain a compound of Formula I or a pharmaceutically acceptable salt thereof,
  • R 5 is selected from alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is independently optionally substituted with one or two or three substituents R 9 ;
  • LG is a leaving group
  • R 6 , R 7 and R 8 which may be the same or different, are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or (R 6 and R 7 ) and/or (R 7 and R 8 ) together with the atom (s) to which they are attached, each form a ring selected from heterocyclyl and heteroaryl rings optionally substituted with one or two or three substituents R 9 ;
  • the condensation reaction of an amine of Formula Ia and a protected carbamoyl compound of Formula Ib is conducted in an organic solvent. In one embodiment, the condensation reaction is conducted with a solution of an amine of Formula Ia in an organic solvent and a protected carbamoyl compound of Formula Ib. In one embodiment, the condensation reaction is conducted with an amine of Formula Ia and a solution of a protected carbamoyl compound of Formula Ib in an organic solvent.
  • the condensation reaction is conducted in an anhydrous condition. In one embodiment, the condensation reaction is conducted by adding a protected carbamoyl compound of Formula Ib into a solution of an amine of Formula Ia in an organic solvent.
  • the organic solvent is typically selected from the group consisting of a non-polar solvent, a polar protic solvent and a polar aprotic solvent, or a mixture thereof.
  • Suitable polar aprotic solvents include, but are not limited to, N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, ethyl acetate, acetone, N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide.
  • Suitable polar protons solvents include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, and acetic acid.
  • Suitable non-polar solvents include, but are not limited to, dioxane, toluene, hexane, cyclohexane and diethyl ether.
  • the organic solvent is a polar aprotic solvent.
  • the organic solvent is N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl Ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, ethyl acetate, acetone, N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide, or a mixture of two or more.
  • the organic solvent is N-methylmorpholine, dimethyl sulfoxide or a mixture of both.
  • the amount of the organic solvent there is no particular limitation to the amount of the organic solvent, provided that the amine of Formula Ia is sufficiently dissolved.
  • the condensation reaction is conducted in vacuum. In a further embodiment, the condensation reaction is conducted in a vacuum as low as about -0.10 MPa.
  • the condensation reaction is conducted at a temperature of about 10 to 50°C or at a temperature of about 15 to 25°C. In a further embodiment, the condensation reaction is conducted at a temperature of about 20 ⁇ 5°C.
  • the condensation reaction is carried out for at least about 0.5 hours, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours. In a further embodiment, the condensation reaction is carried out for about 3 hours.
  • the content of impurity-1 in the product of the condensation reaction is below 0.5%, even less than 0.05% (detected by HPLC) at the best mode.
  • R 1 and R 2 are both hydrogen.
  • R 5 is aryl, optionally substituted with one or two or three substituents R 9 .
  • R 5 is phenyl, optionally substituted with one or two or three halogen.
  • R 5 is 2, 4, 5-trifluorophenyl.
  • the compound of Formula I is 1- ( (1S, 1aS, 6bS) -5- ( (7-oxo-5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-4-yl) oxy) -1a, 6b-dihydro-1H-cyclopropa [b] benzofuran-1-yl) -3- (2, 4, 5-trifluorophenyl) urea or a pharmaceutically acceptable salt thereof.
  • the acid is a mineral acid, for example selected from the group consisting of hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid and nitric acid; and an organic acid, for example selected from the group consisting of malic acid, maleic acid, and fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, benzoic acid, salicylic acid, stearic acid, alkanoic acid (such as acetic acid and HOOC- (CH 2 ) n -COOH, wherein n is selected from 0-4) .
  • an organic acid for example selected from the group consisting of malic acid, maleic acid, and fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, 2-
  • the compound of Formula Ia-2 is prepared by reacting a compound of Formula Ia-1 in (Boc) 2 O/t-BuOH in the presence of a catalyst,
  • Impurity-1 is also formed during the Curtis rearrangement reaction of the acyl azide of formula Ia-1 and t-butanol, the solubility and polarity of Impurity-1 differ greatly from Formula Ia-2. Therefore, Impurity-1 can easily be removed by filtering with a silica gel pad during the reaction, thereby obtaining the intermediate amine of the formula Ia free of impurities. In one embodiment, Impurity-1 may be removed after formation of the t-butyl carbamate of Formula Ia-2 from the acyl azide of Formula Ia-1.
  • a method for treating or preventing a disease or disorder responsive to inhibition of Raf kinases in a subject comprising administering to said subject a therapeutically effective amount of Compound 1, wherein Compound 1 is in the amorphous solid dispersion as disclosed herein or in the complex as disclosed herein or the crystalline form disclosed herein or the neat amorphous form disclosed herein.
  • the administered dosage of Compound 1 is 1-200 mg/day, and the administration frequency is one to three times a day.
  • the pharmaceutical compositions can be administrated orally in forms such as capsules, tablets, pills, powders, sustained release injection in such form as a sterile solution, suspension or emulsion; through a local treatment form such as paste, cream, or ointment; or via a rectal form such as suppositories.
  • the pharmaceutical compositions may be in a unit dosage form that is suitable for precise dosing applications.
  • the active compound can be mixed with a variety of sweeteners or flavoring agents, pigments or dye combinations. If necessary, a variety of emulsifiers can be employed or suspensions generated; diluents such as water, ethanol, propylene glycol, glycerin, or their combination can be utilized.
  • compositions are preferably administrated orally.
  • compositions are preferably in the capsule or tablet form.
  • alkyl herein refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 6, carbon atoms.
  • alkyl group can be selected from methyl, ethyl, 1-propyl or n-propyl ( “n-Pr” ) , 2-propyl or isopropyl ( “i-Pr” ) , 1-butyl or n-butyl ( “n-Bu” ) , 2-methyl-1-propyl or isobutyl ( “i-Bu” ) , 1-methylpropyl or s-butyl ( “s-Bu” ) , and 1, 1-dimethylethyl or t-butyl ( “t-Bu” ) .
  • cycloalkyl refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups.
  • the cycloalkyl group may comprise from 3 to 12, such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms.
  • the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as 3 to 8, 3 to 6 carbon atoms.
  • Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups.
  • bicyclic ring systems such as 7 to 12 membered bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected, for example, from naphthalene, indane, and 1, 2, 3, 4-tetrahydroquinoline; and
  • tricyclic ring systems such as 10 to 15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • halogen or halo refers to F, Cl, Br or I.
  • heteroaryl herein refers to a group selected from:
  • 5-to 7-membered aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon;
  • 8-to 12-membered bicyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and
  • 11-to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.
  • the heteroaryl group includes a 5-to 7-membered heterocyclic aromatic ring fused to a 5-to 7-membered cycloalkyl ring.
  • the point of attachment may be at the heteroaromatic ring or at the cycloalkyl ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heterocyclic or “heterocycle” or “heterocyclyl” herein refers to a ring selected from 4-to 12-membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings comprising at least one carbon atoms in addition to at least one heteroatom, such as from 1-4 heteroatoms, further such as from 1-3, or further such as 1 or 2 heteroatoms, selected from oxygen, sulfur, and nitrogen.
  • Heterocycle herein also refers to a 5-to 7- membered heterocyclic ring comprising at least one heteroatom selected from N, O, and S fused with 5-, 6-, and /or 7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring, provided that the point of attachment is at the heterocyclic ring when the heterocyclic ring is fused with a carbocyclic aromatic or a heteroaromatic ring, and that the point of attachment can be at the cycloalkyl or heterocyclic ring when the heterocyclic ring is fused with cycloalkyl.
  • Heterocycle herein also refers to an aliphatic spirocyclic ring comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the heterocyclic ring.
  • the rings may be saturated or have at least one double bond (i.e. partially unsaturated) .
  • the heterocycle may be substituted with oxo.
  • the point of the attachment may be carbon or heteroatom in the heterocyclic ring.
  • a heterocycle is not a heteroaryl as defined herein.
  • heterocycle examples include, but not limited to, (as numbered from the linkage position assigned priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1, 2-dithietanyl, 1, 3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,
  • X-ray intensity data from a colorless plate-like crystal were measured at 173 (2) K using a Bruker APEX-II CCD diffractometer (Cu K ⁇ radiation, ) . Polarized light microscopic picture was captured at room temperature.
  • the temperature was cooled to -20 °C and the solution was transferred into the above 3 L 4-necked round-bottom flash. Then the mixture was stirred for 1 hour below 20 °C and the value of pH was confirmed to be between 4 ⁇ 7.
  • the organic layer was separated and washed with 25%NaCl (17 volumes) . Then the organic phase was concentrated to 5 volumes and EtOAc (17 volumes) was charged into the mixture and concentrated to 5 volumes. EtOAc (17 volumes) was charged into the mixture and concentrated to 5 volumes. The solution was used for the next step directly.
  • the solution of INTQ-3 in EtOAc was charged into a reactor. The solution was stirred and cooled to -5 ⁇ 5 °C. HCl was introduced into the mixture at -5 ⁇ 5 °C for 2 hrs. Then the mixture was heated to 20 ⁇ 30 °C. HPLC was used to monitor the reaction every 2 hrs after reacting for 5 hrs until the content of INTQ-3 was less than 0.5%. The reaction mixture was concentrated to 10 volumes and cooled to 0 ⁇ 5 °C. The residue was stirred for 1 hour at 0 ⁇ 5 °C. The mixture was filtered and the filter cake was charged into H 2 O (15 volumes) . The mixture was stirred for 2 hrs at 20 ⁇ 30 °C.
  • Step 5 Syntheses of INTQ-5
  • Amberlyst-15 (3.8 Kg, 0.1 wt) was added to toluene (760 L, 20 volumes) .
  • the system was heated to 110 °C under N 2 protection.
  • the solution of INTQ-7 (38 Kg/Batch, 3 batches, 1.0 equiv) in toluene was dropwise added while maintaining the temperature at 105 ⁇ 110 °C.
  • the reaction system was concentrated under constant pressure at 105 ⁇ 110 °C to 17 volumes after reacting 1 hour.
  • Toluene (3 volumes) was charged to the system.
  • the reaction mixture was cooled to 20 ⁇ 40 °C after reaction completion as monitored by HPLC.
  • the mixture was filtered through Celite (0.1 wt) and the filter cake was washed with toluene (0.5 volumes) .
  • 1-Dodecanethiol 147.0 Kg, 3.5 equiv was added to a solution of INTQ-8 (43 Kg, 1.0 equiv) in NMP (260 L, 6 volumes) .
  • the system was heated to 75 ⁇ 5 °C.
  • Sodium ethoxide (69.0 Kg, 3.5 equiv) was added in portions while maintaining the temperature below 120 °C.
  • the reaction mixture was heated to 130 ⁇ 5 °C.
  • the mixture was sampled each hour for HPLC until the content of INTQ-8 ⁇ 3.0%after reacting for 16 hours at 130 ⁇ 5°C.
  • the reaction mixture was cooled to 60 ⁇ 5 °C, and then 8 volumes water was charged to the mixture.
  • Et 3 N 48.2 Kg, 2.0 equiv was added to the solution of INTQ-9 (32 Kg, 1.0 equiv) in dichloromethane (10 volumes) below 40°C.
  • the mixture was cooled to -5 ⁇ 5 °C.
  • TMSCl 1.3 equiv in dichloromethane (1 volumes) was dropwise added while maintaining the temperature at -5 ⁇ 5 °C.
  • the mixture was sampled each hour for gas chromatography until the content of INTQ-9 ⁇ 2.0%after reacting for 1 hour at -5 ⁇ 5°C.
  • the mixture was concentrated to 3 volumes under pressure below 40°C. 15 volumes of n-hexane was charged to the residue and the mixture was stirred for at least 30 minutes.
  • Step 13 INTQ-12 was charged to EtOAc (1.5 volumes) and n-heptane (20 volumes) , the mixture was heated to 75 ⁇ 85°C until to clear. The clear solution was stirred for 1 hour at 75 ⁇ 85°C and then gradually cooled to 15 ⁇ 20 °C. The mixture was filtered and washed with n-heptane (2 volumes) to afford the product. The wet product was dried at 55 ⁇ 5°C for at least 16 hours to give INTQ-13 as light yellow to off-white solid.
  • Step 14 INTQ-13 (16 Kg, 1.0 equiv) and INTQ-6 (12.7 Kg, 1.05 equiv) were added to DMF (5 volumes) .
  • the system was heated to 55 ⁇ 5 °C.
  • Cesium carbonate (29.6 Kg, 1.25 equiv) was added.
  • the reaction mixture was heated to 110 ⁇ 5 °C.
  • the mixture was sampled each hour for HPLC until the content of INTQ-13 ⁇ 0.5%after reacting for 2 hours at 110 ⁇ 5°C.
  • Water (30 volumes) was added to the mixture at 25 ⁇ 5 °C.
  • the mixture was stirred for 1 ⁇ 2 hours and filtered to afford wet product.
  • the wet product was re-slurry with water (5 volumes) .
  • the filter cake was used for next step directly.
  • a reactor was vacuumed to ⁇ -0.08 MPa and then charged with inert nitrogen to atmosphere. 1, 4-dioxane (10.0 volumes) , INTQ-15 (3.6kg, 1.0 eq) were added to the reactor. The mixture was concentrated to 6.0-6.5 volumes below 50 °C and the mixture was sampled for the content of water. Et3N (1.1 eq) was charged to the reactor. The mixture was heated to 30 ⁇ 5 °C, and DPPA (1.1 eq) was dropwise added into the reactor. The mixture was sampled for HPLC analysis after reacting 2 hours at 30 ⁇ 5°C until the content of INTQ-15 ⁇ 1.0%. The solution of INTQ-16 was obtained.
  • the reactor was vacuumed to ⁇ -0.08 MPa and then charged with inert nitrogen to atmosphere.
  • THF 6.0 volumes
  • H 2 O 3.0 volumes
  • 2, 4, 5-trifluoroaniline 1.0eq
  • NaHCO 3 1.2eq
  • the mixture was cooled to 0°C
  • phenyl chloroformate was added slowly at 0 ⁇ 5°C.
  • the mixture was stirred for at least 2 hours.
  • the mixture was sampled for LCMS until 2, 4, 5-trifluoroaniline ⁇ 0.2%.
  • EA (15.0 volumes) was then added.
  • the organic phase was washed with H 2 O (5.0 volumes) , and then washed with 5wt%HCl aq.
  • the reactor was vacuumed to ⁇ -0.08 MPa and then charged with inert nitrogen to atmosphere.
  • DMSO (9.0 volumes) , INTQ-18 (1.63kg, 1.0eq) and N-methyl morpholine (1.0eq) were charged to the reactor.
  • the mixture was stirred for at least 0.5 hour at 20 ⁇ 5°C.
  • INTQ-19 (1.27kg, 0.9eq) was charged to the reactor at 20 ⁇ 5°C.
  • the mixture was sampled for HPLC analysis after reacting for 3 hours at 20 ⁇ 5°C until the content of INTQ-19 ⁇ 0.3%.
  • the cake was then dried under vacuum at 45 ⁇ 5°C for at least 8 hours until LOD ⁇ 3.0%. If the solvent residue cannot meet the criteria, removal of residual solvent by slurry: purified water (40.0 volumes) and product were charged to a reactor, and the mixture was stirred for at least 4 hours at 20 ⁇ 5°C, and then centrifuged. The filter cake was washed with purified water (5.0 volumes ⁇ 2) . The cake was dried under vacuum at 45 ⁇ 5°C for at least 8 hours until LOD ⁇ 3.0%. The cakes were sampled for solvent residue. If solvent residue cannot meet criteria, the procedure “removal of residual solvent by slurry” is repeated until solvent residue meets the criterion.
  • the material was sampled for HPLC analysis with the criterion of Compound 1 ⁇ 98.0%purity (2.02 kg) and the criterion of impurity-1 less than 0.5%. HPLC analysis determined that the content of Impurity-1 was less than 0.1%herein.
  • the product was packaged in double LDPE bags with desiccant, stored at room temperature.
  • Example 1 The resulting powder prepared in Example 1 was evaluated to amorphous or crystalline nature by the X-ray powder diffraction (XRPD) pattern technique.
  • the resulting powder prepared in Example 1 was determined to be crystalline (sometimes referred to as “Form A” throughout the application) as evidenced by the crystalline peaks in the XRPD pattern in Figure 1.
  • the resulting power was also characterized by 1 H-NMR spectra and 13 C-NMR spectra, as shown Figure 16 and Figure 17, respectively.
  • the XRPD Pattern of the crystalline form of Compound 1 has the following characteristic peak diffraction angles (where “spacing” is shown as the “d-value” in Figure 1) :
  • Form A Due to the low bioavailability observed in preclinical study, Form A therefore has limited use for direct pharmaceutical formulation.
  • Form A is a good candidate for purifying API and used as the starting materials for manufacturing the amorphous solid dispersion due to the above-mentioned long-term stability of Form A (i.e., no significant chemical purity change occurred when stored at 25°C°C/60%RH for up to 24 months and no optical purity changes were observed when stored at 25°C°C/60%RH for up to 24 months and at 40°C /75%RH condition for up to 6 months) .
  • the intermediate INTQ-20 was synthesized in a similar manner to Example 1A, step 19, and then subjected to a condensation reaction with the intermediate INTQ-18 to obtain Compound 1.
  • INTQ-20 is unstable and most of the products comprising INTQ-20 are by-product Impurity-2, and Impurity-3 (possibly due to the reaction of the methanol used in the LCMS mobile phase for separating the intermediate INTQ-20) .
  • the intermediate INTQ-22 was synthesized in a similar manner to Example 1A, step 19, and then subjected to a condensation reaction with the intermediate INTQ-18 to obtain Compound 1.
  • INTQ-22 was not successfully isolated from the synthesis of the intermediate INTQ-22.
  • the isolated products are mainly Impurity-2 (possibly due to the reason that the p-nitrophenol group can easily be removed so that Impurity-2 can easily be formed from the active ester and other trifluoroaniline molecule) and p-nitrophenol.
  • the shell vial was sealed by the PE-Plug with one pinhole on it and placed in the fume hood for slow evaporation at ambient temperature and humidity. After six days, plate-shaped crystal sample (CP ID: 810323-A4) was obtained.
  • the structure of the plate-shaped crystal was determined using a set of diffraction data collected from a single crystal grown by slow cooling in EtOAc and was referred to as single crystal of Compound 1 or Form A**. Crystal data and structure refinement of Form A**are listed in Figure 3-6.
  • a solution of Form A of Compound 1 in DCM/MeOH (2: 1) was spray-dried to give a white powder.
  • the operating parameters of the spray dryer (BUCHI-290 &BUCHI-295) were as follows: inlet temperature: 60°C; outlet temperature: 35°C, Aspirator: 100 %; pump%: 15%; nozzle cleaner: 2.
  • the XRPD pattern method was used to characterize the structure of the resulting powder, which was confirmed to be amorphous, as Figure 7 has no any peak diffraction angles.
  • the amorphous form of Compound 1 is referred to as Neat Amorphous Form of Compound 1 or Form B throughout the application.
  • 1 H-NMR spectra for Form B is shown in Figure 21.
  • Form B was determined as having a glass transition temperature of 138.3 °C.
  • the XRPD data of the testing sample showed that Form B was stable at 14 days at 40°C/75%RH condition as the XRPD pattern data of the testing sample at 14 days in Figure 29 did not show any crystalline peaks.
  • HPMCAS-LF, HPMCAS-MF and HPMCAS-HF are commercially available from Shin-Etsu Chemical Co. Ltd unless indicated otherwise.
  • the amorphous solid dispersion of Compound 1 as microprecipitation bulk powder was prepared as follows: Form A of Compound 1 as a poorly soluble drug and Hypromellose acetate succinate (HPMCAS-MF) in a ratio of 2: 3 (w/w) were dissolved in DMA or DMF. The resulting solution was added into a stirred acidic aqueous solution (0.01 N HCl) cooled at 2-8 °C. The drug was then co-precipitated out with HPMCAS from the acidic aqueous solution. After further stirring and filtering, the solid was washed a few times with 0.01 N HCl solution and water and then dried under vacuum at below 50 °C to give a microprecipitation bulk powder suitable for drug product manufacture.
  • HPMCAS-MF Hypromellose acetate succinate
  • the drug loading was determined as 20.2%. As Figure 11 does not show any crystalline peaks, the powder was determined to be amorphous (referred to as Form F or amorphous solid dispersion of Compound 1 of Form F) .
  • 1 H-NMR spectra for Form F is shown in Figure 18.
  • Hygroscopicity (i.e., Moisture sorption) of Form F by DVS is shown in Figure 20.
  • the water content of Form F was reported as 0.70% (initial and at 0 month) , 0.80% (at 1 month) , 1.39% (at 3 month) , 1.86% (at 6 month) , 0.62% (at 9 month) , 0.89% (at 12 month) , 2.35% (at 18 month) and 0.55% (at 24 month) and the variation of the water content was found to be consistent with that of environmental humidity and actually had no substantial change during the 24 month storage period.

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KR1020217026908A KR20210120039A (ko) 2019-01-25 2020-01-23 B-raf 키나제 이합체 억제제의 안정적인 고체 분산액, 이의 제조 방법 및 용도
JP2021542104A JP7591504B2 (ja) 2019-01-25 2020-01-23 Ｂ－ｒａｆキナーゼ二量体阻害剤の安定な固体分散体、その調製方法及び使用
SG11202107849RA SG11202107849RA (en) 2019-01-25 2020-01-23 Stable solid dispersions of b-raf kinase dimer inhibitor, methods of preparation, and uses therefor
US17/423,600 US12582604B2 (en) 2019-01-25 2020-01-23 Stable solid dispersion of a B-RAF kinase dimer inhibitor, methods of preparation, and uses therefor
BR112021014563-0A BR112021014563A2 (pt) 2019-01-25 2020-01-23 Dispersão sólida amorfa, complexo da fórmula (i), formas cristalina de composto 1, cristal isolado, métodos de preparação da dispersão sólida amorfa, de tratamento ou prevenção de doenças, de preparação de compostos da fórmula i, composto da fórmula ia
MX2021008884A MX2021008884A (es) 2019-01-25 2020-01-23 Dispersion solida estable de un inhibidor del dimero de la cinasa b-raf, metodos de preparacion y usos de la misma.
CA3123476A CA3123476A1 (en) 2019-01-25 2020-01-23 Stable solid dispersions of b-raf kinase dimer inhibitor, methods of preparation, and uses therefor
EP20744694.9A EP3914591A4 (en) 2019-01-25 2020-01-23 STABLE SOLID DISPERSIONS OF A B-RAF KINASE DIMER INHIBITOR, PROCESS FOR THEIR PREPARATION AND THEIR USES
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CN202080010548.8A CN113330011A (zh) 2019-01-25 2020-01-23 B-raf激酶二聚体抑制剂的稳定的固体分散体、制备方法及其用途
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WO2024073364A1 (en) * 2022-09-26 2024-04-04 Beigene, Ltd. Combinations of a b-raf inhibitor, and an anti-egfr antibody for the treatment of cancer
WO2025079036A1 (en) 2023-10-12 2025-04-17 Beigene Switzerland Gmbh Solid forms comprising a b-raf kinase dimer inhibitor, methods of preparation, and uses therefor
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