Stable solid dispersion of b-RAF kinase dimer inhibitor, and methods of preparation and uses thereof

Abstract

To provide, e.g., a new form of a particularly poorly water-insoluble compound, i.e., Compound 1, which shows better bioavailability and has chemical and physical stability during formulation and storage of this drug.SOLUTION: Disclosed herein are: 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; a method of preparing the same; uses of the solid dispersion; and a crystalline form of Compound 1.SELECTED DRAWING: None

Description

[Technical field]

[0001] Disclosed herein are physically stable solid dispersions comprising compound 1, the B-RAF kinase dimeric 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 certain stabilizing polymers, methods for preparing the same, and uses of the solid dispersions. Also disclosed herein are stable crystalline forms of compound 1, namely Form A, and neat amorphous forms of compound 1, methods for preparing the same. Also disclosed herein are methods for mass producing the B-RAF kinase dimeric inhibitors disclosed herein. [Background technology]

[0002] 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 (also referred to throughout this specification as compound 1) has been disclosed as a second generation B-RAF inhibitor (see WO 2014 / 206343A1). The structure of compound 1 is shown below. [ka]

[0003] The B-RAF inhibitors of WO 2014 / 206343 A1 were prepared by the reaction of 1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carbonyl azide (intermediate I) with substituted anilines. However, in the reported synthetic routes of WO 2014 / 206343 A1 (e.g., preparation of the compound of formula I from compound 10 and aniline on page 34 or especially step K on page 51), a dimeric impurity, i.e. impurity-1, was always generated in an amount ranging from several percent to as much as 50%, and could not be completely removed by the general recrystallization process. [ka]

[0004] It was found that the main cause of the formation of impurity-1 was due to the water present in the reaction system. Even if the water content in the reaction system was strictly controlled, the amount of impurity-1 was found to be significantly higher (>>1%). In addition, impurity-1 has extremely low solubility in water and other common recrystallization solvents, so it is impossible to control it to less than 0.5% (the minimum requirement for good API quality) by the recrystallization procedure. Because compound 1 and impurity-1 have similar polarity, repeated column chromatography procedures had to be used to completely remove impurity-1 from compound 1. This costly and laborious chromatographic process allows the production of pure compound 1 only on a small scale (milligram or gram scale). A novel process without column chromatography for the production of compound 1 with high quality on a large industrial scale is highly desirable.

[0005] As a second-generation B-RAF inhibitor, compound 1 has shown strong inhibitory activity against the RAF family of serine / threonine kinases, especially the BRAF / CRAF dimer. It is a molecular targeted therapeutic agent for the treatment of cancers with abnormalities in the MAPK pathway, including B-RAF mutations and K-RAS / N-RAS mutations, and has shown improvement over first-generation B-RAF inhibitors, such as vemurafenib and dabrafenib.

[0006] However, Compound 1 itself, either in crystalline or neat amorphous form, has shown low solubility in various solutions including water or 0.1 HCl and buffers with various pH values. The crystalline form of Compound 1 also exhibits moderate hygroscopicity as evidenced by DVS testing, and the crystalline hydrate form of Compound 1 has been shown to be moderately hygroscopic with a sample weight gain of 4.96% at 80% relative humidity.

[0007] In addition, preliminary drug metabolism and pharmacokinetic (DMPK) studies showed that the oral absorption of the crystalline form of compound 1 was relatively low, with a bioavailability of about 20% in rats. A systematic screen was conducted for suitable salt forms of compound 1 with better bioavailability. Unfortunately, we failed to identify a stable crystalline salt, possibly due to the low basicity of compound 1.

[0008] For poorly water-soluble compounds, crystalline nanoparticles of such compounds act as seeds that induce crystallization upon storage, resulting in increased crystalline order and decreased solubility over time. For some poorly water-soluble compounds, the amorphous form has a high tendency to crystallize, and thus may easily crystallize even in small experiments, e.g., in large-scale production.

[0009] Several techniques have been developed to improve the desired properties of these poorly soluble pharmaceutical compounds, including but not limited to particle size reduction (micronization), lipid incorporation, co-solvents, complexation, co-crystallization and solid dispersions.

[0010] Among various techniques, solid dispersions, in which poorly soluble active pharmaceutical compounds are dispersed in a matrix of solid-state polymers, have been reported to provide fast dissolution rates and / or appreciable solubility in gastric and intestinal fluids. See, for example, ATM Serajuddin, J.Pharm.Sci., 88(10):1058-1066 (1999) and MJ Habib, Pharmaceutical Solid Dispersion Technology, Technomic Publishing Co., Inc., 2001. In the mixture, the active pharmaceutical compounds may be present in amorphous or microcrystalline form. Various processes have been used to prepare solid dispersions, including co-precipitation and spray drying. Although solid dispersions prepared by various processes provide different physicochemical properties, no evidence has been suggested in the literature to show the superiority of one method over another in achieving the desired pharmacokinetic profile. See, US Patent Publication No. 20080293787A1.

[0011] Specifically, amorphous forms of solid dispersions containing poorly soluble compounds dispersed in a polymer matrix have been reported to provide stable amorphous formulations (e.g., U.S. Pat. No. 6,350,786) or to provide improved solubility and better bioavailability (e.g., U.S. Pat. No. 6,548,555).

[0012] However, there are many important factors that can affect the stability of the amorphous form of a solid dispersion. For example, Navnit Shah, et.al., (International Journal of Pharmaceutics, 438 (2012), 53-60, "Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs") summarize the following as important determinants for the stabilization of the amorphous form: - API properties such as Tg, Tm, log P, heat of fusion, molecular weight and ionic properties; - the properties of the stabilizing polymer, e.g. ionic properties, Tg, molecular weight, hydrogen bond donor / acceptor and interaction capacity, - drug loading in the solid dispersion; - Process choices, e.g. solubility of API and polymer in organic solvents, rate of precipitation / solidification, potential interactions, physical properties of amorphous material (bulk density, porosity and particle size).

[0013] US20080293787A1 discloses a pharmaceutical composition of a poorly soluble drug, namely (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 polymer matrix. US20080293787A1 discloses that solid dispersions prepared by different processes can have different properties. For example, solid dispersions prepared by spray drying do not provide an amorphous form of the drug. Solid dispersions containing API and HPMCAS prepared by hot melt extrusion showed higher bioavailability, better dose proportionality and physical stability compared to solid dispersions containing the same components prepared by coprecipitation. Indeed, the API started to crystallize in the co-precipitated product in aqueous suspension (2% hydroxypropylcellulose).

[0014] WO2010114928A3 (also published as EP2955180A1) discloses that solid dispersions comprising the API propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-2,4-difluoro-phenyl}-amide and various polymers in various ratios can form stable amorphous solid dispersions.

[0015] Despite the variety of formulation tools available in the pharmaceutical industry, it can be difficult to easily determine whether an active pharmaceutical compound can be combined with certain excipients to form a stable amorphous formulation that exhibits improved bioavailability and long-term stability, is manufacturable on a large scale, and is stable. Summary of the Invention [Problem to be solved by the invention]

[0016] There is a great need for a new form of the particularly poorly water-insoluble compound, namely compound 1, which shows better bioavailability and has chemical and physical stability during the formulation and storage of this drug. Furthermore, there is a need for a form of compound 1 (e.g., crystalline or amorphous form) that has stable physicochemical properties and is suitable for pharmaceutical production, and a need for a method for mass-producing the B-RAF kinase dimer inhibitor disclosed herein. Therefore, there is a need for a new process for preparing compound 1 that can be used to prepare compound 1 on a large scale while controlling the content of impurity-1 to less than 0.5%, even less than 0.05%, and does not use high-cost column chromatography, significantly reducing the production cost. [Means for solving the problem]

[0017] The inventors of the present application have found that the amorphous solid dispersion containing Compound 1 as a poorly water-soluble drug and a stabilizing polymer prepared by microprecipitation bulk powder (MBP) technology shows superior oral bioavailability (more than 90%) compared to the crystalline form of Compound 1 or the neat amorphous form of Compound 1. The amorphous solid dispersion of the present application also has unexpected and exceptional long-term physicochemical stability (e.g., up to nearly 2 years at RT) and pharmaceutical processability (e.g., high Tg and good flowability). The high bioavailability, long-term stability and exceptional pharmaceutical processability of the amorphous solid dispersion prepared by MBP of the present application suggest that the amorphous solid dispersion as MBP is suitable for the production of formulations in clinical trials and large-scale commercial use.

[0018] In a first aspect, disclosed herein is a stable amorphous solid dispersion comprising Compound 1 and a stabilizing polymer, wherein Compound 1, in its solid state, is molecularly dispersed in a polymeric matrix formed by the stabilizing polymer.

[0019] In a second aspect, the present disclosure provides a compound of formula (I) comprising Compound 1 and HPMCAS. [ka] (wherein HPMCAs is hydroxypropyl methylcellulose acetate succinate and compound 1 is [ka] and m is a number such that the weight ratio of Compound 1 in the free base form to HPMCAS in the complex is from about 1:9 to about 9:1. A complex of the formula is disclosed.

[0020] In a third aspect, disclosed herein is a crystalline form of Compound 1.

[0021] In a fourth aspect, disclosed herein is a method of preparing a stable amorphous solid dispersion or complex disclosed herein, comprising co-precipitating Compound 1 and HPMCAS.

[0022] In a fifth aspect, disclosed herein is an amorphous form of Compound 1.

[0023] In a sixth aspect, disclosed herein is a process for preparing an amorphous form of Compound 1.

[0024] In a seventh aspect, disclosed herein is a method for mass producing a B-RAF kinase dimer inhibitor disclosed herein.

[0025] In an eighth aspect, disclosed herein is a method of treating or preventing a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of Compound 1, wherein Compound 1 is in an amorphous solid dispersion as disclosed herein, or a complex as disclosed herein, or a crystalline form as disclosed herein, or a neat amorphous form as disclosed herein. [Brief description of the drawings]

[0026] [Figure 1] 1 shows the XRPD pattern of one crystalline form of Compound 1 (Form A) (crystallized from isopropanol / water). [Diagram 2] 1 shows the XRPD pattern of another crystalline form of Compound 1 (Form A*). [Diagram 3] 1 shows the absolute structure of a single crystal of Compound 1 (Form A**) (single crystal obtained by crystallization from ethyl acetate / heptane). [Figure 4] FIG. 1 shows the crystal packing of a single crystal of Compound 1 (Form A**). [Diagram 5] 1 shows hydrogen bonds in a single crystal of Compound 1 (Form A**). [Figure 6] 1 shows the theoretical XRPD pattern of a single crystal of Compound 1 (Form A**) calculated using MERCURY software. [Figure 7] 1 shows the XRPD pattern of the neat amorphous form of Compound 1 (Form B). [Figure 8] FIG. 1 shows the XRPD pattern of an amorphous solid dispersion of Compound 1 as MBP (Form C) from a 3:7 ratio of Compound 1:HPMCAS-MF. [Figure 9] FIG. 1 shows the XRPD pattern of an amorphous solid dispersion of Compound 1 as MBP (Form D) from a 2:3 ratio of Compound 1:HPMCAS-MF. [Figure 10] FIG. 1 shows the XRPD pattern of an amorphous solid dispersion of Compound 1 as MBP (Form E) from a 1:9 ratio of Compound 1:HPMCAS-LF. [Figure 11] FIG. 1 shows the XRPD pattern of an amorphous solid dispersion of Compound 1 as MBP (Form F) from a 1:4 ratio of Compound 1:HPMCAS-LF. [Figure 12] FIG. 1 shows the XRPD pattern of an amorphous solid dispersion of Compound 1 as MBP (Form G) from a 3:7 ratio of Compound 1:HPMCAS-LF. [Figure 13]FIG. 1 shows the XRPD pattern of an amorphous solid dispersion of Compound 1 as MBP (Form H) from a 2:3 ratio of Compound 1:HPMCAS-LF. [Figure 14] FIG. 1 shows the XRPD pattern of an amorphous solid dispersion of Compound 1 as MBP (Form I) from a 1:4 ratio of Compound 1:HPMCAS-HF. [Figure 15] FIG. 1 shows the XRPD pattern of an amorphous solid dispersion of Compound 1 as MBP (Form J) from a 1:4 ratio of Compound 1:HPMCAS-MF. [Figure 16] 1 shows the 1H NMR spectrum of the crystalline form of Compound 1 (Form A). [Figure 17] 1 shows the 13C-NMR spectrum of the crystalline form of Compound 1 (Form A). [Figure 18] 1 shows the 1H NMR spectrum of an amorphous solid dispersion (Form F) of Compound 1 as MBP (Compound 1:LF=1:4). [Figure 19] FIG. 1 shows the hygroscopicity (i.e., water sorption) of the crystalline form of Compound 1 (Form A) by DVS. [Figure 20] FIG. 1 shows the hygroscopicity (i.e., water sorption) of an amorphous solid dispersion of Compound 1 as MBP (Form F) (Compound 1:HPMCAS-LF=1:4) by DVS. [Figure 21] 1 shows the 1H NMR spectrum of the neat amorphous form of Compound 1 (Form B). [Figure 22] FIG. 1 shows the H NMR spectrum of an amorphous solid dispersion of Compound 1 as MBP (Form C) (Compound 1:MF=3:7). [Diagram 23] FIG. 1 shows the H NMR spectrum of an amorphous solid dispersion of Compound 1 as MBP (Form D) (Compound 1:MF=2:3). [Figure 24] 1 shows the 1H NMR spectrum of an amorphous solid dispersion of Compound 1 as MBP (Form E) (Compound 1:LF=1:9). [Diagram 25] FIG. 1 shows the H NMR spectrum of an amorphous solid dispersion of Compound 1 as MBP (Form G) (Compound 1:LF=3:7). [Figure 26] FIG. 1 shows the H NMR spectrum of an amorphous solid dispersion of Compound 1 as MBP (Form H) (Compound 1:LF=2:3). [Figure 27] 1 shows the 1H NMR spectrum of an amorphous solid dispersion of Compound 1 as MBP (Form I) (Compound 1:HF=1:4). [Figure 28] FIG. 1 shows the H NMR spectrum of an amorphous solid dispersion (Form J) of Compound 1 as MBP (Compound 1:MF=1:4). [Figure 29] 1 shows an XRPD overlay of the neat amorphous form of Compound 1 (Form B). [Diagram 30] FIG. 1 shows an XRPD overlay of an amorphous solid dispersion of Compound 1 as MBP (Form C) from a 3:7 ratio of Compound 1:HPMCAS-MF. [Diagram 31] FIG. 1 shows an XRPD overlay of an amorphous solid dispersion of Compound 1 as MBP (Form D) from a 2:3 ratio of Compound 1:HPMCAS-MF. [Diagram 32] FIG. 1 shows an XRPD overlay of an amorphous solid dispersion of Compound 1 as MBP (Form E) from a 1:9 ratio of Compound 1:HPMCAS-LF. [Diagram 33] 1 shows the XRPD of the recovered precipitate of Form F. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] In a first aspect, disclosed herein is a stable amorphous solid dispersion comprising Compound 1 and a stabilizing polymer, wherein Compound 1, in its solid state, is molecularly dispersed in a polymeric matrix formed by the stabilizing polymer.

[0028] Many polymers have been reported as stabilizing polymeric additives for pharmaceutical formulations. See US Patent Publication No. 20080293787A1, US Patent No. 6,350,786 and US Patent No. 6,548,555. Polymers for this purpose can be either cationic or anionic polymers, have a molecular weight greater than about 80,000 D, a glass transition temperature of about 50° C. or higher, are relatively insoluble in water, and preferably have a pH-dependent solubility. Examples of such polymers include: polyacrylates (e.g., Eudragit®, Rohm America), chitosan, Carbopol® (BF Goodrich), polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropyl methylcellulose phthalate, cellulose acetate terephthalate, hydroxypropyl methylcellulose acetylsuccinate, carboxymethylcellulose and low-substituted hydroxypropylcellulose. However, the properties of the API itself may also affect the properties of the resulting solid dispersion.

[0029] The inventors of the present application have found that compound 1 disclosed herein cannot be homogeneously dispersed in Eudragit® L100-55 (a copolymer of methacrylic acid and ethyl acrylate), which is a commonly used stabilizing polymer additive.

[0030] Unexpectedly, the inventors of the present application have found that HPMCAS (hypromellose acetate succinate, i.e., hydroxypropyl methylcellulose acetate succinate), as an enteric coating agent for enteric or sustained release formulations, can be co-precipitated with a particular API, compound 1 disclosed herein, to form a stable amorphous solid dispersion as MBP, which exhibits high bioavailability, long-term stability and exceptional pharmaceutical processability.

[0031] The structure of HPMCAS is shown below. [ka]

[0032] There are several types of HPMCAS with various contents of acetyl and succinoyl groups in the polymer, which dissolve at different pH levels. Type LF has a high ratio of succinoyl to acetyl substitution (S / A ratio), while Type HF has a low S / A ratio and Type MF has an intermediate S / A ratio. Due to the high S / A ratio, HPMCAS-LF dissolves at a lower pH (≧5.5) compared to Type MF at pH≧6.0 and Type HF at pH≧6.8. Type LF typically has 5.0-9.0% acetyl groups and 14.0-18.0% succinoyl groups, Type MF typically has 7.0-11.0% acetyl groups and 10.0-14.0% succinoyl groups, and Type HF typically has 10.0-14.0% acetyl groups and 4.0-8.0% succinoyl groups.

[0033] The LF, MF and HF nominal compositions are summarized in the table below.

[0034] [Table 1]

[0035] In one embodiment, the stabilizing polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS), preferably HPMCAS with a high ratio of succinoyl to acetyl substitution (S / A ratio). In other embodiments, the stabilizing polymer is any one of HPMCAS-LF, HPMCAS-MF, or HPMCAS-HF, or a mixture of two or more of the above materials.

[0036] In one embodiment, the weight ratio of Compound 1 in the free base form to the polymer is about 1:9 to about 9:1, preferably about 1:4 to about 2:3, preferably about 3:7 or about 1:4, more preferably about 1:4. Unless otherwise specified, the ratio of Compound 1:HPMCAS is weight / weight (w / w).

[0037] In one embodiment, the stable amorphous solid dispersion has a drug loading of about 10% to 40%. In a preferred embodiment, the weight ratio of compound 1 to polymer is about 1:4, and the drug loading of the resulting dispersion is about 20%. In an even more preferred embodiment, the stable amorphous solid dispersion comprises: compound 1 in the form of a free base and HPMCAS-MF in a weight ratio of 3:7 or compound 1 in the form of a free base and HPMCAS-MF in a weight ratio of 2:3, compound 1 in the form of a free base and HPMCAS-MF in a weight ratio of 1:4, compound 1 in the form of a free base and HPMCAS-LF in a weight ratio of 1:9, compound 1 in the form of a free base and HPMCAS-LF in a weight ratio of 1:4, compound 1 in the form of a free base and HPMCAS-LF in a weight ratio of 3:7, compound 1 in the form of a free base and HPMCAS-LF in a weight ratio of 2:3, or compound 1 in the form of a free base and HPMCAS-HF in a weight ratio of 1:4.

[0038] In one embodiment, the stable amorphous solid dispersion is prepared by microprecipitation bulk powder (MBP) technology.

[0039] In one embodiment, the stable amorphous solid dispersion has a glass transition temperature of about 110-115°C, preferably about 111°C.

[0040] In one embodiment, the stable amorphous solid dispersion is formulated into an oral dosage form, such as a tablet or capsule.

[0041] In a second aspect, the present disclosure provides a compound of formula (I) comprising Compound 1 and HPMCAS. [ka] (wherein HPMCAs is hydroxypropyl methylcellulose acetate succinate and compound 1 is [ka] and m is a number such that the weight ratio of Compound 1 in the free base form to HPMCAS in the complex is from about 1:9 to about 9:1. A complex of the formula:

[0042] In one embodiment, the HPMCAS has a high succinoyl to acetyl substitution ratio (S / A ratio), hi other embodiments, the HPMCAS is HPMCAS-LF, HPMCAS-MF, or HPMCAS-HF, or a mixture of two or more of the foregoing.

[0043] In one embodiment, m is a number such that the weight ratio of compound 1 in the free base form to the polymer in the complex is preferably about 1:4 to about 2:3, preferably about 3:7 or about 1:4, more preferably about 1:4. In an even more preferred embodiment, the complex comprises: compound 1 in the free base form and HPMCAS-MF in a weight ratio of 3:7 or compound 1 in the free base form and HPMCAS-MF in a weight ratio of 2:3, compound 1 in the free base form and HPMCAS-MF in a weight ratio of 1:4, compound 1 in the free base form and HPMCAS-LF in a weight ratio of 1:9, compound 1 in the free base form and HPMCAS-LF in a weight ratio of 1:4, compound 1 in the free base form and HPMCAS-LF in a weight ratio of 3:7, compound 1 in the free base form and HPMCAS-LF in a weight ratio of 2:3 or compound 1 in the free base form and HPMCAS-HF in a weight ratio of 1:4.

[0044] In one embodiment, the complex is in an amorphous form.

[0045] In one embodiment, the complex is prepared by microprecipitation bulk powder (MBP) technology.

[0046] In one embodiment, the composite has a glass transition temperature of about 110-115°C, preferably about 111°C.

[0047] In one embodiment, the conjugate is formulated into an oral dosage form, such as a tablet or capsule.

[0048] In a third aspect, disclosed herein is a crystalline form of Compound 1 that exhibits long-term stability. For example, the stable crystalline form of Compound 1 exhibits no significant change in chemical purity when stored at 25° C. / 60% RH for up to 12 months, and no change in optical purity when stored at 25° C. / 60% RH for up to 12 months and at 40° C. / 75% RH for up to 6 months, suggesting that the stable crystalline form is a good candidate for purifying the API and being used as a starting material for producing its amorphous solid dispersion.

[0049] In one embodiment, the crystalline form is Form A characterized by an XRPD pattern comprising: at least three, four, five, or six diffraction peaks having 2θ angle values ​​independently selected from the group consisting of 4.7±0.2, 9.4±0.2, 13.6±0.2, 14.0±0.2, 14.9±0.2, and 15.6±0.2 degrees. Preferably, the crystalline form is Form A characterized by an XRPD pattern comprising: at least three, four, five, or six diffraction peaks having 2θ angle values ​​independently selected from the group consisting of 4.7±0.2, 9.4±0.2, 13.6±0.2, 14.0±0.2, 14.9±0.2, 15.6±0.2, 21.2±0.2, 24.3±0.2, 24.7±0.2, 25.1±0.2, and 29.1±0.2 degrees. More preferably, the crystalline form is Form A characterized by an XRPD pattern comprising: 4.7±0.2, 9.4±0.2, 10.2±0.2, 13.6±0.2, 14.0±0.2, 14.9±0.2, 15.6±0.2, 17.2±0.2, 17.4±0.2, 18.7±0.2, 20.0±0.2, 20.4±0.2, 21.2±0.2, 22.3±0.2. Diffraction peaks having 2θ angle values ​​independently selected from the group consisting of 24.3±0.2, 24.7±0.2, 25.1±0.2, 25.5±0.2, 26.8±0.2, 27.4±0.2, 27.8±0.2, 28.6±0.2, 29.1±0.2, 30.2±0.2, 31.8±0.2, 32.0±0.2, 33.1±0.2, 34.1±0.2 and 34.6±0.2 degrees.

[0050] In one embodiment, the crystalline form is Form A, characterized by an XRPD pattern substantially as shown in FIG.

[0051] In other embodiments, the crystalline form is Form A* characterized by an XRPD pattern comprising at least three, four, five, or six diffraction peaks having 2θ angle values ​​independently selected from the group consisting of 9.2±0.2, 14.0±0.2, 15.4±0.2, 18.7±0.2, 20.5±0.2, 24.0±0.2, and 24.9±0.2 degrees. Preferably, the crystalline form is Form A* characterized by an XRPD pattern comprising 9.2±0.2, 10.8±0.2, 12.3±0.2, 14.0±0.2, 15.4±0.2, 16.5±0.2, 18.1±0.2, 18.7±0.2, 19.3±0.2, 19.8±0.2, 20.5±0.2, 21. Diffraction peaks having 2θ angle values ​​independently selected from the group consisting of 0.6±0.2, 22.3±0.2, 23.2±0.2, 24.0±0.2, 24.9±0.2, 26.7±0.2, 27.8±0.2, 28.7±0.2, 29.4±0.2, 30.9±0.2, 33.2±0.2, 37.9±0.2 and 38.2±0.2 degrees.

[0052] In one embodiment, Form A has an onset temperature of 168.7° C. by DSC.

[0053] In one embodiment, Form A has a particle size distribution in the range of about 50 to about 70 μm, preferably with a D90 of about 62 μm.

[0054] In one embodiment, Form A is characterized by a DVS substantially as shown in FIG.

[0055] In one embodiment, the crystalline form is Form A*, characterized by an XRPD pattern substantially as shown in FIG.

[0056] In one embodiment, the crystalline form is Form A**, which is a single crystal substantially as shown in Figures 3-6.

[0057] In one embodiment, the crystalline form is single crystalline, ie, Form A**, and is substantially characterized by the experimental and calculated XRPD pattern as shown in FIG.

[0058] In one embodiment, the single crystal form A** has the following lattice parameters: a=8.7232(5)Å b=12.9311(7)Å c=24.0303(14)Å α=90° β=99.513(2)゜ γ=90°

[0059] In one embodiment, the single crystal form A** has a monoclinic P21 lattice space.

[0060] In one embodiment, compound 1 is in neat amorphous form, which is characterized by an XRPD pattern that is absent of diffraction peaks having values ​​of 2θ angles.

[0061] Methods for preparing crystalline Form A are also disclosed. Methods for preparing crystalline Form A include crystallization (including cooling crystallization, evaporative crystallization, vacuum crystallization, reaction and salting out crystallization), recrystallization, fractional crystallization, and the like. In one embodiment, crystalline Form A is prepared by a slurrying process comprising slurrying Compound 1 in a solvent. The method includes stirring during the slurrying process, such as stirring for 1-4 hours or longer, preferably stirring for at least 4 hours, such as stirring for 5 hours. The method also includes separating the slurry material comprising a precipitate of Compound 1. In one embodiment, the solvent is a polar solvent such as an ether, a carboxylic acid ester, a nitrile, a ketone, an amide, a sulfone, a sulfoxide, or a halogenated hydrocarbon, more preferably the polar solvent includes, but is not limited to, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

[0062] In one embodiment, the present invention provides a crystalline form of Compound 1 (Form A), prepared or purified according to the procedures depicted in Scheme 1. Notably, the methods disclosed herein are particularly suitable for reproducibly producing Compound 1 on a commercial scale with high quality and good yield. [ka]

[0063] The free base of compound 1 was obtained in crystalline form A during the synthesis process, which is moderately hygroscopic, absorbing 4.96% water from 0 to 80% RH. Crystalline form A transformed into crystalline form A* after dynamic vapor sorption.

[0064] Crystallization of the crystalline forms of the present invention can also be carried out in a suitable solvent system containing at least one solvent, including evaporation of the solvent, cooling, and / or addition of an anti-solvent (a solvent in which Compound 1 is poorly soluble, including but not limited to those described herein) to reach supersaturation in the solvent system.

[0065] The crystallization can be carried out in the presence or absence of seed crystals as described in this invention.

[0066] Each crystalline form provided by the present invention develops under certain conditions depending on the specific kinetic and equilibrium properties of its crystallization process. Therefore, those skilled in the art will know that the crystals formed are the result of the kinetic and dynamic properties of its crystallization process. Under certain conditions (e.g., solvent, temperature, pressure and compound concentration), a particular crystalline form may be more stable than other crystalline forms (or is in fact more stable than various other crystalline forms). However, the relatively low kinetic stability of a particular crystal may be favorable for kinetic stability. Apart from kinetics, additional factors such as time, impurity distribution, stirring and the presence or absence of seed crystals may also affect crystalline form.

[0067] In a fourth aspect, disclosed herein is a method of preparing a stable amorphous solid dispersion or complex disclosed herein, comprising co-precipitating Compound 1 and HPMCAS.

[0068] In one embodiment, Compound 1 and HPMCAS are precipitated simultaneously to form a molecular dispersion of Compound 1 in a matrix formed by HPMCAS.

[0069] In one embodiment, the method comprises a step of solvent controlled precipitation. In a preferred embodiment, the method comprises a step of microprecipitation bulk powder (MBP) technology.

[0070] In one embodiment, the HPMCAS has a high succinoyl to acetyl substitution ratio (S / A ratio), hi other embodiments, the HPMCAS is HPMCAS-LF, HPMCAS-MF, or HPMCAS-HF, or a mixture of two or more of the foregoing.

[0071] In one embodiment, compound 1 is in a crystalline or amorphous form. In a preferred embodiment, compound 1 is in Form A as disclosed herein.

[0072] In one embodiment, the weight ratio of Compound 1 in the form of the free base to HPMCAS is from about 1:9 to about 9:1, preferably from about 1:4 to about 2:3, preferably about 3:7 or about 1:4, more preferably about 1:4.

[0073] In one embodiment, HPMCAS is HPMCAS-LF, or HPMCAS-MF, or HPMCAS-HF, and Compound 1 in the form of the free base and HPMCAS-MF are in a 3:7 weight ratio, or Compound 1 in the form of the free base and HPMCAS-MF are in a 2:3 weight ratio, or Compound 1 in the form of the free base and HPMCAS-MF are in a 1:4 weight ratio, or Compound 1 in the form of the free base and HPMCAS-LF are in a 1:9 weight ratio, or Compound 1 in the form of the free base and HPMCAS-LF are in a 1:4 weight ratio, or Compound 1 in the form of the free base and HPMCAS-LF are in a 3:7 weight ratio, or Compound 1 in the form of the free base and HPMCAS-LF are in a 2:3 weight ratio, or Compound 1 in the form of the free base and HPMCAS-HF are in a 1:4 weight ratio.

[0074] In one embodiment, the method includes dissolving Compound 1 and HPMCAS in an organic solvent. In a preferred embodiment, the organic solvent is N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) or N-methyl-2-pyrrolidone (NMP).

[0075] In one embodiment, the solution obtained from Compound 1 and HPMCAS is added to water or an aqueous acidic solution, whereby Compound 1 and HPMCAS precipitate simultaneously to form a solid dispersion or complex as disclosed herein. In a preferred embodiment, the aqueous acidic solution is an aqueous hydrochloric acid (HCl) solution. In a preferred embodiment, the water or aqueous acidic solution is optionally cooled. In a further preferred embodiment, the water or aqueous acidic solution is optionally cooled to 2-8°C.

[0076] In one embodiment, the resulting solid may be dried to give an amorphous solid dispersion or complex of MBP.

[0077] In one embodiment, the resulting solid is optionally further micronized, for example by jet milling, to give a powder with a particle size suitable for pharmaceutical formulation, for example a D90 of less than 150 μm or 200 μm.

[0078] In one embodiment, the solid dispersion or complex is in an amorphous form.

[0079] In one embodiment, the solid dispersion or complex has a glass transition temperature of about 110-115°C, preferably about 111°C.

[0080] In one embodiment, the method disclosed herein comprises the steps of: a) dissolving compound 1 and HPMCAS in an organic solvent; b) co-precipitating compound 1 and HPMCAS by adding the solution of a) to water or an acidic aqueous solution; and c) washing the obtained solid with water and / or aqueous hydrochloric acid to remove the organic solvent.

[0081] In one embodiment, the solid amorphous dispersions disclosed herein may be prepared by a spray drying method.

[0082] In a fifth aspect, disclosed herein is a neat amorphous form of Compound 1. The neat amorphous form of Compound 1 disclosed herein has the potential to be used in pharmaceutical formulations because (1) it does not show any change in crystalline form during the 14 day test period, i.e., it does not show any crystalline peaks at 14 days, and (2) it shows relatively higher bioavailability than crystalline Form A.

[0083] In one embodiment, the neat amorphous form of Compound 1 disclosed herein is substantially characterized by an XRPD pattern having no peak diffraction angles, as seen in FIG.

[0084] In one embodiment, the neat amorphous form of Compound 1 disclosed herein is substantially characterized by a 1H-NMR pattern as seen in FIG.

[0085] In one embodiment, the neat amorphous form of Compound 1 disclosed herein has a glass transition temperature of about 135-143°C, preferably about 138.3°C.

[0086] In one embodiment, the neat amorphous form of Compound 1 disclosed herein has a particle size distribution D90 in the range of about 60 to about 80 μm, a particle size distribution D50 in the range of about 2 to about 6 μm, and a particle size distribution D10 in the range of about 1 to about 2 μm, preferably a particle size distribution D90 of about 69.9 μm, a particle size distribution D50 of 3.5 μm, and a particle size distribution D10 of 1.4 μm.

[0087] Also disclosed herein is a method for preparing a neat amorphous form of Compound 1, comprising spray drying a crystalline form of Compound 1 in a polar solvent to obtain a powdered material.

[0088] The polar solvent preferably comprises an ether, a carboxylic acid ester, a nitrile, a ketone, an amide, a sulfone, a sulfoxide, or a halogenated hydrocarbon. More preferably, the polar solvent comprises, but is not limited to, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, undecyl butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. The polar solvent is preferably a mixture of halogenated hydrocarbon / amide, such as a mixture of DCM / MeOH.

[0089] Spray drying is preferably carried out using a spray dryer. It is preferable to set the inlet temperature of the spray dryer to about 50 to 70° C. and the outlet temperature of the spray dryer to about 25 to 45° C. It is more preferable to set the inlet temperature of the spray dryer to about 60° C. and the outlet temperature of the spray dryer to about 35° C.

[0090] In a seventh aspect, the present specification discloses a method for mass production of the B-RAF kinase dimer inhibitors disclosed herein. Specifically, the method disclosed herein is suitable for preparing the B-RAF kinase dimer inhibitors disclosed herein, particularly compound 1, with high quality, high yield, reproducible, and commercial scale. The method disclosed herein significantly reduces the production cost by not using high-cost column chromatography and controlling the content of impurity-1 to less than 0.5% under the conditions disclosed herein, and even less than 0.05% under optimized conditions.

[0091] In one embodiment, the method comprises subjecting an amine of formula Ia to a condensation reaction with a protected carbamoyl compound of formula Ib to obtain a compound of formula I or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, R1 and R2 may be the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkynyl, -CN, -NR6R7, -OR6, -COR6, -CO2R6, -CONR6R7, -C(=NR6)NR7R8, -NR6COR7, -NR6CONR7R8, -NR6CO2R7, -SO2R6, -NR6SO2NR7R8, -NR6SO2R7 and -NR6SO2aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, aryl and heterocyclyl are each independently optionally substituted with 1, 2 or 3 substituents R9; R5 is independently selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents R9; LG is a leaving group, R6, R7 and R8 may be the same or different and are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or (R6 and R7) and / or (R7 and R8) together with the atoms to which they are bonded form a ring selected from heterocyclyl and heteroaryl rings, respectively, optionally substituted with 1, 2 or 3 substituents R9; R9 is selected from halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, -alkyl-NRaRb, -CN, -ORa, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -C(=NRa)NRbRc, nitro, -NRaCORb, -NRaCONRaRb, -NRaCO2Rb, -SO2Ra, -SO2aryl, -NRaSO2NRbRc, NRaSO2Rb and -NRaSO2aryl, wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl is selected from the group consisting of -NRaCORb, -NRaCONRaRb, -NRaCO2Rb, -SO2Ra, -SO2aryl, -NRaSO2NRbRc, NRaSO2Rb and -NRaSO2aryl; R, R and R are each independently selected from H, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or (R and R) and / or (R and R) together with the atoms to which they are bonded form a ring selected from heterocyclyl and heteroaryl rings, respectively, optionally substituted with halogen and alkyl. Includes.

[0092] In one embodiment, the condensation reaction of an amine of formula Ia with a protected carbamoyl compound of formula Ib is carried out in an organic solvent. In one embodiment, the condensation reaction is carried out with a solution of an amine of formula Ia with a protected carbamoyl compound of formula Ib in an organic solvent. In one embodiment, the condensation reaction is carried out with a solution of an amine of formula Ia with a protected carbamoyl compound of formula Ib in an organic solvent.

[0093] In one embodiment, the condensation reaction is carried out under anhydrous conditions. In one embodiment, the condensation reaction is carried out by adding the protected carbamoyl compound of formula Ib to a solution of the amine of formula Ia in an organic solvent.

[0094] In one embodiment, the organic solvent is typically selected from the group consisting of non-polar solvents, polar protic solvents and polar aprotic solvents or mixtures 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 dimethylsulfoxide. Suitable polar protic 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.

[0095] In a further embodiment, the organic solvent is a polar aprotic solvent. In yet a further embodiment, the organic solvent is N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, ethyl acetate, acetone, N,N-dimethylformamide, acetonitrile and dimethylsulfoxide or a mixture of two or more thereof. In a further embodiment, the organic solvent is N-methylmorpholine, dimethylsulfoxide or a mixture of both.

[0096] In one embodiment, there is no particular limit to the amount of organic solvent, provided that the amine of Formula Ia is sufficiently dissolved.

[0097] In one embodiment, the condensation reaction is carried out in a vacuum. In a further embodiment, the condensation reaction is carried out in a low vacuum, such as about -0.10 MPa.

[0098] In one embodiment, the condensation reaction is carried out at a temperature of about 10-50° C. or about 15-25° C. In a further embodiment, the condensation reaction is carried out at a temperature of about 20±5° C.

[0099] In one embodiment, 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, hi a further embodiment, the condensation reaction is carried out for about 3 hours.

[0100] In one embodiment, the content of impurity-1 in the product of the condensation reaction is less than 0.5%, and in the best case less than 0.05% (detected by HPLC).

[0101] In one embodiment, R1 and R2 are both hydrogen.

[0102] In one embodiment, R5 is aryl optionally substituted with 1, 2, or 3 substituents R9. In a further embodiment, R5 is phenyl optionally substituted with 1, 2, or 3 halogens. In yet a further embodiment, R5 is 2,4,5-trifluorophenyl.

[0103] In one embodiment, 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 pharma- ceutically acceptable salt thereof.

[0104] There is no particular restriction on the leaving group, but in one embodiment, LG is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or -ORa, where alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more substituents selected from halogen, nitro, hydroxy or alkoxy, and R is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally substituted with one or more substituents selected from halogen, nitro, -CN, hydroxy or alkoxy. In a further embodiment, LG is -ORa, where R is phenyl, optionally substituted with one or more substituents selected from halogen, nitro, -CN, hydroxy or alkoxy. In yet a further embodiment, LG is unsubstituted phenoxy.

[0105] In yet a further embodiment, the compound of formula Ib is [ka] It is.

[0106] In one embodiment, the compound of formula Ia can be prepared by reacting a compound of formula Ia-2 in the presence of an acid in an organic solvent. [ka] It is prepared by

[0107] In a further embodiment, the organic solvent is selected from the group consisting of non-polar solvents, polar protic solvents and polar aprotic solvents or mixtures 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 dimethylsulfoxide. Suitable polar protic 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: dioxins alkanes, toluene, hexane, cyclohexane and diethyl ether. In yet a further embodiment, the solvent is ethanol or dichloromethane.

[0108] In further embodiments, the acid is a mineral acid, e.g., selected from the group consisting of hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, and nitric acid, or an organic acid, e.g., 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 acids (e.g., acetic acid and HOOC-(CH)-COOH, where n is selected from 0 to 4).

[0109] There is no particular limitation on the reaction temperature, but the reaction is usually carried out at room temperature.

[0110] In one embodiment, the compound of formula Ia-2 can be prepared by reacting the compound of formula Ia-1 in (Boc)2O / t-BuOH in the presence of a catalyst. [ka] It is prepared by

[0111] The preparation of the compound of formula Ia-2 from the compound of formula Ia-1 is usually carried out at a temperature of about 70-100°C, preferably about 85±5°C.

[0112] During the Curtius rearrangement reaction of the acyl azide of formula Ia-1 with t-butanol, impurity-1 is also produced, but the solubility and polarity of impurity-1 are significantly different from those from formula Ia-2. Therefore, impurity-1 can be easily removed during the reaction by filtration using a silica gel pad, thereby obtaining the intermediate amine of formula Ia free of impurities. In one embodiment, impurity-1 can be removed after the t-butyl carbamate of formula Ia-2 is formed from the acyl azide of formula Ia-1. In another embodiment, impurity-1 can be removed after the amine of formula Ia is formed from the tert-butyl carbamate of formula Ia-2, which is more convenient and can further reduce costs. Methods for removing impurity-1 include conventional methods, such as silica gel pad filtration or diatomaceous earth filtration and other suitable industrial procedures.

[0113] In one embodiment, the catalyst is DMAP.

[0114] As used herein, the formula Ia [ka] (wherein R1 and R2 are as defined above). or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound of formula Ia is [ka] or a pharma- ceutically acceptable salt thereof. In a further embodiment, the compound of formula Ia is [ka] It is.

[0115] In an eighth aspect, disclosed herein is a method of treating or preventing a disease or disorder responsive to inhibition of Raf kinase in a subject, comprising administering to the subject a therapeutically effective amount of Compound 1, wherein Compound 1 is in an amorphous solid dispersion as disclosed herein, or a complex as disclosed herein, or a crystalline form as disclosed herein, or a neat amorphous form as disclosed herein.

[0116] In one embodiment, the disease or disorder is a cancer selected from the group consisting of: brain cancer, lung cancer, kidney cancer, osteosarcoma, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, melanoma, skin cancer, adrenal cancer, cervical cancer, lymphoma or thyroid tumors and complications thereof.

[0117] In yet another embodiment, the disease is a BRAF (V600E or non-V600E) or NRAS or KRAS mutant cancer selected from: brain cancer, lung cancer, kidney cancer, osteosarcoma, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, melanoma, skin cancer, adrenal cancer, cervical cancer, lymphoma, or thyroid tumors and complications thereof.

[0118] In yet another embodiment, the dosage of Compound 1 is 1-200 mg / day, and the administration frequency is 1-3 times a day.

[0119] In yet another embodiment, the dosage of Compound 1 is 2.5 to 100 mg / day, and the administration frequency is 1 to 3 times a day.

[0120] In yet another embodiment, the dosage of Compound 1 is 5 to 50 mg / day, and the administration frequency is once a day.

[0121] In one embodiment, the subject is a rat, dog or human.

[0122] In a sixth aspect, disclosed herein is a pharmaceutical composition comprising an effective amount of Compound 1, particularly Compound 1 in any of the various forms A, A*, A**, B, C, D, E, F, G, H, I, J or K disclosed herein. The active ingredient compound can be 1-99% by weight, preferably 1-50% by weight, more preferably 1-30% by weight, and most preferably 1-20% by weight of the composition.

[0123] The pharmaceutical compositions may be administered orally, for example in the form of capsules, tablets, pills, powders, sustained release injections, for example sterile liquids, suspensions or emulsions, topical treatments, for example pastes, creams or ointments, or rectally, for example suppositories. The pharmaceutical compositions may be in the form of unit dosage forms suitable for precise dosing applications.

[0124] Suitable pharmaceutical carriers include water, various organic solvents, and various inert diluents or excipients. If necessary, the pharmaceutical composition may contain various additives, such as flavorings, adhesives, and pharmaceutical additives. For oral administration, tablets and capsules may contain various pharmaceutical additives, such as citric acid, various disintegrating agents, such as starch, alginic acid, and some silicates, and various adhesives, such as sucrose, gelatin, and gum arabic. In addition, lubricants, including magnesium stearate and talc fillers, are also commonly used in the manufacture of tablets. Similar types of solid ingredients can also be used to prepare soft and hard gelatin capsules. When aqueous suspensions are required for oral administration, the active ingredient compound can be mixed with a combination of various sweeteners or flavorings, pigments, or dyes. If necessary, various emulsifying agents can be employed or suspensions can be generated, or diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof can be used.

[0125] The pharmaceutical compositions described above are preferably administered orally.

[0126] The pharmaceutical composition described above is preferably in the form of a capsule or tablet.

[0127] As used herein, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise. The following abbreviations and terms have the indicated meanings throughout this specification.

[0128] The term "alkyl" as used herein refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 18, such as 1 to 12, further such as 1 to 10, and even further such as 1 to 6 carbon atoms. Exemplary alkyl groups may be selected from methyl, ethyl, 1-propyl, i.e., n-propyl ("n-Pr"), 2-propyl, i.e., isopropyl ("i-Pr"), 1-butyl, i.e., n-butyl ("n-Bu"), 2-methyl-1-propyl, i.e., isobutyl ("i-Bu"), 1-methylpropyl, i.e., s-butyl ("s-Bu"), and 1,1-dimethylethyl, i.e., t-butyl ("t-Bu"). Further examples of alkyl groups may be selected from the following: 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2 CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2) and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 groups.

[0129] The term "alkenyl" as used herein refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18, for example 2 to 6, carbon atoms. Examples of alkenyl groups can be selected from the following: ethenyl, i.e. vinyl (-CH=CH2), prop-1-enyl (-CH=CHCH3), prop-2-enyl (-CH2CH=CH2), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl groups.

[0130] The term "alkynyl" as used herein refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, e.g., 2 to 6, carbon atoms. Examples of alkynyl groups include: ethynyl (-C≡CH), 1-propynyl (-C≡CCH3), 2-propynyl (propargyl, -CH2C≡CH), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0131] The term "cycloalkyl" as used herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, the cycloalkyl group may contain 3 to 12, such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4 carbon atoms. Further, for example, the cycloalkyl group may be selected from monocyclic groups containing 3 to 12, such as 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a bicyclic ring selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring structures, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include bicyclic rings selected from [5,6] and [6,6] ring structures, such as: [ka] (wherein the wavy line represents the point of attachment) The rings may be saturated or may have at least one double bond (i.e., partially unsaturated), but are not fully conjugated and are not aromatic (as aromatic is defined herein).

[0132] The term "aryl," as used herein, refers to a group selected from the following: 5- and 6-membered carbocyclic aromatic rings, such as phenyl, Bicyclic ring systems, for example 7-12 membered bicyclic ring systems, in which at least one ring is selected from carbocyclic and aromatic, such as naphthalene, indane and 1,2,3,4-tetrahydroquinoline; Tricyclic ring structures, for example 10-15 membered tricyclic ring structures in which at least one ring is carbocyclic and aromatic, such as fluorene.

[0133] The term “halogen” or “halo” as used herein refers to F, Cl, Br or I.

[0134] The term "heteroaryl," as used herein, refers to a group selected from the following: a 5- to 7-membered aromatic, monocyclic ring containing at least one heteroatom, for example 1 to 4, or in some embodiments 1 to 3, selected from N, O and S, with the remaining atoms in the ring being carbon; an 8-12 membered bicyclic ring containing at least one heteroatom, for example 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms, selected from N, O and S, the remaining atoms in the ring are carbon, and at least one ring is aromatic, and at least one heteroatom is in the aromatic ring; and An 11-14 membered tricyclic ring containing at least one heteroatom, for example 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms, selected from N, O and S, the remaining atoms in the ring are carbon, and at least one ring is aromatic, and at least one heteroatom is in the aromatic ring.

[0135] For example, the heteroaryl group includes a 5- to 7-membered heteroaromatic ring fused to a 5- to 7-membered cycloalkyl ring. In such fused bicyclic heteroaryl ring systems, where only one of the rings contains at least one heteroatom, the point of attachment can be at the heteroaromatic ring or at the cycloalkyl ring.

[0136] When the combined number of S and O atoms in the heteroaryl group exceeds 1, the heteroatoms are not adjacent to one another. In some embodiments, the combined number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the combined number of S and O atoms in the aromatic heterocyclyl is 1 or less.

[0137] Examples of heteroaryl groups include, but are not limited to, the following (numbered from the attachment point assigned to priority 1): pyridyl (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl, ... Dinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-2,6-diazolyl, 1-thia-2,7-diazolyl, 1-thia-2,8-diazolyl, 1-thia-2,9-diazolyl, 1-thia-2,10-diazolyl, 1-thia-2,2 ...10-diazolyl, 1-thia-2,2-diazolyl, 1-thia-2,3-diazolyl, 1-thia ,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

[0138] The term "heterocyclic", or "heterocycle", or "heterocyclyl" as used herein refers to a ring selected from 4-12 membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings containing at least one heteroatom, such as 1-4 heteroatoms, further such as 1-3 or further such as 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen, plus at least one carbon atom. The term "heterocycle" as used herein also refers to a 5- to 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, fused to a 5-, 6- and / or 7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring, provided that when the heterocyclic ring is fused to a carbocyclic aromatic or heteroaromatic ring, the point of attachment is on the heterocyclic ring, and when the heterocyclic ring is fused to a cycloalkyl, the point of attachment can be on the cycloalkyl or heterocyclic ring. The term "heterocycle" as used herein also refers to an aliphatic spirocyclic ring containing at least one heteroatom selected from N, O, and S, provided that the attachment point is at the heterocyclic ring. The rings can be saturated or have at least one double bond (i.e., partially unsaturated). The heterocycle can be substituted with oxo. The attachment point can be at a carbon atom or a heteroatom in the heterocyclic ring. A heterocycle is not a heteroaryl as defined herein.

[0139] Examples of heterocycles include, but are not limited to, the following (numbered from the attachment point assigned to 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, aza-, aryl, aryl- ... Dithithiolanyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianiyl, 1,4-dioxepanyl, 1,4-oxathianiyl, 1,4-o 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyl 1,4-dithianyl, 1,4-azathiyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl , indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Substituted heterocycles also include ring structures substituted with one or more oxo residues, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0140] The term "about" as used herein, unless otherwise specified, indicates that a certain number (e.g., temperature, pH, volume, etc.) may vary within ±10%, preferably within ±5%.

[0141] The following synthetic methods, specific examples and efficacy tests further illustrate various aspects of the present invention, but are not intended to restrict or limit the scope of the invention in any way. EXAMPLES

[0142] The following examples are for illustrative purposes and efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but experimental error and deviation should be allowed for. Temperatures are in degrees Celsius unless otherwise noted. Reactants were purchased from commercial suppliers, such as Sigma-Aldrich, Alfa Aesar, or TCI, and used without further purification unless otherwise noted.

[0143] Unless otherwise noted, reactions depicted below were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents using drying tubes, reaction flasks were fitted with rubber septa for introduction of substrates and reactants via syringe, and glassware was oven-dried and / or heat-dried.

[0144] Unless otherwise stated, purification by column chromatography was performed on a Biotage system (manufacturer: Dyax Corporation) equipped with a silica gel column or a silica SepPak cartridge (Waters), or on a Teledyne Isco Combiflash purification system using prepacked silica gel cartridges.

[0145] 1H NMR spectra and 13C NMR were recorded at 400 MHz on a Varian instrument.

[0146] X-ray intensity data from colorless plate-like crystals were measured using a Bruker APEX-II CCD diffractometer (Cu Kα radiation, λ = 1.54178 Å) at 173(2) K. Polarized light micrographs were taken at room temperature.

[0147] In the examples below, the following abbreviations have been used: AcOH Acetic acid ACN Acetonitrile API Active Pharmaceutical Ingredient Aq Water-based Brine Saturated sodium chloride solution Bn Benzyl BnBr Benzyl bromide CH2Cl2 Dichloromethane DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide Dppf 1,1'-Bis(diphenylphosphino)ferrocene DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DIEA or DIPEA N,N-Diisopropylethylamine DMAP 4-N,N-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EtOAc Ethyl acetate EtOH Ethanol Et2O or ether diethyl ether g grams h or hr Time HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HCl Hydrochloric acid HPLC High Performance Liquid Chromatography HPMCAS Hypromellose Acetate Succinate IPA or i-PrOH 2-propanol, i.e. isopropyl alcohol mg milligram mL Milliliters Mmol millimolar MeCN Acetonitrile MeOH Methanol Min ms or MS mass spectrum Na2SO4 Sodium sulfate PE Petroleum Ether PPA Polyphosphoric acid Rt retention time Rt or rt Room temperature TBAF Tetra-butylammonium fluoride TBSCl tert-Butyldimethylsilyl chloride TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography TMSCl Trimethylsilyl chloride μL microliter XRPD X-ray particle diffraction

[0148] Example 1 Example 1A - Preparation of Crystalline Form A of Compound 1 Step 1: Synthesis of INTQ-1 [ka] 1,4-dioxane (1.5 vol) was added to a 2 L 4-neck round bottom flask, the flask was evacuated and flushed with nitrogen three times. Pd(OAc)2 (2 wt%, 0.50 kg) and XantPhos (9 wt%, 2.25 kg) were then added to the flask, the flask was evacuated and flushed with nitrogen three times. The mixture was stirred at room temperature under nitrogen atmosphere for 0.5-1 h. NaOH (12.25 kg, 1.6 eq), H2O (1 vol, 25 L) and 1,4-dioxane (8 vol, 200 L) were charged in a 20 L reactor. The mixture was stirred until clear, and then SM3 (26.75 kg, 1.2 eq) was added to the mixture. The catalyst solution was transferred to the reactor under nitrogen atmosphere. SM1 (25.00 kg, 1.0 eq) was then added dropwise to the reactor. The system was heated to 65±5° C. and held at 65±5° C. for at least 5 hours. The reaction was monitored using HPLC until the content of SM1 was 1.0% or less. The reaction mixture was cooled to 30±5° C., filtered, and the cake was washed with 1,4-dioxane (1.0 vol). H2O (4 vol) was added to the filtrate and concentrated to 5 vol. H2O (2 vol) was then added to the residue and concentrated to 5 vol. The residue was cooled to room temperature and filtered. The cake was washed with H2O (2 vol). The filter cake was then slurried with IPA (2 vol) at 25±5° C. for 3 hours. The mixture was filtered, and the filter cake was washed with IPA (0.5 vol). The solid was dried in an oven under reduced pressure.

[0149] Steps 2 and 3: Synthesis of INTQ-3 [ka] THF (25 vol) and INTQ-1 (16.00 kg, 1.0 equiv) were charged into a reactor. The mixture was stirred and cooled to -80 to -70 °C. Then, n-BuLi (n-hexane solution, 2.5 M, 51.20 kg, 2.5 equiv) was added dropwise to the mixture at -80 to -70 °C. After 1-2 hours of reaction at -80 to -70 °C, the reaction was monitored by TLC. Then, a solution of DMF (9.92 kg, 1.8 equiv) in THF (1.4 vol) was added dropwise to the reaction system at -80 to -70 °C. After 1-2 hours of reaction at -80 to -70 °C, the reaction was monitored by TLC. A solution of AcOH in THF (1.4 vol) was added dropwise to the mixture at -80 to -70 °C, and the pH value was adjusted to 6-7. The reaction was then charged with TEA (8.00 kg, 1.05 equiv.) at -80 to -70 °C. A solution of methyl triphenyl phosphoranylidene acetate (26.4 kg, 1.05 equiv.) in DCM (19 vol.) was added dropwise to the reaction mixture. The mixture was stirred at -80 to -70 °C for 10 h and the reaction was monitored by TLC. In a separate reactor, H2O (10.5 vol.) and citric acid (32.00 kg, 2.1 equiv.) were charged. The mixture was stirred to dissolve and cooled to 0-5 °C. The temperature was cooled to -20 °C and the solution was transferred into the 3 L 4-neck round bottom flask. The mixture was then stirred below 20 °C for 1 h and the pH value was confirmed to be 4-7. The organic layer was separated and washed with 25% NaCl (17 vol.). The organic phase was then concentrated to 5 vol and the mixture was charged with EtOAc (17 vol) and concentrated to 5 vol. The mixture was charged with EtOAc (17 vol) and concentrated to 5 vol. The solution was used directly in the following step.

[0150] Step 4: Synthesis of INTQ-4 [ka] A 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 hours. The mixture was then heated to 20-30°C. The reaction was monitored every 2 hours using HPLC and after 5 hours of reaction, 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 at 0-5°C for 1 hour. The mixture was filtered and the filter cake was charged in H2O (15 volumes). The mixture was stirred at 20-30°C for 2 hours. The mixture was filtered and the filter cake was washed with H2O (3 volumes). The filtrate was then transferred to another reactor and the mixture was charged with Na2CO3 to adjust the PH value to 8-9. The mixture was then filtered and the filter cake was washed with H2O (4 volumes). After drying in a vacuum oven, 20.73 kg (yield: 69.0%, purity: 95.0%) of INTQ-4 was obtained.

[0151] Step 5: Synthesis of INTQ-5 [ka] INTQ-4 (10.40 kg, 1.0 equiv.), Pd / C (15 wt%, 1.25 kg) and THF (11 vol) were charged into a reactor. The mixture was stirred and heated to 30-35° C. Hydrogen was charged to a pressure of 10 atm. The reaction was monitored by HPLC every 2 h and after 15 h reaction, the content of INTQ-4 was less than 0.5%. The reaction mixture was cooled to 20-30° C. and filtered through Celite (0.2 wt). The filter cake was washed with THF (2 vol). The filtrate was concentrated to 3 vol and EtOH (6 vol) was added into the mixture. The solution was concentrated to 3 vol and EtOH (6 vol) was charged into the mixture. The mixture was concentrated to 3 vol and used directly in the following step.

[0152] Step 6 Synthesis of BGB-INTQ-6 [ka] A solution of INTQ-5 (from the previous step) in EtOH (3 vol), EtOH (7 vol) and Et3N (22 wt%, 2.29 kg) were charged into a reactor. The solution was heated to 70-80°C. The reaction was monitored every 2 hours using HPLC and after 15 hours of reaction, the content of INTQ-5 was less than 1.0%. The reaction mixture was cooled to 30-40°C and concentrated to 5 vol. The mixture was cooled to -5-0°C and stirred for 2 hours. The mixture was filtered and the filter cake was washed with EtOH (1 vol). After drying in an oven at 45±5°C, 7.58 kg (yield: 87.1%, purity: 99.5%) of INTQ-6 was obtained.

[0153] Step 7: Synthesis of INTQ-7 [ka] Potassium hydroxide (49.9 Kg, 1.7 equiv.) was added to a solution of 4-methoxyphenol (65 Kg, 1.0 equiv.) in DMSO (65 L, 1 vol.). The system was heated to 120° C. Bromoacetaldehyde diethyl acetal (123.8 Kg, 1.2 equiv.) was added dropwise while maintaining the temperature at 120-140° C. After the reaction was completed as monitored by HPLC, the reaction mixture was cooled to 20-40° C. The reaction mixture was charged with n-heptane (2 vol.) and water (2 vol.). The mixture was filtered through Celite (0.2 wt.) and the filter cake was washed with n-heptane (0.5 vol.). The filtrate was allowed to settle for at least 30 minutes. The organic layer was separated and the aqueous layer was extracted with n-heptane (2 vol.). The organic layers were combined and washed with 2N aqueous NaOH (2 vol.). The organic layer was washed twice with 15% aqueous NaCl (2 vol). The organic layer was concentrated to 3 vol. Toluene (3 vol) was added followed by concentration to 3 vol. The toluene solution of INTQ-7 was used directly in the following step.

[0154] Step 8: Synthesis of INTQ-8 [ka] Amberlyst-15 (3.8 Kg, 0.1 wt) was added to toluene (760 L, 20 vol). The system was heated to 110°C under N2 protection. A solution of INTQ-7 (38 Kg / batch, 3 batches, 1.0 equiv) in toluene was added dropwise while maintaining the temperature at 105-110°C. After 1 hour reaction, the reaction was concentrated to 17 vol at 105-110°C under constant pressure. The system was charged with toluene (3 vol). After completion of the reaction as monitored by HPLC, the reaction mixture was cooled to 20-40°C. The mixture was filtered through Celite (0.1 wt) and the filter cake was washed with toluene (0.5 vol). The filtrate was washed with 2N aqueous NaOH (2 vol). The organic layer was washed twice using 20% ​​aqueous NaCl (2 vol). The organic layer was concentrated to 2 vol. The crude product was distilled below 110° C. to give INTQ-8 as an off-white solid (43 Kg, yield=61.2%, purity≧98.0%).

[0155] Step 9: Synthesis of INTQ-9 [ka] To a solution of INTQ-8 (43 Kg, 1.0 equiv.) in NMP (260 L, 6 vol.) was added 1-dodecanethiol (147.0 Kg, 3.5 equiv.). 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 hourly for HPLC and after 16 hours of reaction at 130±5° C., the INTQ-8 content was below 3.0%. The reaction mixture was cooled to 60±5° C. and then 8 volumes of water were charged to the mixture. The reaction mixture was cooled to 25±5° C. and then 3 volumes of petroleum ether were charged to the mixture. The mixture was stirred for at least 30 minutes and allowed to stand for at least 30 minutes before separation. The organic phase was temporarily set aside. The aqueous phase was adjusted to pH=1-2 with 6N HCl. The aqueous phase was extracted with 5 and 3 volumes of ethyl acetate, respectively. The aqueous residue was combined with the temporary organic phase and then charged with 4 volumes of ethanol and 4 volumes of petroleum ether. The mixture was stirred for at least 30 minutes and allowed to stand for at least 30 minutes and then separated. The aqueous phase was adjusted to pH=1-2 with 6N HCl. The aqueous phase was extracted with 5 volumes of ethyl acetate. The organic phases of ethyl acetate were combined and concentrated to 3 volumes under pressure at less than 50° C. The residue was charged with 5 volumes of n-heptane and the mixture was adjusted to PH=9-10 with 5% NaOH. The mixture was stirred for at least 30 minutes and allowed to stand for at least 30 minutes and then separated. The aqueous phase was adjusted to pH=1-2 with 6N HCl. The aqueous phase was extracted with 5 and 3 volumes of ethyl acetate, respectively. The ethyl acetate organic phases were then combined and washed with 6 volumes of 10% H2O2 and concentrated HCl (0.15 wt). The organic phase was then washed with 6 volumes of 5% H2O2 and concentrated HCl (0.15 wt). The organic layer was washed with 4 volumes of 5% Na2SO3. The organic layer was washed three times with 3 volumes of brine. The organic layer was concentrated to 3 volumes. Dichloromethane (5 volumes) was added and concentration was continued until no clear fractions were present. The crude INTQ-9 was used directly in the following step.

[0156] Step 10: Synthesis of INTQ-10 [ka] To a solution of INTQ-9 (32 Kg, 1.0 equiv.) in dichloromethane (10 vol.) was added Et3N (48.2 Kg, 2.0 equiv.) below 40° C. The mixture was cooled to −5±5° C. TMSCl (1.3 equiv.) in dichloromethane (1 vol.) was added dropwise while maintaining the temperature at −5±5° C. The mixture was sampled every hour for gas chromatography and showed that the content of INTQ-9 was below 2.0% after 1 hour of reaction at −5±5° C. The mixture was concentrated to 3 volumes under pressure below 40° C. The residue was charged with 15 volumes of n-hexane and the mixture was stirred for at least 30 minutes. The mixture was filtered and the filtrate was concentrated under pressure below 40° C. until no clear fractions were present. The crude product was distilled below 120° C. to give INTQ-10 as a pale yellow oil (40 Kg, yield=81.4%, purity≧97.5%).

[0157] Step 11: Synthesis of INTQ-11 [ka] INTQ-10 (20 Kg / batch, 2 batches, 1.0 equiv.) in dichloromethane (5 vol.) was slurried with CuI (0.1 wt.) at 25±5°C for 2-3 h. Copper(I) triflate (2:1 complex with toluene, 0.11 wt.%) and (S,S)-2,2-bis(4-phenyl-2-oxazolin-2-yl)propane (0.15 wt.%) were stirred in dichloromethane (4 vol.) at 20-30°C for 2-3 h under N2 atmosphere. A solution of INTQ-10 in dichloromethane was added through a micropore filter and a solution of ethyl diazoacetate (2.0 equiv.) in dichloromethane (10 vol.) was slowly added dropwise at 20-30°C for 15-25 h. The mixture was stirred at 20-30° C. for 30-60 min, and the mixture was washed three times with 4 volumes of 0.05 N sodium edetate dihydrate aqueous solution at 20-30° C. The organic portion was washed twice with 3 volumes of 25% NaCl aqueous solution. The organic portion was concentrated under vacuum at <35° C. until the system was 3 volumes or less. The crude product of INTQ-11 was used directly in the following step.

[0158] Steps 12 and 13: Synthesis of INTQ-13 [ka] Step 12: The crude product of INTQ-11 was dissolved in methanol (3 vol) and 38% HCl in EtOH (0.1 vol) was added to the mixture and stirred at 20-30°C for 2-3 hours. Et3N was added dropwise to the mixture to adjust PH=7. The mixture was concentrated under pressure to 2 vol. Ethyl acetate (2 vol) was charged and continued to concentrate under pressure to 2 vol. n-Heptane (2 vol) was charged and continued to concentrate under pressure to 2 vol. Dichloromethane (2 vol) was charged to completely dissolve the material. The residue was purified by silica gel chromatography (eluent EtOAc:PE=1:5, total ca. 100 vol) to give INTQ-12 as a yellow solid.

[0159] Step 13: INTQ-12 was charged in EtOAc (1.5 vol) and n-heptane (20 vol) and the mixture was heated to 75-85 °C to clarify. The clear solution was stirred at 75-85 °C for 1 h and then slowly cooled to 15-20 °C. The mixture was filtered and washed with n-heptane (2 vol) to give the product. The wet product was dried at 55 ± 5 °C for at least 16 h to give INTQ-13 as a pale yellow to off-white solid.

[0160] Steps 14 and 15: Synthesis of INTQ-15 [ka] Step 14: INTQ-13 (16 Kg, 1.0 equiv.) and INTQ-6 (12.7 Kg, 1.05 equiv.) were added to DMF (5 vol.). 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 every hour for HPLC and the content of INTQ-13 was less than 0.5% after 2 hours of reaction at 110±5° C. The reaction mixture was cooled to 30±5° C. and then adjusted to pH=6 with acetic acid (5 wt.) at 30±5° C. Water (30 vol.) was added to the mixture at 25±5° C. The mixture was stirred for 1-2 hours and filtered to give a wet product. The wet product was reslurried with water (5 vol.). The filter cake was used directly in the following step.

[0161] Step 15: The wet product of INTQ-14 was added to a mixture of 1N NaOH (10 vol) and THF (20 vol). The system was stirred at 25±5°C. Timewise sampling for HPLC showed that the content of INTQ-14 was less than 0.5% after 4 h reaction at 25±5°C. The system was adjusted to pH=4-5 with 4N HCl at 25±5°C and stirred for 1 h. The system was concentrated to 8 vol under pressure at <50°C and filtered to give the wet product. The wet product was reslurried with THF (10 vol). The mixture was stirred for 1-2 h and filtered to give the wet product. The wet product was dried at 55±5°C for at least 30 h to give INTQ-15 as a light brown to off-white solid.

[0162] Steps 16, 17, and 18: Synthesis of INTQ-18 [ka] The reactor was evacuated to below -0.08 MPa and then charged with inert nitrogen to atmospheric pressure. 1,4-dioxane (10.0 vol) and INTQ-15 (3.6 kg, 1.0 equiv.) were added to the reactor. The mixture was concentrated to 6.0-6.5 vol at below 50°C and the mixture was sampled for water content. Et3N (1.1 equiv.) was charged to the reactor. The mixture was heated to 30±5°C and DPPA (1.1 equiv.) was added dropwise to the reactor. The mixture was sampled for HPLC analysis and after 2 hours of reaction at 30±5°C, the content of INTQ-15 was below 1.0%. A solution of INTQ-16 was obtained.

[0163] Another reactor was evacuated to -0.08 MPa and then charged with inert nitrogen to atmospheric pressure. The reactor was charged with t-BuOH (20.0 vol), (Boc)2O (0.5 eq) and DMAP (0.02 eq). The mixture was heated to 85±5°C and stirred for 2-3 hours, and the mixture was sampled for water content, with a criterion of KF≦0.01%. A solution of INTQ-16 was added dropwise to the above reactor in t-BuOH at 85±5°C (over at least 3 hours). The mixture was sampled for HPLC analysis, and after 2 hours of reaction at 85±5°C, the content of INTQ-16 was ≦1.0%. The mixture was then cooled to <50°C and concentrated to 3.0-4.0 vol at <50°C.

[0164] The residue was charged with DCM (10.0 vol×2) and the mixture was concentrated below 50° C. to 3.0-4.0 vol. The residue was charged with DCM (10.0 vol). The reactor was then charged with 1 wt % aqueous NaOH (20.0 vol) and stirred at 25±5° C. for at least 1 h. The mixture was filtered through Celite and then separated. The organic phase was washed with water (5.0 vol) and separated. The organic phase was further washed with 25 wt % brine (5.0 vol) and separated through silica gel to remove some impurities. The organic phase was concentrated below 40° C. to 6.0-7.0 vol. DCM was charged to 7.0 vol. The mixture was then cooled below 15° C. and hydrochloric acid (1.2 vol) was added dropwise to the reactor at a temperature below 15° C. The mixture was sampled for HPLC analysis and showed an INTQ-17 content of 4.0% or less after 3 hours of reaction at 15±5° C. The mixture was heated to 25±5° C. and water (3.0 vol) was added to the reactor. INTQ-16:1H NMR(400MHz,DMSO-d6)δ 10.48(s,1H),7.95(d,J=5.6Hz,1H),7.34(d,J=2.4Hz,1H),7.05(d,J=8.4Hz,1H),7.00(dd,J=8.8,2.4Hz,1H),6.25(d,J=5.6Hz,1H),5.42(d,J=5.2Hz,1H),3.56(dd,J=5.2,2.8Hz,1H),2.92(t,J=7.6Hz,2H),2.54(d,J=8.0Hz,2H),1.51(d,J=3.2Hz,1H).MS:M / e 364(M+1)+. INTQ-17:1H NMR(400MHz,DMSO-d6)δ 10.49(s,1H),7.94(d,J=6.0Hz,1H),7.34(s,1H),7.18(s,1H),6.96-6.83(m,2H),6.22(d,J=5.6Hz,1H),4.86(d,J=5.6Hz,1H),2.92(t,J=7.6Hz,2H),2.86(d,J=4.8Hz,1H),2.54(t,J=7.6Hz,2H),2.12(s,1H),1.39(s,9H).MS:M / e 410(M+1)+.

[0165] pH adjustment process: 4 wt% NaOH aqueous solution was added dropwise into the reactor to adjust the pH value to 2.7-3.1. If the pH was higher than 3.1, hydrochloric acid (0.2 vol) was charged, and then 4 wt% NaOH aqueous solution was added dropwise into the reactor to adjust the pH value to 2.7-3.1 (pH paper accuracy, range 2.7-4.7). The mixture was separated, and the emulsion phase was collected as the aqueous phase. The mixture was filtered through Celite, and the aqueous phase thus obtained was washed once with DCM (2.0 vol). DCM (6.0 vol) and EtOH (5.0 vol) were charged into the aqueous phase remaining in the reactor. 10.0 wt% Na2CO3 solution was added dropwise into the reaction liquid at 25±5°C to adjust the pH value to 8-9. The mixture was stirred for 10-15 min and allowed to stand for 10-15 min. The mixture was separated and the aqueous phase was extracted twice with DCM (4.0 vol). The organic phases were combined, washed with water (2.0 vol), separated and the organic phase was washed once with 25 wt% brine (5.0 vol). The organic phase was concentrated to 3.0-4.0 vol below 45°C and the residue was charged with n-heptane (4.0 vol). The mixture was concentrated to 3.0-4.0 vol below 45°C and the residue was charged with n-heptane (4.0 vol). The mixture was concentrated to 3.0-4.0 vol below 45°C. The residue was cooled to 25±5°C, centrifuged and the solids were washed with n-heptane (2.0 vol). The cake was transferred to a vacuum oven and the mixture was sampled for loss on drying (LOD), which was less than 1.0% after drying for 4 hours at 45±5°C (box temperature). The purity of INTQ-18 (2.25 kg) was reported. The product was sealed in double LDPE plastic bags and stored at 2-30°C. INTQ-18:1H NMR(400MHz,DMSO-d6)δ 10.81(s,1H),8.87(s,3H),8.05(d,J=6.0Hz,1H),7.33(t,J=1.2Hz,1H),7.07-6.95(m,2H),6.34(d,J=6.0Hz,1H),5 .24(d,J=6.0Hz,1H),3.32(dd,J=6.0,2.0Hz,1H),2.97(t,J=7.6Hz,2H),2.59(t,J=7.6Hz,2H),2.46(s,1H).MS:M / e 310(M+1)+.

[0166] Step 19: Synthesis of INTQ-19 [ka] The reactor was evacuated to below -0.08 MPa and then charged with inert nitrogen to atmospheric pressure. The reactor was charged with THF (6.0 vol), H2O (3.0 vol), 2,4,5-trifluoroaniline (1.0 equiv), and NaHCO3 (1.2 equiv). The mixture was cooled to 0°C and phenyl chloroformate was added slowly at 0±5°C. The mixture was stirred for at least 2 hours. The mixture was sampled for LCMS to ensure 2,4,5-trifluoroaniline was below 0.2%. EA (15.0 vol) was then added. The organic phase was washed with H2O (5.0 vol), then washed twice with 5 wt% aqueous HCl (5.0 vol) and twice with saturated NaCl (5.0 vol). The organic phase was concentrated to 10.0 vol below 45°C. The residue was charged with n-heptane (10.0 vol). The mixture was concentrated to 10.0 vol and the residue was charged with n-heptane (10.0 vol). The mixture was concentrated to 10.0 vol, centrifuged and the solid was washed with n-heptane (2.0 vol). The cake was sampled for LCMS analysis and was greater than 99% of the quality standard for INTQ-19. The cake was then transferred to a vacuum oven, sampled for LOD and dried at 35±5°C (box temperature) for 10 hours to an LOD of 2.0% or less. The purity of INTQ-19 was reported. The product was sealed in double LDPE plastic bags and stored at 2-30°C. INTQ-19:1H NMR(400MHz,DMSO-d6)δ 10.20(s,1H),7.82(dt,J=12.0,8.0Hz,1H),7.66(td,J=10.8,7.6Hz,1H),7.44(t,J=7.6Hz,2H),7.33-7.20(m,3H).

[0167] Step 20: Synthesis of the Crystalline Form of Compound 1 (Form A) [ka] The reactor was evacuated to -0.08 MPa and then charged with inert nitrogen to atmospheric pressure. The reactor was charged with DMSO (9.0 vol), INTQ-18 (1.63 kg, 1.0 equiv), and N-methylmorpholine (1.0 equiv). The mixture was stirred at 20±5° C. for at least 0.5 h. The reactor was charged with INTQ-19 (1.27 kg, 0.9 equiv) at 20±5° C. The mixture was sampled for HPLC analysis and showed INTQ-19 content of 0.3% or less after 3 h reaction at 20±5° C. After the reaction was completed, the compound 1 mixture was added dropwise through a microfilter into a 0.5% hydrochloric acid solution, which was then filtered through a micron filter (30.0 vol) at 20±5° C. The mixture was stirred for at least 4 h and centrifuged. The filter cake was washed with purified water (5.0 vol x 2).

[0168] Slurry procedure: DMSO (9.0 vol) and 0.5% hydrochloric acid were charged to a reactor through a micron filter (30.0 vol), and the filter cake was charged to the reactor, and the mixture was stirred at 20±5°C for at least 4 hours before being centrifuged. The filter cake was washed with purified water (5.0 vol×2). The cake was sampled for HPLC analysis for Compound 1 quality standard of 98.0% or more, and if Compound 1 was less than 98.0%, the "Slurry procedure" was repeated. Purified water (40.0 vol) and the filter cake were charged to a reactor, and the mixture was stirred at 20±5°C for at least 4 hours before being centrifuged. The filter cake was washed with purified water (5.0 vol×2). The cake was then dried under vacuum at 45±5°C for at least 8 hours to an LOD of 3.0% or less. If the solvent residue does not meet the acceptance criteria, purified water (40.0 vol) and product were charged into a reactor to remove residual solvent by slurry, and the mixture was stirred at 20±5° C. for at least 4 hours, and then centrifuged. The filter cake was washed with purified water (5.0 vol×2). The cake was dried under vacuum at 45±5° C. for at least 8 hours to obtain an LOD of 3.0% or less. The cake was sampled for residual solvent. If the solvent residue does not meet the acceptance criteria, the procedure of "removal of residual solvent by slurry" was repeated until the solvent residue meets the quality criteria. The material was sampled for HPLC analysis, and the purity (2.02 kg) of the quality criteria of compound 1 is 98.0% or more and the quality criteria of impurity-1 is less than 0.5%. The content of impurity-1 in this case was less than 0.1% as determined by HPLC analysis. The product was sealed in a double LDPE bag with desiccant and stored at room temperature. Compound 1:1H NMR(400MHz,DMSO-d6)δ 10.47(s,1H),8.54(s,1H),8.23-8.07(m,1H),7.96(d,J=5.6Hz,1H),7.65-7.51(m,1H),7.23(s,1H),7.01(d,J=2.0Hz,1H),6.96-6.87(m ,2H),6.25(d,J=5.6Hz,1H),4.98(d,J=6.0Hz,1H),2.97(dd,J=5.6,1.6Hz,1H),2.93(t,J=7.6Hz,2H),2.54(t,J=7.6Hz,2H),2.26(s,1H).

[0169] The powder obtained by preparation in Example 1 was characterized as being amorphous or crystalline by X-ray powder diffraction (XRPD) pattern method. The powder obtained by preparation in Example 1 was determined to be crystalline (sometimes referred to as "Form A" throughout this application) as demonstrated by the crystalline peaks in the XRPD pattern in Figure 1. The powder so obtained was also confirmed by the 1H-NMR spectrum and 13C-NMR spectrum shown in Figures 16 and 17, respectively.

[0170] The XRPD pattern of the crystalline form of Compound 1 (Form A) has the following characteristic peak diffraction angles (where "planar spacing" is shown as "d value" in FIG. 1):

[0171] [Table 2]

[0172] Long-term stability of Form A Long-term stability studies of Form A showed that no significant change in chemical purity occurred when stored at 25°C / 60% RH for up to 24 months (total impurities: T0=1.0%, T24=1.0%) and at 40°C / 75% RH for up to 6 months (total impurities: T0=1.0%, T6=1.0%). In addition, no change in optical purity was observed when stored at 25°C / 60% RH for up to 24 months and at 40°C / 75% RH for up to 6 months. XRPD data of test samples showed that Form A was stable at 40°C / 75% RH for 6 months, and Form A was also stable at 25°C / 60% RH for 6 months, but converted to a crystalline form (sometimes referred to as "Form A*") at 12 months.

[0173] The XRPD pattern of Form A* is shown in Figure 2. The XRPD pattern of Form A* has the following characteristic peak diffraction angles (where "planar spacing" is shown as "d value" in Figure 2):

[0174] [Table 3]

[0175] Stability studies have shown that Form A is chemically stable and can be stored for more than 12 months without any appreciable decomposition.

[0176] The hygroscopicity of Form A was also evaluated by dynamic vapor sorption (DVS) as shown in Figure 19. Figure 19 shows that Form A has moderate hygroscopicity with a weight gain of 4.96% at 80% RH.

[0177] As noted later in preclinical studies, oral absorption of Form A was relatively poor in rats with a bioavailability of 21%, due in part to the low solubility of Form A (found to be less than 0.1 μg / mL in water).

[0178] Due to the low bioavailability observed in preclinical studies, Form A has limited direct use in pharmaceutical formulations. However, Form A is a good candidate for purifying APIs and is used as a starting material for producing amorphous solid dispersions due to its long-term stability as mentioned above (i.e., no significant change in chemical purity was observed after storage at 25°C / 60% RH for up to 24 months, and no change in optical purity was observed after storage at 25°C / 60% RH for up to 24 months and at 40°C / 75% RH for up to 6 months). A change in crystalline form (i.e., from Form A to Form A*) was observed at 12 months under the above conditions, and the long-term storage (i.e., 24 months) does not pose any problem for the subsequent production of amorphous MBP, since in any case Compound 1 undergoes coprecipitation after dissolution in DMA.

[0179] The physicochemical properties of Form A prepared in Example 1 are summarized in Table 3.

[0180] [Table 4]

[0181] Example 1B Intermediate INTQ-20 was synthesized in a similar manner as in Example 1A, step 19, and then subjected to a condensation reaction with intermediate INTQ-18 to give compound 1. [ka]

[0182] However, INTQ-20 is unstable, and most of the products containing INTQ-20 are by-products impurity-2 and impurity-3 (probably due to the reaction of methanol used in the mobile phase of the LCMS to separate the intermediate INTQ-20). [ka]

[0183] Although the synthetic route was optimized, i.e., the reaction solution of intermediate INTQ-20 and intermediate INTQ-18 were directly subjected to a one-pot reaction, the product still contained a large amount of impurity-2.

[0184] Example 1C Intermediate INTQ-21 was synthesized in a similar manner as in Example 1A, step 19, and then subjected to a condensation reaction with intermediate INTQ-18 to give compound 1. [ka]

[0185] However, when intermediate INTQ-21 was subjected to a condensation reaction with intermediate INTQ-18, the formation of compound 1 was not detected at room temperature, and even when the reaction was carried out at a temperature of 100° C., no compound 1 was found at all.

[0186] Example 1D Intermediate INTQ-22 was synthesized in a similar manner as in Example 1A, step 19, and then subjected to a condensation reaction with intermediate INTQ-18 to give compound 1. [ka]

[0187] However, INTQ-22 was not well isolated from the synthesis of the intermediate INTQ-22: the isolated products were mainly impurity-2 (presumably because the p-nitrophenol group is easily cleaved, thus allowing the easy formation of impurity-2 from the active ester and another trifluoroaniline molecule) and p-nitrophenol.

[0188] Example 2 Single crystal of compound 1 (form A**) The plate-shaped single crystals of EtOAc solvate of compound 1 used for single crystal X-ray diffraction structure analysis were crystallized from EtOAc solvent by slow evaporation. The experimental details are described below. First, 1.8 mg of compound 1 was weighed into a 3 mL glass vial and 0.5 mL of EtOAc solvent was added. After manual shaking and ultrasonic shaking to promote dissolution, the suspension was filtered through a PTFE filter membrane (0.45 μM) and the filtrate was transferred to a clean 4 mL shell vial (44.6 mm × 14.65 mm). The shell vial was then sealed with a Pe stopper with one pinhole on it and placed in a fume hood for slow evaporation at ambient temperature and humidity. After 6 days, a plate-shaped crystal sample (CP ID: 810323-A4) was obtained.

[0189] The structure of the plate-shaped crystals was determined using a set of diffraction data obtained from a single crystal grown by slow cooling in EtOAc, which was designated as single crystal of Compound 1 or Form A**. The crystal data and structural details of Form A** are shown in Figures 3-6.

[0190] [Table 5]

[0191] As can be seen in Figure 3, the asymmetric unit of the single structure is composed of two independent compound 1 molecules and two EtOAc solvent molecules, indicating that the crystal is an EtOAc solvate of compound 1. Taking compound 1 molecule as an example, the measurement of its single crystal structure confirmed that the absolute configuration of compound 1 is {C15(S), C16(S), C17(S)}. The unit cell of the single crystal is composed of four compound 1 molecules and four EtOAc solvent molecules, as shown in Figure 4. The possible classical H-bonds in the single crystal structure are shown in Figure 5. The theoretical XRPD pattern of the single crystal form of compound 1 (i.e., Form A**), calculated using MERCURY software, is shown in Figure 6.

[0192] Example 3 Preparation of the neat amorphous form of Compound 1 (Form B) [ka] A solution of compound 1 form A in DCM / MeOH (2:1) was spray-dried to obtain a white powder. The spray-drying conditions were as follows: a solution of compound 1 form A (2.0 g) in 100 mL of mixed solvent (DCM / MeOH=2:1, volume ratio) was sprayed by a spray dryer (BUCHI-290 and BUCHI-295). The product powder was dried by infrared lamp at 50° C. for 16 hours. 1.06 g of powder was obtained. The operating parameters of the spray dryer (BUCHI-290 and BUCHI-295) were as follows: inlet temperature: 60° C.; outlet temperature: 35° C.; aspirator: 100%; pump %: 15%; nozzle cleaner: 2.

[0193] The structure of the powder thus obtained was characterized using XRPD pattern method, which confirmed that it was amorphous as no peak diffraction angle was observed in FIG. 7. The amorphous form of Compound 1 is referred to as neat amorphous form of Compound 1 or Form B throughout this application. 1H-NMR spectrum for Form B is shown in FIG. 21. Form B was measured to have a glass transition temperature of 138.3° C. The sample was a white powder with particle sizes of D90=69.9 μm, D50=3.5 μm, D10=1.4 μm. The XRPD data of the test sample showed that Form B was stable at 40° C. / 75% RH for 14 days since no crystalline peak was observed in the XRPD pattern data of the test sample at 14 days shown in FIG. 29.

[0194] Although the neat amorphous form of Compound 1 was found to have relatively high bioavailability compared to the crystalline form (ie, Form A), the long-term stability of Form B is uncertain.

[0195] Throughout the specification of this application, HPMCAS-LF, HPMCAS-MF and HPMCAS-HF are commercially available from Shin-Etsu Chemical Co., Ltd. unless otherwise stated.

[0196] Example 4 Preparation of Amorphous Solid Dispersion of Compound 1 (Form C) [ka] Amorphous solid dispersions of Compound 1 as microprecipitation bulk powder were prepared as follows: Compound 1 Form A as a poorly soluble drug and hypromellose acetate succinate (HPMCAS-MF) were dissolved in DMA or DMF in a ratio of 3:7 (w / w). The so-obtained solution was added under stirring to an acidic aqueous solution (0.01N HCl) cooled at 2-8°C. The drug was then co-precipitated with HPMCAS from the acidic aqueous solution. After further stirring and filtration, the so-obtained solid was washed several times with 0.01N HCl solution and water, and then dried under vacuum at less than 50°C to obtain a microprecipitation bulk powder suitable for production of formulations.

[0197] The powder so obtained was evaluated by XRPD pattern method to determine its amorphous nature. Since no crystalline peaks were observed in FIG. 8, the powder was determined to be amorphous (referred to as Form C or amorphous solid dispersion of Compound 1 in Form C). Form C was measured to have a glass transition temperature of 112.5° C. The drug loading was measured to be 29.0%. The particle sizes were D90=173.3 μm, D50=60 μm, and D10=12.3 μm. The 1H-NMR spectrum for Form C is shown in FIG. 22. The XRPD pattern data of the test sample showed that Form C was stable at 40° C. / 75% RH for one month since no crystalline peaks were observed in the XRPD pattern data of the test sample at 14 days shown in FIG. 30.

[0198] Example 5 Preparation of Amorphous Solid Dispersion of Compound 1 (Form D) [ka] Amorphous solid dispersions of Compound 1 as microprecipitation bulk powder were prepared as follows: Compound 1 Form A as a poorly soluble drug and hypromellose acetate succinate (HPMCAS-MF) were dissolved in DMA or DMF in a ratio of 2:3 (w / w). The so obtained solution was added to an acidic aqueous solution (0.01N HCl) cooled at 2-8°C under stirring. The drug was then co-precipitated with HPMCAS from the acidic aqueous solution. After further stirring and filtration, the solid was washed several times with 0.01N HCl solution and water, and then dried under vacuum at less than 50°C to obtain a microprecipitation bulk powder suitable for production of a formulation.

[0199] The powder so obtained was evaluated by XRPD pattern method to determine its amorphous nature. Since no crystalline peaks were observed in FIG. 9, the powder was determined to be amorphous (referred to as Form D or amorphous solid dispersion of Compound 1 in Form D). Form D was measured to have a glass transition temperature of 113.1° C. The drug loading was measured to be 38.1%. The particle sizes were D90=244.8 μm, D50=81.4 μm, and D10=16.2 μm. The 1H-NMR spectrum for Form D is shown in FIG. 23. The XRPD data of the test sample showed that Form D was stable at 40° C. / 75% RH for 7 days since no crystalline peaks were observed in the XRPD pattern data of the test sample at 7 days shown in FIG. 31.

[0200] Example 6 Preparation of Amorphous Solid Dispersion of Compound 1 (Form E) [ka] Amorphous solid dispersions of Compound 1 as microprecipitation bulk powder were prepared as follows: Compound 1 Form A as a poorly soluble drug and hypromellose acetate succinate (HPMCAS-LF) were dissolved in DMA or DMF in a ratio of 1:9 (w / w). The so obtained solution was added to an acidic aqueous solution (0.01N HCl) cooled at 2-8°C under stirring. The drug was then co-precipitated with HPMCAS from the acidic aqueous solution. After further stirring and filtration, the solid was washed several times with 0.01N HCl solution and water, and then dried under vacuum at less than 50°C to obtain a microprecipitation bulk powder suitable for production of a formulation.

[0201] The powder so obtained was evaluated to determine its amorphous nature by XRPD pattern method. Since no crystalline peaks were observed in FIG. 10, the powder was determined to be amorphous (referred to as Form E or amorphous solid dispersion of Compound 1 in Form E). Form E was measured to have a glass transition temperature of 113.8° C. The drug loading was measured to be 9.3%. The particle sizes were D90=575.8 μm, D50=265.9 μm, D10=101.4 μm. The 1H-NMR spectrum for Form E is shown in FIG. 24. The XRPD data of the test sample showed that Form E was stable at 40° C. / 75% RH for 4 months since no crystalline peaks were observed in the XRPD data of the test sample at 4 months shown in FIG. 32.

[0202] Example 7 Preparation of Amorphous Solid Dispersion of Compound 1 (Form F) [ka] Amorphous solid dispersions of Compound 1 as a microprecipitation bulk powder were prepared as follows.

[0203] Reactor 1 was evacuated to -0.08 MPa or less and then charged with inert nitrogen to atmospheric pressure. The reactor was charged with DMAc (32.9 kg, 25.0 vol) and hypromellose acetate succinate (HPMCAS-LF) (5.6 kg, 4.0 wt) through a 0.2 μm micron filter. The mixture was stirred at 20±5° C. for at least 2 hours to clarify the mixture. The reactor was then charged with compound 1 (1.4 kg, 1.0 wt) and stirred at 20±5° C. for at least 10 hours to clarify the system, which was named System A.

[0204] The reactor 2 was evacuated to -0.08 MPa or less, and then charged with inert nitrogen to atmospheric pressure. 0.01 mol / L hydrochloric acid was charged into the reactor through a 0.2 μm micron filter, and cooled to 0-5°C. This was named System B.

[0205] Solidification: System A was charged to system B at 0-5° C. The mixture was stirred for at least 2 hours and then centrifuged. The filter cake was washed with purified water (10.0 vol).

[0206] Slurry with dilute hydrochloric acid: A reactor was charged with 0.01 mol / L hydrochloric acid (125.0 vol) through a 0.2 μm micron filter. The filter cake described above was charged into the reactor and stirred at 10±10° C. for at least 2 hours. The mixture was centrifuged and the filter cake was washed with purified water (10.0 vol). The slurry with dilute hydrochloric acid was repeated once more.

[0207] Slurry with purified water: A reactor was charged with purified water (125.0 vol). The filter cake described above was charged to the reactor and stirred for at least 2 hours at 10±10° C. The mixture was centrifuged and the filter cake was washed with purified water (10.0 vol).

[0208] The cake is then dried at 20±5° C. for at least 10 hours with a N2 stream and sampled for Karl Fischer titration to less than 1.0% moisture and solvent residue to less than the quality standard of DMAc 1090 ppm. If the solvent residue does not meet the quality standard, the cake is dried again under vacuum at 50±5° C. to bring the solvent residue into compliance.

[0209] The dried material was collected and sampled for HPLC analysis with the criterion of drug loading (%w / w) being 19%-21%. The crude MBP product was ground and sieved through a 60 mesh sieve and then jet milled to obtain a D90 of less than 200 μm. The material was sampled for XRPD pattern analysis to determine the amorphous nature of the powder. The product was packed into double LDPE bags, sealed with cable ties, and stored at 2-8°C in heat sealed aluminum foil bags with desiccant.

[0210] The drug loading was measured to be 20.2%. Since no crystalline peaks are observed in FIG. 11, the powder was determined to be amorphous (referred to as Form F or amorphous solid dispersion of Compound 1 in Form F). The 1H-NMR spectrum for Form F is shown in FIG. 18. The hygroscopicity (i.e., water sorption) of Form F by DVS is shown in FIG. 20.

[0211] Long-term stability studies of Form F showed that no significant changes in chemical purity occurred when stored at 25° C. / 60% RH for up to 24 months (total impurities: T0=1.0%, T24=0.9%) and at 40° C. / 75% RH for up to 6 months (total impurities: T0=1.0%, T6=1.1%). In addition, no changes in optical purity were observed when stored at 25° C. / 60% RH for up to 24 months and at 40° C. / 75% RH for up to 6 months. There were no changes in chiral purity and polymorphic results when stored at 25° C. / 60% RH for up to 24 months. The moisture content of Form F was reported to be 0.70% (initial and 0 months), 0.80% (1 month), 1.39% (3 months), 1.86% (6 months), 0.62% (9 months), 0.89% (12 months), 2.35% (18 months) and 0.55% (24 months), with the moisture fluctuations being consistent with fluctuations in environmental humidity and in fact remaining virtually unchanged over the 24 month storage period.

[0212] XRPD data showed that no conversion from the amorphous to crystalline form occurred even after prolonged storage at 2-8 °C or 25 °C / 60% RH for 24 months and at 40 °C / 75% RH for 6 months.

[0213] To mimic the absorption environment in the GI system upon oral administration, a sample of aged MBP was stirred in pH 6.8 buffer for 2 hours, and the remaining precipitate was filtered, washed with water, and dried in vacuum. The XRPD of the recovered precipitate showed no change from the amorphous form in Figure 33. Instead, neat HPMCAS-LF was completely dissolved in the same buffer under the same conditions. This exceptional amorphous form stability of Form F plus the favorable physicochemical and mechanical properties make it highly desirable for clinical trial material or drug production for commercial use.

[0214] [Table 6]

[0215] It was concluded that the amorphous solid dispersion of Form F is not simply a physical mixture of Compound 1 and HPMCAS, but has unique physicochemical properties, as summarized in Table 6.

[0216] [Table 7]

[0217] Example 8 Preparation of Amorphous Solid Dispersion of Compound 1 (Form G) [ka] Amorphous solid dispersions of Compound 1 as microprecipitation bulk powder were prepared as follows: Compound 1 Form A as a poorly soluble drug and hypromellose acetate succinate (HPMCAS-LF) were dissolved in DMA or DMF in a ratio of 3:7 (w / w). The so obtained solution was added under stirring to an acidic aqueous solution (0.01N HCl) cooled at 2-8°C. The drug was then co-precipitated with HPMCAS from the acidic aqueous solution. After further stirring and filtration, the solid was washed several times with 0.01N HCl solution and water, and then dried under vacuum at less than 50°C to obtain a microprecipitation bulk powder suitable for production of a formulation.

[0218] The powder so obtained was evaluated by XRPD pattern method to determine its amorphous nature. Since no crystalline peaks are observed in FIG. 12, the powder was determined to be amorphous (referred to as Form G or amorphous solid dispersion of Compound 1 in Form G). Form G was measured to have a glass transition temperature of 111.5° C. The drug loading was measured to be 30.3%. The particle sizes were D90=181.6 μm, D50=74.1 μm, D10=16.4 μm. The 1H-NMR spectrum for Form G is shown in FIG. 25.

[0219] Example 9 Preparation of Amorphous Solid Dispersion of Compound 1 (Form H) [ka] Amorphous solid dispersions of Compound 1 as microprecipitation bulk powder were prepared as follows: Compound 1 Form A as a poorly soluble drug and hypromellose acetate succinate (HPMCAS-LF) were dissolved in DMA or DMF in a ratio of 2:3 (w / w). The so obtained solution was added to an acidic aqueous solution (0.01N HCl) cooled to 2-8°C under stirring. The drug was then co-precipitated with HPMCAS from the acidic aqueous solution. After further stirring and filtration, the solid was washed several times with 0.01N HCl solution and water, and then dried under vacuum at less than 50°C to obtain a microprecipitation bulk powder suitable for production of a formulation.

[0220] The powder so obtained was evaluated by XRPD pattern method to determine its amorphous nature. Since no crystalline peaks are observed in FIG. 13, the powder was determined to be amorphous (referred to as Form G or amorphous solid dispersion of Compound 1 in Form G). Form G was measured to have a glass transition temperature of 114.2° C. The drug loading was measured to be 39.4%. The particle sizes were D90=180.4 μm, D50=62.4 μm, D10=13.6 μm. The 1H-NMR spectrum for Form G is shown in FIG. 26.

[0221] Example 10 Preparation of Amorphous Solid Dispersion of Compound 1 (Form I) [ka] Amorphous solid dispersions of Compound 1 as microprecipitation bulk powder were prepared as follows: Compound 1 Form A as a poorly soluble drug and hypromellose acetate succinate (HPMCAS-HF) were dissolved in DMA or DMF in a ratio of 1:4 (w / w). The so obtained solution was added to an acidic aqueous solution (0.01N HCl) cooled at 2-8°C under stirring. The drug was then co-precipitated with HPMCAS from the acidic aqueous solution. After further stirring and filtration, the solid was washed several times with 0.01N HCl solution and water, and then dried under vacuum at less than 50°C to obtain a microprecipitation bulk powder suitable for production of a formulation.

[0222] The powder so obtained was evaluated by XRPD pattern method to determine its amorphous nature. Since no crystalline peaks are observed in FIG. 14, the powder was determined to be amorphous (referred to as Form I or amorphous solid dispersion of Compound 1 in Form I). Form I was determined to have a glass transition temperature of 111.6° C. The drug loading was determined to be 19.5%. The particle sizes were D90=217.4 μm, D50=84.4 μm, D10=21 μm. The 1H-NMR spectrum for Form I is shown in FIG. 27.

[0223] Example 11 Preparation of Amorphous Solid Dispersion of Compound 1 (Form J) [ka] Amorphous solid dispersions of Compound 1 as microprecipitation bulk powder were prepared as follows: Compound 1 Form A as a poorly soluble drug and hypromellose acetate succinate (HPMCAS-MF) were dissolved in DMA or DMF in a ratio of 1:4 (w / w). The so obtained solution was added to an acidic aqueous solution (0.01N HCl) cooled at 2-8°C under stirring. The drug was then co-precipitated with HPMCAS from the acidic aqueous solution. After further stirring and filtration, the solid was washed several times with 0.01N HCl solution and water, and then dried under vacuum at less than 50°C to obtain a microprecipitation bulk powder suitable for production of formulations.

[0224] The powder so obtained was evaluated by XRPD pattern method to determine its amorphous nature. Since no crystalline peaks are observed in FIG. 15, the powder was determined to be amorphous (referred to as Form J or amorphous solid dispersion of Compound 1 in Form J). Form J was measured to have a glass transition temperature of 115.3° C. The drug loading was measured to be 18.2%. The particle sizes were D90=273.1 μm, D50=116.8 μm, D10=32.9 μm. The 1H-NMR spectrum for Form J is shown in FIG. 28.

[0225] Example 12 Preparation of Amorphous Solid Dispersion of Compound 1 (Form K) [ka] Amorphous solid dispersion of compound 1 as microprecipitation bulk powder was prepared as follows: A mixture of compound 1 form A (2.0 g) as a poorly soluble drug and Eudragit® L100-55 (8.0 g) was stirred in DMA (80 mL) for 16 hours to obtain a clear solution A (concentrated solution). The solution A thus obtained was added dropwise to a mechanically stirred aqueous HCl solution (0.01N, 800 mL) at 5° C. using a dropping funnel. When the addition was completed, all the solids were attached to the stirrer and could not be dispersed in the solution. The preparation of amorphous solid dispersion of compound 1 using Eudragit® L100-55 was unsuccessful.

[0226] Example 13 Pharmacokinetics of amorphous solid dispersion (Form F) of Compound 1 as MBP A fully validated LC-MS / MS method was used for the pharmacokinetic (PK) study of amorphous solid dispersions of Compound 1 as MBP (Form F) in Sprague-Dawley rats and beagle dogs following single and multiple dosing.

[0227] Amorphous solid dispersions of Compound 1 as MBP (Form F) have high oral bioavailability in both rats (18.4%-74.8%) and dogs (68.6%-112%). The elimination half-lives ranged from 1.7 to 3.2 hours in rats and 12 to 28 hours in dogs after oral administration.

[0228] Kinetics were linear over doses of 0.5-5 mg / kg in rats and 0.2-2 mg / kg in dogs. Accumulation (approximately 1.5-fold) was observed in rats after multiple dosing. This slight accumulation was statistically significant in female rats but not in male rats. No accumulation was observed in dogs, even after multiple dosing.

[0229] Example 14 Pharmacokinetic Comparison of Forms A, B, C, D, E, F, G and H in Rats 1. Drugs and reactants: Powder of form A having a particle size of D90=62.4 μm after atomization. Its substance content (purity) was 98.0% or more.

[0230] After atomization, powder of form B with particle sizes of D90=69.9 μm, D10=3.5 um, D50=1.4 um. Its substance content (purity) was 98.0% or more.

[0231] Powders of forms C, D, E, F, G and H having a particle size of D90<600 μm after atomization. The substance content (purity) was 98.0% or more.

[0232] 2. Experimental animals: Male and female rats were used in this study.

[0233] 3. Pharmaceutical preparations: An appropriate amount of each substance was weighed and dispersed in 0.5% sodium carboxymethylcellulose. For each substance, a suspension was prepared with the desired concentration of Compound 1. In this study, all doses and concentrations of Compound 1 were calculated using the free base.

[0234] 4. Dosing and sample collection: Dosing solutions were prepared fresh immediately prior to drug administration. Actual body weight and actual volume injected were recorded for each dose. Rats were fasted overnight and allowed to eat 4 hours after dosing. Rats were orally administered each suspension at doses ranging from 0.5 to 5 mg / kg. Blood samples (approximately 1.0 mL) were collected via the cephalic venous plexus before and at various times up to 36 hours after dosing. Whole blood was processed by centrifugation and plasma samples were collected and stored in a freezer until analysis. Plasma samples were processed by protein precipitation. Compound 1 concentrations in plasma samples were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Plasma concentration-time data were analyzed using a non-compartmental model using Pharsight WinNonlin. Cmax and areas under the concentration-time curves for each substance are shown in Table 7.

[0235] [Table 8]

[0236] Compared to the crystalline form (Form A), the neat amorphous form of Compound 1 (Form B) also exhibited higher Cmax (ng / mL), AUC0-inf (ng·h / mL) and F (%). The oral bioavailability of the neat amorphous form of Compound 1 (Form B) was about 50% of that of intravenous injection, whereas the oral bioavailability of Form A was about 20% of that of intravenous injection. Furthermore, the above experiments showed that the solid Cmax (ng / mL) and AUC0-inf (ng·h / mL) of Forms C, D, E, F, G and H, i.e., the amorphous solid dispersions as MBP, were almost 2-4 times higher than that of Form A (i.e., the crystalline form). Compared to the crystalline form, the neat amorphous form of Compound 1 (Form B) exhibited even higher Cmax (ng / mL) and AUC0-inf (ng·h / mL). However, the Cmax (ng / mL) and AUC0-inf (ng h / mL) values ​​of Form B were lower than those of either of the solid amorphous solid dispersions. Thus, the solid amorphous solid dispersion as MBP of the present application has significantly better relative bioavailability than the crystalline and neat amorphous forms of Compound 1.

[0237] Example 15 Pharmacokinetic comparison of Form A and Form F in dogs 1. Drugs and reactants: Powder of form A having a particle size of D90=62.4 μm after atomization. Its substance content (purity) was 98.0% or more.

[0238] After atomization, powder of form B with particle sizes of D90=69.9 μm, D10=3.5 um, D50=1.4 um. Its substance content (purity) was 98.0% or more.

[0239] After atomization, powder of form F with a particle size of D90<200 μm. Its substance content (purity) was 98.0% or more.

[0240] 2. Experimental animals: Male and female beagle dogs were used in this study.

[0241] 3. Pharmaceutical preparations: An appropriate amount of each substance was weighed and dispersed in 0.5% sodium carboxymethylcellulose. For each substance, a suspension was prepared with the desired concentration of Compound 1. In this study, all doses and concentrations of Compound 1 were calculated using the free base.

[0242] 4. Dosing and sample collection: Dosing solutions were prepared fresh immediately prior to drug administration. Actual body weight and actual volume injected were recorded for each dose. Dogs were fasted overnight and allowed to eat 4 hours after dosing. Dogs were orally administered each suspension at doses ranging from 0.5 to 5 mg / kg. Blood samples (approximately 1.0 mL) were collected via the cephalic venous plexus before and at various times up to 36 hours after dosing. Whole blood was processed by centrifugation and plasma samples were collected and stored in a freezer until analysis. Plasma samples were processed by protein precipitation. Compound 1 concentrations in plasma samples were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Plasma concentration-time data were analyzed using a non-compartmental model using Pharsight WinNonlin. Cmax and areas under the concentration-time curves for each compound are shown in Table 8.

[0243] [Table 9]

[0244] The above experiments demonstrated that the Cmax (ng / mL) and AUC0~inf (ng h / mL) of Compound 1 were dramatically improved in Form F (i.e., amorphous solid dispersion as MBP) compared to the crystalline form (Form A) of Compound 1. Thus, Form F and its corresponding formulations have significantly better relative bioavailability than the crystalline form, suggesting a role for amorphous solid dispersion of Compound 1 in clinical applications.

[0245] The above examples and description of some embodiments should be taken as illustrative rather than limiting the invention defined in the claims. As can be easily understood, many variations and combinations of the features described above are available without departing from the invention described in the claims. All such variations are considered to be within the scope of the present invention. All references cited are incorporated herein by reference in their entirety.

Claims

1. A stable amorphous solid dispersion comprising Compound 1 and a stabilizing polymer, wherein Compound 1, in its solid state, is molecularly dispersed in a polymeric matrix formed by said stabilizing polymer.

2. 2. The amorphous solid dispersion of claim 1, wherein the stabilizing polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS), preferably HPMCAS with a high ratio of succinoyl to acetyl substitution (S / A ratio).

3. 2. The amorphous solid dispersion of claim 1, wherein the stabilizing polymer is any one of HPMCAS-LF, HPMCAS-MF or HPMCAS-HF or a mixture of two or more of the above materials.

4. 2. The amorphous solid dispersion of claim 1, wherein the weight ratio of Compound 1 in the free base form to the polymer is from about 1:9 to about 9:1, preferably from about 1:4 to about 2:3, preferably about 3:7 or about 1:4, more preferably about 1:

4.

5. 10. The amorphous solid dispersion of claim 1 having a drug loading of about 10% to 40%.

6. 2. The amorphous solid dispersion of claim 1, comprising Compound 1 and HPMCAS-MF in the form of the free base in a weight ratio of 3:7, or Compound 1 and HPMCAS-MF in the form of the free base in a weight ratio of 2:3, Compound 1 and HPMCAS-MF in the form of the free base in a weight ratio of 1:4, Compound 1 and HPMCAS-LF in the form of the free base in a weight ratio of 1:9, Compound 1 and HPMCAS-LF in the form of the free base in a weight ratio of 1:4, Compound 1 and HPMCAS-LF in the form of the free base in a weight ratio of 3:7, Compound 1 and HPMCAS-LF in the form of the free base in a weight ratio of 2:3, or Compound 1 and HPMCAS-HF in the form of the free base in a weight ratio of 1:

4.

7. 2. The amorphous solid dispersion of claim 1, prepared by microprecipitation bulk powder (MBP) technique.

8. 2. The amorphous solid dispersion of claim 1, having a glass transition temperature of about 110-115°C, preferably about 111°C.

9. 10. The amorphous solid dispersion of claim 1, formulated into an oral dosage form, such as a tablet or capsule.

10. Compound 1 and HPMCAS, 【Chemistry 1】 (wherein HPMCAs is hydroxypropyl methylcellulose acetate succinate and compound 1 is 【Chemistry 2】 and m is a number such that the weight ratio of Compound 1 in the free base form to HPMCAS in the complex is from about 1:9 to about 9:

1. A complex of.

11. 10. The complex of claim 9, wherein HPMCAS has a high ratio of succinoyl to acetyl substitution (S / A ratio).

12. 10. The composite of claim 9, wherein the HPMCAS is HPMCAS-LF, HPMCAS-MF or HPMCAS-HF or a mixture of two or more of the above materials.

13. 10. The conjugate of claim 9, wherein m is a number such that the weight ratio of compound 1 in the free base form to said polymer in the conjugate is preferably from about 1:4 to about 2:3, preferably about 3:7 or about 1:4, more preferably about 1:

4.

14. 10. The complex of claim 9, comprising Compound 1 and HPMCAS-MF in the form of the free base in a weight ratio of 3:7, or Compound 1 and HPMCAS-MF in the form of the free base in a weight ratio of 2:3, Compound 1 and HPMCAS-MF in the form of the free base in a weight ratio of 1:4, Compound 1 and HPMCAS-LF in the form of the free base in a weight ratio of 1:9, Compound 1 and HPMCAS-LF in the form of the free base in a weight ratio of 1:4, Compound 1 and HPMCAS-LF in the form of the free base in a weight ratio of 3:7, Compound 1 and HPMCAS-LF in the form of the free base in a weight ratio of 2:3, or Compound 1 and HPMCAS-HF in the form of the free base in a weight ratio of 1:

4.

15. 10. The complex of claim 9, which is in amorphous form.

16. 10. The composite of claim 9 prepared by microprecipitation bulk powder (MBP) technique.

17. 10. The composite of claim 9 having a glass transition temperature of about 110-115°C, preferably about 111°C.

18. 10. The conjugate of claim 9, formulated into a formulation for oral administration, such as a tablet or capsule.

19. A crystalline form of Compound 1, Form A, characterized by an XRPD pattern comprising at least three, four, five, or six diffraction peaks having 2θ angle values ​​independently selected from the group consisting of 4.7±0.2, 9.4±0.2, 13.6±0.2, 14.0±0.2, 14.9±0.2, and 15.6±0.2 degrees.

20. 19. The crystalline form of claim 18, wherein the crystalline form is Form A characterized by an XRPD pattern comprising at least three, four, five, or six diffraction peaks having values ​​of 2-theta angles independently selected from the group consisting of 4.7±0.2, 9.4±0.2, 13.6±0.2, 14.0±0.2, 14.9±0.2, 15.6±0.2, 21.2±0.2, 24.3±0.2, 24.7±0.2, 25.1±0.2, and 29.1±0.2 degrees.

21. 4.7±0.2, 9.4±0.2, 10.2±0.2, 13.6±0.2, 14.0±0.2, 14.9±0.2, 15.6±0.2, 17.2±0.2, 17.4±0.2, 18.7±0.2, 20.0±0.2, 20.4±0.2, 21.2±0.2, 22.3±0.2, 24.3±0.2, 24.7±0.2, 25.1±0.2, 25.5±0.2, 26.8±0.

20. The crystalline form of claim 18, wherein the crystalline form is Form A characterized by an XRPD pattern comprising diffraction peaks having values ​​of 2θ angles independently selected from the group consisting of 2, 27.4±0.2, 27.8±0.2, 28.6±0.2, 29.1±0.2, 30.2±0.2, 31.8±0.2, 32.0±0.2, 33.1±0.2, 34.1±0.2 and 34.6±0.2 degrees.

22. 19. The crystalline form of claim 18, which is Form A characterized by an XRPD pattern substantially as shown in Figure 1.

23. A crystalline form of Compound 1, Form A*, characterized by an XRPD pattern containing at least three, four, five, or six diffraction peaks having 2θ angle values ​​independently selected from the group consisting of 9.2±0.2, 14.0±0.2, 15.4±0.2, 18.7±0.2, 20.5±0.2, 24.0±0.2, and 24.9±0.2 degrees.

24. 9.2±0.2, 10.8±0.2, 12.3±0.2, 14.0±0.2, 15.4±0.2, 16.5±0.2, 18.1±0.2, 18.7±0.2, 19.3±0.2, 19.8±0.2, 20.5±0.2, 21.6±0.2, 22.3±0.2, 23.2±0.2, 24.0±0.2, 24.9±0.2, 26 20. The crystalline form of claim 18, wherein the crystalline form is Form A* characterized by an XRPD pattern comprising diffraction peaks having values ​​of 2-theta angles independently selected from the group consisting of: 27.7±0.2, 27.8±0.2, 28.7±0.2, 29.4±0.2, 30.9±0.2, 33.2±0.2, 37.9±0.2 and 38.2±0.2 degrees.

25. 20. The crystalline form of claim 18, which is Form A* substantially characterized by an XRPD pattern as shown in Figure 2.

26. A single crystal of Compound 1 substantially as shown in FIGS.

27. A method for preparing a stable amorphous solid dispersion or complex as disclosed herein, comprising the step of co-precipitating Compound 1 and HPMCAS.

28. 26. The method of claim 25, wherein Compound 1 and HPMCAS are precipitated simultaneously to form a molecular dispersion of Compound 1 in a matrix formed by HPMCAS.

29. 26. The method of claim 25, comprising a step of solvent-controlled precipitation.

30. 26. The method according to claim 25, comprising the step of microprecipitation bulk powder (MBP) technology.

31. 29. The method of any one of claims 25 to 28, wherein HPMCAS has a high ratio of succinoyl to acetyl substitutions (S / A ratio).

32. A method according to any one of claims 25 to 28, wherein the HPMCAS is HPMCAS-LF, HPMCAS-MF or HPMCAS-HF or a mixture of two or more of the above substances.

33. The method of any one of claims 25 to 28, wherein compound 1 is in crystalline or amorphous form, preferably form A as disclosed herein.

34. 29. The method of any one of claims 25 to 28, wherein the weight ratio of compound 1 in the form of its free base to HPMCAS is from about 1:9 to about 9:1, preferably from about 1:4 to about 2:3, preferably about 3:7 or about 1:4, more preferably about 1:

4.

35. HPMCAS is HPMCAS-LF, or HPMCAS-MF, or HPMCAS-HF, and the free base forms of Compound 1 and HPMCAS-MF are in a weight ratio of 3:7, or the free base forms of Compound 1 and HPMCAS-MF are in a weight ratio of 2:3, or the free base forms of Compound 1 and HPMCAS-MF are in a weight ratio of 1:4, or the free base forms of Compound 1 and HPMCAS-LF are 29. The method of any one of claims 25 to 28, wherein the free base forms of compound 1 and HPMCAS-LF are in a 1:9 weight ratio, or the free base forms of compound 1 and HPMCAS-LF are in a 1:4 weight ratio, or the free base forms of compound 1 and HPMCAS-LF are in a 3:7 weight ratio, or the free base forms of compound 1 and HPMCAS-LF are in a 2:3 weight ratio, or the free base forms of compound 1 and HPMCAS-HF are in a 1:4 weight ratio.

36. 29. The method of any one of claims 25 to 28, comprising dissolving compound 1 and HPMCAS in an organic solvent.

37. 35. The method of claim 34, wherein the organic solvent is N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) or N-methyl-2-pyrrolidone (NMP).

38. 29. The method of any one of claims 25 to 28, wherein the resulting solution of compound 1 and HPMCAS is added to water or an acidic aqueous solution, whereby compound 1 and HPMCAS precipitate simultaneously to form the solid dispersion or complex disclosed herein.

39. 37. The method of claim 36, wherein the acidic aqueous solution is an aqueous hydrochloric acid (HCl) solution.

40. 38. The method of claim 37, wherein the water or the acidic aqueous solution is optionally cooled.

41. 39. The method of claim 38, wherein the water or the acidic aqueous solution is optionally cooled to 2-8°C.

42. 37. The method of claim 36, wherein the resulting solid is dried to provide the amorphous solid dispersion or the complex as MBP.

43. 41. The method of claim 40, wherein the obtained solid is optionally further micronized, e.g. by jet milling, to give a powder with a particle size suitable for pharmaceutical formulation, e.g. D90 less than 150 μm or 200 μm.

44. 42. The method of claim 41 , wherein the solid dispersion or the complex is in amorphous form.

45. 42. The method of claim 41, wherein the solid dispersion or the complex has a glass transition temperature of about 110-115°C, preferably about 111°C.

46. a) dissolving compound 1 and HPMCAS in an organic solvent; b) adding the solution of a) to water or an acidic aqueous solution to co-precipitate compound 1 and HPMCAS; and c) washing the resulting solid with water and / or aqueous hydrochloric acid to remove the organic solvent; 26. The method of claim 25, comprising:

47. 26. A method of treating or preventing a disease or disorder responsive to inhibition of Raf kinase in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein compound 1 is in an amorphous solid dispersion according to any one of claims 1 to 8, or in a complex according to any one of claims 9 to 17, or in a crystalline form according to any one of claims 18 to 23.

48. 46. ​​The method of claim 45, wherein the disease or disorder is a cancer selected from the group consisting of brain tumor, lung cancer, kidney cancer, osteosarcoma, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, melanoma, skin cancer, adrenal cancer, cervical cancer, lymphoma or thyroid tumor and complications thereof.

49. 46. ​​The method of claim 45, wherein the disease is a BRAF (V600E or non-V600E) or NRAS or KRAS mutant cancer selected from brain tumors, lung cancer, renal cancer, osteosarcoma, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, melanoma, skin cancer, adrenal cancer, cervical cancer, lymphoma or thyroid tumors and complications thereof.

50. 46. ​​The method of claim 45, wherein the dosage of Compound 1 is 1-200 mg / day and the administration frequency is 1-3 times per day.

51. 46. ​​The method of claim 45, wherein the dosage of Compound 1 is 2.5-100 mg / day and the administration frequency is 1-3 times a day.

52. 46. ​​The method of claim 45, wherein the dosage of Compound 1 is 5-50 mg / day and the administration frequency is once a day.

53. A method for preparing a compound of formula I, comprising subjecting an amine of formula Ia to a condensation reaction with a protected carbamoyl compound of formula Ib to obtain a compound of formula I or a pharma- ceutically acceptable salt thereof. 【Chemistry 3】 (In the formula, R1 and R2 may be the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkynyl, -CN, -NR6R7, -OR6, -COR6, -COR6, -CONR6R7, -C(=NR6)NR7R8, -NR6COR7, -NR6CONR7R8, -NR6CO2R7, -SO2R6, -NR6SON2NR7R8, -NR6SO2R7 and -NR6SO2aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, aryl and heterocyclyl are each independently optionally substituted with 1, 2 or 3 substituents R9; R5 is independently selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents R9; LG is a leaving group, R6, R7 and R8 may be the same or different and are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or (R6 and R7) and / or (R7 and R8) together with the atom to which they are attached form a ring selected from heterocyclyl and heteroaryl rings, respectively, optionally substituted with 1, 2 or 3 substituents R9; R9 is selected from halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, -alkyl-NRaRb, -CN, -ORa, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -C(=NRa)NRbRc, nitro, -NRaCORb, -NRaCONRaRb, -NRaCO2Rb, -SO2Ra, -SO2aryl, -NRaSO2NRbRc, NRaS02Rb and -NRaSO2aryl, wherein said cycloalkyl, aryl, heteroaryl or heterocyclic alkyl is selected from the group consisting of -NRaS02NRbRc, -NRaS02Rb and -NRaS02aryl; R, R and R are each independently selected from H, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or (R and R) and / or (R and R) together with the atoms to which they are attached form a ring selected from heterocyclyl and heteroaryl rings, respectively, optionally substituted with halogen and alkyl. The method includes:

54. 52. The method of claim 51, wherein the condensation reaction of the amine of formula Ia with the protected carbamoyl compound of formula Ib is carried out in an organic solvent.

55. 52. The method of claim 51 , wherein the organic solvent is selected from the group consisting of a non-polar solvent, a polar protic solvent, and a polar aprotic solvent, or a mixture thereof.

56. 54. The method of claim 53, wherein the polar aprotic solvent is selected from N-methylpyrrolidone, N-methylmorpholine, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, ethyl acetate, acetone, N,N-dimethylformamide, acetonitrile and dimethylsulfoxide, the polar protic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and acetic acid, and the non-polar solvent is selected from dioxane, toluene, hexane, cyclohexane and diethyl ether.

57. The method of any one of claims 51 to 54, wherein the condensation reaction is carried out in vacuum.

58. 55. The method of any one of claims 51 to 54, wherein the condensation reaction is carried out at a temperature of about 10 to 50°C or at a temperature of about 15 to 25°C.

59. 57. The method of any one of claims 51 to 56, wherein 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.

60. 58. The method of any one of claims 51 to 57, wherein R1 and R2 are both hydrogen.

61. 59. The method of any one of claims 51 to 58, wherein R5 is aryl optionally substituted with 1, or 2, or 3 substituents R9, preferably R5 is phenyl optionally substituted with 1, or 2, or 3 halogen, more preferably R5 is 2,4,5-trifluorophenyl.

62. 60. The method of any one of claims 51 to 59, wherein LG is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or -ORa, wherein said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more substituents selected from halogen, nitro, hydroxy or alkoxy, and Ra is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally substituted with one or more substituents selected from halogen, nitro, -CN, hydroxy or alkoxy.

63. 61. The method of claim 60, wherein LG is -ORa, where Ra is phenyl optionally substituted with one or more substituents selected from halogen, nitro, -CN, hydroxy, or alkoxy.

64. 62. The method of claim 61 , wherein LG is unsubstituted phenoxy.

65. The compound of formula Ia can be prepared by reacting a compound of formula Ia-2 in the presence of an acid in an organic solvent. 【Chemistry 4】 The method of any one of claims 51 to 62, wherein the composition is prepared by

66. 64. The method of claim 63, wherein the organic solvent is selected from the group consisting of non-polar solvents, polar protic solvents and polar aprotic solvents or mixtures thereof.

67. 65. The method of claim 64, wherein the acid is a mineral acid or an organic acid.

68. The compound of formula Ia-2 can be prepared by reacting a compound of formula Ia-1 in (Boc)2O / t-BuOH in the presence of a catalyst. 【Chemistry 5】 The method of any one of claims 63 to 65, wherein the composition is prepared by

69. The compound of formula Ib is 【Chemistry 6】 60. The method of claim 59, wherein:

70. 68. The method of any one of claims 51 to 67, wherein 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 pharma- ceutically acceptable salt thereof.

71. 69. The method of claim 68, wherein the content of impurity-1 in the product of the condensation reaction is less than about 0.5% (as detected by HPLC).

72. 69. The method of claim 68, wherein the content of impurity-1 in the product of the condensation reaction is less than about 0.2% (as detected by HPLC).

73. 69. The method of claim 68, wherein the content of impurity-1 in the product of the condensation reaction is less than about 0.05% (as detected by HPLC).

74. Formula Ia 【Chemistry 7】 (Wherein R1 and R2 are as defined in claim 51) or a pharma- ceutically acceptable salt thereof.

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