Spray-dried dispersoid and formulation of (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1h-pyrazole-4-carboxamide

Abstract

To provide a spray-dried dispersoid and a pharmaceutical composition in treatment of cancer, autoimmune disease and inflammatory disease.SOLUTION: There is provided a pharmaceutical composition including: a spray-dried dispersoid; and one or more medical fillers. The spray-dried dispersoid includes: (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof; and at least one polymer selected from hypromellose, vinylpyrrolidone-vinyl acetate copolymer, and polyvinyl pyrrolidone polymer.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to a compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof. More specifically, the present invention relates to a pharmaceutical composition comprising the compound of the present invention, a spray-dried dispersion (SDD) thereof, or a pharmaceutical composition thereof. In particular, it is believed that BTK-related diseases and disorders can be treated with BTK inhibitors. The present invention relates to compositions of compounds of formula I that are useful for the treatment and prevention of certain diseases. [Background technology]

[0002] BTK is a cytoplasmic non-receptor tyrosine kinase that belongs to the Tec family of kinases. (Herman, SEM et al., Blood. 2011, 117(23 The structure of BTK consists of several domains: the N-terminal plexiform domain It contains a proline-rich TEC homology domain, two SRC homology domains, and It has an SH3 domain followed by SH2, and a C-terminal kinase domain (BTK-KD) Marcotte,DJet al.,Protein Sci.2010,19( 3):429-439).

[0003] BTK is expressed in hematopoietic cells, except for T cells and plasma cells, and is involved in the proliferation, maturation, differentiation, and apoptosis of hematopoietic cells. are involved in all aspects of B cell development, including cytosis and cell migration (Wu J., et al. l., J Hematol Oncol. 2016;9:80). BTK is a monocyte / macrophage It is also expressed on certain myeloid cells, including phages, neutrophils, and mast cells. In cells, BTK is involved in immune complex-mediated activation of FcγR and FcεR and is involved in the regulation of inflammatory cytokines. It may be involved in the pathogenesis of rheumatoid arthritis (Whang 2014). Because BTK is also required for cellular maturation, inhibiting it prevents bone erosion associated with rheumatoid arthritis. It is possible to do so.

[0004] PIP3 (phosphatidylinositol-3,4,5-triphosphate) generation and P Binding to the H domain and the Tyr-551 binding of BTK by Src family kinases Phosphorylation stimulates membrane localization and activation of BTK. BTK activation is mediated by Ca 2+ Recruitment and activity of NF-κB and MAP (mitogen-activated protein) kinase pathways (Honigberg et al. Proc. Natl. Acad. Sc iUSA2010 Jul 20;107(29):13075-13080) .

[0005] Aberrant BTK expression and / or activity has been demonstrated in a variety of cancers and autoimmune diseases. is.

[0006] Examples of BTK inhibitors are disclosed in WO17 / 103661.

[0007] To provide improved formulations for BTK inhibitors, particularly BTK inhibitors exhibiting low solubility. In addition, there is a need for a method to increase and / or consistently increase plasma concentrations of BTK inhibitors. There is a need to provide formulations that provide optimal plasma concentrations of riboflavin. The present invention addresses one of these needs. The present invention provides a variety of formulations that address one or more of the above-mentioned issues. Summary of the Invention

[0008] In one aspect, the present invention relates to a composition comprising a compound of formula I present in an amount of about 5% w / w to about 30% w / w. , [ka] HPMCAS polymer present in an amount of about 5% w / w to about 30% w / w, and about 30% w / w microcrystalline cellulose present in an amount of about 10% w / w to about 60% w / w; Mannitol or lactose monohydrate, or a combination thereof, present in a total amount of w In addition, sodium starch glycolate, which is present in a total amount of about 0.5% w / w to about 5% w / w, or croscarmellose sodium, or a combination thereof, and about 0.05% Magnesium stearate present in an amount of from about 2% w / w to about 2% w / w, and optionally and silicon dioxide in an amount of about 0.3% w / w to about 0.6% w / w, the total amount being 10 The present invention provides a pharmaceutical composition having a .

[0009] In one aspect, the present invention relates to a composition comprising a compound of formula I present in an amount of about 5% w / w to about 30% w / w. , HPMCAS polymer present in an amount of about 5% w / w to about 30% w / w, and about 30% w / w microcrystalline cellulose present in an amount of about 10% w / w to about 60% w / w; Mannitol or lactose monohydrate, or a combination thereof, present in a total amount of / w Combined, sodium starch glycolate is present in a total amount of about 0.5% w / w to about 5% w / w. 0.05g or croscarmellose sodium, or a combination thereof % w / w to about 2% w / w of magnesium stearate, and optionally and silicon dioxide in an amount of about 0.3% w / w to about 0.6% w / w, the total being 1 The present invention provides a pharmaceutical composition having a molecular weight of 0.00% or less.

[0010] In one aspect, the present invention relates to a composition comprising a compound of formula I present in an amount of about 5% w / w to about 30% w / w. , HPMCAS polymer present in an amount of about 5% w / w to about 30% w / w, and about 30% w / w microcrystalline cellulose present in an amount of about 10% w / w to about 60% w / w; and lactose monohydrate, present in a total amount of about 0.5% w / w to about 5% w / w. Croscarmellose sodium, present in an amount of about 0.05% w / w to about 2% w / w and, when present, from about 0.3% w / w to about 0.6% w / w and silicon dioxide in an amount of 0.1 to 100%, the total being up to 100%.

[0011] In one embodiment, the ratio of the compound of formula I to the HPMCAS polymer is from about 1:4 to about 4:1. In another embodiment, the ratio of the compound of formula I to the HPMCAS polymer is about 1:1. do.

[0012] In another aspect, the present invention provides a compound of formula I present in an amount of about 21% w / w to about 23% w / w. and an HPMCAS polymer present in an amount of about 21% w / w to about 23% w / w. % w / w to about 39% w / w of microcrystalline cellulose, and about 12% w / w to about 1 Mannitol, present in an amount of 3% w / w, and glycerol, present in an amount of about 4% w / w to about 6% w / w. Sodium starch glycolate, present in an amount of about 0.4% w / w to about 0.6% w / w. and magnesium stearate, the total of which is not more than 100%. do.

[0013] In another aspect, the present invention provides a compound of formula I present in an amount of about 21% w / w to about 23% w / w. and an HPMCAS polymer present in an amount of about 21% w / w to about 23% w / w. % w / w to about 34% w / w of microcrystalline cellulose, and about 16% w / w to about 1 Lactose monohydrate, present in an amount of about 7% w / w, and lactose monohydrate, present in an amount of about 2% w / w to about 6% w / w. croscarmellose sodium, present in an amount of about 0.4% w / w to about 0.6% w / w Magnesium stearate present in an amount of about 0.4% w / w to about 0.6% w / w and silicon dioxide, the total of which is 100% or less.

[0014] In another aspect, the present invention provides a compound of formula I present in an amount of about 21% w / w to about 23% w / w. and an HPMCAS polymer present in an amount of about 21% w / w to about 23% w / w. % w / w to about 26% w / w of microcrystalline cellulose, and about 25% w / w to about 2 Mannitol, present in an amount of 6% w / w, and glycerol, present in an amount of about 4% w / w to about 6% w / w. Sodium starch glycolate, present in an amount of about 0.4% w / w to about 0.6% w / w. and magnesium stearate, the total of which is not more than 100%. do.

[0015] In yet another aspect, the present invention provides a composition comprising a compound of formula I present in an amount of about 8% w / w and a composition comprising a compound of formula I present in an amount of about 8% w / w. HPMCAS polymer present in an amount of about 40% w / w and microcrystalline cellulose, mannitol present in an amount of about 40% w / w, and cellulose in an amount of about 3.5% w / w. sodium starch glycolate present in an amount of about 0.3% w / w and magnesium phosphate.

[0016] In one embodiment, the pharmaceutical composition is formulated as a tablet. The pharmaceutical composition comprises from about 25 mg to about 220 mg of the compound of formula I. In the present invention, the pharmaceutical composition is selected from one of about 25 mg, about 50 mg, and about 100 mg. The composition comprises a selected amount of a compound of formula I.

[0017] In another aspect, the present invention provides a method for treating a BTK-associated cancer in a subject in need of treatment for a BTK-associated cancer. A method for treating cancer, comprising administering to a subject a pharmaceutical composition as described above. In one embodiment, the BTK associated cancer is mantle cell lymphoma, chronic lymphocytic Leukemia, small lymphocytic lymphoma, Waldenström macroglobulinemia, and hepatoma Marginal zone lymphoma.

[0018] In another aspect, the present invention provides a method of treating cancer in a subject in need thereof. The method comprises administering to the subject a compound of formula I at a dose of about 20 mg to about 120 mg. Cancers include the following: mantle cell lymphoma, chronic lymphocytic leukemia, small bowel disease, Myeloblastic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma In certain embodiments, the dose is selected from about 25 mg, about 50 mg, and about 10 mg. 0 mg.

[0019] In another aspect, the present invention provides a method for administering a compound of formula I in a dosage of about 20 mg to about 120 mg. , mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenst For the treatment of BTK-related cancers selected from the group consisting of Rehm's macroglobulinemia, and marginal zone lymphoma In certain embodiments, the compound of formula I is administered The dose given is selected from about 25 mg, about 50 mg and about 100 mg.

[0020] In yet another aspect, the present invention relates to a method for treating mantle cell lymphoma, chronic lymphocytic leukemia, small bowel disease, and the like. Lymphocytic lymphoma, Waldenström macroglobulinemia, and marginal zone lymphoma The present invention provides a pharmaceutical composition as described above for use in treating a BTK-associated cancer selected from the group consisting of bronchial and non-bronchial carcinomas. In certain embodiments, the compound of formula I is administered in doses of about 25 mg, about 50 mg, and about 100 mg. The dose is selected from one of the following:

[0021] In another aspect, the present invention relates to a method for treating BTK-related diseases and disorders, including those with BTK inhibitors. The spray-dried dispersion or pharmaceutical composition is useful for the treatment and prevention of diseases that can be caused by A compound of formula I is provided: [ka]

[0022] Thus, herein, the compound of formula I and hypromellose acetate succinate ( A spray-dried dispersion is provided comprising a polymer (HPMCAS).

[0023] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is amorphous, Alternatively, the ratio of polymorphic form to HPMCAS polymer is about 1:4 to about 4:1. In some embodiments, the ratio of the compound of formula I to the HPMCAS polymer is about 1:1. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

[0024] As used herein, the compound of formula I is dissolved in one or more organic solvents before being spray dried. Also provided is a process for preparing a spray-dried dispersion comprising: The compound, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, is spray dried. Before being mixed, the dichloromethane:methanol ratio is preferably about 80:20 wt / wt. In some embodiments, the compound of formula I is dissolved in methanol. In yet another embodiment, Form A of the compound of formula I is one or It is dissolved in a number of organic solvents.

[0025] As used herein, a first composition comprising a spray-dried dispersion and one or more pharmaceutical excipients is provided. Also provided is a pharmaceutical composition comprising a spray-dried dispersion of an HPMCAS polymer and a compound of formula I. or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof.

[0026] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, in the spray-dried dispersion is The ratio of the salt, amorphous or polymorphic form to the HPMCAS polymer is about 1:4 to 1:5. In some embodiments, the ratio of the compound of formula I, or Ratio of its pharma- ceutically acceptable salt, amorphous, or polymorphic form to HPMCAS polymer. is about 1:1. In some embodiments, the HPMCAS polymer is HPMCAS- It's MG.

[0027] In some embodiments, the spray-dried dispersion comprises about 20% to about 75% w / w of the first composition. In some embodiments, the spray-dried dispersion is present in an amount of about 30 w of the first composition. In some embodiments, the spray-dried dispersion is present in an amount of from about 60% to about 60% w / w. In some embodiments, the composition is present in an amount of about 40% to about 50% w / w. The dry dispersion is present in an amount of about 45% w / w of the first composition.

[0028] In some embodiments, the pharmaceutical excipients include fillers, lubricants, and combinations thereof. is selected from the group consisting of:

[0029] In some embodiments, the filler is present in an amount of about 25% to about 80% w / w of the first composition. In some embodiments, the filler is present in an amount of about 45% to about 65% w / w of the first composition. In some embodiments, the filler is present in an amount of about 55% w / w of the first composition. is present in an amount of

[0030] In some embodiments, the filler is a saccharide, gelatin, a synthetic polymer, or the like. In some embodiments, the filler is selected from the group consisting of scrub, ... Lactose, microcrystalline cellulose, methylcellulose, ethylcellulose, hydro Hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, xylitol ethanol, sorbitol, mannitol, polyvinylpyrrolidone, polyethylene glycol, Polyvinyl alcohol, polymethacrylate, poloxamer, magnesium stearate , Calcium Stearate, Sodium Stearate, Stearic Acid, Hydrogenated Vegetable Oil, Mineral Oil Oil, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate , sodium benzoate, sodium stearyl fumarate, colloidal silicon dioxide, Sodium benzoate, sodium oleate, sodium acetate, and combinations thereof The compound is selected from the group consisting of:

[0031] In some embodiments, the filler is a binder, a disintegrant, or a combination thereof. do.

[0032] In some embodiments, the binder is present in an amount of about 30% to about 80% w / w of the first composition. In some embodiments, the binder is present in an amount of about 40% to about 60% w / w of the first composition. In some embodiments, the binder is present in an amount of about 52% w / w of the first composition. is present in an amount of

[0033] In some embodiments, the binder is microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose, cellulose ether ... Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Sodium carboxylate Dimethylcellulose starch, methylcellulose, ethylcellulose, hydroxypropyl cellulose, mannitol, xylitol, sorbitol, lactose, sucrose, Sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol, polyvinyl selected from the group consisting of alcohols, polymethacrylates, and combinations thereof .

[0034] In some embodiments, the binder is microcrystalline cellulose, mannitol, or the like. It is a combination of the above.

[0035] In some embodiments, the microcrystalline cellulose comprises about 5% to about 55% w / w of the first composition. In some embodiments, the microcrystalline cellulose is present in an amount of about 1 / w / w of the first composition. In some embodiments, the microcrystalline cellulose is present in an amount of about 10% to about 40% w / w. The stearate is present in an amount of about 20% to about 30% w / w of the first composition. Preferably, the microcrystalline cellulose is present in an amount of about 30% to about 60% w / w of the first composition. In some embodiments, the microcrystalline cellulose is present in an amount of about 26% w / w of the first composition. exist.

[0036] In some embodiments, mannitol comprises about 5% to about 55% w / w of the first composition. In some embodiments, mannitol is present in an amount of about 10% to about In some embodiments, mannitol is present in the first composition in an amount of 40% w / w. In some embodiments, mannitol is present in an amount of about 20% to about 30% w / w. , is present in an amount of about 26% w / w of the first composition.

[0037] In some embodiments, the disintegrant is present in an amount of about 0.5% to about 5% w / w of the first composition. In some embodiments, the disintegrant is present in an amount of from about 1.5% to about 3.5% of the first composition. In some embodiments, the disintegrant is present in an amount of about 2.5% w / w of the first composition. Present in w / w amount.

[0038] In some embodiments, the disintegrants are sodium starch glycolate, alginic acid, Sodium alginate, croscarmellose sodium anion exchange resin, and In some embodiments, the disintegrant is selected from the group consisting of starch, It is sodium glycolate.

[0039] In some embodiments, the lubricant comprises from about 0.05% to about 2.5% w / w of the first composition. In some embodiments, the lubricant is present in an amount of from about 0.1% to about 1% of the first composition. % w / w of the first composition. In some embodiments, the lubricant is present in an amount of about 0.2 It is present in an amount of 5% w / w.

[0040] In some embodiments, the lubricant is magnesium stearate, calcium stearate, Urea, Sodium Stearate, Stearic Acid, Hydrogenated Vegetable Oil, Mineral Oil, Polyethylene Glycol Cole, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate Lyceryl, Sodium Benzoate, Sodium Stearyl Fumarate, Colloidal Silicon Dioxide sodium benzoate, sodium oleate, sodium acetate, and combinations thereof In some embodiments, the lubricant is selected from the group consisting of malt stearate, ... It is magnesium.

[0041] In some embodiments, the spray-dried dispersion comprises about 20% to about 75% w / w of the first composition. The filler is present in an amount of about 25% to about 80% w / w of the first composition, and the moisturizing agent is present in an amount of about 25% to about 80% w / w of the first composition. The lubricant is present in an amount of about 0.05% to about 2% w / w of the first composition.

[0042] In some embodiments, the spray-dried dispersion is present in an amount of about 45% w / w of the first composition. the filler is present in an amount of about 55% w / w of the first composition, and the lubricant is present in an amount of about 55% w / w of the first composition. is present in an amount of about 0.25% w / w.

[0043] In some embodiments, the spray-dried dispersion comprises about 40% to about 50% w / w of the first composition. and microcrystalline cellulose is present in an amount of about 20% to about 30% w / w of the first composition. and mannitol is present in an amount of about 20% to about 30% w / w of the first composition. Sodium starch glycolate is present in an amount of about 0.5% to about 5% w / w of the first composition. The magnesium stearate is present in an amount of about 0.05% to about 2% w / w of the first composition. There is.

[0044] In some embodiments, the spray-dried dispersion and pharmaceutical excipients are blended. In some embodiments, the first composition is granulated. is granulated by roller compaction.

[0045] Also provided herein is a pharmaceutical composition comprising the first composition and one or more pharmaceutical excipients. will be done.

[0046] In some embodiments, the first composition is present in an amount of about 15% to about 99% w / w of the total composition. It exists in.

[0047] In some embodiments, the one or more pharmaceutical excipients include fillers, lubricants, and the like. The compound is selected from the group consisting of:

[0048] In some embodiments, the lubricant is present in an amount of about 0.05% to about 2% w / w of the total composition. In some embodiments, the lubricant is present in an amount of from about 0.1% to about 1.0% w / w of the total composition. In another embodiment, the lubricant is present in an amount of about 0.1% to about 0.8% w / w of the total composition. In another embodiment, the lubricant is present in an amount of about 0.4% to about 0.6% w / w of the total composition. In yet another embodiment, the lubricant is present in an amount of about 0.3% w / w of the total composition. is present in an amount of

[0049] In some embodiments, the lubricant is magnesium stearate, calcium stearate, Urea, Sodium Stearate, Stearic Acid, Hydrogenated Vegetable Oil, Mineral Oil, Polyethylene Glycol Cole, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate Lyceryl, Sodium Benzoate, Sodium Stearyl Fumarate, Colloidal Silicon Dioxide sodium benzoate, sodium oleate, sodium acetate, and combinations thereof In some embodiments, the lubricant is selected from the group consisting of malt stearate, ... It is magnesium.

[0050] In some embodiments, the filler is present in an amount of about 1% to about 85% w / w of the total composition. do.

[0051] In some embodiments, the filler is sucrose, lactose, microcrystalline cellulose, Methylcellulose, Ethylcellulose, Hydroxypropylcellulose, Hydroxypropyl Pyrmethylcellulose, starch, xylitol, sorbitol, mannitol, polyvinyl chloride Nylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate , Poloxamer, Magnesium stearate, Calcium stearate, Sodium stearate Thorium, Stearic Acid, Hydrogenated Vegetable Oil, Mineral Oil, Sodium Lauryl Sulfate, Lauryl Sulfate Magnesium, glyceryl palmitostearate, sodium benzoate, stearyl fumarate Sodium phosphate, colloidal silicon dioxide, sodium benzoate, sodium oleate , sodium acetate, and combinations thereof.

[0052] In some embodiments, the filler is a binder, a disintegrant, or a combination thereof. do.

[0053] In some embodiments, the disintegrant is present in an amount of about 0.5% to about 5% w / w of the total composition. In some embodiments, the disintegrant is present in an amount of about 4% to about 6% w / w of the total composition. In some embodiments, the disintegrant is present in an amount of about 2.5% w / w of the total composition. .

[0054] In some embodiments, the disintegrants are sodium starch glycolate, alginic acid, Sodium alginate, croscarmellose sodium anion exchange resin, and In some embodiments, the disintegrant is selected from the group consisting of starch, It is sodium glycolate.

[0055] In some embodiments, the first composition is present in an amount of about 90% to about 99% w / w of the total composition. In some embodiments, the first composition is present in an amount of about 97% w / w of the total composition. It exists in.

[0056] In some embodiments, the first composition is present in an amount of about 15% to about 60% w / w of the total composition. In some embodiments, the first composition is present in an amount of about 30% to about 40% of the total composition. In some embodiments, the first composition is present in an amount of about 35% by weight of the total composition. Present in w / w amount.

[0057] In some embodiments, the binder is present in an amount of about 40% to about 85% w / w of the total composition. In some embodiments, the binder is present in an amount of about 55% to about 75% w / w of the total composition. exist.

[0058] In some embodiments, the binder is microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose, cellulose ether ... Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Sodium carboxylate Dimethylcellulose starch, cellulose, methylcellulose, ethylcellulose, hydro oxypropyl cellulose, mannitol, xylitol, sorbitol, lactose, Sucrose, sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol , polyvinyl alcohol, polymethacrylate, and combinations thereof. are selected.

[0059] In some embodiments, the binder is microcrystalline cellulose, mannitol, or the like. It is a combination of the above.

[0060] In some embodiments, microcrystalline cellulose comprises about 25% to about 35% w / w of the total composition. In some embodiments, the microcrystalline cellulose is present in an amount of about 31 wt% of the total composition. Present in an amount of % w / w.

[0061] In some embodiments, mannitol is present in an amount of about 25% to about 35% w / w of the total composition. In some embodiments, mannitol is present in an amount of about 31% w / w of the total composition. It exists in.

[0062] In some embodiments, the first composition is blended with a pharmaceutical excipient. In embodiments, the pharmaceutical compositions are co-milled.

[0063] In some embodiments, the pharmaceutical composition is formulated as a tablet. So, a compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, In some embodiments, the compound of formula I is present in an amount of about 10 mg to about 50 mg. The pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof is about 25 mg to about 220 mg. More preferably, the amount is about 50 mg to about 150 mg, and even more preferably, the amount is about 80 mg. In an even more preferred embodiment, the amount is about 100 mg. It exists in.

[0064] Also provided herein is a pharmaceutical composition, the pharmaceutical composition comprising: (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl (phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo and HPMCAS polymer; and one or more pharmaceutical excipients.

[0065] In some embodiments, the HPMCAS polymer is HPMCAS-MG.

[0066] In some embodiments, the one or more pharmaceutical excipients include fillers, lubricants, and the like. The compound is selected from the group consisting of:

[0067] In some embodiments, the filler is sucrose, lactose, microcrystalline cellulose, Methylcellulose, Ethylcellulose, Hydroxypropylcellulose, Hydroxypropyl Pyrmethylcellulose, starch, xylitol, sorbitol, mannitol, polyvinyl chloride Nylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylate , Magnesium stearate, Calcium stearate, Sodium stearate, Ste Allicin, Hydrogenated Vegetable Oil, Mineral Oil, Sodium Lauryl Sulfate, Magnesium Lauryl Sulfate, Glyceryl palmitostearate, sodium benzoate, sodium stearyl fumarate , colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate and combinations thereof.

[0068] In some embodiments, the lubricant is magnesium stearate, calcium stearate, Urea, Sodium Stearate, Stearic Acid, Hydrogenated Vegetable Oil, Mineral Oil, Polyethylene Glycol Cole, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate Lyceryl, Sodium Benzoate, Sodium Stearyl Fumarate, Colloidal Silicon Dioxide sodium benzoate, sodium oleate, sodium acetate, and combinations thereof The combination is selected from the group consisting of

[0069] In some embodiments, the composition comprises: (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl (phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo and HPMCAS polymer; Microcrystalline cellulose; Mannitol, Sodium starch glycolate, and magnesium stearate.

[0070] In some embodiments, the composition comprises: (S)-5-amino-3-(4-(( 5-Fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trimethylphenyl) (trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide, an HPMCAS polymer present in an amount of about 5% to about 30% w / w of the composition; microcrystalline cellulose present in an amount of about 30% to about 60% w / w of the composition; Mannitol present in an amount of about 30% to about 60% w / w of the composition; Sodium starch glycolate, present in an amount of about 0.5% to about 5% w / w of the composition; , and magnesium stearate, present in an amount of about 0.05% to about 2% w / w of the composition. nothing.

[0071] In some embodiments, the composition comprises: (S)-5-amino-3-(4-((5-fluoro)phenyl)-2,4-di ... 2-Methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoro propan-2-yl)-1H-pyrazole-4-carboxamide, an HPMCAS polymer present in an amount of about 8% w / w of the composition; microcrystalline cellulose present in an amount of about 40% w / w of the composition; Mannitol present in an amount of about 40% w / w of the composition; Sodium starch glycolate present in an amount of about 3.5% w / w of the composition; and magnesium stearate present in an amount of about 0.3% w / w of the composition.

[0072] In some embodiments, the composition comprises: (S)-5-amino-3-(4-( (5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1- (trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide, an HPMCAS polymer present in an amount of about 10% to about 30% w / w of the composition; microcrystalline cellulose present in an amount of about 20% to about 30% w / w of the composition; Mannitol present in an amount of about 20% to about 30% w / w of the composition; sodium starch glycolate present in an amount of about 2% to about 8% w / w of the composition; and magnesium stearate, present in an amount of about 0.05% to about 2% w / w of the composition. nothing.

[0073] In some embodiments, the composition comprises: (S)-5-amino-3-(4-((5-fluoro)phenyl)-2,4-diamino-1,2-diphenyl-2,4-diphenyl ...2,5-diphenyl-2,6-diphenyl-2,7-diphenyl-2,8-diphenyl-2,9-diphenyl-2,1-dimethyl-1,2-propanediol, present in an amount of about 22% w / w of the composition. (2-Methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoro 1H-pyrazole-4-carboxamide, an HPMCAS polymer present in an amount of about 22% w / w of the composition; microcrystalline cellulose present in an amount of about 25% w / w of the composition; Mannitol present in an amount of about 25% w / w of the composition; Sodium starch glycolate present in an amount of about 5% w / w of the composition; and magnesium stearate present in an amount of about 0.5% w / w of the composition.

[0074] In some embodiments, the HPMCAS polymer is HPMCAS-MG.

[0075] In some embodiments, the pharmaceutical composition is formulated as a tablet. In the present case, the tablets are coated.

[0076] Also provided herein is a method for preparing a pharmaceutical composition, the method comprising: (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl (phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo The mixture was mixed with aryl-4-carboxamide, HPMCAS polymer, and organic solvent to form the mixture. Forming, spray drying the mixture to form a spray-dried dispersion; and granulating the spray-dried dispersion to form a first composition.

[0077] In some embodiments, the organic solvent is a mixture of dichloromethane and methanol. In some embodiments, the organic solvent is 80:20 dichloromethane:methanol. In some embodiments, the spray dried dispersion may be treated with one or more pharmaceutical agents prior to being granulated. In some embodiments, the spray-dried dispersion is blended with excipients prior to granulation. In some embodiments, the spray-dried dispersion is dried in an oven prior to being granulated. In some embodiments, the spray-dried composition is blended with one or more pharmaceutical excipients. The dispersion is granulated by roller compaction. In some embodiments, the first composition comprises: In some embodiments, the first composition is blended with one or more pharmaceutical excipients. In some embodiments, the first composition is compressed into a tablet. In some embodiments, the tablets are coated. The coating may include a polymer, a plasticizer, a pigment, or a combination thereof.

[0078] In some embodiments, the (S)-5-amino-3-(4-(( 5-Fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trimethylphenyl) Trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide and HPMCA In some embodiments, the ratio of the spray-dried polymer to the S polymer is about 1:4 to about 4:1. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide) in powder form 1-(1,1,1-trifluoropropan-2-yl)-1H The ratio of -pyrazole-4-carboxamide to HPMCAS polymer is about 1:1. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

[0079] Also provided herein is a crystalline form of the compound of Formula I, having the formula: [ka]

[0080] Herein, the values ​​are 15.8±0.2, 16.2±0.2, and 11.9±0.2°2. Formula I, characterized in that it has an X-ray powder diffraction (XRPD) pattern that includes a peak at a value of θ Also provided is Form A of the compound.

[0081] Herein, 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0± X-ray powder diffraction (XRPD) patterns included peaks at °2θ values ​​of 0.2, 0.2, and 18.3±0.2. Also provided is Form A of the compound of formula I, which is characterized as having a turn.

[0082] Herein, 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0± The peaks were measured at °2θ values ​​of 0.2, 18.3±0.2, 23.8±0.2, and 20.5±0.2. The compound of formula I is characterized by having an X-ray powder diffraction (XRPD) pattern that includes Form A is also provided.

[0083] Herein, 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0± 0.2, 18.3±0.2, 23.8±0.2, 20.5±0.2, 25.7±0.2, X-ray powder diffraction (XR) with peaks at °2θ values ​​of 20.1±0.2 and 9.5±0.2 Also provided is Form A of compound of formula I, characterized as having a PD) pattern.

[0084] Herein, 15.8±0.2, 16.2±0.2, 11.9±0.2, 19.0± 0.2, 18.3±0.2, 23.8±0.2, 20.5±0.2, 25.7±0.2, 20.1±0.2, 9.5±0.2, 25.0±0.2, and 11.1±0.2°2 The compound represented by formula I is characterized by having an X-ray powder diffraction (XRPD) pattern including a peak at a value of θ Form A of the compound is also provided.

[0085] Provided herein is a compound of formula I having an XRPD pattern substantially as shown in FIG. 4A. Product form A is also provided.

[0086] As used herein, a differential scanning calorimetry (DSC) curve containing an endotherm with an onset of about 185° C. is Also provided is Form A of the compound of Formula I having the formula:

[0087] Provided herein is a compound of formula I having a DSC thermogram substantially as shown in FIG. 4C. Form A of the compound is also provided.

[0088] Also provided herein are solid oral pharmaceutical compositions comprising a pharmaceutical excipient and a crystalline form of the compound of formula I. Provided.

[0089] As used herein, crystalline forms of the compound of formula I prepared by mixing with pharmaceutical excipients are Also provided is a solid oral pharmaceutical composition comprising:

[0090] As used herein, a method for preparing a crystalline form of the compound of formula I in a solid state is provided, comprising mixing the crystalline form with a pharmaceutical excipient. A process for making the oral pharmaceutical composition is also provided.

[0091] Also provided herein are methods for treating cancer in a subject in need thereof. The method comprises administering to a subject a spray-dried dispersion, a pharmaceutical composition, or a therapeutically effective amount of a compound of formula I. In some embodiments, the cancer is a BTK-associated cancer.

[0092] Also provided herein is a method of treating cancer in a subject in need thereof, comprising: This method is (a) the BTK gene, the BTK kinase, or the expression or activity of any of them; or dysregulation of levels of (b) a compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof; administering the spray-dried dispersion, or a pharmaceutical composition thereof, to a subject.

[0093] Also provided herein is a method of treating a BTK-associated cancer in a subject, the method comprising: Compounds of formula I, or pharma- ceutically acceptable salts thereof, amorphous or polymorphic forms thereof, The spray-dried dispersion, or a pharmaceutical composition thereof, is used to identify or diagnose a patient as having a BTK-associated cancer. The method includes administering the therapeutic agent to a subject who has been diagnosed with a disease.

[0094] Also provided herein is a method of treating a BTK-associated cancer in a subject, the method comprising: The BTK gene, the BTK kinase, or the expression or activity of any of them Detecting dysregulation of levels; Compounds of formula I, or pharma- ceutically acceptable salts thereof, amorphous or polymorphic forms thereof, or a pharmaceutical composition thereof, and administering to a subject.

[0095] Also provided herein are methods of treating a subject, the methods comprising administering a compound of formula I, or or a pharma- ceutically acceptable salt, amorphous, or polymorphic form of, or a spray-dried dispersion thereof; These pharmaceutical compositions are administered to a subject who has a BTK gene, a BTK kinase, or any of the foregoing. A subject having clinical documentation indicating that he or she has dysregulation of expression or activity or level of This includes administering to

[0096] Provided herein are methods for inhibiting cancer metastasis in a subject in need thereof. Also provided is a method of preparing a compound of formula I, or a pharma- ceutically acceptable salt thereof, and administering to a subject a polymorphic or polymorphic form thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. This includes giving.

[0097] In some embodiments, the cancer is a BTK-associated cancer.

[0098] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is amorphous, or polymorphic forms, spray dried dispersions thereof, or pharmaceutical compositions thereof, may be used in combination with another chemical Used in combination with forensic drugs.

[0099] Also provided herein is a method for selecting a treatment for a subject, the method comprising: A compound of formula I, or a pharmacopoeial equivalent thereof, is administered to a subject identified or diagnosed as having cancer. Acceptable salts, amorphous or polymorphic forms thereof, spray-dried dispersions thereof, or pharmaceutical compositions thereof Selecting a treatment that involves administering a pharmaceutical composition.

[0100] Also provided herein is a method of selecting a treatment for a subject having cancer, the method comprising: , The BTK gene, the BTK kinase, or any of their expression or detecting dysregulation of activity or level; A compound of formula I, or a pharma- ceutically acceptable salt thereof, amorphous or polymorphous, is administered to a subject. and selecting a treatment that involves administration of the compound of formula (I), a spray-dried dispersion thereof, or a pharmaceutical composition thereof. This includes:

[0101] As used herein, a compound of formula I, or a pharma- ceutically acceptable salt thereof, amorphous or polymorphous, is for the treatment of diseases comprising administering the pharmaceutical composition, a spray-dried dispersion thereof, or a pharmaceutical composition thereof Also provided is a method of selecting a subject, the method comprising: Identifying a subject having a BTK-associated cancer; Compounds of formula I, or pharma- ceutically acceptable salts thereof, amorphous or polymorphic forms thereof, and selecting a subject for treatment comprising administration of a spray-dried dispersion of, or a pharmaceutical composition thereof. This includes: As used herein, a compound of formula I, or a pharma- ceutically acceptable salt thereof, amorphous or polymorphous, is for the treatment of diseases comprising administering the pharmaceutical composition, a spray-dried dispersion thereof, or a pharmaceutical composition thereof Also provided is a method for selecting a subject with cancer, the method comprising: The BTK gene, the BTK kinase, or any of their expression or detecting dysregulation of activity or level; Compounds of formula I, or pharma- ceutically acceptable salts thereof, amorphous or polymorphic forms thereof, and selecting a subject for treatment comprising administration of a spray-dried dispersion of, or a pharmaceutical composition thereof. This includes:

[0102] In some embodiments, the method for determining whether a cancer in a subject is a BTK-associated cancer is The step of detecting the BTK gene, the BTK kinase protein, or or any of them. In some embodiments, the method includes performing an assay for the detection of a marker in a sample from a subject. In some embodiments, the sample is a biopsy sample. In embodiments, the assay is performed by sequencing, immunohistochemistry, immunoblotting, enzyme-linked immunosorbent assay, or the like. and fluorescent in situ hybridization (FISH). In some embodiments, the FISH is a break-apart FISH analysis. In some embodiments, the sequencing is performed by pyrosequencing or next generation sequencing. It is gu.

[0103] In some embodiments, the BTK gene, the BTK kinase protein, or their Dysregulation in the expression or activity or level of any one of these mediates BCR signaling. Pathway genes, BCR (breakpoint cluster protein) signaling pathway proteins or dysregulation in the expression or activity or level of any of them. Here are the results.

[0104] In some embodiments, the BCR signaling pathway gene or Tract proteins include cyclin-D1, CARD11, CD79B, CD79A, and MYD8. 8, and combinations thereof.

[0105] In some embodiments, the BCR signaling pathway genes, BCR signaling pathway genes, or a modulation in the expression or activity or level of any one of them. The deficiency is the result of one or more genetic alterations.

[0106] In some embodiments, the one or more genetic alterations are a chromosomal translocation t(11;14 )(q13;q32), deletion of chromosomal region 17p13, deletion of chromosomal region 11q23, deletion of chromosome region 13q14, and trisomy of chromosome 12. .

[0107] In some embodiments, the one or more genetic alterations are in the BCR signaling pathway. It is one or more point mutations in genes that code for proteins.

[0108] In some embodiments, the BCR signaling pathway is One or more point mutations in the BCR signal transduction vector having one or more amino acid substitutions leading to the translation of transduction pathway proteins, where the BCR signaling pathway proteins CARD11, CD79B, CD79A, MYD88, and their combinations In some embodiments, the BCR signaling pathway protein is selected from the group consisting of: One or more point mutations in the MYD88 gene L265 Amino acid position of BCR signaling pathway having one or more amino acid substitutions in one or more of In some embodiments, the amino acid substitution results in the translation of a tract protein. L265P It is.

[0109] In some embodiments, the BTK gene, the BTK kinase, or any of them The dysregulation of expression or activity or level is due to one or more In some embodiments, one or more point mutations in the BTK gene. has one or more amino acid substitutions at one or more of the following amino acid positions: BTK protein translation: 117, 316, 474, 481, 528 , 560, 562, and 601. In some embodiments, one in the BTK gene or multiple point mutations, including the following amino acid substitutions: T117P, T316A, T474I, T 474M, T474S, C481S, C481F, C481T, C481G, C481R , L528W, P560L, R562W, R562G, and F601L or more.

[0110] Also provided herein is a method of treating cancer in a subject in need thereof, comprising: This method is (a) a BCR signaling pathway gene, a BCR signaling pathway protein, or detecting dysregulation of the expression or activity or level of any of these; (b) a compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof; administering the spray-dried dispersion, or a pharmaceutical composition thereof, to a subject.

[0111] Also provided herein are methods of treating a subject, the methods comprising administering a compound of formula I, or or a pharma- ceutically acceptable salt, amorphous, or polymorphic form of, or a spray-dried dispersion thereof; The pharmaceutical compositions are administered to a subject who is a patient having an infection with BCR signaling pathway genes, BCR signaling pathway or a dysregulation of the expression or activity or level of any of them. This includes administering to a subject with clinical documentation indicating that

[0112] In some embodiments, the BTK associated cancer is Hodgkin lymphoma, diffuse large cell type B DLBCL (e.g., activated B-cell-like DLBCL (ABC-DLBCL) )), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom's lymphoma Chronic globulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (AL) L), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia, hairy cell leukemia, acute osteoporosis Myeloid leukemia (AML), chronic myelogenous leukemia, multiple myeloma, plasma cell myeloma, plasmacytoma , bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, Selected from the group consisting of intestinal cancer, uterine cancer, hepatocellular carcinoma, head and neck cancer, or glioma. .

[0113] In some embodiments, the BTK-associated cancer is a hematological cancer. Blood cancers include leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease, and myeloma. is selected from the group consisting of:

[0114] In some embodiments, the hematological cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic Myeloid leukemia (CML), chronic myelogenous monocytic leukemia (CMML), chronic neutrophilic leukemia ( CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphoma Paracytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with lineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), bone marrow Dysplastic syndromes (MDS), myeloproliferative disorders (MPD), diffuse large B-cell lymphoma (DLBCL) (e.g., activated B-cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma) lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia Lymphoplasmacytic lymphoma (LPL), primary central nervous system lymphoma, small lymphoma Myeloblastic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, undifferentiated Large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma and MM.

[0115] In some embodiments, the BTK-associated cancer is a B cell malignancy. Morphologically, B-cell malignancies include Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLC), and LBCL) (e.g., activated B-cell-like DLBCL (ABC-DLBCL)), follicular lymphoma lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma, Splenic marginal zone lymphoma, Burkitt's lymphoma, Waldenstrom's macroglobulinemia lymphoplasmacytic lymphoma (LPL), primary central nervous system lymphoma, small lymphocytic Lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia (ALL), B-cell prolymphocyte leukemia, precursor B lymphoblastic leukemia, or hairy cell leukemia. .

[0116] In some embodiments, the BTK associated cancer is mantle cell lymphoma, chronic lymphocytic leukemia, Hematologic malignancies, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, and marginal lymphoma lymphoma, myeloma, and ovarian tumors.

[0117] In some embodiments, the BTK-associated cancer is not transformed. Non-limiting examples of transformations in cancer include Richter's transformation, prolymphocytic transformation (e.g. For example, prolymphocytic transformation of CLL, transformed non-Hodgkin's lymphoma, and blastoma. and cytoid lymphomas (e.g., blastoid variant mantle cell lymphoma).

[0118] In some embodiments, the BTK-associated cancer is a cancer known to involve the central nervous system by lymphoma. It is not a cancer that is being treated.

[0119] In some embodiments, the BTK-associated cancer is a solid tumor.

[0120] In some embodiments, the solid tumor is bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular carcinoma, head and neck cancer, and glioma.

[0121] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is amorphous, or polymorphic forms, spray dried dispersions thereof, or pharmaceutical compositions thereof, can be.

[0122] In some embodiments, the method further comprises administering to a subject an additional therapy or therapeutic agent (e.g., The method further comprises administering to the subject a therapeutic agent.

[0123] In some embodiments, an additional therapeutic agent is nt) are used in combination with radiation therapy, cytotoxic chemotherapy agents, and kinase-targeted therapy (TRT). ics), apoptosis regulators, signal transduction inhibitors, immune targeting therapy, transcription regulator inhibitors, and angiogenesis targeted therapy. In some embodiments, the additional therapy is selected from the group consisting of: In some embodiments, the therapeutic agent is selected from one or more kinase targeted therapeutic agents. The kinase targeted therapeutic agent is selected from JAK, Src, IRAK, and combinations thereof. The target kinase is a kinase from a selected kinase family.

[0124] In some embodiments, the additional therapeutic agent is selected from one or more protein inhibitors. In some embodiments, the one or more protein inhibitors are selected from the group consisting of anti-apoptotic cis proteins, heat shock proteins, nuclear export proteins, kinases, histone deacetylases Acetylase, E3 ubiquitin ligase, histone-lysine N-methyltransferase and combinations thereof. In embodiments, the one or more protein inhibitors are selected from the group consisting of PI3K, JAK-2, IRA K1, IRAK4, BMX, TAK1, Src family, HDAC6, MDM2, BC L-2, EZH2, EHMT2, PIM, JAK3, mTOR, ROR-1, Syk, P KC, Hsp90, XPO1, and combinations thereof. In some embodiments, two additional therapeutic agents are administered (e.g., , inhibitors of mTOR and inhibitors of BCL-2).

[0125] In some embodiments, the additional therapeutic agent is an anti-apoptotic protein, a heat shock protein, Proteins, nuclear export proteins, kinases, histone deacetylases, E3 ubiquitin ligands gauze, histone-lysine N-methyltransferase, and their combinations The present invention inhibits a protein selected from the group consisting of:

[0126] In some embodiments, the additional therapeutic agent is a PI3K, JAK-2, IRAK1, IR AK4, BMX, TAK1, Src family, HDAC6, MDM2, BCL-2, E ZH2, EHMT2, PIM, JAK3, mTOR, ROR-1, Syk, PKC, Hs p90, XPO1, and combinations thereof. To harm.

[0127] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is amorphous, or polymorphic forms thereof, spray dried dispersions thereof, or pharmaceutical compositions thereof, and an additional treatment. The drugs are administered simultaneously in separate doses.

[0128] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is amorphous, or polymorphic forms thereof, spray dried dispersions thereof, or pharmaceutical compositions thereof, and an additional treatment. The drugs are administered in separate dosages sequentially in any order.

[0129] Also provided herein is a method of treating a subject having cancer, the method comprising: (a) administering to a subject one or more doses of a first BTK inhibitor for a period of time. , (b) after (a), cancer cells in a sample obtained from the subject are subjected to the first B At least one compound that confers increased resistance to treatment with TK inhibitors on cancer cells or tumors determining whether the patient has one or more BTK inhibitor resistance mutations; and (c) determining whether the subject has increased resistance to treatment with the first BTK inhibitor in step (a). Cancer cells that have at least one BTK inhibitor resistance mutation that confers resistance to the cancer cells or tumors When a compound of formula I has a therapeutic effect, the spray dried dispersion or pharmaceutical composition may be used as a monotherapy or or administering to a subject in combination with another anticancer agent; or (d) determining whether the subject has increased resistance to treatment with the first BTK inhibitor of step (a). If the cancer cells or tumors have cancer cells that do not have BTK inhibitor resistance mutations, administering an additional dose of the first BTK inhibitor of step (a) to the subject.

[0130] In some embodiments, the anticancer agent in step (c) is a second BTK inhibitor, immunotherapy, or a combination thereof.

[0131] In some embodiments, the anti-cancer agent in step (c) is It is the first BTK inhibitor to be identified.

[0132] In some embodiments, the anticancer agent in step (c) is one or more quinine. In some embodiments, the kinase targeted therapeutic agent is selected from the group consisting of JA kinase targeted therapeutic agents. Kinase families selected from K, Src, IRAK, and combinations thereof It targets these kinases.

[0133] In some embodiments, the anti-cancer drug in step (c) is an anti-apoptotic protein. Proteins, heat shock proteins, nuclear export proteins, kinases, histone deacetylases , E3 ubiquitin ligases, histone-lysine N-methyltransferases, and A protein inhibitor that inhibits a protein selected from the group consisting of the above combinations. do.

[0134] In some embodiments, the anti-cancer drug in step (c) is an anti-apoptotic protein. Proteins, heat shock proteins, nuclear export proteins, kinases, histone deacetylases , E3 ubiquitin ligases, histone-lysine N-methyltransferases, and and combinations thereof. The protein inhibitor is selected from the group consisting of ribozyme, ribozyme-binding protein inhibitors.

[0135] In some embodiments, the protein inhibitor is a PI3K, JAK-2, IRAK1, IRAK4, BMX, TAK1, Src family, HDAC6, MDM2, BCL-2 , EZH2, EHMT2, PIM, JAK3, mTOR, ROR-1, Syk, PKC, A protein selected from the group consisting of Hsp90, XPO1, and combinations thereof. Inhibits.

[0136] In some embodiments, the subject is administered an additional dose of the first BTK inhibitor of step (a). and the method further comprises (e) administering to the subject another anti-cancer agent.

[0137] In some embodiments, the anti-cancer agent in step (e) is a second BTK inhibitor, an immunotherapy law, or a combination of both.

[0138] In some embodiments, the anticancer drug in step (e) is a compound of formula I, or A physiologically acceptable salt, amorphous, or polymorphic form thereof, a spray-dried dispersion thereof, or and a pharmaceutical composition thereof.

[0139] Also provided herein is a method of treating a subject having cancer, the method comprising: (a) administering to a subject one or more doses of a first BTK inhibitor for a period of time. , (b) after (a), cancer cells in a sample obtained from the subject are subjected to the first B At least one compound that confers increased resistance to treatment with TK inhibitors on cancer cells or tumors determining whether the patient has a BTK inhibitor resistance mutation; (c) determining whether the subject has increased resistance to treatment with the first BTK inhibitor in step (a). Cancer cells that have at least one BTK inhibitor resistance mutation that confers resistance to the cancer cells or tumors If patients have pulmonary circulation problems, a second BTK inhibitor may be administered as monotherapy or in combination with another anticancer drug. and administering the same to a subject; or (d) determining whether the subject has increased resistance to treatment with the first BTK inhibitor of step (a). If the cancer cells or tumors have cancer cells that do not have BTK inhibitor resistance mutations, administering to the subject an additional dose of the first BTK inhibitor of step (a), wherein the mutation is , a substitution at amino acid position 481, e.g., C481S, C481F, C481T, C 481G, and C481R.

[0140] In some embodiments, the anticancer agent of step (c) is administered in step (a). It is the first BTK inhibitor.

[0141] In some embodiments, the subject is administered an additional dose of the first BTK inhibitor of step (a). and the method further comprises (e) administering another anti-cancer agent.

[0142] In some embodiments, the anti-cancer agent in step (e) is a second BTK inhibitor, an immunotherapy law, or a combination of both.

[0143] In some embodiments, the anticancer drug in step (e) is a compound of formula I, or and pharmaceutical compositions of physiologically acceptable salts.

[0144] Also provided herein is a method of treating a subject having cancer, the method comprising: (a) administering to a subject one or more doses of a first BTK inhibitor for a period of time. , (b) after (a), cancer cells in a sample obtained from the subject are subjected to the first B At least one compound that confers increased resistance to treatment with TK inhibitors on cancer cells or tumors determining whether the patient has a BTK inhibitor resistance mutation; (c) determining whether the subject has increased resistance to treatment with the first BTK inhibitor in step (a). Cancer cells that have at least one BTK inhibitor resistance mutation that confers resistance to the cancer cells or tumors When the compound of formula I or a pharma- ceutically acceptable salt thereof is used as a spray-dried dispersion, administering the pharmaceutical composition to a subject as a monotherapy or in combination with another anti-cancer agent. Or, (d) determining whether the subject has increased resistance to treatment with the first BTK inhibitor of step (a). If the cancer cells or tumors have cancer cells that do not have BTK inhibitor resistance mutations, administering to the subject an additional dose of the first BTK inhibitor of step (a), wherein the mutation is , PLCγ2 amino acid positions, 244, 257, 334, 495, 664, 665, 70 One of 7, 708, 742, 845, 848, 993, 1140, or 1141 or It is substitution in the plural.

[0145] Also provided herein is a method of treating a subject having cancer, the method comprising: (a) a patient with cancer and who has previously received one or more doses of a first BTK inhibitor; The cancer cells in the sample obtained from the subject were treated with a first BTK inhibitor previously administered to the subject. one or more B-cells that confer increased resistance to treatment with a cancer cell or tumor determining whether the patient has a TK inhibitor resistance mutation; and (b) the subject experiences an increased resistance to treatment with a first BTK inhibitor previously administered to the subject; Cancers with at least one BTK inhibitor resistance mutation that confers additional potency to cancer cells or tumors When the cells are present, a spray-dried dispersion of a compound of formula I or a pharma- ceutical acceptable salt thereof is administering the pharmaceutical composition to a subject as a monotherapy or in combination with another anti-cancer agent. Or, (c) the subject experiences an increased resistance to treatment with a first BTK inhibitor previously administered to the subject; Addition of BTK inhibitors to cancer cells or tumors administering to the subject an additional dose of the first BTK inhibitor.

[0146] Also provided herein is a method of treating a subject having cancer, the method comprising: (a) a patient with cancer and who has previously received one or more doses of a first BTK inhibitor; The cancer cells in the sample obtained from the subject were treated with a first BTK inhibitor previously administered to the subject. one or more B-cells that confer increased resistance to treatment with a cancer cell or tumor determining whether the patient has a TK inhibitor resistance mutation; and (b) the subject experiences an increased resistance to treatment with a first BTK inhibitor previously administered to the subject; Cancers with at least one BTK inhibitor resistance mutation that confers additional potency to cancer cells or tumors If the subject has a BTK inhibitor, a second BTK inhibitor may be administered to the subject as a monotherapy or in combination with another antibody. Administering to a subject in combination with a cancer drug; or (c) the subject experiences an increased resistance to treatment with a first BTK inhibitor previously administered to the subject; Addition of BTK inhibitors to cancer cells or tumors administering to the subject an additional dose of the first BTK inhibitor previously administered to the subject.

[0147] Also provided herein is a method of treating a subject having cancer, the method comprising: (a) administering one or more doses of a compound of formula I, or a pharma- ceutical acceptable salt thereof, administering the spray dried dispersion or pharmaceutical composition for a period of time; (b) after (a), detecting a compound of formula I in step (a) in a sample obtained from the subject; For treatment with a spray-dried dispersion or pharmaceutical composition of the compound or a pharma- ceutical acceptable salt thereof One or more BTK inhibitor resistance mutations that confer increased resistance to the cancer cell or tumor and determining whether the patient has (c) The object is a spray-dried dispersion or a dispersion according to any one of claims 1 to 3 in step (a). or an increase in resistance to treatment with a pharmaceutical composition according to any one of claims 7 to 93, Cancer cells that have one or more BTK inhibitor resistance mutations that confer resistance to the cancer cells or tumors If patients have pulmonary circulation problems, a second BTK inhibitor may be administered as monotherapy or in combination with another anticancer drug. and administering the same to a subject; or (d) spray-dried dispersion of the compound of formula I or a pharma- ceutically acceptable salt thereof of step (a). BT that confers increased resistance to treatment with a drug or pharmaceutical composition on cancer cells or tumors A subject having cancer cells that do not have a K inhibitor resistance mutation is administered an additional dose of the compound of formula I in step (a). or a pharma- ceutical composition comprising the compound of formula (I) or a pharma- ceutical acceptable salt thereof. thing.

[0148] Also provided herein is a method of treating a subject having cancer, the method comprising: (a) a patient having cancer and receiving one or more doses of a compound of formula I, or The subject was previously administered a spray-dried dispersion or pharmaceutical composition of a physiologically acceptable salt. The cancer cells in the sample are then subjected to a compound of formula I or a pharma- ceutical acceptable salt thereof that was previously administered to the subject. and increasing the resistance of cancer cells or tumor cells to treatment with a spray-dried dispersion or pharmaceutical composition of the salt. The aim of this study was to determine whether a tumor has one or more BTK inhibitor resistance mutations that confer resistance to BTK inhibitors. and, (b) the subject is treated with a spray-dried dispersion of a compound of formula I, or a pharma- ceutically acceptable salt thereof; The present invention relates to one or more compounds that confer increased resistance to treatment with pharmaceutical compositions on cancer cells or tumors. If the patient has cancer cells with multiple BTK inhibitor resistance mutations, a second BTK inhibitor may be administered. Administering to a subject as a monotherapy or in combination with another anti-cancer agent; or (c) spray drying a compound of formula I or a pharma- ceutical acceptable salt thereof that has been previously administered to a subject; Confers increased resistance to treatment with the dispersion or pharmaceutical composition on cancer cells or tumors Subjects with cancer cells that do not have BTK inhibitor resistance mutations were given an additional dose of a previously administered A spray-dried dispersion or pharmaceutical composition of the compound of formula I or a pharma- ceutical acceptable salt thereof is administered. To do so.

[0149] Also provided herein is a method of treating a BTK-associated cancer in a subject, the method comprising: Including below: (a) as monotherapy, one or more doses of a compound of formula I or a pharmacopoeitic The spray-dried dispersion or pharmaceutical composition of an acceptable salt is used to treat or treat a patient identified as having a BTK-associated cancer. administering to the diagnosed subject; (b) determining the level of circulating tumor DNA in a biological sample obtained from the subject after step (a); To judge, (c) a spray-dried dispersion or pharmaceutical composition of a compound of formula I, or a pharma- ceutically acceptable salt thereof; The composition, and additional therapeutic agents or therapies, were compared to the reference levels of circulating tumor DNA at approximately the same administering to a subject identified as having single or elevated levels of circulating tumor DNA.

[0150] In some embodiments, the additional therapeutic agent is a second BTK kinase inhibitor. In some embodiments, the additional therapeutic agent or treatment is radiation therapy, a chemotherapy agent, a chemoreceptor agent, or a combination of both. or one or more of a first kinase inhibitor, surgery, and one or more second kinase inhibitors. Includes multiple.

[0151] In some embodiments, the reference level of circulating tumor DNA is determined by measuring the circulating tumor DNA level in the subject prior to step (a). is the level of circulating tumor DNA in biological samples obtained from

[0152] Also provided herein is a method of treating a BTK-associated cancer in a subject, the method comprising: A spray-dried dispersion or pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt thereof. The pharmaceutical composition and the additional therapeutic agent or treatment are administered to a subject (i) identified as having or having a BTK-associated cancer. (ii) administering to a subject diagnosed with a complication, a complication, or a complication of the complication, one or more doses of a compound of formula I, or a combination thereof; The patient was previously administered a spray-dried dispersion or pharmaceutical composition of a physiologically acceptable salt as monotherapy. and (ii) administering to the subject one or more doses of a compound of Formula I, or a pharma- ceutical acceptable salt thereof. Circulating tumor D was detected after administration of a spray-dried dispersion or pharmaceutical composition of a tolerable salt as monotherapy. had similar or elevated levels of circulating tumor DNA compared to the reference level of NA. The method includes administering the method to a subject identified as having

[0153] In some embodiments, the reference level of circulating tumor DNA is determined by one or more doses of Compounds of formula I, or pharma- ceutically acceptable salts thereof, amorphous or polymorphic forms thereof, The spray-dried dispersion or pharmaceutical composition thereof was administered as a monotherapy to a subject. Levels of circulating tumor DNA in biological samples.

[0154] In some embodiments, the additional therapeutic agent is a second BTK kinase inhibitor. In some embodiments, the additional therapeutic agent or treatment is radiation therapy, a chemotherapy agent, a chemoreceptor agent, or a combination of both. one or more of an in vivo protein inhibitor, surgery, and one or more second protein inhibitors includes plural.

[0155] Also provided herein is a method of selecting a treatment for a subject, the method comprising administering a therapeutically effective amount of or a pharma- ceutical composition comprising a compound of formula I, (i) administering to a subject identified or diagnosed with a BTK-associated cancer, and to subjects who have previously received one or more doses of a second BTK kinase inhibitor. and (ii) after administration of one or more doses of a second BTK kinase inhibitor, have approximately the same or elevated levels of circulating tumor DNA compared to reference levels of tumor DNA The method includes selecting for subjects identified as having the disease.

[0156] Also provided herein is a method of selecting a treatment for a subject, the method comprising administering a therapeutically effective amount of or a pharma- ceutical composition comprising a compound of formula I, and additional therapeutic treatments, such as (i) BTK. (ii) one or more times to a subject identified or diagnosed with a relevant cancer; A spray-dried dispersion or pharmaceutical composition of a compound of formula I, or a pharma- ceutical acceptable salt thereof, (ii) to subjects who have previously received the composition as monotherapy, and Spray-dried dispersion or pharmaceutical composition of a compound of formula I, or a pharma- ceutically acceptable salt thereof - Patents.com After administration of the drug, the levels of circulating tumor DNA were approximately the same or increased compared to the reference levels. Selecting for subjects identified as having circulating tumor DNA.

[0157] In some embodiments, the reference level of circulating tumor DNA is determined by one or more doses of Compounds of formula I, or pharma- ceutically acceptable salts thereof, amorphous or polymorphic forms thereof, The spray-dried dispersion or pharmaceutical composition thereof was administered as a monotherapy to a subject. In some embodiments, the level of circulating tumor DNA in a biological sample is an additional therapeutic treatment. In some embodiments, the additional therapeutic treatment is a second BTK kinase inhibitor. However, the present invention is not limited to the use of radiation therapy, chemotherapy drugs, checkpoint inhibitors, and one or more second The compound includes one or more of the protein inhibitors.

[0158] Also provided herein is a method of determining the efficacy of a treatment in a subject, the method comprising: (a) obtained from a subject identified or diagnosed as having a BTK-associated cancer at a first time point; determining a first level of circulating tumor DNA in the biological sample; (b) administering one or more doses of a compound of formula I after the first time point and before the second time point. or a pharma- ceutical composition comprising the compound, administering it to elephants; (c) determining a second level of circulating tumor DNA in a biological sample obtained from the subject at a second time point; To determine the (d) A reduced second level of circulating tumor DNA compared to the first level of circulating tumor DNA. Identifying a subject determined to have NA for which a treatment is effective; or A second level of circulating tumor DNA that is nearly identical or elevated compared to the first level Identifying subjects who have been determined to have tumor DNA for whom treatment is ineffective include.

[0159] Also provided herein is a method for determining whether a subject has developed resistance to a treatment, comprising: This method is (a) obtained from a subject identified or diagnosed as having a BTK-associated cancer at a first time point; determining a first level of circulating tumor DNA in the biological sample; (b) administering one or more doses of a compound of formula I after the first time point and before the second time point. or a pharma- ceutical composition comprising the compound, administering it to elephants; (c) determining a second level of circulating tumor DNA in a biological sample obtained from the subject at a second time point; To determine the (d) A reduced second level of circulating tumor DNA compared to the first level of circulating tumor DNA. determining that a subject with NA has not developed resistance to treatment; or A second level of circulating tumor DNA that is nearly identical or elevated compared to the first level determining that a subject having tumor DNA has developed resistance to the treatment. .

[0160] In any of the above embodiments, the subject has an active, uncontrolled autoimmune hematoma. In some embodiments, the subject is diagnosed with an autoimmune cytopenia. In some embodiments, the subject has not had a history of 6 Within months, clinically significant, uncontrolled cardiac disease, cardiovascular disease, or myocardial infarction In some embodiments, the subject has no history of a heart disease or cardiovascular disease. In some embodiments, the subject has not had a myocardial infarction. In embodiments, the subject does not have a clinically significant active malabsorption syndrome. In some embodiments, the subject has not been diagnosed with a malabsorption syndrome. Elephants showed potent cytochrome P450 3A4 expression during any of the treatments described herein. (CYP3A4) inhibitors (e.g., ritonavir, indinavir, nelfinavir, saquinavir Birmingham, clarithromycin, telithromycin, chloramphenicol, ketoconazole , itraconazole, posaconazole, voriconazole, nefazodone, and covicis tat), or inducers (e.g., carbamazepine, dexamethasone, ethosuximide, Glucocorticoids, griseofulvin, phenytoin, primidone, progesterone, Rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, pheno Barbiturates, phenylbutazone, rofecoxib (mild), St. John's wort, rufadimidine, sulfinpyrazone, and troglitazone) In some embodiments, the subject has been initiating any of the treatments described herein. Within 7 days, use of a proton pump inhibitor (e.g., omeprazole, lansoprazole, dexamethasone, Slansoprazole, esomeprazole, pantoprazole, rabeprazole, ilapra In some embodiments, the subject has not been treated with an active second In some embodiments, the subject is free of a malignancy. The patient has a chronic tumor and the life expectancy of the subject is greater than 2 years.

[0161] Also provided herein are methods for inhibiting BTK kinase activity in mammalian cells. The method comprises injecting a mammalian cell with a compound of formula I or a pharma- ceutical acceptable salt thereof. The method includes contacting the spray-dried dispersion, pharmaceutical composition, or polymorphic form with the spray-dried dispersion.

[0162] Also provided herein is a method of treating an autoimmune or inflammatory disease in a subject, the method comprising administering to said subject a therapeutically effective amount of The method comprises administering to a subject identified or diagnosed with an autoimmune or inflammatory disease an antibody of formula I A spray-dried dispersion or pharmaceutical composition of the compound, or a pharma- ceutical acceptable salt thereof, is administered to a subject. This includes giving.

[0163] Unless otherwise defined, all technical and scientific terms used herein are within the meaning of the present invention. The term "compound" has the same meaning as commonly understood by a person skilled in the art to which the present invention pertains. Methods and materials for use are described herein. Any suitable methods and materials may also be used. The materials, methods, and examples are for illustrative purposes only. All publications, publications, and publication references mentioned herein are by way of illustration and not by way of limitation. All patent applications, patents, sequences, database entries, and other references are hereby incorporated by reference. in its entirety. In case of conflict, the present specification, including definitions, will control.

[0164] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will become apparent from the description and drawings, as well as from the patent. This will be apparent from the claims. [Brief description of the drawings]

[0165] [Figure 1] 1 is an X-ray powder diffraction scan of Form A of compound of formula I (free base). [Figure 2A] FIG. 2A is a differential scanning calorimetry (DSC) scan of a mixture of Forms A and B of the compound of Formula I. FIG. 2A is a differential scanning calorimetry (DSC) scan of a mixture of polymorphic Forms A and B of the compound of Formula I. [Figure 2B] FIG. 2B is a scan of a mixture of Forms A and B of the compound of Formula I. FIG. 2B is a 1H NMR spectrum of a mixture of polymorphic Forms A and B of the compound of Formula I. [Figure 3A] FIG 3A is a scan of Form C of the compound of Formula I. FIG 3A is a 1H NMR spectrum of Form C of the compound of Formula I. [Figure 3B] 3A is a scan of Form C of the compound of Formula I. FIG 3B is a differential scanning calorimetry scan of Form C of the compound of Formula I (hemi-1,4-dioxane solvate). [Figure 4A] 4A is a scan of Form A of the compound of Formula I. FIG 4A is an X-ray powder diffraction scan of Form A of the compound of Formula I. [Figure 4B] FIG 4A is a scan of Form A of the compound of Formula I. FIG 4B is a 1H NMR spectrum of Form A of the compound of Formula I. [Figure 4C] 4A is a scan of Form A of the compound of Formula I. FIG 4C is a differential scanning calorimetry scan of Form A of the compound of Formula I. [Diagram 5] 1 is a modulated DSC scan of a spray-dried dispersion prototype of the compound of Formula I. [Figure 6]1 is an X-ray powder diffraction scan of a spray dried dispersion prototype of the compound of Formula I. [Figure 7] 1 is a thermogravimetric analysis (TGA) scan of a spray-dried dispersion prototype of the compound of Formula I. [Figure 8] FIG. 1 shows the dissolution of a tablet containing a spray dried dispersion of a compound of formula I and an HPMCAS polymer. [Figure 9] 1 shows the concentration of the compound of Formula I in plasma over time from an in vivo dog bioavailability and pharmacokinetic study. [Figure 10A] Figures 10A and 10B are Western blots showing the dose-response effect of the compound of formula I and ibrutinib on Y223 autophosphorylation in HEK293 cells stably expressing BTK (tBTK) (referring to total BTK) (Figure 10A) and BTK C481S (Figure 10B). Figures 10C and 10D are dose-response curves generated from the Western blot data of Y223 autophosphorylation in HEK293 cells stably expressing BTK (Figure 10C) and BTK C481S (Figure 10D). The compound of formula I inhibited BTK Y223 autophosphorylation with IC50 values ​​of 8.6±0.3nM and 8.8±1.8nM, respectively, in both wild-type and C481S mutant proteins. Ibrutinib inhibited BTK wild-type with an IC50 of 5.7 ± 0.5 nM, and its activity against the C481S mutant could not be fitted with an IC50 curve. [Figure 10B] Same as above. [Figure 10C] Same as above. [Figure 10D] Same as above. [Figure 11A] 1 is a Western blot showing dose response of the compound of Formula I on BTK Y223 and PLCγ2 Y1217 phosphorylation in Ramos RA1 cells. [Figure 11B]1 is a plot of Western blot data for BTK Y223 in Ramos RA1 cells. The compound of Formula I inhibited BTK Y223 autophosphorylation with an IC50 of 3.2±0.6 nM and PLCγ2 Y1217 phosphorylation with an IC50 of 8.2 nM±4.3. [Figure 11C] 1 is a plot of Western blot data for PLCγ2 Y1217 phosphorylation in Ramos RA1 cells. The compound of Formula I inhibited BTK Y223 autophosphorylation with an IC50 of 3.2±0.6 nM and PLCγ2 Y1217 phosphorylation with an IC50 of 8.2 nM±4.3. [Figure 12A] 1 is a plot showing dose-response inhibition of compounds of Formula I on TMD8 proliferation. [Figure 12B] 12B is a plot showing the area under the curve (AUC) (mean ± SD) versus inhibitor concentration from FIG. 12A. Quantification of the area under the curve (AUC) for each individual curve allowed the determination of an IC50 of 2.33 nM for the compound of formula I against TMD8 proliferation. [Figure 13A] Figure 13 shows dose-dependent inhibition of tumor growth in OCI-Ly10 human B cell lymphoma cell line xenograft tumor mouse model. Figure 13A shows tumor growth by tumor volume expressed as mean ± SEM in human B cell lymphoma cell line xenograft tumor mouse model administered with vehicle or inhibitor as indicated. [Figure 13B] Figure 13B shows dose-dependent inhibition of tumor growth in a human B cell lymphoma cell line xenograft tumor mouse model of OCI-Ly10. Figure 13B shows tumor growth after treatment is stopped in a human B cell lymphoma cell line xenograft tumor mouse model. [Figure 13C] Figure 13C shows dose-dependent inhibition of tumor growth in an OCI-Ly10 human B cell lymphoma cell line xenograft tumor mouse model. Figure 13C shows normalized body weight values ​​expressed as mean ± SEM of mice over the course of treatment. [Figure 14A]Figure 14 shows dose-dependent inhibition of tumor growth in TMD8 human B cell lymphoma cell line xenograft tumor mouse model. Figure 14A shows tumor growth by tumor volume expressed as mean ± SEM in TMD8 human B cell lymphoma cell line xenograft tumor mouse model administered with vehicle or inhibitor as indicated. [Figure 14B] Figure 14B shows the dose-dependent inhibition of tumor growth in TMD8 human B cell lymphoma cell line xenograft tumor mouse model. Figure 14B shows the tumor weight after 14 days of administration of the compound of formula I in TMD8 human B cell lymphoma cell line xenograft tumor mouse model. [Figure 14C] Figure 14C shows dose-dependent inhibition of tumor growth in a TMD8 human B cell lymphoma cell line xenograft tumor mouse model. Figure 14C shows normalized body weight values ​​expressed as mean ± SEM of mice over the course of treatment. [Figure 15A] The concentrations of the compound of formula I in dog plasma over a 48 hour period are shown in Figure 15A. Figure 15A shows the concentrations of the compound of formula I in the plasma of fed and fasted dogs for dogs administered the crystalline compound of formula I in suspension. [Figure 15B] Figure 15B shows the concentration of the compound of Formula I in dog plasma over a 48 hour period. Figure 15B shows the concentration of the compound of Formula I in the plasma of fed and fasted dogs for dogs administered 50% SDI of the compound of Formula I.

[0166] Like reference symbols in the various drawings indicate like elements. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0167] definition As used herein, the term "polymorph" refers to a result of the ordering of molecules within a crystal lattice. Polymorphism refers to crystals of the same compound that have different physical properties as different polymorphs of a single compound. are characterized by one or more distinct chemical, physical, mechanical, electrical, thermodynamic, and The differences in physical properties exhibited by polymorphs may be due to storage Stability, compressibility, density (important in the formulation and manufacturing of the product), dissolution rate (bio- (important factors for determining availability), solubility, melting point, chemical stability, physical stability, It can affect pharmaceutical parameters such as powder flowability, moisture sorption, compaction, and particle morphology. Differences in stability can be attributed to chemical reactivity (e.g., greater reactivity in one polymorph than in another). When constructed, the dosage form may discolor more rapidly due to different oxidation) or mechanical changes (e.g. For example, during storage when a kinetically favored polymorph converts to a thermodynamically more stable polymorph. changes in the crystal structure of the compound, or both (e.g., one polymorph is more hygroscopic than the other). Some transitions may be effective as a result of differences in solubility / decomposition. In addition, the physical properties of the crystals can be important in processing, e.g. One polymorph is more likely to form a solvate or can be filtered and washed to remove impurities. It can be difficult to exclude particles from the rest of the sample (i.e., the particle shape and size distribution may differ from other (The term "polymorphic form" may vary between one polymorphic form as compared to the other polymorphic form). As used herein, "polymorphs" does not include amorphous forms of a compound. "Amorphous" refers to a non-crystalline form of a compound, which may be a solid state form of the compound or a solubilized form of the compound. For example, "amorphous" refers to a material that does not have a regular repeating arrangement of molecules or external planes. "Compound form" refers to a compound that is not in a solid form (e.g., a solid form of a compound).

[0168] As used herein, the term "anhydrous" refers to a compound of formula I having 1% or less water by weight. Refers to the crystalline form of a compound. For example, less than 0.5% by weight, less than 0.25% by weight, or less than 0. It is less than 1% water by weight.

[0169] As used herein, the term "solvate" refers to a compound in which the crystal lattice is one or more It refers to a crystalline form of a compound of formula I, including a polymorphic form of the compound, including a solvent of crystallization.

[0170] "Purity" refers to a composition that contains a polymorph of a compound of Formula I. One particular polymorphic form of the compound of formula I in a composition versus another polymorphic form or amorphous form. For example, a composition containing polymorphic Form 1 having a purity of 90% would be 90 parts by weight of Form 1 and 10 parts by weight of other polymorphic forms and / or amorphous forms of the compound of formula I and

[0171] As used herein, a compound or composition does not contain significant amounts of other components. Thus, a compound or composition is "substantially free" of one or more such other components. For example, the composition may contain less than 5%, 4%, 3%, 2%, or 1% by weight of other ingredients. Such components may include starting materials, residual solvents, or the components described herein. Other compounds and compositions that may result from the preparation and / or isolation of the compounds and compositions provided herein. In some embodiments, the polymorphic forms provided herein may contain impurities. In some embodiments, a particular polymorph of the compound of formula I is When a particular polymorph constitutes at least about 95% by weight of the compound of formula I in existence, other "Substantially free" of polymorphs. In some embodiments, a particular polymorph of a compound of formula I is is at least about 97%, about 98%, or about 100% by weight of a compound of formula I that exists in a particular polymorphic form. When it constitutes 99% by weight, or about 99.5% by weight, it is considered to be "substantially free" of other polymorphs. In certain embodiments, the particular polymorph of the compound of formula I has an amount of water that is about 2% by weight of the polymorph. , about 1%, or about 0.5% by weight or less of water.

[0172] As used herein, "substantially pure" refers to a polymorphic form of the compound of formula I. When used, 91%, 92%, 93%, 94%, or Including 95%, 96%, 97%, 98%, and 99% as well as approximately 100%. "Polymorphic" means a sample of a polymorphic form of a compound having a purity of greater than 90%, including greater than 90%. The remaining material may be other form(s) of the compound, and / or reaction impurities and / or For example, polymorphic forms of the compound of formula I are known in the art and include process impurities arising from its preparation. When measured by means currently known and generally accepted in the field, The purity of the polymorphic form of the compound of formula I is greater than 90%, with less than 10% of the remaining material being the compound of formula I. and / or reaction impurities and / or process impurities. It may be considered to be substantially pure in that it is free of reaction and / or processing impurities. The present invention can be applied to a wide variety of applications, including, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy. This can be determined by any analytical technique known in the art.

[0173] Values ​​for DSC, TGA, TG, (glass transition temperature) or DTA (differential thermal analysis) The term "about" precedes the term "temperature" and is reported as a degree Celsius temperature with an acceptable variation of ±5°C.

[0174] In order to provide a more concise description, some of the quantitative expressions herein may be expressed as from about X to about A range of Y is recited. When a range is recited, the range includes the recited upper and lower limits. and the degree of approximation, but rather the entire range from approximation X to approximation Y, or any range therein. Includes enclosure.

[0175] "Room temperature" or "RT" refers to typical laboratory ambient temperature, typically about 25°C. do.

[0176] "Spray drying" refers to a process for producing a dry powder from a solution or slurry. The slurry is then sprayed or rapidly dried with hot gas, e.g., air or nitrogen. The dispersion is then dried, which allows the solvent to evaporate quickly and uniformly. It refers to the powder obtained from the drying process.

[0177] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any Any and all solvents, co-solvents, complexing agents, dispersants, etc. that are not biologically or otherwise undesirable. These include dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, it is not intended to be used in conjunction with the Supplementary active ingredients may also be incorporated into the compositions. In addition, various excipients, as commonly used in the art, may be included. These and other such compounds can be found in the literature, e.g., Merck Inde x, Merck & Company, Rahway, NJ. For a discussion of the inclusion of various ingredients in s.)(2010);Goodman and Gilman's: The Pharm Acological Basis of Therapeutics,12th Ed .,The McGraw-Hill Companies.

[0178] As used herein, the terms "subject," "individual," or "patient" are used interchangeably. Used in mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, and sheep The term "animal" refers to any animal, including mammals such as horses, primates, and humans. In some embodiments, the subject is a human.

[0179] In some embodiments, the subject is at least one individual with a disease or disorder to be treated and / or prevented. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom. , the BTK gene, the BTK protein, or the expression or activity of any of them. have been identified or diagnosed as having cancer with dysregulated levels of BTK (BTK-associated cancer). (e.g., determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit) In some embodiments, the subject is diagnosed with a BTK gene, a BTK protein, or The present study included tumors positive for dysregulation of the expression, activity, or levels of any of these. (e.g., as determined using a regulatory agency-approved assay or kit). The TK gene, the BTK protein, or the expression or activity or level of either of them The subject may have a tumor(s) that is positive for dysregulation of bell (e.g., a regulatory (identified as positive using an approved, e.g., FDA-approved, assay or kit) The subject is a patient whose tumor expresses the BTK gene, the BTK protein, or either of these. or a subject having a dysregulated activity or level (e.g., a tumor Identified as such using an agency-approved, e.g., FDA-approved, kit or assay. In some embodiments, the subject is suspected of having a BTK-associated cancer. In some embodiments, the subject has been identified or diagnosed as having a hematological cancer. In embodiments, the subject has been identified or diagnosed as having a B cell malignancy. In embodiments, the subject is a subject who has a BTK gene, a BTK protein, or any of the foregoing. Clinical records showing that the patient has a tumor with dysregulated expression or activity or level of and optionally, the clinical record includes a clinical record of the subject's use of the compositions provided herein. In some embodiments, the subject is a pediatric patient. is a person.

[0180] As used herein, the term "pediatric patient" refers to a patient under the age of 21 at the time of diagnosis or treatment. The term "pediatric" refers to patients with months to 2 years), children (2 to 12 years), and adolescents (12 to 21 years). The number of people who are considered to be 20 or over is estimated at 20,000 yen (up to, but not including, their 22nd birthday). Berhman RE, Kliegman R, Arvin AM, Nelson WE's Textbook of Pediatrics, 15t h Ed.Philadelphia:WBSaunders Company,1 996, Rudolph AM et al. Rudolph's Pediatrics, 21s Ed. New York: McGraw-Hill, 2002, and Avery MD, First LR Pediatric Medicine, 2nd Ed.Ba see Eltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric patient is from birth to 28 days of age, from 29 days of age to less than 2 years of age, from 2 Between the ages of 12 and 12, or between the ages of 12 and 21 (up to their 22nd birthday, but In some embodiments, the pediatric patient is administered the following starting from birth to 28 days after birth: 29 days to under 1 year old, 1 month to under 4 months old, 3 months to under 7 months old, 6 months to under 1 year old, 1 year to under 2 years old, 2 years to under 3 years old, 2 years to under 7 years old, 3 years to under 5 years old Full-age, 5 to under 10 years old, 6 to under 13 years old, 10 to under 15 years old, or 15 to 22 years old is less than.

[0181] As used herein, the terms "treat" or "treatment" refer to therapeutic or Beneficial or desirable clinical outcomes include detectable or undetectable outcomes. Regardless of the cause, the total or partial alleviation of symptoms associated with a disease or disorder or condition, the progression of the disease, a decrease in severity, a stable (i.e., not worsening) state of disease, a delay in disease progression, or Slowing, improving or alleviating a disease state (e.g., one or more symptoms of a disease), and remission This includes, but is not limited to, a solution (whether partial or total). " also means the length of time that a patient has survived compared with the length of time that would be expected if no treatment was administered. You can also taste it.

[0182] The term "therapy" refers to one or more doses administered to a subject as part of a treatment regimen. refers to the administration of an active compound or pharmaceutical agent.

[0183] In one embodiment, as used herein, the term "preventing" refers to The onset, recurrence or spread of any disease or condition described herein, or any of its symptoms, in whole or in part. This means prevention of.

[0184] The term "progression" is defined by the National Cancer Institute (NCI Cancer Dictionary) as For example, progression refers to the progression of cancer cells in a subject. an increase in the number of tumors, an increase in the size of one or more tumors in a subject, an increase in tumor burden, metastasis an increase in the rate or severity of symptoms related in whole or in part to the cancer, or the extent of the disease "Progression" can also include an increase in the progression of the disease without treatment, and / or an accelerated progression of the disease. It can also mean shortened survival compared to the expected survival in the same patient. In some embodiments, progression is characterized by an increase in the percentage of blasts, an increase in the myeloid to erythroblast ratio, aberrant Increased bone marrow plasma cell percentage and increased leukocyte dysplasia (e.g., leukodysplasia) The method may include detecting one or more of: an increase in the percentage of marrow lymphocytes; See, for example, Sever, et al., A rch Pathol Lab Med.2016 Sep;140(9):932-4 9). In some embodiments, progression is characterized by the expression of leukocytes (e.g., polymorphonuclear leukocytes). ), a decrease in platelet count, and a decrease in hemoglobin in peripheral blood. In some embodiments, the tumor burden may include detecting one or more of the following: Evaluate using ECIST (e.g., RECIST version 1 or version 1.1). See, for example, Eisenhower, "Chemicals and Biomolecules for the Prevention of Cardiovascular Disease," incorporated herein by reference in its entirety. nhauer et al.,Eur.J.Cancer.2009,45(2):22 See, e.g., 8-47. In some embodiments, tumor burden is assessed using PERCIST. For example, Watson et al., supra, which is incorporated herein by reference in its entirety. See hl,et al.J.nucl.med.2009,50:122S-150S I want to be.

[0185] The term "recurrence" is defined by the National Cancer Institute (NCI) Cancer Glossary: As used herein, "return of a disease or the signs and symptoms of a disease after a period of improvement" For example, relapse can be an increase in the number of cancer cells in a subject after a period of improvement, or an increase in size of multiple tumors, an increase in tumor burden, an increase in the rate or extent of metastasis, overall or worsening of symptoms, increase in extent of disease, and / or progression of disease that are partly or partially related to the cancer In some embodiments, relapse may include detecting an acceleration of progression after a period of improvement. In some embodiments, the period of improvement may include progression of cancer. a reduction in the size of one or more tumors in a subject, a reduction in tumor burden, or the rate of metastasis. or reduction in the extent of, or improvement in symptoms related in whole or in part to, cancer, or reduction in the extent of, the disease and / or detecting a delay in progression of the disease. Relapse is characterized by an increase in the percentage of blasts, an increase in the myeloid-to-erythroblast ratio, and atypia after a period of improvement. Increased proliferation (e.g., leukodysplasia), increased percentage of bone marrow plasma cells, and increased bone marrow The method may include detecting one or more of the following: an increase in the percentage of lymphocytes. In some embodiments, the period of improvement includes a decrease in the percentage of blasts, a decrease in the myeloid to red blood cell ratio, or reduction in dysplasia (e.g., leukodysplasia), reduction in the percentage of bone marrow plasma cells, and and a decrease in the percentage of bone marrow. In some embodiments, relapse is characterized by a decrease in white blood cell (e.g., polymorphonuclear leukocyte) counts after a period of improvement. One of the following: increased blood count, decreased platelet count, and decreased hemoglobin in peripheral blood In some embodiments, the period of improvement may include detecting a white blood cell count ( For example, a decrease in the percentage of polymorphonuclear leukocytes (PLNs), an increase in platelet count, and a decrease in peripheral blood hemoglobin (Hb) levels. The method may include detecting one or more of an increase in tyrosine phosphate globin.

[0186] "Relapse" is also a term used by the National Cancer Institute to describe a period when cancer usually goes undetected. may include "recurrence," defined as cancer that has returned after a period of time Cancer may come back in the same place in the body as the original (primary) tumor or in another place in the body. (NCI Cancer Glossary). In some embodiments, failure to detect cancer is a not detect cancer cells in subjects, not detect tumors in subjects, and / or or may include the total or partial absence of symptoms related to cancer.

[0187] As used herein, the terms "intolerance" and "intolerant" refer to a condition that occurs during therapy. unplanned hospitalization, discontinuation of therapy and / or reduction in therapy dose, and therapy-related functional decline , and / or result in a decrease in performance status; severe; disabling; In some embodiments, performance may be affected by a number of adverse events, including but not limited to: A decrease in performance status is consistent with the Eastern Cooperative Oncology Group (ECOG) schedule of performance status. The assay can be performed using a RT-PCR tool (see, for example, the US Pat. No. 6,343,313, which is incorporated herein by reference in its entirety). Oken et al. Am. J. Clin. Oncol. 5:649-655 (1982), which is incorporated by referenc. (See e in its entirety herein.) In terms of morphology, the decline in performance status was due to the Karnofsky performance status. The assay can be evaluated using a method such as the one described herein, which is incorporated by reference in its entirety. Peus et al., BMC Med.Inform.Decis.Mak. 13:72 (2013). In some embodiments, the subject is a pediatric patient. Performance status is assessed by the Lansky Performance Score. (See, e.g., Lansky et al., herein incorporated by reference in its entirety). ., Cancer. 60(7):1651-6 (1987).

[0188] As used herein, the term "prevent" refers to preventing or preventing a disease or condition as described herein. means preventing the onset, recurrence or spread of a condition, or its symptoms, in whole or in part.

[0189] The term "administration" or "administering" refers to administration to a mammal, bird, fish, or amphibian, including a spinal cord or spinal cord. It refers to a method of administering a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate. The preferred method of administration will depend on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, and the severity of the disease. It may vary depending on the severity of the condition.

[0190] As provided herein, a "therapeutically effective amount" or a "pharmaceutical effective amount" of a compound refers to a and the amount of the compound is sufficient to achieve the desired effect, depending on the nature and severity of the disease state and the A therapeutic effect may vary according to the efficacy of the drug. The term "cure" refers to the elimination of symptoms of an active disease. However, even after a cure has been achieved, certain long-term or permanent symptoms of the disease may persist. There may be consequences (eg, widespread tissue damage, etc.).

[0191] "The expression or activity or level of a gene, protein, or any of them The term "dysregulated" refers to genetic mutations (e.g., kinase domains and fusion partners) that Chromosomal translocation resulting in expression of a fusion protein containing A mutation in a gene that results in the expression of a protein containing a deletion of one amino acid, A genetic variant that results in the expression of a protein that contains one or more point mutations compared to the normal protein. Mutations in the offspring, including at least one inserted amino acid compared to the wild-type protein Mutations in genes that result in the expression of proteins that cause In regulatory sequences (e.g., promoters and / or enhancers) that result in an increase Mutation), a deletion of at least one amino acid in a protein compared to the wild-type protein alternatively spliced ​​versions of mRNA resulting in a protein with a deletion, or (e.g., when compared to control non-cancerous cells) is a pathological event in mammalian cells caused by dysregulated autocrine / paracrine signaling It refers to an increased expression (e.g., increased levels) of a native protein. Dysregulation of expression or activity or levels of a gene, protein, or any of them is a protein encoded by a gene that is constitutively active or does not contain a mutation. The mutation may be in a gene that encodes a protein that has increased activity compared to its original quality. For example, the expression or activity of a gene, protein, or any of them. Dysregulation of levels is observed in the first part of the protein that contains a functional kinase domain and in the second part and a second portion of a donor protein (i.e., not the first protein). In some instances, the mutation may be the result of a genetic or chromosomal translocation that results in the expression of a protein. Modulation of expression or activity or levels of genes, proteins, or any of them The deficiency may be the result of a genetic translocation of one gene with another.

[0192] "The BTK gene, the BTK kinase, or any of their expression or activity or The phrase "dysregulated levels of BTK" refers to increased expression of BTK kinase, transcription of the BTK gene, and This refers to an increase in the level of BTK kinase activity or an increase in its phosphorylation. Gene, BTK kinase, or expression or activity or level of any of them Dysregulation can be caused by genetic mutations (e.g., BTK gene translocations leading to expression of a fusion protein, A BTK protein that contains at least one amino acid deletion compared to the wild-type BTK protein. The BTK gene is associated with a deletion or one or more point mutations that result in expression of the protein (a mutation in the BTK gene that results in expression of the BTK protein) or B A pathological increase in the activity of the kinase domain of the TK protein (e.g., the BTK protein) Overexpression of the BTK gene in cells results in a constitutively active kinase domain of 1,2-diaminobutyric acid (1,2-diaminobutyric acid) that is essential for the synthesis of BTK. BTK gene expression, which leads to overexpression or autocrine activity of the BTK protein As another example, the BTK gene, the BTK protein, or Dysregulation of the expression, activity or level of either BTK mRNA Spliced ​​versions, or alternative promoters, compared to wild-type BTK mRNA In some embodiments, the BTK mRNA is transcribed starting at . Alternatively spliced ​​versions of the mRNA were compared to the wild-type BTK protein. to result in a BTK with a deletion of at least one amino acid in the BTK protein. In some embodiments, the BTK kinase is transcribed from an alternative promoter compared to the wild-type BTK kinase. The mRNA for BTK expressed a 100% methylated 1-methyltransferase (MTT) kinase at the N-terminus of the BTK kinase compared to the wild-type BTK kinase. As another example, a BTK kinase having at least one additional amino acid is provided. K gene, BTK protein, or the expression or activity or level of any of them Dysregulation of the BTK gene is either constitutively active or does not contain a mutation. B encoding a BTK protein having increased activity compared to the protein The BTK gene, the BTK protein, or their Further examples of dysregulation of either expression or activity or level include BTK inhibitor resistance. Non-limiting examples of BTK inhibitor resistance mutations are listed in Table 2.

[0193] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression or activity or levels of BCR signaling pathway genes, BCR Signal transduction pathway proteins, or the expression or activity or levels of any of them In some embodiments, the BCR signaling pathway genes, BCR Signal transduction pathway proteins, or the expression or activity or levels of any of them Dysregulation of the receptor may result in activation of one or more of the downstream signaling components within the BCR complex. mutations, continuous BCR stimulation by microbial or autoantigens present in the tissue microenvironment, or ligand-independent, resulting in pathogenic increases in BTK protein expression or activation. In some embodiments, the BCR signaling pathway is a sustained BCR signaling pathway. tract genes, BCR signaling pathway proteins, or the expression or Dysregulation of activity or levels of one or more BCR signaling pathway proteins For example, the overexpression or overactivation of the BTK gene, the BTK protein, or Dysregulation of the expression or activity or levels of any of them disrupts BCR signaling Genetic mutations in pathway proteins (e.g., BCR pathway leading to expression of fusion proteins) signaling pathway gene translocations, and fewer BCR signaling pathway proteins compared to wild-type B, which results in the expression of BCR signaling pathway proteins that contain a single amino acid deletion BCR signaling pathway gene deletions or BCR signaling pathway gene deletions or BCR signaling pathway gene deletions mutations in BCR signaling pathway genes that result in expression of null transduction pathway proteins; BCR signaling pathway proteins compared to wild-type BCR signaling pathway proteins The present invention provides a method for the production of a BCR signaling pathway protein that results in a deletion of at least one amino acid in the Alternative splicing versions of BCR signaling pathway protein mRNAs Non-limiting examples of BCR signaling pathway mutations are listed in Table 4. The BTK gene, the BTK protein, or the expression or activity of any of them A further example of dysregulated levels of BCR signaling is BTK inhibitor resistance mutations. Non-limiting examples of BTK inhibitor resistance mutations in pathway proteins are listed in Table 3. .

[0194] As used herein, the term "BTK-associated disease or disorder" refers to a disorder characterized by a BTK gene expression profile or disorder. BTK kinase (referred to herein as BTK kinase protein or BTK kinase (also referred to as "protein-linked nucleotide sequence"), or the expression or activity of any (e.g., one or more) thereof. or dysregulation of levels (e.g., any type of BTK gene described herein, BTK Kinase, BTK kinase domain, or expression or activity of any of them refers to a disease or disorder associated with or having dysregulation of BTK levels. Non-limiting examples of related diseases or disorders include, for example, cancer and autoimmune diseases such as arthritis and lupus. Includes epidemics.

[0195] As used herein, the term "BTK-associated cancer" refers to a cancer that is caused by a mutation in the BTK gene, Kinase (also referred to herein as BTK kinase protein or BTK kinase) or associated with dysregulation of the expression or activity or levels of any of them Non-limiting examples of BTK-associated cancers are described herein. It has been done.

[0196] The term "activating mutation" refers to a mutation that, when assayed under identical conditions, e.g., a wild-type Mutations in genes that result in the expression of proteins with increased activity compared to the For example, an activating mutation can be expressed in a fusion protein comprising a kinase domain and a fusion partner. In another example, an activating mutation can result in expression of a protein, e.g., and / or a combination of one or more of the following: A number (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of amino acid substitutions (e.g., For example, any combination of any of the amino acid substitutions described herein. In another example, an activating mutation can be a mutation in a gene that results in expression of a protein. For example, when assayed under identical conditions, one or more Containing multiple (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid deletions In another example, an activating mutation may be present in a gene that results in the expression of a protein that activates the The difference is, for example, small when compared to the wild-type protein when assayed under identical conditions. At least one (e.g., at least two, at least three, at least four, at least five, at least 6, at least 7, at least 8, at least 9, at least 10, at least 1 2, at least 14, at least 16, at least 18, or at least 20) The inserted amino acid may be a mutation in the gene that results in expression of a protein having the inserted amino acid.

[0197] In some embodiments, an "activating mutation" is, for example, an For example, expression of a BTK kinase having increased kinase activity compared to wild-type BTK kinase. For example, an activating mutation refers to a mutation in the BTK kinase gene that results in This can result in the expression of a fusion protein comprising the enzyme domain and a fusion partner. In an example, an activating mutation may be, for example, an activating mutation that is more potent than, for example, a wild-type BTK kinase when assayed under identical conditions. Increased kinase activity compared to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid substitutions (e.g., amino acids described herein) B, which results in expression of BTK kinase having any of the substitutions (any combination of the In another example, the activating mutation can be a mutation in the TK kinase gene. When assayed under conditions, the BTK kinase exhibits one or more of the following: For example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid deletions Another example may be a mutation in the BTK kinase gene that results in expression of TK kinase. For example, an activating mutation may be a mutation that, when assayed under the same conditions, e.g., as described herein, When compared to wild-type BTK kinase, such as a representative wild-type BTK kinase, at least 1 (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, a few at least 14, at least 16, at least 18, or at least 20) Mutations in the BTK kinase gene resulting in expression of a BTK kinase with altered amino acids Further examples of activating mutations are known in the art.

[0198] In some embodiments, an "activating mutation" is, for example, an For example, a BCR signaling pathway protein that has increased activity compared to a wild-type BCR signaling pathway protein. In BCR signaling pathway protein genes leading to expression of null transduction pathway proteins For example, activating mutations refer to mutations in BCR signaling pathway protein domains and In another example, an activating mutant can result in the expression of a fusion protein comprising the activating mutant and a fusion partner. The difference may be, for example, a difference between the wild-type BCR signaling pathway and the wild-type BCR signaling pathway when assayed under identical conditions. Increased activity compared to the protein, one or more (e.g., 2, 3, 4, 5, 6, 7 , 8, 9, or 10) amino acid substitutions (e.g., amino acid substitutions described herein). BCR serotype leading to expression of BTK kinase having any of the following genes (any combination of the above): In another example, the activating mutation can be a mutation in a signal transduction pathway protein gene. For example, when assayed under identical conditions, wild-type BCR signaling pathway proteins, e.g. Compared to quality, one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 1 BC leading to expression of BCR signaling pathway proteins with a 0 amino acid deletion In another example, an activating mutation in a gene encoding a protein of the R signaling pathway. For example, when assayed under identical conditions, wild-type BCR signaling pathway protein When comparing with, at least 1 (e.g., at least 2, at least 3, at least 4 , at least 5, at least 6, at least 7, at least 8, at least 9, at least At least 10, at least 12, at least 14, at least 16, at least 18, or Expression of BCR signaling pathway proteins with inserted amino acids (at least 20) The mutation may be in a BCR signaling pathway protein gene that results in activation. Further examples of mutations are known in the art.

[0199] The term "wildtype" or "wild-type" does not have a BTK-associated disease, e.g., a BTK-associated cancer (and optionally Not at increased risk of developing the disease and / or not suspected of having a BTK-related disease ) or have no BTK-associated disease, e.g., BTK-associated cancer. and optionally, no increased risk of developing a BTK-associated disease and / or Nucleic acids (e.g., nucleic acids) found in cells or tissues from subjects (not suspected of having a B-related disease) TK gene or BTK mRNA) or protein (e.g., BTK protein) Represents.

[0200] The term "regulatory authority" refers to the national authority that approves the medical use of medicines in each country. For example, one non-limiting example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0201] As defined herein, a "BTK kinase inhibitor" includes any compound that exhibits BTK inhibitory activity. In some embodiments, the BTK kinase inhibitor is a BTK kinase inhibitor. Exemplary BTK kinase inhibitors are selective for the assays described herein. When measured by the method of (a), the concentration is less than about 1000 nM, less than about 500 nM, less than about 200 nM, or less than about 10 Less than 0 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM , inhibitory activity against BTK kinase (IC 50 In some embodiments, The BTK kinase inhibitor has a potency of less than about 25 nM as measured by the assay provided herein. less than about 10 nM, less than about 5 nM, or less than about 1 nM of inhibition of BTK kinase. Harmful activity (IC 50 ) can be shown.

[0202] As used herein, a "first BTK kinase inhibitor" or "first BTK inhibitor" refers to a An "inhibitory agent" is a BTK kinase inhibitor as defined herein, but is not limited to a BTK kinase inhibitor as defined herein. Compound of formula I, or a pharma- ceutically acceptable salt thereof, amorphous, polymorphic form, or spray-dried form thereof As used herein, the term "second B" does not include a second B A "BTK kinase inhibitor" or a "second BTK inhibitor" refers to a BTK kinase inhibitor, as defined herein. The compound of formula I as defined herein, or a pharma- ceutically acceptable derivative thereof, is an agonist, The methods provided herein do not include salts, amorphous, or polymorphic forms thereof. When both BTK inhibitors are present, the first and second BTK kinase inhibitors are different.

[0203] The term "immunotherapy" refers to agents that modulate the immune system. In some embodiments, Immunotherapy can increase the expression and / or activity of regulators of the immune system. In some embodiments, immunotherapy involves reducing the expression and / or activity of regulators of the immune system. In some embodiments, immunotherapy can mobilize and enhance the activity of immune cells. The present invention may be modified and / or enhanced.

[0204] As used herein, the term "pharmaceutical combination" refers to a mixture of two or more active ingredients. It refers to pharmaceutical treatments resulting from fixed and non-fixed combinations of active ingredients. This includes both.

[0205] The term "fixed combination" refers to a compound of formula I, or a pharma- ceutically acceptable salt thereof. , amorphous, or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof; and at least one additional therapeutic agent (e.g., a chemotherapeutic agent), both in a single composition or It is meant to be administered to a subject simultaneously in the form of a single dosage.

[0206] The term "non-fixed combination" refers to a compound of formula I, or a pharma- ceutically acceptable salt thereof. salts, amorphous or polymorphic forms, spray-dried dispersions thereof, or pharmaceutical compositions thereof; and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) when they are in need thereof. Can be administered simultaneously, concomitantly, or sequentially with various time interval limits to subjects and such administration results in effective levels of two or more compounds in the subject's body. These are meant to be formulated as separate compositions or dosages, such as capsules. The present invention also applies to therapeutic treatments, for example the administration of three or more active ingredients.

[0207] The term "metastasis" is an art-recognized term that refers to the degeneration of a subject or a primary site in a subject. This refers to the formation of additional tumors (e.g., solid tumors) at sites distant from the primary tumor. The tumor contains the same or similar cancer cells as the primary tumor.

[0208] The phrase "risk of developing metastases" refers to a condition in which a subject with a primary tumor or a subject is at risk of developing metastases. or forming additional tumors (e.g., solid tumors) in the subject at sites distant from the primary tumor. This refers to the risk of developing a new tumor that contains the same or similar cancer cells as the primary tumor. The present invention provides a method for reducing the risk of developing metastases in a subject having cancer or in a subject. It's stated in the fine print.

[0209] The phrase "risk of developing further metastases" refers to the risk of developing metastases from the primary tumor and from sites distant from the primary tumor. one or more additional tumors at the site (wherein the one or more additional tumors are A subject or subject having a tumor (including the same or similar cancer cells as the primary tumor) is The term "risk" refers to the risk of developing one or more additional tumors in the presence of a primary tumor. Contains the same or similar cancer cells as the tumor; reduces the risk of developing further metastases The methods are described herein.

[0210] As used herein, the term "contacting" refers to an in vitro system or an in vivo system. The term "system" refers to the bringing together of the indicated moieties in a system. For example, the BTK kinase is provided herein. "Contacting" a compound provided herein refers to contacting an individual, such as a human, with BTK kinase or Administering a compound provided herein to a subject and administering, e.g., a compound provided herein, introducing the mixture into a sample containing cells or a purified preparation containing BTK kinase; include.

[0211] The term "effective amount" means that, when administered to a subject in need of such treatment, (i) (ii) to treat a specific disease, condition, or disorder associated with the BTK kinase; (iii) reduce, ameliorate, or eliminate one or more symptoms of the disorder; or Delay the onset of one or more symptoms of a specific disease, condition, or disorder described in the literature means an amount of a compound of formula I corresponding to such an amount, or its pharma- ceutically acceptable salts, amorphous or polymorphic forms, spray-dried dispersions thereof, and The amount of such pharmaceutical compositions may vary depending on the particular compound, the disease state and its severity, the severity of the disease, and the need for treatment. This may vary depending on factors such as the individual characteristics of the subject (e.g., weight), but nevertheless This can be routinely determined by one of ordinary skill in the art.

[0212] 1. Pharmaceutical Compositions of Compounds of Formula I The present disclosure relates to a polymer and a compound of formula I: [ka] or a pharma- ceutical composition comprising a pharma- ceutical acceptable salt, amorphous, or polymorphic form thereof. More specifically, it is a BTK kinase inhibitor, including for BTK-related diseases and disorders. Compounds of formula I and their pharmaceutical compositions are useful in the treatment and prevention of diseases that can be treated. US20100232633A1 - Spray dried dispersion or oral pharmaceutical composition of a therapeutically acceptable salt, amorphous or polymorphic form - Google Patents do.

[0213] spray dried dispersion As used herein, the compound of formula I and hypromellose acetate succinate (HPMCAS ) a polymer. Non-limiting examples of HPMCAS polymers include Includes HPMCAS-MG, HPMCAS-LF, HPMCAS-LG, HPMCAS- MF, HMPCAS-HF, and HPMCAS-HG. HPMCAS type L is a polymer with a high ratio of succinoyl substitution to acetyl substitution (S / A ratio). However, Type H HPMCAS is a polymer with a low S / A ratio, while Type M HPMCA S polymers have a medium S / A ratio. HPMCAS types F and G are fine particles, respectively. In some embodiments, the compound of formula I and the HPMCAS polymer are In some embodiments, the ratio of the compound of formula I to the polymer is about 1:4 to about 4:1. The ratio of HPMCAS polymer is about 4:1, about 3:1, about 7:3, about 13:7, about 3:2 , 11:9, 1:1, 9:11, 2:3, 7:13, 3:7, 1:3, In some embodiments, the ratio of the compound of formula I to the HPMCAS polymer is about 1:4. In some embodiments, the HPMCAS polymer is HPMCA S-LF, HPMCAS-LG, HPMCAS-MF, HMPCAS-HF, HPMCA S-HG, or a combination thereof. The reflector is HPMCAS-MG.

[0214] Also provided herein is a method for preparing a spray-dried dispersion of a compound of formula I. The method comprises adding an HPMCAS polymer to a compound of formula I and spray drying the mixture to form a spray-cured product. and forming a dry dispersion. In some embodiments, the compound of formula I and the HPM are In some embodiments, the ratio of the CAS polymer to the CAS polymer is about 1:4 to about 4:1. The ratio of compound to HPMCAS polymer is about 4:1, about 3:1, about 7:3, about 13:7, Approx. 3:2, Approx. 11:9, Approx. 1:1, Approx. 9:11, Approx. 2:3, Approx. 7:13, Approx. 3:7, Approx. 1 In some embodiments, the ratio of the compound of formula I to the HPMCAS polymer is about 1:3, or about 1:4. In some embodiments, the ratio of the compound of formula I to HPMCAS is about 1:1. In some embodiments, the HPMCAS polymer is H PMCAS-MG.

[0215] In some embodiments, the compound of formula I is added to one or more of the compounds in a solution prior to being spray dried. In some embodiments, the solvent is one or more organic solvents. In some embodiments, the organic solvent is methanol, acetone, dichloromethane, methane, tetrahydrofuran, and combinations thereof. In some embodiments, the solvent is a mixture of an organic solvent and water. The solvent is a mixture of tetrahydrofuran and water. For example, the organic solvent is 95:5 tetrahydrofuran. In some embodiments, the organic solvent is dichloromethane. For example, the organic solvent is a mixture of dichloromethane and methanol (80:20 w / w% by volume). In another example, the solvent is 100% methanol. In some embodiments, Form A of the compound of Formula I is dissolved in one or more organic solvents. .

[0216] In some embodiments, the solution of the compound of formula I is added to the HPMCAS polymer prior to the addition of the HPMCAS polymer. In some embodiments, the compound of formula I and the HPMCAS polymer are The solution is polish filtered before being spray dried. The polymer is HPMCAS-MG.

[0217] In some embodiments, the HPMCAS polymer is dissolved in an organic solvent. In an embodiment, the HPMCAS polymer is HPMCAS-MG.

[0218] In some embodiments, the HPMCAS polymer is dissolved in one or more solvents. In some embodiments, the solvent is one or more organic solvents. In an embodiment, the organic solvent is methanol, acetone, dichloromethane, tetrahydrofuran. In some embodiments, the solvent is selected from the group consisting of is a mixture of an organic solvent and water. In some embodiments, the solvent is tetrahydrofuran. and water. For example, the organic solvent is 95:5 tetrahydrofuran:water. In some embodiments, the organic solvent is a mixture of dichloromethane and methanol. For example, the organic solvent can be 80:20 w / w% dichloromethane:methanol. In another example, the solvent is 100% methanol. The compound of formula I is then added and dissolved. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

[0219] The method further comprises spray drying a solution of the compound of formula I and the HPMCAS polymer. In some embodiments, the HPMCAS polymer is HPMCAS-MG. .

[0220] In some embodiments, the method further comprises drying the spray-dried dispersion. In some embodiments, the spray-dried dispersion is dried, e.g., to remove residual solvent. In some embodiments, the spray-dried dispersion is dried in an oven. In some embodiments, the spray-dried dispersion is dried at a temperature of about 30° C. to about 50° C. In the spray-dried dispersion, the dispersion is dried at a temperature of about 35°C to about 45°C, for example, about 40°C. In some embodiments, the spray-dried dispersion is 2 It is dried in vacuum under purge. In some embodiments, the spray dried dispersion is dried for about 10 to about 40 hours, about 30 to about 60 hours, or about 50~80, 70~100 hours, 40 hours, 50 hours, 60 hours, 70 hours In some embodiments, the mixture is dried for about 80 hours, about 90 hours, or about 100 hours. In the spray dried dispersion, the solvent is removed by about 20,000 ppm until less than about 40,000 ppm of solvent remains. until less than 10,000 ppm of solvent remains, approximately 5000 ppm until less than 2,500 ppm of solvent remains, approximately 1,000 ppm It is dried until less than ppm of solvent remains, or until less than about 600 ppm of solvent remains. In some embodiments, the solvent is a mixture of dichloromethane and methanol, and is spray-dried. The dry dispersion contains less than about 2000 ppm dichloromethane and less than about 15,000 ppm Less than about 1,500 ppm dichloromethane and about 10,000 ppm methanol remaining. until less than ppm methanol remains, or less than about 600 ppm dichloromethane and The mixture is dried until less than about 3,000 ppm of methanol remains. In some embodiments using ethanol, the spray-dried dispersion has less than about 3,000 ppm The mixture is dried until 100% methanol remains.

[0221] Pharmaceutical Compositions Provided herein is a pharmaceutical composition comprising a spray-dried dispersion of a compound of formula I and an HPMCAS polymer. In some embodiments, the HPMCAS polymer is HPMCAS-MG It is.

[0222] In some embodiments, the pharmaceutical composition comprises a spray-dried dispersion and one or more pharmaceutical agents. The spray-dried dispersion comprises a first composition having an excipient, the first composition comprising an HPMCAS polymer and the In some embodiments, the HPMCAS polymer comprises a compound of formula I as described herein. HPMCAS-MG.

[0223] In some embodiments, the spray-dried dispersion comprises about 20% to about 75% w / w of the first composition. In some embodiments, the spray-dried dispersion is present in an amount of about 20 w of the first composition. % to about 50% w / w, about 50% to about 75% w / w, or about 30% to about 60% w / w For example, about 20% to about 40% w / w, about 30% to about 50% w / w of the first composition. In some cases, the concentration is about 40% to about 60% w / w, or about 50% to about 75% w / w. In embodiments, the spray-dried dispersion comprises about 30% to about 40% w / w of the composition, about 40% to about 50% % w / w, about 50% to about 60% w / w, for example about 35% of the first composition. w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, or about It is 60% w / w.

[0224] In some embodiments, the pharmaceutical excipients of the first composition include fillers, lubricants, and the like. and combinations thereof.

[0225] In some embodiments, the first composition described herein may include a filler. The agents include binders, diluents, disintegrants, glidants, and surfactants that are added to the pharmaceutical composition. In some embodiments, the filler may include a saccharide (e.g., sugar, starch, and cellulose), gelatin, and synthetic polymers [e.g., polyvinylpyrrolidone, Polyethylene glycol, and poloxamers (e.g., poloxamer 188, polyoxamer Exemplary fillers include copolymers of diethylene and polyoxypropylene. Glucose, sucrose, lactose, (e.g., Foremost Fast Flow 316 Lactose monohydrate), starch [sodium starch glycolate (e.g. (including modified starches such as EXPLOTAB®), xylitol, dextrose Phosphorus, sucrose, sorbitol, mannitol [e.g., PARTECK (registered trademark)] ) M200 (mannitol with an average particle size of about 50 μm to about 500 μm) or PARTEC K(R)M100 (mannitol with an average particle size of less than 212 μm)] or Mann ogemEZ Spray Dried Mannitol, Cellulose, Polyvinylpyrrolidone, Polyethylene Glycol, polyvinyl alcohol, polymethacrylate, dibasic calcium phosphate, Magnesium stearate, calcium stearate, sodium stearate, stearate Phosphoric acid, hydrogenated vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, pa Glyceryl lumitostearate, sodium benzoate, sodium stearyl fumarate, Colloidal silicon dioxide (e.g., sodium benzoate, sodium oleate, sodium acetate) Thorium, alginic acid, alginate (e.g., Syloid 244FP) alginic acid These include, but are not limited to, sodium, calcium silicate, and ion exchange resins. Exemplary cellulose fillers include microcrystalline cellulose [e.g., AVICEL (registered trademark)]. PH-101 (microcrystalline cellulose with an average particle size of approximately 50 μm) or AVICE L® PH200 (microcrystalline cellulose having an average particle size of about 180 μm)], or AVICEL® PH102 Methylcellulose, Ethylcellulose, Croscal Sodium melose (e.g., AC-Di Sol®), hydroxypropyl Exemplary polyvinyl chlorides include cellulose, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose. The rupyrrolidone filler is KOLLIDON (registered trademark) CL (average particle size 90 μm to 1 30 μm crospovidone) or KOLLIDON® CL-SF (average particle size Cross-linked polyvinylpyrrolidone such as crospovidone having a particle size of 10 μm to 30 μm is included. Other fillers known to those of ordinary skill in the art may also be useful when incorporated into the compositions described herein. It is believed to be useful.

[0226] In some embodiments, the filler is glucose, sucrose, lactose, starch. [Modified starch such as sodium starch glycolate (EXPLOTAB®)] [Contains glycerin], xylitol, dextrin, sucrose, sorbitol, mannitol [For example, PARTECK (registered trademark) M200 (average particle size is about 50 μm to about 500 μm mannitol) or PARTECK® M100 (average particle size less than 212 μm) full mannitol)], cellulose, polyvinylpyrrolidone, polyethylene glycol, Polyvinyl alcohol, polymethacrylate, dibasic calcium phosphate, stearic acid Magnesium, calcium stearate, sodium stearate, stearic acid, hydrogen Chemically modified vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, palmitostear Glyceryl phosphate, sodium benzoate, sodium stearyl fumarate, colloidal diglyceride Silicon oxide (e.g., sodium benzoate, sodium oleate, sodium acetate, Ligic acid, alginates (e.g., sodium alginate), calcium silicate, ions exchange resins, or combinations thereof. In one embodiment, the cellulose is microcrystalline cellulose (e.g., AVICEL® ) PH-101 (microcrystalline cellulose with an average particle size of about 50 μm) or AVICEL (registered trademark) Registered trademark) PH200 (microcrystalline cellulose with an average particle size of approximately 180 μm), methyl cellulose cellulose, ethylcellulose, croscarmellose sodium, hydroxypropyl cellulose hydroxypropyl methylcellulose, or a combination thereof. In some embodiments, the polyvinylpyrrolidone is selected from the group consisting of KOLLIDON® and KOLLIDON®. Trademark) CL (crospovidone with an average particle size of 90 μm to 130 μm), KOLLIDON ( (registered trademark) CL-SF (crospovidone with an average particle size of 10 μm to 30 μm), or and combinations thereof.

[0227] In some embodiments, the filler is present in an amount of about 25% to about 80% w / w of the first composition. For example, about 25% to about 50% w / w, about 50% to about 80% w / w of the first composition. In some embodiments, the filler is from about 40% to about 70% w / w of the first composition. Approximately 30% to 50% w / w, approximately 45% to 65% w / w, approximately 55% to 75% w / w For example, about 40% w / w, about 45% w / w, about 50% w / w, or about 50% of the first composition. w / w, about 55% w / w, about 60% w / w, about 65% w / w, or about 70% w / w. do.

[0228] In some embodiments, the filler is selected from the group consisting of a binder, a disintegrant, or a combination thereof. Be selected.

[0229] Binders include agents that hold active pharmaceutical ingredients and inactive ingredients together into a cohesive mixture. Exemplary binders include glucose, sucrose, lactose, starch [starch including modified starches such as sodium glycolate (EXPLOTAB®). , xylitol, dextrin, sucrose, sorbitol, mannitol [e.g. PARTECK (registered trademark) M200 (mannite with an average particle size of about 50 μm to about 500 μm) PARTECK® M100 (mannitol having an average particle size of less than 212 μm) ), cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol These include cholesteryl, polymethacrylate, and sodium starch glycolate. Exemplary cellulose fillers include microcrystalline cellulose [e.g., A VICEL® PH-101 (microcrystalline cellulose with an average particle size of approximately 50 μm) or AVICEL (registered trademark) PH200 (microcrystalline cellulose with an average particle size of about 180 μm) cellulose)], or methylcellulose, ethylcellulose, croscarmellose sodium, Hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Exemplary polyvinylpyrrolidone fillers include KOLLIDON® CL (average Crospovidone with a particle size of 90 μm to 130 μm) or KOLLIDON® C Cross-linked polyvinylpyrrolidone such as L-SF (crospovidone with an average particle size of 10 μm to 30 μm) Other binders known to those of skill in the art may also be used in the compositions described herein. It is believed to be useful when combined.

[0230] In some embodiments, the binder is present in an amount of about 30% to about 80% w / w of the first composition. For example, about 30% to about 50% w / w, about 50% to about 80% w / w of the first composition. In some embodiments, the filler is from about 40% to about 70% w / w of the first composition. About 30% to about 50% w / w, about 35% to about 55% w / w, about 40% to about 60% w / w In particular, the amount of the glycerol is about 45% to about 65% w / w, about 55% to about 75% w / w. 1, about 40% w / w, about 45% w / w, about 50% w / w, about 52% w / w, about 55% w / w, about 60% w / w, about 65% w / w, or about 70% w / w.

[0231] In some embodiments, the binder is microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose, cellulose ether ... Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Sodium carboxylate Dimethylcellulose starch, methylcellulose, ethylcellulose, hydroxypropyl cellulose, mannitol, xylitol, sorbitol, lactose, sucrose, Sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol, polyvinyl selected from the group consisting of alcohols, polymethacrylates, and combinations thereof .

[0232] In some embodiments, the binder is microcrystalline cellulose, mannitol, or the like. In some embodiments, the microcrystalline cellulose is a combination of the first composition. For example, about 5% to about 40% of the first composition. w / w, about 40% to about 80% w / w, about 20% to about 60% w / w, about 5% to about 30% w / w, about 30% to about 55% w / w, about 10% to about 40% w / w, or about 15% to about 35% In some embodiments, the microcrystalline cellulose is present in an amount of about 1% by weight of the first composition. 0% to about 20% w / w, about 20% to about 30% w / w, about 30% to about 40% w / w, about 40 % to about 50% w / w, about 50% to about 60% w / w, or about 60% to about 70% w / w For example, about 15% w / w, about 20% w / w, about 25% w / w of the first composition. w, about 26%w / w, about 30%w / w, about 35%w / w, about 40%w / w, about 45%w / w, about 50% w / w, or about 60% w / w.

[0233] In some embodiments, mannitol comprises about 5% to about 80% w / w of the first composition. For example, about 5% to about 40% w / w, about 40% to about 80% of the first composition. w / w, about 20% to about 60% w / w, about 5% to about 30% w / w, about 30% to about 55% w / w / w, about 10% to about 40% w / w, or about 15% to about 35% w / w. In an embodiment, mannitol comprises about 10% to about 20% w / w of the first composition, about 20% to about About 30% w / w, about 30% to about 40% w / w, about 40% to about 50% w / w, about 50% to about 60% w / w, or about 60% to about 70% w / w. For example, the first composition of about 15%w / w, about 20%w / w, about 25%w / w, about 26%w / w, about 30%w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, or about 60 %w / w.

[0234] In some embodiments, the binder is a combination of microcrystalline cellulose and mannitol. In some embodiments, the microcrystalline cellulose comprises from about 5% to about 40% w / w, about 40% to about 75% w / w, about 20% to about 60% w / w, about 5% to about 30 % w / w, about 30% to about 55% w / w, about 10% to about 40% w / w, or about 15% to about 35% w / w, and mannitol is present in an amount of about 5% to about 40% w / w of the first composition. , about 40% to about 75% w / w, about 20% to about 60% w / w, about 5% to about 30% w / w, about 30% to about 55% w / w, about 10% to about 40% w / w, or about 15% to about 35% w / w In some embodiments, the microcrystalline cellulose is present in an amount of about 10% to about 20% w / w, about 20% to about 30% w / w, about 30% to about 40% w / w, about 4 0% to about 50% w / w, about 50% to about 60% w / w, or about 60% to about 70% w / w The mannitol is present in an amount of about 10% to about 20% w / w, about 20% to about 20% w / w of the first composition. About 30% w / w, about 30% to about 40% w / w, about 40% to about 50% w / w, about 50% to about 60% w / w, or about 60% to about 70% w / w. The loin may comprise about 15% w / w, about 20% w / w, about 25% w / w, about 26% w / w, or about 30% w / w of the first composition. %w / w, about 30%w / w, about 35%w / w, about 40%w / w, about 45%w / w, about 50 % w / w, or about 60% w / w, of the first composition, and mannitol is present in an amount of about 1 5%w / w, about 20%w / w, about 25%w / w, about 26%w / w, about 30%w / w, about 35 % w / w, about 40% w / w, about 45% w / w, about 50% w / w of the initial composition, or about It is present in an amount of 60% w / w.

[0235] Disintegrants include any agent that facilitates the breakdown of a formulation in an aqueous environment. This is to facilitate more rapid release of the drug ingredient. Exemplary disintegrants include starch and Modified starches such as sodium starch glycolate, croscarmellose sodium, Alginic acid, alginates such as sodium alginate, polyvinylpyrrolidone, silicic acid Examples of suitable anion exchange resins include, but are not limited to, calcium, and anion exchange resins. In the present embodiment, the disintegrants are sodium starch glycolate and sodium croscarmellose. Other disintegrants known to those skilled in the art may also be used in the compositions described herein. It is believed to be useful when combined with

[0236] In some embodiments, the disintegrant is present in an amount of about 0.5% to about 5% w / w of the first composition. For example, about 0.5% to about 2.5% w / w of the first composition, about 2.5% w / w In some embodiments, the amount is from about 1.5% to about 3.5% w / w. The disintegrant may be present in an amount of about 0.5% to about 2% w / w, about 1% to about 3% w / w, about 2% to about 5% w / w, or about 1% to about 6% w / w of the first composition. % to about 4% w / w, or about 3% to about 5% w / w. For example, the first composition of about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w , about 3.5% w / w, or about 4% w / w.

[0237] In some embodiments, the disintegrants are sodium starch glycolate, alginic acid, Sodium alginate, croscarmellose sodium anion exchange resin, and In one embodiment, the disintegrant is selected from the group consisting of starch glycols and combinations thereof. The active ingredient is selected from sodium phosphate, and croscarmellose sodium.

[0238] In some embodiments, the sodium starch glycolate comprises about 0. It is present in an amount of 5% to about 5% w / w, for example, about 0.5% to about 2.5% w / w of the first composition. / w, about 2.5% w / w to about 5% w / w, or about 1.5% to about 3.5% w / w In some embodiments, the sodium starch glycolate comprises about 0.05% of the first composition. 0.5% to about 2% w / w, about 1% to about 3% w / w, about 2% to about 4% w / w, or about 3% to It is present in an amount of about 5% w / w. For example, it may be present in an amount of about 1% w / w, about 1.5% w / w, or about 2.5% w / w of the first composition. w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, or about 4% w / w.

[0239] In some embodiments, the first composition described herein may include a lubricant. Lubricants are agents added to pharmaceutical formulations to reduce friction during processing. Exemplary lubricants include Magnesium stearate, calcium stearate, sodium stearate, Thearic Acid, Hydrogenated Vegetable Oil, Mineral Oil, Polyethylene Glycol, Sodium Lauryl Sulfate, Magnesium lauryl sulfate, glyceryl palmitostearate, sodium benzoate, Sodium tearyl fumarate, colloidal silicon dioxide, sodium benzoate, olein Examples of suitable glycerols include, but are not limited to, sodium phosphate, and sodium acetate. Other lubricants which have been reported to be useful in the compositions described herein are also known to be useful. It is possible.

[0240] In some embodiments, the lubricant comprises from about 0.05% to about 2.5% w / w of the first composition. For example, from about 0.05% w / w to about 1.25% w / w of the first composition, 1.25% to about 2.5% w / w, or about 0.1% to about 1% w / w. In an embodiment, the lubricant comprises from about 0.05% to about 0.15% w / w of the first composition, about 0.1 5%~about 0.25%w / w, about 0.25%~about 0.35%w / w, about 0.35%~about 0. 45% w / w, about 0.45% to about 0.55% w / w. In the first composition, the lubricant is present in an amount of about 0.2% to about 0.3% w / w. In some embodiments, the lubricant comprises about 0.1%, about 0.15%, about 0.2%, or about 0.4% of the first composition. w / w, about 0.25% w / w, about 0.3% w / w, about 0.35% w / w, about 0.4% w / in an amount of about 0.45% w / w, about 1% w / w, about 1.5% w / w, or about 2% w / w exist.

[0241] In some embodiments, the lubricant is magnesium stearate and / or dioxide. In some embodiments, magnesium stearate, about 100% of the first composition. It is present in an amount of 0.05% to about 2.5% w / w. For example, it is present in an amount of about 0.05% w / w of the first composition. / w to about 1.25% w / w, about 1.25% to about 2.5% w / w, or about 0.1% to about 1 % w / w. In some embodiments, magnesium stearate is present in the first composition. of about 0.05% to about 0.15% w / w, about 0.15% to about 0.25% w / w, about 0.2 5%~about 0.35%w / w, about 0.35%~about 0.45%w / w, about 0.45%~about 0. In some embodiments, magnesium stearate is present in an amount of 55% w / w. In some embodiments, the first composition is present in an amount of about 0.2% to about 0.3% w / w. , magnesium stearate is about 0.1%, about 0.15%, about 0.2%, %w / w, about 0.25%w / w, about 0.3%w / w, about 0.35%w / w, about 0.4%w / w, about 0.45% w / w, about 1% w / w, about 1.5% w / w, or about 2% w / w It exists in.

[0242] In some embodiments, the spray-dried dispersion and the pharmaceutical excipient form a first composition. In some embodiments, the first composition is granulated. In some embodiments, the first composition is granulated by roller compaction.

[0243] Pharmaceutical composition comprising the first composition As used herein, a first composition and one or more additional pharmaceutical excipients as described herein Also provided are pharmaceutical compositions comprising the agent. In some embodiments, the first composition comprises the entire composition. is present in an amount of about 15% to about 99% w / w.

[0244] In some embodiments, the additional pharmaceutical excipients include fillers, lubricants, glidents, and combinations thereof.

[0245] In some embodiments, the lubricant is present in an amount of about 0.05% to about 2% w / w of the total composition. For example, about 0.05% to about 1% w / w, about 1% to about 2% w / w, or In some embodiments, the lubricant is present in the total composition at about 0.5% to about 1.5% w / w. About 0.05% to about 0.5% w / w, about 0.1% to about 0.8% w / w, or about 0.5% to about 1% w / w. For example, about 0.1% w / w, about 0.2% w / w, w, about 0.3% w / w, about 0.4% w / w, or about 0.5% w / w.

[0246] In some embodiments, the lubricant is magnesium stearate, calcium stearate, Urea, Sodium Stearate, Stearic Acid, Hydrogenated Vegetable Oil, Mineral Oil, Polyethylene Glycol Cole, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate Lyceryl, Sodium Benzoate, Sodium Stearyl Fumarate, Colloidal Silicon Dioxide sodium benzoate, sodium oleate, sodium acetate, and combinations thereof The combination is selected from the group consisting of

[0247] In some embodiments, the lubricant is magnesium stearate and / or dioxide. In some embodiments, magnesium stearate comprises about 0.05% of the total composition. It is present in an amount of from about 0.05% to about 2% w / w, for example from about 0.05% to about 1% w / w of the total composition. w / w, about 1% to about 2% w / w, or about 0.5% to about 1.5% w / w. In embodiments, magnesium stearate is present in an amount of about 0.05% to about 0.5% w / w of the total composition. , about 0.1% to about 0.8% w / w, or about 0.5% to about 1% w / w. For example, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% of the total composition. w / w, or about 0.5% w / w.

[0248] In some embodiments, the filler is present in an amount of about 1% to about 85% w / w of the total composition. In some embodiments, the filler is glucose, sucrose, lactose, starch. Modified starch such as sodium starch glycolate (EXPLOTAB®) [Contains pun], xylitol, dextrin, sucrose, sorbitol, mannitol For example, PARTECK (registered trademark) M200 (average particle size is about 50 μm to about 500 μm) mannitol), PARTECK® M100 (average particle size less than 212 μm mannitol)], cellulose, polyvinylpyrrolidone, polyethylene glycol, poly Vinyl alcohol, polymethacrylate, dibasic calcium phosphate, stearic acid malate Magnesium, calcium stearate, sodium stearate, stearic acid, hydrogenated Vegetable oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, palmitostearyl Glyceryl Phosphate, Sodium Benzoate, Sodium Stearyl Fumarate, Colloidal Diacid Silicon hydrates (e.g., sodium benzoate, sodium oleate, sodium acetate, ant Glycic acid, alginates (e.g., sodium alginate), calcium silicate, ion exchange Some of the preferred embodiments of the present invention are selected from the group consisting of aryl esters, ... In embodiments, the cellulose is microcrystalline cellulose (e.g., AVICEL® PH-101 (microcrystalline cellulose with an average particle size of approximately 50 μm) or AVICEL (registered Trademark) PH200 (microcrystalline cellulose with an average particle size of approximately 180 μm), methylcellulose , ethyl cellulose, croscarmellose sodium, hydroxypropyl cellulose , hydroxypropyl methylcellulose, or a combination thereof In some embodiments, the polyvinylpyrrolidone is KOLLIDON®. CL (Crospovidone with an average particle size of 90 μm to 130 μm), or KOLLIDO Crosslinking agent such as N(registered trademark) CL-SF (crospovidone with an average particle size of 10 μm to 30 μm) In some embodiments, the filler is a binder, a disintegrant, or a combination thereof.

[0249] In some embodiments, the filler comprises a disintegrant. In some embodiments, the disintegrant , is present in an amount of about 0.5% to about 5% w / w of the total composition. For example, about 0.5% of the total composition. about 2.5% w / w, about 2.5% to about 5% w / w, or about 1% to about 4% w / w. In some embodiments, the disintegrant comprises about 1% to about 2% w / w, about 1.5% to about 2% w / w, of the total composition. About 2.5% w / w, about 2% to about 3% w / w, about 2.5% to about 3.5% w / w, or about 3 % to about 4% w / w of the total composition. w, about 2.5% w / w, about 3% w / w, or about 3.5% w / w.

[0250] In some embodiments, the disintegrants are sodium starch glycolate, alginic acid, Selected from the group consisting of sodium alginate, anion exchange resins, and combinations thereof. It is selected.

[0251] In some embodiments, the disintegrant is sodium starch glycolate or crosca In some embodiments, sodium starch glycolate is The gel is present in an amount of about 0.5% to about 5% w / w of the total composition. For example, about 0. 5% to about 2.5% w / w, about 2.5% to about 5% w / w, or about 1% to about 4% w / w. In some embodiments, sodium starch glycolate is present in an amount of about 1% of the total composition. ~2% w / w, ~1.5%~2.5% w / w, ~2%~3% w / w, ~2.5%~ It is present in an amount of about 3.5% w / w, or about 3% to about 4% w / w of the total composition. About 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, or about 3.5% w / w.

[0252] In some embodiments, the composition comprises a glidant that is magnesium stearate. The glidant is present in an amount of from about 0.1% to about 1% wt / wt of the total composition weight. In embodiments, the glidant is preferably present in an amount of about 0.25% to 0.75% wt / wt of the total composition. More preferably, it is present in an amount of about 0.5% wt / wt.

[0253] In some embodiments, the first composition is present in an amount of about 90% to about 99% w / w of the total composition. In some embodiments, the pharmaceutical composition comprises a first composition, a disintegrant, and a moisturizer. In some embodiments, the first composition comprises about 90% to about 99% of the total composition. The disintegrant is present in an amount of about 0.5% to about 5% w / w of the total composition, and the moisturizer is present in an amount of about 0.5% to about 5% w / w of the total composition. The lubricant is present in an amount of about 0.05% to about 2% w / w of the total composition. The first composition is present in an amount of about 97% w / w of the total composition, and the disintegrant is present in an amount of about 97% w / w of the total composition. 2.5% w / w, and the lubricant is present in an amount of about 0.25% w / w of the total composition. .

[0254] In some embodiments, the disintegrant is sodium starch glycolate and the lubricant is Magnesium stearate. In some embodiments, sodium starch glycolate. The sodium is present in an amount of about 0.5% to about 5% w / w of the total composition, and magnesium stearate. The starch glycol is present in an amount of about 0.05% to about 2% w / w of the total composition. Sodium phosphate is about 0.5% to about 2.5% w / w of the total composition, about 2.5% to about 5% w / w Magnesium stearate is present in an amount of about 1% to about 4% w / w of the total composition. About 0.05% to about 1% w / w, about 1% to about 2% w / w, or about 0.5% to about 1.5% w / w of the substance % w / w. In some embodiments, sodium starch glycolate is present. , about 1% to about 2% w / w, about 1.5% to about 2.5% w / w, about 2% to about 3% of the total composition w / w, about 2.5% to about 3.5% w / w, or about 3% to about 4% w / w. Magnesium allyl phosphate is about 0.05% to about 0.5% w / w, about 0.1% to about 0.2% w / w, It is present in an amount of about 0.8% w / w, or about 0.5% to about 1% w / w. For example, starch Sodium glycolate is about 1.5% w / w, about 2% w / w, about 2.5% of the total composition. w / w, about 3% w / w, or about 3.5% w / w, and magnesium stearate The amount of the glycerin in the total composition is about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, or about 0.5% w / w. % w / w, or about 0.5% w / w.

[0255] In other embodiments, the first composition is present in an amount of about 15% to about 60% w / w of the total composition. For example, about 15% to about 35% w / w, about 35% to about 60% w / w, or In some embodiments, the first composition comprises about 25% to about 45% w / w of the total composition. About 20% to about 30% w / w, about 25% to about 35% w / w, about 30% to about 40% w / In some embodiments, the glycerol is present in an amount of about 35% to about 45% w / w, or about 40% to about 50% w / w. For example, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, About 40% w / w, about 45% w / w, or about 50% w / w.

[0256] In some embodiments, the binder is present in an amount of about 40% to about 85% w / w of the total composition. For example, about 40% to about 60% w / w, about 60% to about 85% w / w, or or about 55% to about 75% w / w of the total composition. , about 40% to about 50% w / w, about 45% to about 55% w / w, about 50% to about 60% w / w, About 55% to about 65% w / w, about 60% to about 70% w / w, about 65% to about 75% w / w, In some embodiments, the binder is present in an amount of about 70% to about 80% w / w. About 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 62% w / w of the composition %w / w, about 65%w / w, about 70%w / w, about 75%w / w, or about 80%w / w exist.

[0257] In some embodiments, the binder is microcrystalline cellulose, cellulose ether, hydroxypropyl cellulose, cellulose ether ... Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Sodium carboxylate Dimethylcellulose starch, methylcellulose, ethylcellulose, hydroxypropyl cellulose, mannitol, xylitol, sorbitol, lactose, sucrose, Sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol, polyvinyl selected from the group consisting of alcohols, polymethacrylates, and combinations thereof .

[0258] In some embodiments, the binder is microcrystalline cellulose, mannitol, or the like. In some embodiments, the microcrystalline cellulose comprises about 100% of the total composition. Present in an amount of 10% to about 85% w / w, e.g., about 10% to about 45% w / w of the total composition. , about 45% to about 85%, or about 20% to about 60% w / w. The microcrystalline cellulose is about 10% to about 20%, about 15% to about 25%, about 20%~30%, 25%~35%w / w, 30%~40%w / w, 35%~ It is present in an amount of about 45% w / w, or about 40% to about 50% w / w of the total composition. , about 20%w / w, about 25%w / w, about 30%w / w, about 31%w / w, about 35%w / w , about 40% w / w, or about 45% w / w.

[0259] In some embodiments, mannitol is present in an amount of about 10% to about 85% w / w of the total composition. For example, from about 10% to about 45% w / w, from about 45% to about 85%, or In some embodiments, mannitol is present in the total composition at about 20% to about 60% w / w. About 10% to about 20%, about 15% to about 25%, about 20% to about 30%, about 25% to about 3 5% w / w, about 30% to about 40% w / w, about 35% to about 45% w / w, or about 40% to It is present in an amount of about 50% w / w, e.g., about 20% w / w, about 25% w / w of the total composition. , about 30% w / w, about 31% w / w, about 35% w / w, about 40% w / w, or about 45% w / w.

[0260] In some embodiments, the microcrystalline cellulose and mannitol comprise about 1% of the total composition. For example, microcrystalline cellulose is present in an amount of about 10% to about 85% w / w of the total composition. It is present in an amount of 0% to about 45% w / w, about 45% to about 85%, or about 20% to about 60% w / w. Mannitol is present in an amount of about 10% to about 45% w / w, about 45% to about 85%, or In some embodiments, the microcrystalline cellulose is present in an amount of about 20% to about 60% w / w. Rosin is about 10% to about 20%, about 15% to about 25%, or about 20% to about 30% of the total composition. , about 25% to about 35% w / w, about 30% to about 40% w / w, about 35% to about 45% w / w, or about 40% to about 50% w / w, and mannitol is present in an amount of about 10% of the total composition. ~ about 20%, about 15% to about 25%, about 20% to about 30%, about 25% to about 35% w / w, about In amounts of 30% to about 40% w / w, about 35% to about 45% w / w, and about 40% to about 50% w / w For example, microcrystalline cellulose may be present in an amount of about 20% w / w, about 25% w / w, or about 30% w / w of the total composition. w, about 30% w / w, about 31% w / w, about 35% w / w, about 40% w / w, or about 45% w / w % w / w of the total composition, with mannitol being present in an amount of about 20% w / w, about 25% w / w , about 30% w / w, about 31% w / w, about 35% w / w, about 40% w / w, or about 45% Present in w / w amount.

[0261] In some embodiments, the first composition is blended with one or more pharmaceutical excipients. In some embodiments, the pharmaceutical compositions are co-milled.

[0262] In some embodiments, the pharmaceutical compositions described herein are formulated as tablets. In some embodiments, the compound of formula I is present in a pharmaceutical composition formulated as a tablet in an amount of about 1 For example, about 10 mg to about 30 mg, about 30 mg to about In some embodiments, the compound of formula I is The compound is preferably present in a pharmaceutical composition formulated as a tablet at a concentration of about 10 mg to about 20 mg, about 15 mg to about 20 mg, or about 15 mg to about 20 mg. About 25 mg, about 30 mg to about 40 mg, about 35 mg to about 45 mg, or about 40 mg to about For example, about 10 mg, about 15 mg, about 20 mg, about 25 mg, About 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg.

[0263] In some embodiments, the compound of formula I is present in a pharmaceutical composition formulated as a tablet. It is present in an amount of about 25 mg to about 220 mg. For example, about 25 mg to about 120 mg, about 120 mg, In some embodiments, the amount is from about 70 mg to about 170 mg. The compound of formula I is present in a pharmaceutical composition formulated as a tablet in an amount of about 25 mg to about 75 mg. Approximately 50mg to approximately 100mg, approximately 75mg to approximately 125mg, approximately 100mg to approximately 150mg, About 125 mg to about 175 mg, about 150 mg to about 200 mg, or about 175 mg to about 2 In some embodiments, the compound of formula I is present in an amount of about 50 mg to about 6 0 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, Approximately 85mg to approximately 95mg, approximately 90mg to approximately 100mg, 80mg to approximately 120mg, approximately 95 mg ~ approx. 105 mg, approx. 100 mg ~ approx. 110 mg, approx. 105 mg ~ approx. 115 mg, approx. 1 20mg to about 130mg, about 130mg to about 140mg, about 140mg to about 150mg, About 150mg to about 160mg, about 160mg to about 170mg, or about 170mg to about 1 For example, about 50 mg, about 55 mg, about 60 mg, about 65 mg, About 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100 mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 1 30mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, About 160 mg, about 170 mg, about 175 mg, or about 180 mg.

[0264] In some embodiments, the tablets are coated.

[0265] As used herein, a compound of formula I, an HPMCAS polymer, and one or more pharmaceutical excipients are Pharmaceutical compositions comprising the excipient are also provided. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

[0266] In some embodiments, the one or more pharmaceutical excipients include fillers, lubricants, and the like. The compound is selected from the group consisting of:

[0267] In some embodiments, the filler is glucose, sucrose, lactose, starch. [Modified starch such as sodium starch glycolate (EXPLOTAB®)] [Contains glycerin], xylitol, dextrin, sucrose, sorbitol, mannitol [For example, PARTECK (registered trademark) M200 (average particle size is about 50 μm to about 500 μm mannitol), PARTECK® M100 (average particle size of less than 212 μm) mannitol)], cellulose, polyvinylpyrrolidone, polyethylene glycol, poly Vinyl alcohol, polymethacrylate, dibasic calcium phosphate, magnesium stearate Nesium, calcium stearate, sodium stearate, stearic acid, hydrogenated plant Oil, mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, palmitostearin Glyceryl acetate, Sodium benzoate, Sodium stearyl fumarate, Colloidal dioxide Silicon (e.g., sodium benzoate, sodium oleate, sodium acetate, arigi Acids, alginates (e.g., sodium alginate), calcium silicate, ion exchange Resins, or combinations thereof. In an embodiment, the cellulose is microcrystalline cellulose (e.g., AVICEL® P H-101 (microcrystalline cellulose with an average particle size of approximately 50 μm) or AVICEL (registered trademark Target) PH200 (microcrystalline cellulose with an average particle size of approximately 180 μm), methylcellulose , ethyl cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a combination thereof. In some embodiments, the polyvinylpyrrolidone is KOLLIDON® ) CL (crospovidone with an average particle size of 90 μm to 130 μm), or KOLLIDON (registered trademark) CL-SF (crospovidone with an average particle size of 10 μm to 30 μm) and other crosslinking agents It is polyvinylpyrrolidone.

[0268] In some embodiments, the filler is selected from the group consisting of a binder, a disintegrant, or a combination thereof. In some embodiments, the binder is selected from microcrystalline cellulose, cellulose acetate, cellulose acetate ester, and the like. cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium Carboxymethylcellulose starch, methylcellulose, ethylcellulose, hydrocellulose xypropyl cellulose, mannitol, xylitol, sorbitol, lactose, cellulose, sorbitol, gelatin, polyvinylpyrrolidone, polyethylene glycol, From the group consisting of polyvinyl alcohol, polymethacrylate, and combinations thereof In some embodiments, the disintegrant is sodium starch glycolate, a alginic acid, sodium alginate, anion exchange resins, and combinations thereof The compound is selected from the group consisting of:

[0269] In some embodiments, the lubricant is magnesium stearate, calcium stearate, Urea, Sodium Stearate, Stearic Acid, Hydrogenated Vegetable Oil, Mineral Oil, Polyethylene Glycol Cole, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate Lyceryl, Sodium Benzoate, Sodium Stearyl Fumarate, Colloidal Silicon Dioxide sodium benzoate, sodium oleate, sodium acetate, and combinations thereof The combination is selected from the group consisting of

[0270] In some embodiments, the pharmaceutical composition comprises a compound of formula I, an HPMCAS polymer, a conjugate The composition includes a binder, a disintegrant, and a lubricant.

[0271] In some embodiments, the pharmaceutical composition is present in an amount of about 5% to about 30% w / w of the total composition. and HPMCAS present in an amount of about 5% to about 30% w / w of the total composition. A polymer, a binder present in an amount of about 10% to about 90% w / w of the total composition, Disintegrants present in an amount of about 0.5% to about 5% w / w and from about 0.05% to about 2% w / w of the total composition. and a lubricant present in an amount of about 1:1 wt. / wt. In some embodiments, the compound of formula I is The HPMCAS polymer is present in an amount of about 5% to about 15% w / w of the total composition. The binder is present in an amount of about 70% to about 85% w / w of the total composition. The disintegrant is present in an amount of about 2.5% to about 4.5% w / w of the total composition, and the lubricant is present in an amount of about 2.5% to about 4.5% w / w of the total composition. For example, the compound of formula I is present in an amount of about 8% to about 1% w / w of the total composition. % w / w of the total composition, and the HPMCAS polymer is present in an amount of about 8% w / w of the total composition. The binder is present in an amount of about 80% w / w of the total composition, and the disintegrant is present in an amount of about 3.5% w / w of the total composition. The lubricant is present in an amount of about 0.3% w / w of the total composition. In an embodiment, the HPMCAS polymer is HPMCAS-MG.

[0272] In some embodiments, the binder is a combination of mannitol and microcrystalline cellulose. In some embodiments, the compound of formula I is present in an amount of about 5% to about 30% w / w of the total composition. and the HPMCAS polymer is present in an amount of about 5% to about 30% w / w of the total composition; Mannitol and microcrystalline cellulose are present in an amount of about 10% to about 90% w / w of the total composition. the disintegrant is present in an amount of about 0.5% to about 5% w / w of the total composition, and the lubricant is present in an amount of about 0.5% to about 5% w / w of the total composition. In some embodiments, the compound of formula I is present in an amount of about 0.05% to about 2% w / w. The HPMCAS polymer is present in an amount of about 5% to about 15% w / w of the total composition. Mannitol and microcrystalline cellulose are present in an amount of 5% to about 15% w / w of the total composition. and the disintegrant is present in an amount of about 2.5% to about 4.5% of the total composition. The lubricant is present in an amount of about 0.1% to about 1% w / w of the total composition. For example, the compound of formula I is present in an amount of about 8% w / w of the total composition and the HPMCAS polymer is , is present in an amount of about 8% w / w of the total composition, and mannitol and microcrystalline cellulose are The disintegrant is present in an amount of about 3.5% w / w of the total composition. In some embodiments, the lubricant is present in an amount of about 0.3% w / w of the total composition. butylitol and microcrystalline cellulose in a ratio of about 4:1, about 3:2, about 1:1, about 2:3, or In some embodiments, the HPMCAS polymer is present in a ratio of about 1:4. It is AS-MG.

[0273] In some embodiments, the disintegrant is sodium starch glycolate. In one embodiment, the compound of formula I is present in an amount of about 5% to about 30% w / w of the total composition, and HP The MCAS polymer is present in an amount of about 5% to about 30% w / w of the total composition, and the binder is and sodium starch glycolate is present in an amount of about 10% to about 90% w / w of the total composition. and the lubricant is present in an amount of about 0.05% to about 2% w / w of the total composition. In some embodiments, the compound of formula I is present in an amount of about 5% to about 1% by weight of the total composition. 5% w / w, and the HPMCAS polymer is present in an amount of about 5% to about 15% w / w of the total composition. The binder is present in an amount of about 70% to about 85% w / w of the total composition, and the starch The sodium cholate is present in an amount of about 2.5% to about 4.5% w / w of the total composition, and the lubricant is The compound of formula I is present in an amount of about 0.1% to about 1% w / w of the total composition. and the HPMCAS polymer is present in an amount of about 8% w / w of the total composition. and the binder is present in an amount of about 80% w / w of the total composition, sodium starch glycolate. The thorium is present in an amount of about 3.5% w / w of the total composition, and the lubricant is present in an amount of about 0.3% w / w of the total composition. In some embodiments, the HPMCAS polymer is present in an amount of HPMCAS- It's MG.

[0274] In some embodiments, the lubricant is magnesium stearate. In the form, the compound of formula I is present in an amount of about 5% to about 30% w / w of the total composition, and HPMCA The S polymer is present in an amount of about 5% to about 30% w / w of the total composition, and the binder is present in an amount of about 1% to about 30% w / w of the total composition. The disintegrant is present in an amount of about 0.5% to about 5% w / w of the total composition. and magnesium stearate is present in an amount of about 0.05% to about 2% w / w of the total composition. In some embodiments, the compound of formula I is present in an amount of about 5% to about 15% w / w of the total composition. and the HPMCAS polymer is present in an amount of about 5% to about 15% w / w of the total composition; The binder is present in an amount of about 70% to about 85% w / w of the total composition, and the disintegrant is present in an amount of about 2. Magnesium stearate is present in an amount of about 0.1% to about 4.5% w / w of the total composition. For example, the compound of formula I is present in an amount of about 8% w / w of the total composition. The HPMCAS polymer is present in an amount of about 8% w / w of the total composition, and the binder is , in an amount of about 80% w / w of the total composition, and the disintegrant in an amount of about 3.5% w / w of the total composition. and magnesium stearate is present in an amount of about 0.3% w / w of the total composition. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

[0275] In some embodiments, the binder is a combination of microcrystalline cellulose and mannitol. The disintegrant is sodium starch glycolate, and the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 5% to about 30% w / w of the total composition. and H, present in an amount of about 5% to about 30% w / w of the total composition. PMCAS polymer and microcrystalline cellulose present in an amount of about 30% to about 60% w / w of the total composition. and mannitol, present in an amount of about 30% to about 60% w / w of the total composition. sodium starch glycolate present in an amount of about 0.5% to about 5% w / w of the total composition; Magnesium stearate present in an amount of about 0.05% to about 2% w / w of the composition. For example, the compound of formula I is present in an amount of about 8% w / w of the total composition, and the HPMCAS poly The cellulose is present in an amount of about 4% w / w of the total composition. 0% w / w, mannitol is present in an amount of about 40% w / w of the total composition, and dextran is present in an amount of about 50% w / w of the total composition. Sodium starch glycolate is present in an amount of about 3.5% w / w of the total composition, and stearin In some embodiments, the magnesium salt is present in an amount of about 0.3% w / w of the total composition. , the HPMCAS polymer is HPMCAS-MG.

[0276] In other embodiments, the pharmaceutical composition is present in an amount of about 10% to about 30% w / w of the total composition. and a compound of formula I present in an amount of about 10% to about 30% w / w of the total composition. a polymer, a binder present in an amount of about 35% to about 70% w / w of the total composition, and Disintegrants present in an amount of 2% to about 8% w / w and from about 0.05% to about 2% w / w of the total composition. and a lubricant present in an amount of about 100% of the total composition. The HPMCAS polymer is present in an amount of about 15% to about 25% w / w of the total composition. 25% w / w, and the binder is present in an amount of about 40% to about 60% w / w of the total composition. The disintegrant is present in an amount of about 4% to about 6% w / w of the total composition, and the lubricant is present in an amount of about 0.1% w / w of the total composition. For example, the compound of formula I is present in an amount of about 22% w / w of the total composition. and the HPMCAS polymer is present in an amount of about 22% w / w of the total composition, The agent is present in an amount of about 50% w / w of the total composition, and the disintegrant is present in an amount of about 5% w / w of the total composition. In some embodiments, the lubricant is present in an amount of about 0.5% w / w of the total composition. , the HPMCAS polymer is HPMCAS-MG.

[0277] In some embodiments, the binder is a combination of mannitol and microcrystalline cellulose. In some embodiments, the compound of formula I is present in an amount of about 10% to about 30% w / w of the total composition. and the HPMCAS polymer is present in an amount of about 10% to about 30% w / w of the total composition. The amount of mannitol and microcrystalline cellulose is about 35% to about 70% w / w of the total composition. the disintegrant is present in an amount of about 2% to about 8% w / w of the total composition, and the lubricant is present in an amount of about 10% to about 15% w / w of the total composition. In some embodiments, the pharmaceutical composition is present in an amount of about 0.05% to about 2% w / w. A compound of formula I present in an amount of about 15% to about 25% w / w of the total composition, and % to about 25% w / w of the total composition, and HPMCAS polymer present in an amount of about 40% to about 60% w / w of the total composition. Mannitol and microcrystalline cellulose present in an amount of 0% w / w, and approximately 4% of the total composition. A disintegrant present in an amount of about 0.1% to about 1% w / w of the total composition. For example, the compound of formula I is present in an amount of about 22% w / w of the total composition. The HPMCAS polymer is present in an amount of about 22% w / w of the total composition, and the microcrystalline cellulose The cellulose and mannitol are present in an amount of about 50% w / w of the total composition, and the disintegrant is present in an amount of about 50% w / w of the total composition. The binder is present in an amount of about 5% w / w of the total composition and the lubricant is present in an amount of about 0.5% w / w of the total composition. In some embodiments, the ratio of mannitol to microcrystalline cellulose is about 4:1, about 3:2, In some embodiments, the HP is present in a ratio of about 1:1, about 2:3, or about 1:4. The MCAS polymer is HPMCAS-MG.

[0278] In some embodiments, the disintegrant is sodium starch glycolate. In one embodiment, the compound of formula I is present in an amount of about 10% to about 30% w / w of the total composition, The PMCAS polymer is present in an amount of about 10% to about 30% w / w of the total composition, and the binder is The sodium starch glycolate is present in an amount of about 35% to about 70% w / w of the total composition. The lubricant is present in an amount of about 0.05% to about 2% w / w of the total composition. In some embodiments, the compound of formula I is present in an amount of about 15% to about 15% by weight of the total composition. 25% w / w, and the HPMCAS polymer is present in an amount of about 15% to about 25% w / w of the total composition. The binder is present in an amount of about 40% to about 60% w / w of the total composition, and the starch The sodium glycolate is present in an amount of about 4% to about 6% w / w of the total composition, and the lubricant is For example, the compound of formula I may be present in an amount of about 0.1% to about 1% w / w of the total composition. The HPMCAS polymer is present in an amount of about 22% w / w of the total composition. and the binder is present in an amount of about 50% w / w of the total composition, sodium starch glycolate. The thorium is present in an amount of about 5% w / w of the total composition, and the lubricant is present in an amount of about 0.5% w / w of the total composition. In some embodiments, the HPMCAS polymer is present in an amount of HPMCAS-MG It is.

[0279] In some embodiments, the lubricant is magnesium stearate. In the form, the compound of formula I is present in an amount of about 10% to about 30% w / w of the total composition, and HPMC The AS polymer is present in an amount of about 10% to about 30% w / w of the total composition, and the binder is present in an amount of about 10% to about 30% w / w of the total composition. The disintegrant is present in an amount of about 2% to about 8% w / w of the total composition. and magnesium stearate is present in an amount of about 0.05% to about 2% w / w of the total composition. In some embodiments, the compound of formula I is present in an amount of about 15% to about 25% w / w of the total composition. and the HPMCAS polymer is present in an amount of about 15% to about 25% w / w of the total composition. The binder is present in an amount of about 40% to about 60% w / w of the total composition, and the disintegrant is present in an amount of about 4% to about 6% w / w, and magnesium stearate is present in an amount of about 0.1% to about 6% w / w of the total composition. For example, the compound of formula I is present in an amount of about 22% w / w of the total composition. wherein the HPMCAS polymer is present in an amount of about 22% w / w of the total composition, and the binder is , present in an amount of about 50% w / w of the total composition, and the disintegrant, present in an amount of about 5% w / w of the total composition. and magnesium stearate is present in an amount of about 0.5% w / w of the total composition. In an embodiment, the HPMCAS polymer is HPMCAS-MG.

[0280] In some embodiments, the pharmaceutical composition is present in an amount of about 10% to about 30% w / w of the total composition. A compound of formula I present and HPMC present in an amount of about 10% to about 30% w / w of the total composition. The AS polymer and the microcrystalline cellulose present in an amount of about 20% to about 30% w / w of the total composition. and mannitol present in an amount of about 20% to about 30% w / w of the total composition. Sodium starch glycolate present in an amount of about 2% to about 8% w / w of the total composition and magnesium stearate present in an amount of 0.05% to about 2% w / w. In some embodiments, the HPMCAS polymer is HPMCAS-MG.

[0281] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) present in an amount of about 22% w / w of the total composition. Compound I, HPMCAS polymer present in an amount of about 22% w / w of the total composition, Microcrystalline cellulose present in an amount of about 25% w / w of the total composition and starch glycol present in an amount of about 5% w / w of the total composition. sodium phosphate and magnesium stearate present in an amount of about 0.5% w / w of the total composition. In some embodiments, the HPMCAS polymer comprises HPMCAS-MG It is.

[0282] In some embodiments, the pharmaceutical compositions described herein are formulated as tablets. In some embodiments, the tablets are coated.

[0283] Also provided herein are methods for preparing the pharmaceutical compositions described herein, the methods comprising: , mixing a compound of formula I, an HPMCAS polymer, and a solvent to form a solution; spray drying the solution to form a spray-dried dispersion; and granulating the spray-dried dispersion to form a first composition.

[0284] In some embodiments, the HPMCAS polymer is HPMCAS-MG.

[0285] In some embodiments, the solvent is an organic solvent. The solvents used were methanol, acetone, dichloromethane, tetrahydrofuran, and combinations thereof. In some embodiments, the solvent is selected from the group consisting of an organic solvent and water. In some embodiments, the solvent is a mixture of tetrahydrofuran and water. In some embodiments, the mixture is 95:5 tetrahydrofuran:water. In some embodiments, the organic solvent is a mixture of dichloromethane and methanol. In some embodiments, the organic solvent is 80:20 dichloromethane:methanol.

[0286] In some embodiments, the spray dried dispersion may be granulated with one or more pharmaceutical agents. In some embodiments, the spray-dried dispersion is blended with excipients prior to granulation. In some embodiments, the spray-dried dispersion is dried in an oven prior to being granulated. In some embodiments, the spray-dried composition is blended with one or more pharmaceutical excipients. The dispersion is granulated by roller compaction.

[0287] In some embodiments, the first composition is blended with one or more pharmaceutical excipients. In some embodiments, the first composition is co-milled. The first composition is then compressed into a tablet. In some embodiments, the tablet is coated. In some embodiments, the coating comprises a polymer, a plasticizer, a pigment, or Including combinations thereof.

[0288] In some embodiments, the compound of formula I and the HPMCAS polymer in the spray-dried dispersion In some embodiments, the ratio of the compound of formula I to HP is about 1:4 to about 4:1. The ratio of MCAS polymer is about 4:1, about 3:1, about 7:3, about 13:7, about 3:2, about 11:9, approx. 1:1, approx. 9:11, approx. 2:3, approx. 7:13, approx. 3:7, approx. 1:3, or In some embodiments, the ratio of the compound of formula I to the HP in the spray-dried dispersion is about 1:4. The ratio of MCAS polymer to MCAS is about 1:1. The ratio of the compound of formula I to the HPMCAS polymer in the In an embodiment, the HPMCAS polymer is HPMCAS-MG.

[0289] Compounds of formula I, or pharma- ceutically acceptable salts thereof, amorphous or polymorphic forms thereof, The daily dosage of the spray-dried dispersion or a pharmaceutical composition thereof is about 100 mg / day per adult. 1.0 to 10,000 mg or more, or any broad range therein When administered orally, the composition can be administered in an amount appropriate for the symptoms of the subject being treated. The active ingredient for conditioning is 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, It is preferably provided in the form of tablets containing 475 and 500 milligrams. The dosage is usually about 0.1 mg / kg to about 1000 mg / kg of body weight per day, or The range is from about 0.5 to about 500 milligrams per day. g / kg body weight, or any range therein. The range may be from about 1.0 to about 250 mg / kg body weight, or any range therein. The range is from about 0 to 250 mg / kg body weight per day. It may be from about 0.1 to about 100 mg / kg body weight, or any range therein. is about 0.1 to about 50.0 mg / kg body weight per day, or any amount or range therein. As another example, the range may be from about 0.1 to about 15.0 mg / kg of body weight per day. As yet another example, the range may be from about 0 to about 100 mg / day. The dosage may range from about 0.5 to about 7.5 mg / kg body weight, or any amount or range therein. The pharmaceutical compositions provided herein may be administered on a regimen of 1 to 4 times per day, or in a single daily dose. It can be done.

[0290] Optimal dosages to be administered can be readily determined by those skilled in the art and will vary depending on the mode of administration, preparation, It will vary with the strength of the agent, the mode of administration, and the advancement of the disease state. Dosage may vary depending on factors related to the particular subject being treated, including the subject's age, weight, diet, and time of administration. Dosage adjustments may be necessary.

[0291] Those skilled in the art will recognize that suitable known and generally accepted cell and / or animal models are readily available. Both the in vivo and in vitro tests used are intended to treat or prevent a given disorder. It will be appreciated that the present invention predicts the potency of compounds.

[0292] The artisan will further appreciate that the present invention relates to the detection of HIV-1 markers in healthy subjects and / or subjects suffering from a given disorder. First-in-human clinical trials, dose-ranging and efficacy studies in mice have been performed in clinical and medical settings. It will be appreciated that this can be accomplished by methods well known in the art. Determining the appropriate dosage for a patient will depend on the weight, age, and other factors that influence the patient's age, the compound of Formula I, the dosage form, and the dosage regimen. and biologically acceptable salts, or combinations thereof, and body surface area (BSA) clearance. It is possible to establish a pharmacokinetic approach for dosing that takes into account the occurrence of drug-drug interactions. Simcyp® Pediatric Simulation modeling ( Using known methods, including models from CERTARA, Princeton, NJ can be determined.

[0293] 2. Polymorph The present disclosure also provides (S)-5-amino-3-(4-((5-fluoro-2- Methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane -2-yl)-1H-pyrazole-4-carboxamide [ka] and crystalline forms of pharma-ceutically acceptable salts thereof, pharmaceutical compositions comprising crystalline forms of the compound of formula I A process for making a crystalline form of the compound of formula I, and a method for treating BTK-related diseases and disorders and the like. In the treatment and prevention of diseases treatable by BTK kinase inhibitors, including The present invention relates to the use of a crystalline form of the compound of the present invention.

[0294] Provided herein are polymorphic forms of the compound of formula I. Forms include, for example, polymorphic forms of the compound of formula I. The term "solvate" includes the free base, solvates, hydrates, salts, and unsolvated forms of the compound, e.g., polymorphic forms. In some embodiments, the polymorphic form of the compound of formula I is a pharma- ceutically acceptable salt. It is.

[0295] Form A One such polymorph is the polymorph of the compound of formula I known as Form A. In embodiments, Form A has a solubility of 11.9±0.2, 15.8±0.2, and 16.2±0. XRPD patterns obtained with CuKα1 radiation with at least a peak at a 2θ value of 0.2 In some embodiments, Form A has a β-amyloid profile of 11.9±0.2, 15.8±0. 2, 16.2±0.2, 18.3±0.2, and 19.0±0.2°2θ values. In some embodiments, Form A has an XRPD pattern having peaks at 1 1.9±0.2, 15.8±0.2, 16.2±0.2, 18.3±0.2, 19.0± The sample had at least peaks at °2θ values ​​of 0.2, 20.5±0.2, and 23.8±0.2. In some embodiments, Form A has an XRPD pattern of 9.5±0.2, 11.9±0.2, 15.8±0.2, 16.2±0.2, 18.3±0.2, 19.0 ±0.2, 20.1±0.2, 20.5±0.2, 23.8±0.2, and 25.7± It has an XRPD pattern with at least a peak at a °2θ value of 0.2. In some embodiments, Form A has a pH of 9.5±0.2, 11.1±0.2, 11.9±0.2 , 15.8±0.2, 16.2±0.2, 18.3±0.2, 19.0±0.2, 20. 1 ± 0.2, 20.5 ± 0.2, 23.8 ± 0.2, 25.0 ± 0.2, and 25.7 It has an XRPD pattern with at least peaks at °2θ values ​​of ±0.2.

[0296] In some embodiments, provided herein are compositions comprising polymorphic Form A. In some embodiments, the composition may be substantially pure. For example, the composition may be at least about 90 % purity. In some embodiments, the compositions have a purity of at least about 95%. In some embodiments, the composition has a purity of at least about 98%. The composition is at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, or 9%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 9 It may have a purity of 9.7%, 99.8%, or 99.9%. In some embodiments, The composition is substantially free of other forms of the compound of formula I. In some embodiments, the composition The composition contains less than about 15% by weight of other forms of the compound of formula I. For example, the composition may contain less than about 14% by weight of the compound of formula I. %, 13% by weight, 12% by weight, 11% by weight, 10% by weight, 9% by weight, 8% by weight, 7% by weight , 6% by weight, 5% by weight, 4% by weight, 3% by weight, 2% by weight, or less than 1% by weight For example, the composition may contain less than about 15% of the amorphous form. It may include.

[0297] In some embodiments, the sorbed water has a molecular weight of about 185 to about 185% by DSC. Provided herein is polymorphic form A, which exhibits an endotherm observed at 195° C., e.g., about 189.9° C. It will be offered.

[0298] In some embodiments, provided herein is a method for producing a medicament for the treatment of a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of a medicament for the treatment of a pulmonary artery disease, as measured by TGA. , a polymorphic form of the compound of formula I, which exhibits a weight loss of about 0.14% from the start of heating to about 150° C. The state is A.

[0299] Also provided herein is a method for preparing polymorph Form A. In some embodiments, the polymorph has the formula Polymorphic Form A of the compound of formula I can be prepared by dissolving the compound of formula I in a polar protic solvent to give the compound of formula I. In some embodiments, the polar protic solvent is prepared by forming a solution of In some embodiments, the method comprises dissolving a solution of a compound of formula I in about 100 mL of methanol. In some embodiments, the water is added at a rate of about 5 mL / min. to the solution of the compound of Formula I over a period of about 2 hours. The compound of formula I may be precipitated from solution to form a suspension comprising a solid of the compound of formula I suspended in a solvent. In some embodiments, the method comprises heating the suspension at a rate of about 10° C. / hour for about 1 hour. In some embodiments, the method further comprises cooling the cooled suspension to 5° C. The method further includes stirring the suspension at room temperature for about 10 to 20 hours, for example, about 15 hours. In an embodiment of the method, the solid of the compound of formula I is isolated from the suspension by filtration. In some embodiments, the solid of the compound of formula I is dried. In embodiments, the solid of the compound of Formula I is dried under vacuum. The solids are dried at about 55°C.

[0300] In some embodiments, polymorphic Form A of the compound of formula I is a compound of formula I that is substituted with a polar proton. In some embodiments, the compound is prepared by adding the compound to a solvent to form a mixture. The mixture is heated until a solution is formed. The solvent is isopropanol, ethanol, water, or a combination thereof. In some embodiments, the polar protic solvent is isopropanol. In the second step, the solution is slowly cooled to room temperature. In some embodiments, the solution is cooled In some embodiments, the solution is added to a reactor containing water. In some embodiments, the solution is polish filtered before being added to the reactor. In some embodiments, the compound of formula I is precipitated from the solution to form a compound of formula I suspended in the solvent. In some embodiments, the method comprises the step of: and isolating the solid from the suspension by filtration. In some embodiments, the solid of formula I The solid of the compound is dried. In some embodiments, the solid of the compound of formula I is dried under vacuum. In some embodiments, the solid is dried at about 55° C.

[0301] In some embodiments, the compound of formula I may be used in polar protic and non-polar solvents, e.g. It is crystallized using ethanol or ethyl acetate and heptane. Polymorphic Form A of the compound of formula I can be prepared by adding the compound of formula I to a polar protic solvent to form a mixture. In some embodiments, the mixture is prepared by forming a solution. In some embodiments, the mixture is heated to about 70° C. In some embodiments, the polar protic solvent is ethanol. The solution is cooled and charged with seeds of Form A of the compound of Formula I to form a charged solution. In some embodiments, the solution is cooled to about 59° C. The solution is polish filtered before being cooled. In some embodiments, the loaded solution is about 55 The mixture is cooled to 30° C. and heptane is added to the charged solution. In some embodiments, the heptane is added dropwise over a period of about 4 hours. In some embodiments, the compound of formula I is precipitated from the charged solution and suspended in the solvent. In some embodiments, the suspension comprises about 100% solids of the compound of formula I. In some embodiments, the suspension is cooled to about 15° C. over about 1 hour. In some embodiments, the method further comprises: filtering the solid of the compound of formula I through filtration and cooling. Thus, the solid of the compound of formula I is isolated from the suspension. In some embodiments, the solid of the compound of Formula I is dried under vacuum. In some embodiments, the solids are dried at about 55°C.

[0302] In some embodiments, the compound of formula I may be used in polar protic and non-polar solvents, e.g. It is crystallized using ethanol or ethyl acetate and heptane. Polymorphic Form A of the compound of formula I can be prepared by adding the compound of formula I to a polar protic solvent to form a mixture. In some embodiments, the mixture is prepared by forming a solution. In some embodiments, the mixture is heated to about 75° C. In some embodiments, the polar protic solvent is ethyl acetate. The solution is cooled and charged with seeds of Form A of the compound of Formula I to form a charged solution. In some embodiments, the solution is cooled to about 45° C. before being filled. In embodiments, the solution is polish filtered before being cooled. In some embodiments, the compound of formula I is The compound of formula I precipitates from the solution to give a suspension containing the solids suspended in the solvent. In some embodiments, the suspension is incubated with ink to form a suspension. In some embodiments, the suspension is incubated at about 45°C. In some embodiments, the suspension is incubated overnight. In some embodiments, the incubated suspension is cooled. The cooled suspension is cooled to about 24° C. In some embodiments, the method comprises reacting a compound of formula I and isolating the compound solids from the incubated suspension by filtration. In some embodiments, the solid of the compound of Formula I is dried. The solid of the compound of formula I is dried under vacuum. In some embodiments, the solid is dried at about 55° C. It is dried in.

[0303] Forms B and C In addition to Form A, other forms of the compound of formula I have been observed. Form B is a mixture with Form A. The DSC of a mixture of Forms A and B shows an onset of about 120 °C and possibly The melting of B at about 145° C. shows a small exotherm with the onset of melting at about 145° C. Following the melting, there is an exothermic event due to the conversion of the melt to Form A. Onset temperature 180°C. The endothermic event at is due to the melting of Form A. To determine the DSC curve of Form B, A pure sample of B is required.

[0304] In some embodiments, Form B of the compound of formula I can be prepared by: 1) dissolving the compound of formula I in methanol; 2) mixing with Form A by stirring the solution. In some embodiments, the solution is prepared by stirring at a temperature of about 20° C. to about 30° C. In some embodiments, the solution is stirred at about 25° C. In the method of the present invention, the compound of formula I precipitates from the solution to form a solid suspension of the compound of formula I in a solvent. In some embodiments, the method provides a suspension containing a solid of the compound of formula I by filtration. In some embodiments, the solid of the compound of formula I is dried. In some embodiments, the solid of the compound of formula I is dried under vacuum. In an embodiment, the solids are dried at about 55°C.

[0305] Form C is the hemi-1,4-dioxane formed from crystallization of the compound of formula I in 1,4-dioxane. The DSC curve for Form C shows a loss of 1,4-dioxane. The endothermic event is followed by a small exothermic event. , followed by a melting endotherm due to melting of Form A. Desolvation converts to polymorphic Form A. Prior to this, desolvation may occur to provide isomorphous desolvates or different physical forms.

[0306] In some embodiments, Form C of the compound of Formula I can be prepared by: 1) converting the compound of Formula I into a 1,4-dihydropyridine derivative. 2) by dissolving the compound of formula I in xanthene to form a solution of the compound of formula I; and In some embodiments, the solution is stirred at a temperature of about 20° C. to about 30° C. In some embodiments, the solution is stirred at about 25° C. In some embodiments, the compound of formula The compound of formula I may be precipitated from solution to form a suspension comprising a solid of the compound of formula I suspended in the solvent. In some embodiments, the method further comprises isolating the compound of formula I in solid form by filtration. In some embodiments, the solid of the compound of formula I is dried. In some embodiments, the solid of the compound of Formula I is dried under vacuum. The solids are dried at about 55°C.

[0307] XRPD patterns for crystalline forms of the compound of formula I and its pharma- ceutically acceptable salts The 2-theta values ​​may vary slightly from instrument to instrument and may be affected by variations in sample preparation and It may also vary from batch to batch, so quoted values ​​should not be taken as absolute. It will be understood that the peak positions of the XRPD patterns are not to be interpreted as being It is understood that the allowable variation is reported in angular position (2 theta) of ±0.2° 2θ. A variation of ±0.2° 2θ is expected when comparing two powder XRPD patterns. In practice, the diffraction pattern peaks from one pattern are used to measure A range of angular positions (2 theta) that is ±0.2° from the peak position is assigned to those peaks. If the ranges of peak positions overlap, the two peaks are considered to have the same angular position. For example, if the peak position of a pattern is determined to be 11.0° 2θ, The allowable variation for this is to position the peak in the range of 10.8° to 11.2° 2θ. The relative intensities of the peaks can vary depending on orientation effects. and therefore the intensities shown in the XRPD traces contained herein are exemplary; It is not intended to be used for absolute comparisons. Furthermore, for comparison purposes, XRPD trades Some variation in peak intensity from that shown on the source is acceptable. Therefore, it should be understood that "the XRPD pattern is substantially the same as that shown in FIG. 1." The phrase "absolute presence" means that, for purposes of comparison, at least 90% of the peaks shown in FIG. 1 are present. Please understand that.

[0308] The compounds provided herein also include any one or more of the atoms that constitute such compounds. The compounds of formula I may contain unnatural proportions of atomic isotopes. When referred to in relation to an atom, the atom is referred to in its natural abundance, including its naturally occurring isotopes. For example, when hydrogen is referred to, it includes all isotopes and isotopic mixtures of the atoms. teeth, 1 H, 2 H, 3 H, or mixtures thereof, and carbon is referred to When, it is 12 C. 13 C. 14 C, or mixtures thereof; When nitrogen is mentioned, it is 14 N, 15 N, or a mixture of these. It is understood that when oxygen is mentioned, 16 O. 17 O. 18 O, or a mixture of these It is understood that the present invention refers to all isotopic variations of the compounds provided herein. are intended to be included within the scope of the present invention.

[0309] For illustrative purposes, Scheme 1 illustrates the synthesis of compounds and key intermediates provided herein. A general method for the preparation is given. For a more detailed description of the individual reaction steps, see See, for example, International Patent Publication No. WO2017 / 11361, which is incorporated herein by reference in its entirety. See US Pat. No. 5,361,311. Those skilled in the art will recognize that other synthetic routes can be used to synthesize the compounds. It will be understood that certain starting materials and reagents are depicted in the schemes and described below. Other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. It can be provided. [ka]

[0310] Scheme 1 shows a general scheme for the synthesis of compounds of formula I.

[0311] 3.Treatment method Compounds of Formula I, including polymorphic forms and pharma- ceutically acceptable salts thereof, are useful as BTK inhibitors. The ability to use the method is described in International Patent Application Publication WO2017 / 103611 and in Example 1. This can be demonstrated by assays that have been used.

[0312] In some embodiments, the compounds of formula I provided herein have potent and selective B For example, compounds of formula I inhibit wild-type BTK and, for example, C481S. BTK kinases encoded by BTK genes containing BTK kinase inhibitor resistance mutations, In some embodiments, inhibition of C481S is similar to that observed for wild-type BTK.

[0313] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is amorphous, Alternatively, the polymorphic form selectively targets the BTK kinase. For example, the compound of Formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, may be used in combination with another kinase or a non-kinase The BTK kinase can be selectively targeted relative to other targets of the kinase. In an embodiment, the compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorph thereof, The morphology is BRK, CSK, ERBB4, FYN, MEK1, MEK2, TEC, TXK, YES1, BMX, BLK, EGFR, ITK, SRC, JAK1, JAK2, and J Selectively target the BTK kinase over one or more of the AK3 kinases. In an embodiment, the compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorph thereof, The form selectively targets BTK kinase over TEC kinase.

[0314] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is amorphous, Alternatively, the polymorphic form has at least 30-fold greater selectivity for the BTK kinase over another kinase. For example, the compound of formula I, or a pharma- ceutically acceptable salt thereof, amorphous or The polymorphic form is at least 40-fold more selective for the BTK kinase than for another kinase. selectivity, at least 50-fold selectivity, at least 60-fold selectivity, at least 70-fold selectivity , at least 80-fold selective, at least 90-fold selective, at least 100-fold selective , at least 200-fold selectivity, at least 300-fold selectivity, at least 400-fold selectivity Selectivity, at least 500-fold selectivity, at least 600-fold selectivity, at least 700-fold selectivity selectivity, at least 800-fold selectivity, at least 900-fold selectivity, or at least In some embodiments, the compound of formula I or its derivatives is The physiologically acceptable salts, amorphous, or polymorphic forms of BTK kinase are preferred over other kinases. In some embodiments, the kinase exhibits at least 100-fold selectivity against another kinase. In comparison, selectivity for the BTK kinase can be demonstrated using cellular assays (e.g., those provided herein). In some embodiments, the compound of formula I or a combination thereof is The physiologically acceptable salts, amorphous, or polymorphic forms of BTK kinase are preferred over other kinases. Due to its selectivity for , it exhibits lower off-target toxicity.

[0315] Compounds of formula I, or pharma- ceutically acceptable salts thereof, amorphous or polymorphic forms thereof, The spray-dried dispersion of, or a pharmaceutical composition thereof, is useful for treating BTK-related diseases and disorders, e.g. , proliferative disorders such as cancer, including hematological and solid tumors, and rheumatoid arthritis or Inflammatory and autoimmune disorders such as rheumatoid arthritis can be treated with BTK kinase inhibitors. They are useful in treating diseases and injuries.

[0316] As used herein, the present invention relates to a method for treating cancer (e.g., a BTK-associated cancer) in a patient in need of treatment. A method of treating a patient having rheumatoid arthritis is provided, comprising administering to the patient a therapeutically effective amount of a compound of formula I, or or a pharma- ceutically acceptable salt, amorphous, or polymorphic form of, or a spray-dried dispersion thereof; For example, the present invention relates to a method for treating BTK-associated cancers, and administering the pharmaceutical compositions to the patients. A method of treating a BTK-associated cancer in a subject in need thereof is provided, the method comprising: ) detecting in a sample from a subject the BTK gene, the BTK kinase, or any of them; b) detecting dysregulation of expression or activity or level of a compound of formula I; or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, and administering the dry dispersion, or a pharmaceutical composition thereof.

[0317] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression or activity or levels can include increased expression of BTK kinase, BTK gene expression, These include increased gene transcription, or increased activation or phosphorylation of the BTK kinase. In some embodiments, the BTK gene, the BTK protein, or expression of either thereof is also The dysregulation of activity or level may be due to genetic mutations (e.g., regulating the expression of a fusion protein). A BTK gene translocation resulting in at least one amino acid sequence change compared to the wild-type BTK protein. Deletions in the BTK gene that result in expression of the BTK protein, including deletions of 1 in the BTK gene that results in expression of a BTK protein with one or more point mutations Mutations, or at least one agonist of the BTK protein compared to the wild-type BTK protein Alternative splicing of BTK mRNA results in amino acid-deleted BTK protein version), or the activity of the kinase domain of the BTK protein in cells. , resulting in a selective increase in the amount of a constitutively active kinase domain of the BTK protein, Overexpression of the BTK gene in cells leads to overexpression or overexpression of the BTK protein. In some embodiments, the B The TK gene, the BTK protein, or the expression or activity or level of either of them Dysregulation of BELL is mediated by BTK genes that are constitutively active or do not contain mutations Encodes a BTK protein having increased activity compared to the encoded protein The BTK gene may be a mutation. Non-limiting examples of BTK mutations (and fusions) are shown in Table 1. The BTK gene, the BTK protein, or expression of either thereof A further example of dysregulation of activity or levels is a BTK inhibitor resistance mutation. Non-limiting examples of BTK resistance mutations are listed in Tables 2 and 3.

[0318] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression or activity or levels of the BCR complex or downstream signaling components Activating mutations in the molecule result in interaction with microbial or autoantigens present in the tissue microenvironment. This may result in persistent BCR stimulation or a pathogenic increase in BTK protein expression or activation. This is a ligand-independent sustained BCR signaling pathway. For example, the BTK gene, BT Dysregulation of the expression or activity or levels of K proteins, or any of them , genetic mutations in BCR signaling pathway proteins (e.g., expression of fusion proteins) BCR signaling pathway gene translocations that result in expression of wild-type BCR signaling pathway proteins BCR signaling pathway protein that contains at least one amino acid deletion compared to the protein A deletion or multiple deletions of BCR signaling pathway genes that result in expression of a gene BCR signaling pathway leading to expression of mutated BCR signaling pathway proteins Mutations in genes, BCR signaling pathway proteins compared to wild-type proteins BCR signaling leading to deletion of at least one amino acid in a transduction pathway protein Alternative splicing of BCR signaling pathway protein mRNAs leading to pathway proteins Non-limiting examples of BCR signaling pathway mutations include: These are listed in Table 4.

[0319] In some embodiments, the compound of formula I is in a polymorphic form. The compound of formula I is polymorphic Form A.

[0320] In some embodiments, the spray-dried dispersion comprises a compound of formula I and an HPMCAS polymer. In some embodiments, the pharmaceutical composition comprises a spray-dried dispersion of a compound of formula I, In some embodiments, the HPMCAS polymer comprises HPM It is CAS-MG.

[0321] Compounds of formula I, or pharma- ceutically acceptable salts thereof, amorphous or polymorphic forms thereof, A spray-dried dispersion of, or a pharmaceutical composition thereof, may also be used to treat BTK-associated cancers. It is useful.

[0322] In some embodiments of any of the methods or uses described herein, the present invention relates to a method for treating cancer (e.g. , BTK-associated cancers) are hematological cancers. In some embodiments, the cancer (e.g., a BTK-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the present invention relates to a method for treating cancer (e.g., BTK The B-cell related cancers are B-cell malignancies. In some embodiments, the cancer (e.g., a BTK-associated cancer) is Hodgkin's lymphoma, diffuse large intestinal cancer, or diffuse large intestinal cancer. Large B-cell lymphoma (DLBCL) (e.g., activated B-cell-like DLBCL (ABC -DLBCL), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., Extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom's lymphoma Thorem's macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system Nervous system lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia (CLL), acute lymphocytic Leukemia (ALL), B-cell prolymphocytic leukemia, precursor B lymphoblastic leukemia, hairy cell leukemia Hematologic malignancies, acute myeloid leukemia (AML), chronic myeloid leukemia, multiple myeloma, plasma cell myeloma , plasmacytoma, bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer , lung cancer, colon cancer, uterine cancer, hepatocellular carcinoma, head and neck cancer, or glioma.

[0323] In some embodiments, a hematological cancer (e.g., a hematological cancer that is a BTK-associated cancer) Leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma) ), and myelomas, e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), ML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia blood disease (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL) , acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia blood disease (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, trilineage bone marrow AML with dysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplasia Myeloproliferative Disorders (MDS), Myeloproliferative Disorders (MPD), Diffuse Large B-cell Lymphoma (DLB) CL) (e.g., activated B-cell-like DLBCL (ABC-DLBCL)), follicular lymphoma lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma, splenic Visceral marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (Lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma Lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myeloid leukemia, anaplastic large cell leukemia Lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma (MM) Further examples of hematological cancers include polycythemia vera (PV), Essential thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF / IPF / PMF) In one embodiment, the present invention includes hematological cancers (e.g., B TK-related cancers (blood cancers) include mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphoma. pulmonary lymphoma, Waldenström macroglobulinemia, or marginal zone lymphoma be.

[0324] In some embodiments, the BTK-associated cancer is not transformed. Non-limiting examples of transformations in cancer include Richter's transformation, prolymphocytic transformation (e.g. For example, prolymphocytic transformation of CLL, transformed non-Hodgkin's lymphoma, and blastoma. and cytoid lymphomas (e.g., blastoid variant mantle cell lymphoma).

[0325] In some embodiments, the BTK-associated cancer is a cancer known to involve the central nervous system by lymphoma. It is not a cancer that is being treated.

[0326] In some embodiments, the cancer (e.g., a BTK-associated cancer) is a solid tumor. Examples of tumors (e.g., solid tumors that are BTK-associated cancers) include, for example, bone cancer, bone metastases, breast Cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, liver cancer These include, for example, uterine cancer, head and neck cancer, and glioma. Incorporated herein, Campbell, et al., Journal of Cli nical Medicine,2018,7(4):62 and Zucha et al. al., Oncotarget.6(15):13255-68, 2015 sea ​​bream.

[0327] In some embodiments, the B cell malignancy is a B cell non-Hodgkin's lymphoma, In some embodiments, the B cell malignancy is hodgkin's lymphoma, leukemia, or B cell leukemia. Lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., activated B-cell ABC-DLBCL), follicular lymphoma, mantle cell lymphoma, marginal lymphoma Zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's Lymphoma, Waldenström's macroglobulinemia (lymphoplasmacytic lymphoma (L PL), primary central nervous system lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia, acute Myocardial Lymphoblastic Leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia disease, or hairy cell leukemia.

[0328] In some embodiments, the subject has active uncontrolled autoimmune cytopenia. In some embodiments, the subject has not been diagnosed with an autoimmune cytopenia. In some embodiments, the subject receives a steroid injection within 6 months of starting a treatment described herein. , clinically significant, uncontrolled cardiac disease, cardiovascular disease, or a history of myocardial infarction In some embodiments, the subject has not been diagnosed with heart disease or cardiovascular disease. In some embodiments, the subject does not have a myocardial infarction. In some embodiments, the subject does not have a clinically significant active malabsorption syndrome. The subject has not been diagnosed with a malabsorption syndrome. In some embodiments, the subject is During any of the treatments described in In some embodiments, the subject is not being treated with a toxic or inducing agent as described herein. Patients receiving proton pump inhibitor therapy within 7 days of starting any of the above treatments In some embodiments, the subject does not have an active second malignancy. In some embodiments, the subject has an active second malignancy that is in remission, and the subject's average Life expectancy is more than two years.

[0329] In some embodiments, the subject is a human. In some embodiments, the subject is BTK inhibitor naive. In other embodiments of any of the methods or uses, the subject is not BTK inhibitor naive. stomach.

[0330] Thus, the present disclosure provides methods for treating BTK-associated cancers, such as the exemplary cancers disclosed herein. Methods of treating a subject diagnosed or identified as having any of the BTK-associated cancers are also provided. and administering to the subject a therapeutically effective amount of a compound of formula I, or a compound thereof, as defined herein. Pharmaceutically acceptable salts, amorphous or polymorphic forms, spray-dried dispersions thereof, or The method includes administering these pharmaceutical compositions.

[0331] Expression or non-expression of BTK kinase, the BTK gene, or any one or more thereof Dysregulation of the activity or levels of BTK kinase can contribute to tumorigenesis. , the BTK gene, or kinase, or the expression or activity of any of them. Dysregulation of levels of BTK kinase, the BTK gene, or the BTK kinase domain It may be overexpressed, activated, amplified, mutated, or translocated. In some embodiments, the BT Dysregulation of K kinases leads to aberrant cell signaling (e.g., compared to control non-cancer cells). Due to transmission and / or dysregulated autocrine / paracrine signaling, mammalian increased expression (e.g., increased levels) of wild-type BTK kinase in human cells, may be increased activation (e.g., increased phosphorylation). Increased expression of BTK kinase may be due to increased transcription of the BTK gene. In embodiments, dysregulation of BTK kinase is indicative of a deficiency in a cancer cell (e.g., when compared to a control non-cancer cell). ) e.g., aberrant cell signaling and / or autocrine / paracrine signaling Increased expression of wild-type BTK kinase in mammalian cells due to (e.g., increased In some embodiments, the dysregulation of BTK kinase can be (e.g., at elevated levels). For example, the activation may be hyperactivation (e.g., compared to a control non-cancer cell). The hyperactivation may be due to increased phosphorylation of BTK. Mutations in the gene affect the BTK ligand binding site, extracellular domain, kinase domain, and mutations in regions involved in protein:protein interactions and downstream signaling. In some embodiments, a mutation (e.g., an activating mutation) in the BTK gene. is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid substitutions (e.g., BT In some embodiments, the mutation may result in expression of the BTK kinase. In some embodiments, the mutation in the BTK gene (e.g., an activation A mitogenic mutation is a mutation that occurs when at least one amino acid (e.g., At least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, At least 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acids ), resulting in expression of a BTK kinase or BTK receptor lacking In this study, mutations in the BTK gene (e.g., activating mutations) were found to result in increased expression of the wild-type BTK protein. In comparison, at least one amino acid (e.g., at least two, at least three, 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least At least 10, at least 12, at least 14, at least 16, at least 18, at least At least 20, at least 25, at least 30, at least 35, at least 40, The expression of BTK kinase with an inserted amino acid sequence (at least 45 or at least 50 amino acids) was achieved. Translocations can result in the expression of fusion proteins containing the BTK kinase domain and a fusion partner. For example, the fusion protein may contain a genetic translocation that results in the expression of a wild-type BTK protein. Other dysregulations include increased kinase activity relative to the mRNA sequence of BTK. In some embodiments, the wild-type BTK protein includes: 1 is an exemplary wild-type BTK protein described herein.

[0332] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression or activity or level includes overexpression of wild-type BTK kinase. In some embodiments, the BTK gene, the BTK kinase protein, or a combination thereof Dysregulation of the expression or activity or level of any of the kinase domains, e.g. or a portion thereof that is capable of exhibiting kinase activity. The present invention includes overexpression, activation, amplification, or mutation in a chromosomal segment comprising:

[0333] In some embodiments, the BTK gene, the BTK kinase, or any of them The dysregulation of expression or activity or level of BTK kinase may be due to one or more Deletions (e.g., deletion of amino acid position 4), insertions, or point mutations. In some embodiments, the BTK gene, the BTK kinase, or the expression or non-expression of either thereof is Dysregulation of the activity or levels of BTK kinase domain leads to constitutive activity , which contains a deletion of one or more residues from the BTK kinase.

[0334] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression, activity, or levels of one or more of the BTK kinases compared to the wild-type kinase or multiple amino acid substitutions, insertions, or deletions, Contains at least one point mutation in the BTK gene (e.g., a point mutation listed in Table 1) Please refer to. [Table 1]

[0335] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression or activity or levels leads to one or more BTK gene fusions In some embodiments, the BTK gene, the BTK kinase Dysregulation of the expression or activity or levels of any of the The total number of expressed proteins is 100, and the total number of expressed proteins is 100. It is the result of a genetic translocation that contains a minimal functional BTK kinase domain.

[0336] Non-limiting examples of BTK gene fusion proteins are shown in Table 1a. [Table 2]

[0337] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression, activity, or levels of BTK mRNA through alternative splicing In some embodiments, the m variant of alternatively spliced ​​BTK is The RNA was designed to express a BTK kinase with at least one deleted residue (compared to the wild-type BTK kinase). K kinase, resulting in constitutive activity of the BTK kinase domain. Wild-type BTK An example of a BTK kinase that is an alternative splice variant of the kinase is wild-type BTK. p65BTK contains a first exon that is different from that of other kinases. It can start at the putative start codon in exon 4, not exon 2 as in the wild-type BTK kinase. (Grassilli et al., incorporated herein by reference in its entirety). , Oncogene. 35(33):4368-78, 2016). In this study, p65BTK is expressed in colon cancer.

[0338] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression or activity or levels of BTK kinase compared to wild-type BTK kinase At least one amino acid (e.g., at least 2, at least 3 , at least 4, at least 5, at least 6, at least 7, at least 8, at least At least 14, at least 9, at least 10, at least 12 16, at least 18, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50 amino acids, or This results in a BTK with an additional 100 amino acids (compared to the wild-type BTK kinase). Contains BTK mRNA transcribed from an alternative promoter. Examples of BTK kinases that have been studied include BTK-C, which is a mutant of wild-type BTK kinase. It has a first exon that differs due to alternative splicing compared to the wild-type BTK kinase. A different initiation codon results in a BTK kinase with an N-terminal extension of 34 amino acids compared to (Eifert et al., each of which is incorporated herein by reference in its entirety). et al.,Genes Chromosomes Cancer.52(10):9 61-75, 2013 and Kokabee et al. Cancer Biol. her. 16(11):1604-15, 2015). In some embodiments, BTK -C is expressed in prostate or breast cancer.

[0339] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression or activity or levels of BTK kinase compared to wild-type BTK kinase or resulting in the production of a BTK kinase having multiple amino acid insertions or deletions. BTK kinase having one or more amino acid substitutions or insertions or deletions in the gene The present invention further comprises at least one point mutation in the BTK gene that results in the production of a β-lactamase. The resulting BTK kinase may be a wild-type BTK kinase or a BTK kinase that does not contain a mutation. and inhibiting the homing of the BTK kinase by one or more first BTK kinase inhibitors (multiple inhibitors) compared to the homing of the BTK kinase. Such mutations are optional and are more resistant to inhibition of phosphorylation activity. selectively (e.g., compared to cancer cells or tumors that do not contain a specific BTK inhibitor resistance mutation) ) Treatment with a compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof. does not reduce the sensitivity of cancer cells or tumors that contain the BTK kinase to therapeutic agents. In such embodiments, the BTK inhibitor resistance mutation is a mutation that occurs when a first BTK kinase inhibitor is present. and inhibiting the activity of wild-type BTK kinase or a mutant thereof in the presence of the same first BTK kinase inhibitor. When compared to the unaltered BTK kinase, max Increase in ATP K m Decrease in and the K of the first BTK kinase inhibitor D BTK kinase having one or more of the following increases: In other embodiments, the BTK gene, BTK kinase, or the like may be provided. Dysregulation of the expression or activity or levels of any of these kinases is consistent with wild-type BTK kinase. resulting in the production of a BTK kinase having one or more amino acid substitutions compared to a wild-type BTK kinase. A compound of formula I, or or a pharma- ceutically acceptable salt thereof, an amorphous or polymorphic form thereof, or a spray-dried dispersion thereof; or at least one mutation in the BTK gene that increases resistance to such pharmaceutical compositions. In such embodiments, the BTK inhibitor-resistant mutation comprises a compound of formula I or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, of formula I. In the presence of the compound, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, When compared to the V type BTK kinase or a BTK kinase without the mutation, max of Increase, K m Decrease in K D BTK kinase having one or more of the following reductions: This can result.

[0340] Examples of BTK inhibitor resistance mutations include, for example, mutations in gatekeeper residues (e.g., wild-type BTK Kinase amino acid position 474), P-loop residues at or near the DFG motif and ATP cleft solvent front amino acid residues. In addition, point mutations, insertions, or deletions were performed in and near the ATP binding site of the tertiary structure of BTK kinase. Further examples of these types of mutations include deletions or deletions of residues in the activation loop, Residues near or interacting with the activation loop, active or inactive enzyme structures including, but not limited to, residues that contribute to the conformation, enzymatic activity and / or drug binding Changes in residues that may affect the C-helix loop and C-helix In some embodiments, the alterations include mutations, deletions, and insertions in the gene. The wild-type BTK protein is an exemplary wild-type BTK kinase described herein. Specific residues or residue regions that can be altered (e.g., BTK inhibitor resistance mutations) are identified in human The following are listed in Table 2, numbered based on the native BTK protein sequence (e.g., SEQ ID NO:1): As will be appreciated by those skilled in the art, the specific The amino acid positions in the reference protein sequence that correspond to the amino acid positions in the reference protein sequence are can be determined by aligning the sequence to SEQ ID NO:1 (e.g., ClustalW2 (Use software programs such as Sigma-Aldrich, ... Amino acid changes of several amino acids, insertions within or adjacent to the sequence, and The present invention relates to a method for the preparation of a genomic DNA comprising the steps of: tra,GKKanev,OPJVan Linden,R.Leurs,I .JPDe Esch,and C.De Graaf,“KLIFS:A str uctural kinase-ligand interaction databa se,” Nucleic Acids Res.,vol.44,no.D1,pp. See also D365-D371,2016.

[0341] Exemplary sequence of mature human BTK protein (SEQ ID NO:1) [Sequence Table 1] TIFF2025037966000009.tif61163

[0342] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is amorphous, or polymorphic forms, spray-dried dispersions thereof, or pharmaceutical compositions thereof, Treatment with other BTK kinase inhibitors (e.g., a first and / or second BTK Kinase inhibitors) in combination with, or as a follow-on or additional treatment (e.g., BTK inhibitor resistance mutations (e.g., first BTK inhibitor those that confer increased resistance to, e.g., a substitution at amino acid position 481, e.g. , C481S, C481T, C481R, C481G, and / or For the treatment of a subject with a cancer that contains one or more of the BTK inhibitor resistance mutations listed in Exemplary first and second BTK kinase inhibitors are described herein. In some embodiments, the first or second BTK kinase inhibitor is ibrutinib. , PRN1008, PRN473, ABBV-105, AC0058, acalabrutinib , zanubrutinib, spebrutinib, posertinib, evobrutinib, M7583, chira Brutinib, CG'806, ARQ531, BIIB068, Becabrutinib, AS87 1, CB1763, CB988, GDC-0853, RN486, dasatinib, GNE- 504, GNE-309, BCB-311, BTK Max, CT-1530, CGI- 1746, CGI-560, LFM A13, TP-0158, dtrmwxhs-12 , CNX-774, and LOU064. In some embodiments, the first or second BTK kinase inhibitor is a covalent inhibitor. Exemplary covalent inhibitors of ribozyme include ibrutinib, PRN1008, PRN473, A BBV-105, AC0058, acalabrutinib, zanubrutinib, spebrutinib, These include posertinib, evobrutinib, M7583, and tirabrutinib. In some embodiments, the first or second BTK kinase inhibitor is , non-covalent inhibitors. Exemplary non-covalent inhibitors of BTK kinase include CG'8 06, ARQ531, BIIB068, becabrutinib, AS871, CB1763, C These include, but are not limited to, B988, GDC-0853, RN486, and dasatinib. Not determined.

[0343] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is amorphous, or polymorphic forms, spray dried dispersions thereof, or pharmaceutical compositions thereof, Multiple BTK inhibitor resistance mutations (resistance to first or second BTK inhibitors) Substitutions at amino acid position 481, e.g., C481S, C481T, C48 1R, and C481R, or a substitution at, for example, amino acid position 474, e.g., T474 The present invention is useful for treating cancers identified as having the T474I, T474M, and T474S gene. Non-limiting examples of BTK inhibitor resistance mutations are listed in Table 2. [Table 3]

[0344] In another embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, amorphous or The polymorphic forms, spray-dried dispersions thereof, or pharmaceutical compositions thereof may comprise one or more BTK inhibitor resistance mutations (those that result in increased resistance to the first or second BTK inhibitor) at amino acid position 707 in PLCγ2, e.g., S707Y, S70 7P, and S707F, or a substitution at amino acid position 251 in, for example, CARD11 These compounds are useful in treating cancers identified as having BTK inhibitors (e.g., L251P). Non-limiting examples of toxic drug resistance mutations are listed in Table 3. [Table 4]

[0345] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression or activity or levels of the BCR complex or downstream signaling components Activating mutations in the molecule result in interaction with microbial or autoantigens present in the tissue microenvironment. This may result in persistent BCR stimulation or a pathogenic increase in BTK protein expression or activation. In some embodiments, BCR signaling is ligand-independent and sustained. TK gene, BTK kinase, or the expression or activity or level of any of them Dysregulation of the BCR signaling pathway genes, BCR signaling pathway proteins, or dysregulation of the expression or activity or level of any of them. In embodiments, the BCR signaling pathway genes, BCR signaling pathway proteins, or dysregulation of the expression or activity or levels of any of them, or one or more activating mutations in downstream signaling components, present in the tissue microenvironment Continuous BCR stimulation by microbial or autoantigens or expression of the BTK protein Ligand-independent sustained BCR signaling leading to increased expression or activation pathogenicity For example, the BTK gene, the BTK protein, or the expression or non-expression of either of them Dysregulation of activity or levels of BCR signaling pathway proteins is associated with genetic De novo mutations (e.g., BCR signaling pathway gene translocations leading to expression of fusion proteins, Contains at least one amino acid deletion compared to the wild-type BCR signaling pathway protein BCR signaling pathway genes that result in expression of BCR signaling pathway proteins, including Expression of BCR signaling pathway proteins with deletion or one or more point mutations Mutations in BCR signaling pathway genes that result in At least one amino acid of a BCR signaling pathway protein compared to a tract protein BCR signaling pathway resulting in deletion of BCR signaling pathway proteins Alternatively spliced ​​versions of the protein mRNA may be the result.

[0346] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression, activity or levels of wild-type BCR signaling pathway proteins BCR signaling pathway with one or more amino acid insertions or deletions compared to the original target gene. One or more in the BCR signaling pathway genes that lead to the production of tract proteins Production of BCR signaling pathway proteins with amino acid substitutions or insertions or deletions of Several of these include at least one point mutation in a BCR signaling pathway gene that results in In embodiments, the mutation (e.g., activating mutation) in a BCR signaling pathway gene is One or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid substitutions (e.g., BCR sequences having one or more amino acid substitutions In some embodiments, the mutation may result in the expression of a signal transduction pathway protein. In some embodiments, the gene may be a gene amplification of a BCR signaling pathway gene. Mutations in signaling pathway genes (e.g., activating mutations) can abrogate wild-type BCR signaling. At least one amino acid (e.g., at least two, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, At least 9, at least 10, at least 12, at least 14, at least 16, at least At least 18, at least 20, at least 25, at least 30, at least 35, at least at least 40, at least 45, or at least 50 amino acids) of the BCR signal This can result in the expression of a BCR signaling pathway protein or a BCR signaling pathway receptor. In some embodiments, a mutation (e.g., an activating mutation) in a BCR signaling pathway gene is (different) has at least one amino acid difference compared to the wild-type BCR signaling pathway protein (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, At least 7, at least 8, at least 9, at least 10, at least 12, at least At least 14, at least 16, at least 18, at least 20, at least 25, At least 30, at least 35, at least 40, at least 45, or at least 50 This can result in the expression of BCR signaling pathway proteins containing an inserted amino acid sequence. Dysregulation includes mRNA splice variants of the BCR signaling pathway. Non-limiting examples of CR signaling pathway mutations are listed in Table 4. [Table 5]

[0347] In other embodiments, the BTK gene, the BTK kinase, or the expression of either of them is also or dysregulation of activity or levels compared to wild-type BCR signaling pathway proteins. Production of BCR signaling pathway proteins having one or more amino acid substitutions relative to the and a BCR signaling pathway protein or a mutation thereof that does not involve the BCR signaling pathway protein. A compound of formula I, or a pharma- ceutical acceptable salt thereof, or polymorphic forms thereof, spray-dried dispersions thereof, or pharmaceutical compositions thereof. Contains at least one point mutation in a BCR signaling pathway gene that increases .

[0348] Thus, as used herein, a subject diagnosed with (or identified as having) cancer is treated with The method of treating a subject comprises administering to the subject a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt thereof. salts, amorphous or polymorphic forms thereof, spray-dried dispersions thereof, or pharmaceutical compositions thereof The present invention provides a method for treating a patient having a BTK-associated cancer, comprising administering to the patient a A method of treating an identified or diagnosed subject, comprising administering to the subject a therapeutically effective amount of a compound of formula I. or a pharma- ceutically acceptable salt thereof, an amorphous or polymorphic form, or a spray-dried dispersion thereof. Also provided are methods of treating a patient with atopic dermatitis, comprising administering to said patient a pharmaceutical composition comprising ... In one embodiment, the subject is a subject having an IL-1 deficiency in the BTK gene, BTK kinase, or a IL-1 deficiency in a biopsy sample from the subject. To identify dysregulation of expression or activity or levels of any of them. For this purpose, by use of a regulatory approved, e.g., FDA approved, test or assay; or by performing any of the non-limiting examples of assays described herein. In some embodiments, the patient has been identified or diagnosed as having a TK-associated cancer. Or the assay is provided as a kit. In some embodiments, the cancer is a BTK-associated cancer. For example, BTK-associated cancers contain one or more BTK inhibitor resistance mutations. It could be mugan.

[0349] Also provided is a method of treating cancer in a subject in need thereof, comprising: (a) detecting a BTK-associated cancer in a subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I. or a pharma- ceutically acceptable salt thereof, an amorphous or polymorphic form thereof, a spray-dried and administering the dry dispersion, or a pharmaceutical composition thereof. Some embodiments of the method further comprise administering to the patient a second anti-cancer agent (e.g., a second BTK inhibitor or an immunotherapy). In some embodiments, the subject further comprises administering to the subject a first Patients who have been treated with a BTK inhibitor or another anti-cancer treatment, e.g., In some embodiments, the subject has been previously treated with partial resection or radiation therapy. or a biopsy sample from the subject, the BTK gene, the BTK kinase, or In order to identify dysregulation of the expression or activity or level of any of the By use of an approved, e.g., FDA approved, test or assay, or as described herein BTK-associated cancers can be diagnosed by performing any of the non-limiting examples of the assays described in In some embodiments, the test or assay is provided in a kit. In some embodiments, the cancer is a BTK-associated cancer. The cancer may be a cancer that contains one or more BTK inhibitor resistance mutations. In some embodiments, the BTK gene, the BTK kinase, or the expression or activity of either of them. Alternatively, the dysregulation of levels of one or more BCR signaling pathway proteins In some embodiments, the BCR signaling is the result of one or more mutations in the Pathway proteins include cyclin-D1, CARD11, CD79B, CD79A, and MYD. 88, and combinations thereof.

[0350] Also provided is a method of treating a subject, comprising administering to a subject a tumor obtained from the subject. The assay is performed to determine whether the subject is a BTK gene, a BTK kinase, or any of the foregoing. determining whether the subject has a dysregulated expression or activity or level of The BTK gene, the BTK kinase, or the expression or activity or level of any of them A subject determined to have dysregulation of the thyroid gland is administered a therapeutically effective amount of a compound of formula I, or or a pharma- ceutically acceptable salt, amorphous, or polymorphic form of, or a spray-dried dispersion thereof; and administering (specifically or selectively administering) such pharmaceutical compositions. Some embodiments of these methods include administering to the patient a second anti-cancer agent (e.g., a second BTK inhibitor). or immunotherapy) to the subject. In some embodiments, the subject has previously been treated with a first BTK inhibitor or has been treated with another anti-cancer therapy. have been previously treated, for example, with at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having a BTK-associated cancer, Subjects who exhibit one or more symptoms of, or are at high risk for developing, a BTK-associated cancer In some embodiments, the assay is performed using next generation sequencing, pyrosequencing, Use immunostaining, immunohistochemistry, immunoblotting, or break-apart FISH analysis. In some embodiments, the assay is a regulatory approved assay, e.g., an FDA approved assay. In some embodiments, the assay is a liquid biopsy. Further non-limiting assays that can be used in the method are described herein. Assays for the expression of the BTK gene, BTK Dysregulation of the expression or activity or levels of any of the kinases, Contains one or more BTK inhibitor resistance mutations.

[0351] Also provided is a method for the detection of a BTK gene, a BTK kinase, or any of the foregoing. To determine whether the expression or activity or level of For samples obtained from elephants, the BTK gene, the BTK kinase, or either of them The presence of dysregulated expression or activity or levels of BTK indicates that a patient has a BTK-associated cancer. By performing an assay (e.g., an in vitro assay) to identify and the treatment of BTK-associated cancer in a subject identified or diagnosed with BTK-associated cancer. A compound of formula I, or a pharma- ceutically acceptable salt thereof, amorphous or The polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. The subject is a person having a genetic disorder characterized by a deficiency in the BTK gene, the BTK kinase, or the expression or function of either of them. is obtained from the subject to determine whether the subject has dysregulated activity or level. The sample is identified as having a BTK-associated cancer through a step of performing an assay. 2. The method of claim 1, wherein the compound of formula I is a medicament for treating a BTK-associated cancer in a subject diagnosed with or having a BTK-associated cancer is administered to the subject. or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, Any of the methods or uses described herein may be used. In one embodiment, the subject is able to detect, through performance of an assay, the BTK gene, the BTK kinase, or is determined to have dysregulation of the expression, activity or level of any of them. and a compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof. and that the subject is to be administered a pharmaceutical composition thereof, a spray-dried dispersion thereof, or a pharmaceutical composition thereof. The method further includes recording the above-mentioned in a clinical record (e.g., a computer readable medium) of the subject. In some embodiments, the assay is performed using next generation sequencing, pyrosequencing, immunoassay, or other techniques. Utilize immunohistochemistry, immunoblot, or break-apart FISH analysis. In this embodiment, the assay is a regulatory approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy. , the BTK gene, the BTK kinase, or the expression or activity of any of them Dysregulated levels include one or more BTK inhibitor resistance mutations. In such a state, the BTK gene, the BTK kinase, or the expression or activity of either of them is also or dysregulation of levels of one or more BCR signaling pathway proteins. In some embodiments, the mutation is the result of one or more mutations in the BCR signaling pathway. Tract proteins include cyclin-D1, CARD11, CD79B, CD79A, and MYD8. 8, and combinations thereof.

[0352] Also provided is a method for treating a cancer, comprising administering to a subject in need of treatment for a BTK-associated cancer, For use in treating cancer in a subject identified or diagnosed as having Compound I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, Also provided is a method for the preparation of a BTK-related antibody, comprising administering to said patient a BTK-related antibody, a spray-dried dispersion of said antibody, or a pharmaceutical composition thereof. Manufacture of a medicament for treating cancer in a subject identified or diagnosed as having cancer A compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, for , a spray-dried dispersion thereof, or a pharmaceutical composition thereof. In some cases, the cancer may be a BTK-associated cancer, e.g., a cancer that has one or more BTK inhibitor resistance mutations. In some embodiments, the subject has a BTK-associated cancer. In the test sample, the expression or expression level of the BTK gene, the BTK kinase, or any of them is detected. To identify dysregulation of activity or levels, By using the kit for the identification of BTK-associated cancer, a patient can be identified or diagnosed as having BTK-associated cancer. As provided herein, BTK-associated cancers include those described herein, and These include those known in the art.

[0353] In some embodiments of any of the methods or uses described herein, the subject has BT K gene, BTK kinase, or expression or activity or level of any of them The subject has been identified or diagnosed as having a cancer involving dysregulation of In some embodiments of any of the or the uses, the subject has an or dysregulation of expression or activity or levels of any of them. Some embodiments of any of the methods or uses described herein In the present invention, a subject is characterized in that the subject has a BTK gene, a BTK kinase, or an expression or function of any of them. The subject may have a tumor or tumors that are positive for dysregulation of activity or level. In some embodiments of any of the methods or uses described herein, the subject The tumor expresses the BTK gene, the BTK kinase, or neither of their expression or activity. The subject may be a tumor having a dysregulated level of the IL-1 gene. In some embodiments of any of the methods, the subject has a BTK-associated cancer (e.g., one or more or cancer with multiple BTK inhibitor resistance mutations. In some embodiments of any of the methods or uses, the subject is BTK inhibitor naive. In other embodiments of any of the methods or uses described herein, the subject has In some embodiments, the BTK-associated cancers described herein are not inhibitor naive. A method of treating a BTK-associated cancer in a patient in need of treatment is provided, the method comprising: a) detecting in a sample from a patient an expression level of the BTK gene, the BTK kinase, or any of them; and b) detecting dysregulation of the expression or activity or level of Compounds of formula I, or pharma- ceutically acceptable salts thereof, amorphous or polymorphic forms thereof, and administering the spray-dried dispersion, or a pharmaceutical composition thereof. In some embodiments, the BTK gene, the BTK kinase, or the expression or activity of either of them. Alternatively, the dysregulated levels include one or more fusion proteins. Non-limiting examples of fusion proteins are listed in Table 1a. In some embodiments, TK gene, BTK kinase, or the expression or activity or level of any of them Dysregulation of the kinase involves point mutations / insertions / deletions in one or more of the BTK kinase proteins. Non-limiting examples of point mutations / insertions / deletions in the BTK kinase protein are listed in Table 1. In some embodiments, the point mutation / insertion / deletion in the BTK kinase protein is T117P, T316A, T474I, T474M, T474S, C481S, C481 S, C481T, C481G, C481R, L528W, P560L, R562W, R5 In some embodiments, the BTK is selected from the group consisting of F601L, F602G, and F603L. Gene, BTK kinase, or expression or activity or level of any of them The dysregulation includes one or more BTK inhibitor resistance mutations. Non-limiting examples are described in Tables 2 and 3. In some embodiments, the BTK-resistant mutant The mutation is a mutation at amino acid 481 of BTK. In some embodiments, the BTK inhibitor resistance mutation is C481S. 481F. In some embodiments, the BTK inhibitor resistance mutation is T474I. In some embodiments, the BTK inhibitor resistance mutation is a mutation in PLCγ2 (e.g., For example, amino acid positions 244, 257, 334, 495, 664, 665, 707, and 708 , 742, 845, 848, 993, 1140, or 1141). In this study, the expression or activity of the BTK gene, the BTK kinase, or either of them was Dysregulation of the levels of one or more BCR signaling pathway proteins In some embodiments, the BCR signaling pathway is the result of one or more mutations. Proteins include cyclin-D1, CARD11, CD79B, CD79A, and MYD88. In some embodiments, the BT K gene, BTK kinase, or expression or activity or level of any of them Cancers involving dysregulation of In some embodiments, the BTK gene, BTK kinase, or Tumors positive for dysregulation of expression or activity or levels of any of them are tumors that are positive for one or more BTK inhibitor resistance mutations. In embodiments, the BTK gene, the BTK kinase, or the expression or Tumors with dysregulated activity or levels may be treated with a regulatory approved, e.g., FDA approved, This is determined using an assay or kit.

[0354] In some embodiments of any of the methods or uses described herein, the subject has BT K gene, BTK kinase, or expression or activity or level of any of them Tumors with dysregulation of BTK (e.g., tumors with one or more BTK inhibitor resistance mutations) In some embodiments, the clinical record indicates that the subject has: 1. The subject is administered a compound of formula I, as provided herein, or a pharma- ceutically acceptable salt thereof, Treating with amorphous or polymorphic forms, spray-dried dispersions thereof, or pharmaceutical compositions thereof In some embodiments, the BTK gene, the BTK kinase or a cancer involving dysregulation of expression or activity or levels of any of them. In some embodiments, the cancer has one or more BTK inhibitor resistance mutations. The BTK gene, the BTK kinase, or the expression or activity or level of any of them Cancers involving dysregulated signaling can be detected using regulatory approved, e.g., FDA approved, assays or kits. In some embodiments, the BTK gene, BTK kinase, or or positive for dysregulation of expression or activity or level of any of them The tumor is one that is positive for one or more BTK inhibitor resistance mutations. In some embodiments, the BTK gene, the BTK kinase, or the expression or non-expression of either thereof is Tumors with dysregulated activity or levels of cytotoxic T cells are treated with regulatory approved, e.g., FDA approved, The degree of cytotoxicity is determined using an assay or kit.

[0355] Also provided is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of formula I, or or a pharma- ceutically acceptable salt thereof, an amorphous or polymorphic form thereof, or a spray-dried dispersion thereof; or a pharmaceutical composition thereof, have clinical documentation showing dysregulation of expression or activity or level of any Also provided are methods for administering to a subject a gene encoding the BTK gene, kinase, or dysregulation of expression or activity or levels of any of them. A medical device for treating BTK-associated cancer in a subject with clinical documentation showing that he or she has A compound of formula I, or a pharma- ceutically acceptable salt thereof, amorphous or The use of the polymorphic forms, their spray-dried dispersions, or their pharmaceutical compositions. Some embodiments of the methods and uses include assaying (e.g., In one embodiment, an in vitro assay (e.g., an in vitro assay) is performed to determine whether the subject has a BTK gene, BTK kinase, or a combination thereof. and determining whether the expression or activity or level of any of these is dysregulated. and determining whether the subject is a patient that has a BTK gene, a BTK kinase, or expression of either of them. The information that a subject has been identified as having dysregulated activity or level of the subject's and recording the file (eg, a computer readable medium). In some embodiments, the assay is an in vitro assay. For example, the assay , next generation sequencing, immunohistochemistry, immunoblotting, or break-apart FIS In some embodiments, the assay utilizes a regulatory approved, e.g., F The kit is DA approved. In some embodiments, the assay is a liquid biopsy. In some embodiments, the BTK gene, the BTK kinase, or expression of either thereof is also or dysregulation of activity or levels includes one or more BTK inhibitor resistance mutations. In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression or activity or levels may be mediated by one or more BCR signaling pathways. In some embodiments, the B CR signaling pathway proteins include cyclin-D1, CARD11, CD79B, and C D79A, MYD88, and combinations thereof. Also provided herein are methods of treating a subject. In some embodiments, the methods include obtaining a Assays are performed on the collected samples to determine whether the subject is a BTK gene, a BTK protein, or The method determines whether the expression or activity or level of any of these is dysregulated. In some such embodiments, the method also includes determining whether the BTK gene, B Dysregulation of the expression or activity or levels of TK proteins or any of them A therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt thereof, is administered to a subject determined to have salts, amorphous or polymorphic forms thereof, spray-dried dispersions thereof, or pharmaceutical compositions thereof In some embodiments, the method comprises administering to the subject a gene encoding the BTK gene, having dysregulation of the expression or levels of any of the proteins, This includes determining the presence or absence of a specific function by an assay performed on a sample obtained from the subject. In such embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutical or a spray-dried dispersion thereof, or In some embodiments, the BTK gene, BTK kinase, Dysregulation of the expression or activity of any of the BTK kinase proteins Expression of a BTK fusion protein (e.g., any of the BTK fusion proteins described herein) In some embodiments, the BTK gene, BTK kinase protein, or any of their expression or activity or levels Dysregulation in the BTK gene can be caused by one or more point mutations in the BTK gene (e.g., as described herein). BTK point mutations in the BTK gene. Multiple point mutations include, for example, T117P, T316A, T474I, T474M, T474 S, C481S, C481F, C481T, C481G, C481R, L528W, P5 one of the amino acid substitutions R60L, R562W, R562G, and F601L; or In some embodiments, the BTK protein may be translated into a BTK protein having more than one nucleotide. The gene, the BTK kinase protein, or the expression or activity of any of them Dysregulation in the expression level of BTK can be due to one or more BTK inhibitor resistance mutations (e.g., (Any combination of one or more of the BTK inhibitor resistance mutations described in the document). In some embodiments, the BTK gene, the BTK kinase, or expression of either thereof. Alternatively, the dysregulation of activity or levels may be mediated by one or more of the BCR signaling pathways. In some embodiments, the mutation is the result of one or more mutations in the BCR protein. Signaling pathway proteins include cyclin-D1, CARD11, CD79B, and CD7 9A, MYD88, and combinations thereof. Some embodiments of the present invention further comprise administering to the patient a second anti-cancer agent (e.g., a second BTK inhibitor or immunotherapy). to a subject.

[0356] Also provided is a method for treating a subject identified or diagnosed with a BTK-associated cancer. In some embodiments, the method comprises: and administering the treatment to a subject identified or diagnosed as having a BTK-associated cancer. For example, the selected treatment may include a therapeutically effective amount of a compound of formula I, or a pharmaceutical or a spray-dried dispersion thereof, or In some embodiments, the pharmaceutical composition may comprise administering to the subject a sample obtained from the subject. The assay is performed to determine whether the subject has a BTK gene, a BTK kinase, or any of these. B. determining whether the expression or activity or level of the TK gene, BTK kinase, or the expression or activity or level of any of them Subjects determined to have dysregulation of the BTK gene are identified and diagnosed as having BTK-associated cancer. In some embodiments, the method further comprises the steps of: transfecting a nucleic acid sequence of the BTK gene, Dysregulation of the expression or activity or levels of any of the kinases, The result of one or more mutations in one or more BCR signaling pathway proteins In some embodiments, the BCR signaling pathway protein is cyclin- D1, CARD11, CD79B, CD79A, MYD88, and combinations thereof In some embodiments, the cancer is treated with one or more BTK inhibitors. In some embodiments, the subject has a BTK-associated cancer that has a drug resistance mutation. The present invention relates to a method for detecting an expression of the BTK gene, the BTK kinase, or any of them in a biopsy sample from a subject. A regulatory approved method, e.g., for identifying dysregulation of expression or activity or levels of For example, a patient may be identified or diagnosed as having a BTK-associated cancer by use of an FDA-approved kit. In some embodiments, the BTK-associated cancer is any of the cancers described herein or is a cancer known in the art. In some embodiments, the assay comprises an in vitro For example, assays include next-generation sequencing, immunohistochemistry, immunoblotting, and In some embodiments, break-apart FISH analysis is utilized. The kit is regulatory approved, e.g., FDA approved. In some embodiments, , the assay is a liquid biopsy.

[0357] Also provided herein is a method of selecting a treatment for a subject, the method comprising administering to the subject a therapeutic agent obtained from the subject. The assay is performed on the sample to determine whether the subject has an Dysregulation of the expression or activity or level of any of them (e.g., one or more determining whether the patient has a BTK inhibitor resistance mutation; TK kinase, or dysregulation of the expression or activity or level of any of them. identifying and diagnosing the subject as having a BTK-associated cancer. Some embodiments include the selected treatment for a patient having a BTK-associated cancer. The selected treatment may further include administering to the identified or diagnosed subject. a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof; , a spray-dried dispersion thereof, or a pharmaceutical composition thereof, In some embodiments, the assay may include administering the antibody to a subject identified or diagnosed with the antibody. is an in vitro assay. For example, the assay can be performed using next generation sequencing, immunohistochemistry, Utilizing chemical, immunoblot, or break-apart FISH analysis. In some embodiments, the assay is a regulatory approved, e.g., FDA approved, kit. In an embodiment, the assay is a liquid biopsy.

[0358] Also provided is a method of selecting a subject for treatment, comprising: and administering to a subject a therapeutically effective amount of a compound of formula I, or or a pharma- ceutically acceptable salt, amorphous, or polymorphic form of, or a spray-dried dispersion thereof; and selecting a subject for treatment comprising administration of said pharmaceutical composition. Some embodiments identify or diagnose a subject as having a BTK-associated cancer. The term "subject" refers to a method for determining whether a subject has a BTK gene, BTK kinase, or dysregulation of the expression or activity or levels of any of them. determining whether the BTK gene, the BTK kinase, or any of them is present; The subject determined to have dysregulation of expression or activity or level of BTK is and identifying or diagnosing the patient as having an associated cancer. In some embodiments, the method of selecting a subject for treatment includes administering a variety of treatments for a BTK-associated cancer. It can be used as part of a clinical study. In some embodiments, the BTK-associated cancer is In some embodiments, the cancer has one or more BTK inhibitor resistance mutations. The assay is an in vitro assay. For example, the assay can be performed using next generation sequencing, Immunohistochemistry, or break-apart FISH analysis is utilized. In some implementations, the assay is a regulatory approved kit, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy. Dysregulation of the expression or activity or levels of K kinase, or any of them, In some embodiments, the BTK gene comprises one or more BTK inhibitor resistance mutations. , BTK kinase, or dysregulation of the expression or activity or level of any of them. The mutations are expressed as one or more mutations in one or more BCR signaling pathway proteins. In some embodiments, the BCR signaling pathway protein is Cullin-D1, CARD11, CD79B, CD79A, MYD88, and their combinations combinations thereof.

[0359] Similarly, the present invention relates to a method for treating cancer (e.g., a BTK-associated cancer) in a subject in need of treatment. A method of treating cancer using BCMA is provided, the method comprising: a) detecting in a sample from a subject a BCMA antibody; R signaling pathway genes, BCR signaling pathway proteins, or both or one of the expression or activity or level dysregulation; and b) a therapeutically effective amount of or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, or a pharmaceutical composition thereof. Some embodiments of the present invention further comprise subjecting a sample obtained from a subject to an assay (e.g., an in vitro Assay) to determine whether the subject has BCR signaling pathway genes, BCR signaling pathway Dysregulation of the expression or activity or levels of any one of the proteins determining whether the subject has a BCR signaling pathway gene, BCR Signal transduction pathway proteins, or the expression or activity of any one of them The information in the subject's clinical file (e.g., and recording the information on a computer-readable medium. In the present specification, the assay is an in vitro assay. For example, the assay is an assay using next-generation sequencing. Utilize immunofluorescence, immunohistochemistry, immunoblotting, or break-apart FISH analysis. In some embodiments, the assay is performed in a regulatory approved, e.g., FDA approved, kit. In some embodiments, the BCR signaling pathway protein is cyclin-D 1, CARD11, CD79B, CD79A, MYD88, and their combinations The compound is selected from the group consisting of:

[0360] Also provided is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of formula I, or or a pharma- ceutically acceptable salt thereof, an amorphous or polymorphic form thereof, or a spray-dried dispersion thereof; or administering to a subject a pharmaceutical composition thereof, or the expression or activity or level of any one of the pathway proteins. The method includes administering to a subject having clinical documentation indicating that the subject has nodal failure. Some embodiments of the methods include assaying (e.g., immunoassaying) a sample obtained from a subject. In vitro assays are performed to determine whether the subject has BCR signaling pathway genes, BCR signaling pathway genes, Transduction pathway proteins, or the expression or activity or level of any one of them determining whether the subject has dysregulation of a BCR signaling pathway gene; , BCR signaling pathway proteins, or the expression or activity of any one of them. or dysregulation of levels of For example, a computer readable medium. In embodiments, the assay is an in vitro assay. For example, the assay is a next-generation Sequencing, immunohistochemistry, immunoblotting, or break-apart FISH analysis are used to In some embodiments, the assay is a regulatory approved, e.g., FDA approved, In some embodiments, the BCR signaling pathway protein is a cyclin Lin-D1, CARD11, CD79B, CD79A, MYD88, and their combinations The combination is selected from the group consisting of

[0361] In some embodiments of any of the methods or uses described herein, a sample from a subject is The subject is then subjected to a test for the expression of the BTK gene, or the BTK kinase, or either of them. is used to determine whether a patient has a dysregulation of expression, activity or level of Assays include, for example, next generation sequencing, pyrosequencing, immunohistochemistry, Fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting ELISA, FACS (fluorescence activated cell sorting) analysis, Northern blotting, and PCR Based amplification (e.g., RT-PCR (reverse transcription-polymerase chain reaction) and quantitative PCR) As is well known in the art, assays can include, for example, For example, at least one labeled nucleic acid probe or at least one labeled antibody. or an antigen-binding fragment thereof. BTK kinase, or dysregulation of expression or activity or levels of any of them Other detection methods known in the art for detecting See, e.g., the references cited herein. In some embodiments, B TK gene, BTK kinase, or the expression or activity or level of any of them In some embodiments, the dysregulation of the IL-1 gene comprises one or more BTK inhibitor resistance mutations. The sample may be a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a subject. In some embodiments, the subject is a subject suspected of having a BTK-associated cancer, Subjects with one or more symptoms of a BTK-associated cancer and / or who develop a BTK-associated cancer These subjects are at high risk of

[0362] In some embodiments, the BTK gene, the BTK kinase, or any of them Dysregulation of expression or activity or level may be determined by liquid biopsy (such as fluid biopsy or fluid phase biopsy). For example, Karachialio u et al., “Real-time liquid biopsies beco me a reality in cancer treatment”,Ann.Tr See ansl.Med., 3(3):36, 2016. , total tumor burden and / or expression of the BTK gene, BTK kinase, or any of them. The liquid biopsy method can detect dysregulation of expression, activity or level of a subject. It can be performed on biological samples that can be obtained relatively easily (e.g., by a simple blood draw) from In some embodiments, the liquid biopsy method can detect BT at an earlier stage than conventional methods. K gene, BTK kinase, or expression or activity or level of any of them In some embodiments, the liquid can be used to detect the presence of dysregulation of Biological samples used in biopsies include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, and bronchoalveolar lavage. These may include flush fluid, bile, lymphatic fluid, cyst fluid, feces, ascites, and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using a liquid biopsy can be: Circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g. These include, but are not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, and Using highly sensitive detection techniques such as microarray analysis, the BTK gene, BTK kinase To identify a gene encoding a mutated nucleotide sequence, ... or a dysregulation of the expression or activity or level of any of them. It is possible.

[0363] In some embodiments, ctDNA derived from a single gene is isolated using a liquid biopsy. In some embodiments, multiple genes (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more, or any of these numbers In some embodiments, the markers of the markers can be detected using liquid biopsy. ctDNA derived from multiple genes can be used in a variety of commercially available test panels (e.g., BTK gene Modulation of expression or activity or levels of a BTK kinase or any of the above. (commercially available test panels designed to detect deficiencies in Liquid biopsy can be used to identify point mutations or single nucleotide variants (SNVs), Copy number variants (CNVs), gene fusions (e.g., translocations or rearrangements), insertions, deletions , or any combination thereof, Kinase K, or any of their expression, activity or level dysregulation. In some embodiments, to detect germline mutations, a liquid A biopsy can be used. In some embodiments, to detect somatic mutations, Liquid biopsy can be used. In some embodiments, liquid biopsy is used to determine the primary Genetic variants (e.g., primary mutations or fusions associated with the early development of diseases such as cancer) In some embodiments, liquid biopsy can be used to detect primary genetic mutations. Genetic mutations that occur after the onset of In some embodiments, B, identified using liquid biopsy, TK gene, BTK kinase, or the expression or activity or level of any of them Dysregulation of the receptor is also present in cancer cells (e.g., tumors) present in a subject. In embodiments, any type of BTK gene, BTK kinase, or the like described herein is used. Dysregulation of the expression or activity or level of any of the In some embodiments, genetic mutations identified via liquid biopsy can be used to The subject can be identified as a candidate for a particular treatment. The BTK gene, the BTK kinase, or the expression or activity of either of them in Detection of dysregulation of the levels of the compound of formula I or a pharma- ceutical acceptable salt thereof can be achieved by administering to a subject of a salt, amorphous or polymorphic form, a spray-dried dispersion thereof, or a pharmaceutical composition thereof The subject may be shown to be responsive to treatment including administration of the compound.

[0364] At multiple time points during the diagnostic, monitoring, and / or treatment process, A body biopsy may be performed to assess disease progression, efficacy of treatment, or resistance mutations after the subject is treated. one or more clinically relevant parameters, including but not limited to the occurrence of For example, diagnostic processes, monitoring processes, and / or During the course of treatment, a first liquid biopsy is performed at a first time point and a second liquid biopsy is performed at a second time point. In some embodiments, the first time point is a time point at which a subject is diagnosed with a disease. The first time point may be before the subject has diagnosed the disease (e.g., when the subject is healthy), and the second time point may be after the subject has developed the disease. a time point after the subject has contracted the disease (e.g., the second time point can be used to diagnose the subject with the disease) In some embodiments, the first time point may be prior to diagnosing the subject with the disease. The subject may then be monitored and a second The time point can be a time point after the subject is monitored. The time point may be a time point after the subject has been diagnosed with the disease, after which a treatment has been administered to the subject. The second time point may be a time point after the treatment is administered, in which case the second time point may be used As a result, the efficacy of the treatment (e.g., the genetic mutation(s) detected at the first time point are significantly reduced) or undetectable) as a result of treatment The presence of any resulting resistance mutations can be determined. The treatment to be administered comprises administering to a patient a compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof. The pharmaceutical composition may include, for example, a pharmaceutical composition comprising the pharmaceutical composition of the present invention, a spray-dried dispersion thereof, or a pharmaceutical composition thereof.

[0365] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is amorphous, The potency of the polymorphic forms, spray-dried dispersions thereof, or pharmaceutical compositions thereof may vary. cfDNA obtained from a subject at a time point, e.g., cfDNA obtained from a subject at a first time point. Dysregulated alleles of the BTK gene in cfDNA obtained from subjects at time points A and B. The gene frequency can be evaluated, and the compound of formula I, or a pharmaceutical or a spray-dried dispersion thereof, or At least one dose of the pharmaceutical composition is administered to the subject between the first and second time points. Some embodiments of these methods include administering at least one dose of a compound of formula I, or its pharma- ceutically acceptable salts, amorphous or polymorphic forms, spray-dried dispersions thereof, and The method further includes administering the pharmaceutical composition to a subject between the first and second time points. For example, dysregulation of the BTK gene in cfDNA obtained from a subject at a first time point may be detected. BTK in cfDNA obtained from subjects at a second time point compared to allele frequency (AF) A reduction in the dysregulated allele frequency (AF) of a gene (e.g., a reduction of 1% to about 99%, 1 % to about 95% reduction, 1% to about 90% reduction, 1% to about 85% reduction, 1% to about 80% Decrease, Decrease of 1% to about 75%, Decrease of 1% to about 70%, Decrease of 1% to about 65% Small, 1% decrease to about 60% decrease, 1% decrease to about 55% decrease, 1% decrease to about 50% decrease, decrease of 1% to about 45%, decrease of 1% to about 40%, decrease of 1% to about 3 5% decrease, 1% decrease to about 30% decrease, 1% decrease to about 25% decrease, 1% decrease to Approximately 20% decrease, 1% decrease to approximately 15% decrease, 1% decrease to approximately 10% decrease, 1% to approximately 5% reduction, 5% to 99% reduction, 10% to 99% reduction, 15% to 99% reduction reduction, reduction of about 20% to about 99%, reduction of about 25% to about 99%, reduction of about 30% to about 99% Decrease, Decrease of about 35% to about 99%, Decrease of about 40% to about 99%, Decrease of about 45% to about 99% Small, 50% to 99% reduction, 55% to 99% reduction, 60% to 99% reduction , reduction of about 65% to about 99%; reduction of about 70% to about 99%; reduction of about 75% to about 95%; Approximately 80% to 99% reduction, approximately 90% to 99% reduction, approximately 95% to 99% reduction, approximately 5% to 10% decrease, 5% to 25% decrease, 10% to 30% decrease, 20% decrease ~40% reduction, ~25%~50% reduction, ~35%~55% reduction, ~40%~ Approximately 60% decrease, approximately 50% decrease to approximately 75% decrease, approximately 60% decrease to approximately 80% decrease, or about 65% to about 85% reduction) is a compound of formula I, or a pharma- ceutically acceptable salt thereof. , amorphous, or polymorphic forms thereof, spray-dried dispersions thereof, or pharmaceutical compositions thereof Alternatively, cfDNA obtained from the subject at a first time point is BTK gene dysregulation allele frequency (AF) of subjects at a second time point compared to The increase in allele frequency (AF) of dysregulated BTK gene in the resulting cfDNA is expressed as a function of Formula I or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, The dry dispersion, or a pharmaceutical composition thereof, is not effective in the subject (e.g., the subject Compounds of formula I, or pharma- ceutically acceptable salts thereof, amorphous or polymorphic forms thereof, or a pharmaceutical composition thereof) Some embodiments of these methods include administering to a subject a compound of Formula I, or a pharma- ceutically acceptable salt thereof. salts, amorphous or polymorphic forms thereof, spray-dried dispersions thereof, or pharmaceutical compositions thereof or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof. The subject matter for which the form, spray-dried dispersion thereof, or pharmaceutical composition thereof is determined to be effective is Some embodiments of these methods may further comprise administering to an elephant a different treatment. (e.g., a compound of Formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof) as a single agent), in combination with a compound of formula I, or a pharma- ceutically acceptable salt thereof. salts, amorphous or polymorphic forms thereof, spray-dried dispersions thereof, or pharmaceutical compositions thereof It may further include administering the product to a subject for whom it is determined to be ineffective.

[0366] In some examples of these methods, the time difference between the first time point and the second time point is about 1 Days to about 1 year, about 1 day to about 11 months, about 1 day to about 10 months, about 1 day to about 9 months, about 1 day to about 8 months, about 1 day to about 7 months, about 1 day to about 6 months, about 1 day to about 5 months, about 1 day to about 4 months, About 1 day to about 3 months, About 1 day to about 10 weeks, About 1 day to about 2 months, About 1 day to about 6 weeks, About 1 day ~1 month, ~25 days, ~20 days, ~15 days, ~10 days Days, about 1 day to about 5 days, about 2 days to about 1 year, about 5 days to about 1 year, about 10 days to about 1 year, about 15 days or more About 1 year, About 20 days to about 1 year, About 25 days to about 1 year, About 1 month to about 1 year, About 6 weeks to about 1 year, About 2 months to about 1 year, about 3 months to about 1 year, about 4 months to about 1 year, about 5 months to about 1 year, about 6 months ~1 year, 7 months to 1 year, 8 months to 1 year, 9 months to 1 year, 10 months to 1 year ~11 months to 1 year, 1 day to 7 days, 1 day to 14 days, 5 days to 10 days, 5 days ~20 days, ~10 days ~ 20 days, ~15 days ~ 1 month, ~15 days ~ 2 months, ~ 1 week to 1 month, 2 weeks to 1 month, 1 month to 3 months, 3 months to 6 months, It may be 4 months to about 6 months, about 5 months to about 8 months, or about 7 months to about 9 months. In some embodiments of the methods, the subject is diagnosed with a dysregulated BTK gene (e.g., BTK gene dysregulated in any of the examples of ... In some embodiments of these methods, the subject may be Some of these methods include In this embodiment, the subject has one or more metastases (e.g., one or more bone metastases). It is okay to do so.

[0367] In some of the above-described embodiments, the cfDNA is ctDNA, such as BTK-associated ctDNA. For example, cfDNA is ctDNA, such as BTK-associated ctDNA. In some embodiments, at least a portion of the cfDNA is determined to be BTK-associated ctDNA. For example, sequencing and / or quantification of total cfDNA may identify BTK fusions and and / or BTK resistance mutations.

[0368] In the field of medical oncology, a combination of different forms of therapy is used to treat each subject with cancer. In medical oncology, the compositions provided herein are typically used in combination. In addition to the above, other components of such combination treatment or therapy may include surgery, radiation, Therapies, and chemotherapeutic agents, such as kinase inhibitors, signal transduction inhibitors, and / or can be a monoclonal antibody. For example, the surgery is an open surgery or a minimally invasive surgery. Thus, the compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, The embodiments may also be useful as adjuvants in cancer treatment, i.e., they may be one or more Multiple additional therapies or therapeutic agents, e.g., chemicals that act by the same or different mechanisms of action. In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt, amorphous, or polymorphic form thereof, or a spray-dried dispersion thereof. or pharmaceutical compositions thereof may be used in combination with an additional therapeutic agent or therapy. For example, a subject in need of treatment may be administered one or more doses of a compound of formula I, or its pharma- ceutically acceptable salts, amorphous or polymorphic forms, spray-dried dispersions thereof, and The patient may be administered these pharmaceutical compositions for a period of time, followed by at least partial resection of the tumor. In some embodiments, a compound of formula I, or a pharma- ceutically acceptable salt thereof, Amorphous or polymorphic forms, spray-dried dispersions thereof, or pharmaceutical compositions thereof or multiple doses of treatment to reduce the size of the tumor prior to at least partial resection of the tumor. (e.g., reducing tumor burden).

[0369] In some embodiments of any of the methods described herein, a compound of formula I, or a drug thereof, is administered. A physiologically acceptable salt, amorphous, or polymorphic form thereof, a spray-dried dispersion thereof, or These pharmaceutical compositions may contain a therapeutically effective amount of one or more additional therapies or therapeutic agents (e.g., and (ii) administering to the patient in combination with at least one additional therapeutic agent selected from the group consisting of .

[0370] Non-limiting examples of additional therapeutic agents include other BTK-targeted therapeutic agents (i.e., first or second BTK kinase inhibitors), other kinase targeted therapeutics (e.g., JAK, Src, or IRAK family kinase targeted drugs, e.g. JAK1, JAK2, JAK3, TYK 2, IRAK1, IRAK4, Src, Yes, Fyn, Fgr, Lck, Hck, Bl k, Lyn, or Frk inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors , modulators of apoptotic pathways (e.g., obataclax); other protein inhibitors ( For example, anti-apoptotic protein inhibitors, heat shock protein inhibitors, nuclear export proteins, protein inhibitors, histone deacetylase inhibitors, E3 ubiquitin ligase inhibitors, or Histone-lysine N-methyltransferase inhibitors); cytotoxic chemotherapy, angiogenesis These include targeted therapies, immune-targeted drugs including immunotherapy, and radiation therapy.

[0371] In some embodiments, the other BTK targeted therapeutic is a multikinase that exhibits BTK inhibitory activity. In some embodiments, the other BTK targeted therapeutic inhibitor is a BTK enzyme inhibitor. Exemplary BTK kinase inhibitors are those described herein that are selective for the kinase. When measured by an assay, the concentration is less than about 1000 nM, less than about 500 nM, less than about 200 nM, or less than about Less than 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM The inhibitory activity against BTK kinase (IC 50 In some embodiments, The BTK kinase inhibitor has a potency of about 25 nM as measured by the assay provided herein. M, less than about 10 nM, less than about 5 nM, or less than about 1 nM against the BTK kinase. Inhibitory activity (IC 50 ) can be shown.

[0372] Non-limiting examples of BTK-targeted therapeutic agents (e.g., a first BTK inhibitor or a second BTK inhibitor) Notable examples include ibrutinib (PCI-32675, Imbruvica®) 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4 -d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one); AC0058(AC0058TA);N-(3-((2-((3-fluoro-4-(4- Methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin (4-(4-yl)oxy)phenyl)acrylamide; Acalabrutinib (ACP-19) 6. Calquence®, rINN) (4-[8-amino-3-[(2S) -1-but-2-ynoylpyridin-2-yl]imidazo[1,5-a]pyrazine-1- yl]-N-pyridin-2-ylbenzamide; zanubrutinib (BGB-3111) ((7R)-2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidine) 1,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine- 3-carboxamide; Spebrutinib (AVL-292, 1202757-89-8, Cc-292) (N-[3-[[5-fluoro-2-[4-(2-methoxyethoxy)a Nitrilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide; Poselti Nib (HM71224, LY3337641) (N-[3-[2-[4-(4-methylpi Perazin-1-yl)anilino]furo[3,2-d]pyrimidin-4-yl]oxyphen nyl]prop-2-enamide; evobrutinib (MSC2364447, M-2951 )(1-[4-[[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl aryl]amino]methyl]piperidin-1-yl]prop-2-en-1-one); Tinib (ONO-4059, GS-4059, ONO / GS-4059, ONO-WG- 307) (1-[4-[[[6-amino-5-(4-phenoxyphenyl)pyrimidine- 4-yl]amino]methyl]piperidin-1-yl]prop-2-en-1-one); Cabrutinib (SNS-062) ((3R,4S)-1-(6-amino-5-fluoropyridinib) rimidin-4-yl)-3-[(3R)-3-[3-chloro-5-(trifluoromethyl )anilino]-2-oxopiperidin-1-yl]piperidine-4-carboxamide); Dasatinib (Sprycel®; BMS-354825) (N-(2-chloro- -6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazine-1 -yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide voxamide); PRN1008, PRN473, ABBV-105, CG'806, AR Q531, BIIB068, AS871, CB1763, CB988, GDC-0853 , RN486, GNE-504, GNE-309, BTK Max, CT-1530, C GI-1746, CGI-560, LFM A13, TP-0158, dtrmwxhs BTK inhibitors include BTK-12, CNX-774, and LOU064. can be a toxic agent (e.g., a compound that binds to C481 of BTK) or a non-covalent inhibitor. Exemplary covalent inhibitors of BTK kinase include ibrutinib, PRN1008, PR N473, ABBV-105, AC0058, acalabrutinib, zanubrutinib, spe These include brutinib, posertinib, evobrutinib, M7583, and tirabrutinib. Exemplary non-covalent inhibitors of BTK kinase include, but are not limited to, CG '806, ARQ531, BIIB068, becabrutin...

Claims

1. a compound of formula I present in an amount of about 5% w / w to about 30% w / w; 【Chemistry 1】 an HPMCAS polymer present in an amount of about 5% w / w to about 30% w / w; microcrystalline cellulose present in an amount of about 30% w / w to about 60% w / w; Mannitol or lactose present in a total amount of about 10% w / w to about 60% w / w hydrates, or combinations thereof; Sodium starch glycolate, present in a total amount of about 0.5% w / w to about 5% w / w, or croscarmellose sodium, or a combination thereof; magnesium stearate present in an amount of about 0.05% w / w to about 2% w / w, and optionally In the selection, and silicon dioxide, if present, in an amount of about 0.3% w / w to about 0.6% w / w; A pharmaceutical composition, wherein the sum is less than or equal to 100%.

2. a compound of formula I present in an amount of about 5% w / w to about 30% w / w; an HPMCAS polymer present in an amount of about 5% w / w to about 30% w / w; microcrystalline cellulose present in an amount of about 30% w / w to about 60% w / w; lactose monohydrate present in an amount of about 10% w / w to about 60% w / w; croscarmellose sodium present in a total amount of about 0.5% w / w to about 5% w / w; Magnesium stearate present in an amount of about 0.05% w / w to about 2% w / w; and silicon dioxide, if present, in an amount of about 0.3% w / w to about 0.6% w / w; The pharmaceutical composition of claim 1 , wherein the total is less than or equal to 100%.

3. the ratio of the compound of formula I to the HPMCAS polymer is from about 1:4 to about 4:1; The pharmaceutical composition according to claim 1 or 2.

4. 4. The compound of formula I according to claim 1, wherein the ratio of the compound of formula I to the HPMCAS polymer is about 1:

1. The pharmaceutical composition according to any one of claims 1 to 5.

5. a compound of formula I present in an amount of about 21% w / w to about 23% w / w; the HPMCAS polymer present in an amount of about 21% w / w to about 23% w / w; microcrystalline cellulose present in an amount of about 38% w / w to about 39% w / w; Mannitol present in an amount of about 12% w / w to about 13% w / w; sodium starch glycolate present in an amount of about 4% w / w to about 6% w / w; magnesium stearate present in an amount of about 0.4% w / w to about 0.6% w / w; The pharmaceutical composition of claim 1, wherein the total is less than or equal to 100%.

6. a compound of formula I present in an amount of about 21% w / w to about 23% w / w; the HPMCAS polymer present in an amount of about 21% w / w to about 23% w / w; microcrystalline cellulose present in an amount of about 33% w / w to about 34% w / w; lactose monohydrate present in an amount of about 16% w / w to about 17% w / w; croscarmellose sodium present in an amount of about 2% w / w to about 6% w / w; Magnesium stearate present in an amount of about 0.4% w / w to about 0.6% w / w; and silicon dioxide present in an amount of about 0.4% w / w to about 0.6% w / w, in total The pharmaceutical composition of claim 1, wherein the amount of the active ingredient is less than or equal to 100%.

7. a compound of formula I present in an amount of about 21% w / w to about 23% w / w; the HPMCAS polymer present in an amount of about 21% w / w to about 23% w / w; microcrystalline cellulose present in an amount of about 25% w / w to about 26% w / w; Mannitol present in an amount of about 25% w / w to about 26% w / w; sodium starch glycolate present in an amount of about 4% w / w to about 6% w / w; magnesium stearate present in an amount of about 0.4% w / w to about 0.6% w / w; The pharmaceutical composition of claim 1, wherein the total is less than or equal to 100%.

8. The compound of formula I present in an amount of about 8% w / w; the HPMCAS polymer present in an amount of about 8% w / w; microcrystalline cellulose present in an amount of about 40% w / w; Mannitol present in an amount of about 40% w / w; Sodium starch glycolate present in an amount of about 3.5% w / w; and magnesium stearate present in an amount of about 0.3% w / w. The pharmaceutical composition described above.

9. The pharmaceutical composition according to any one of claims 1 to 8, formulated as a tablet.

10. 10. The method according to claim 1, comprising administering to said patient from about 25 mg to about 220 mg of the compound of formula I. The pharmaceutical composition described.

11. about 25 mg, about 50 mg, and about 100 mg of the compound of formula I 11. The pharmaceutical composition of claim 10, comprising a compound of formula:

12. Methods for treating BTK-associated cancer in a subject in need thereof administering to said subject a pharmaceutical composition according to any one of claims 1 to 11. A method comprising:

13. The BTK-related cancer is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, lymphoma, Waldenström macroglobulinemia, and marginal zone lymphoma The method of claim 12, wherein the

14. 1. A method for treating cancer in a subject in need thereof, comprising administering to said subject about 20 mg of administering to said subject a compound of formula I at a dose of about 120 mg to about 150 mg; 【Chemistry 2】 The cancer is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, warts lymphoma, and marginal zone lymphoma. How to do it.

15. The dose is selected from the group consisting of about 25 mg, about 50 mg, and about 100 mg. The method according to claim 14.

16. 1. Use of a compound of formula I for the treatment of a BTK-associated cancer in a subject, comprising: 【Chemistry 3】 The BTK-related cancers are mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, From the group consisting of pulmonary macroglobulinemia, Waldenström's macroglobulinemia, and marginal zone lymphoma and wherein said compound is administered at a dose of about 20 mg to about 120 mg.

17. Mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom and BTK-related lymphoma selected from the group consisting of Rehm's macroglobulinemia and marginal zone lymphoma.

10. The method of claim 1, wherein the dosage is from about 20 mg to about 120 mg for the treatment of multiple cancers. Use of the pharmaceutical composition according to claim 1.

18. Mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom and BTK-related lymphoma selected from the group consisting of Rehm's macroglobulinemia and marginal zone lymphoma. The pharmaceutical composition according to any one of claims 1 to 10 for use in the treatment of cancer.

19. The dose is selected from the group consisting of about 25 mg, about 50 mg, and about 100 mg.

19. The use according to any one of claims 16, 17 or 18.

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