Pharmaceutical compositions and methods of use thereof

Abstract

The present invention provides methods and compositions for treating cancer by using a compound forming a covalent bond with a kinase or pseudokinase, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Description

[0001] Cross-referencing of related patent applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 585,862, filed September 27, 2023, the entire contents of which are incorporated herein by reference for all purposes. Background Technology

[0003] Phosphatidylinositol 3-kinase (PI3K) belongs to the lipid kinase family. It catalyzes the transfer of a phosphate group to the 3-position of the inositol ring in phosphatidylinositol and its derivatives, generating phosphoinositol-3-phosphate (PI(3)P), phosphoinositol-3,4-bisphosphate (PI(3,4)P2), and phosphoinositol-3,4,5-triphosphate (PI(3,4,5)P3). These products then act as second messengers in signaling cascades, anchoring proteins containing the Plekluck substrate protein homology domain, FYVE domain, Phox domain, and other phospholipid-binding domains to various signaling complexes typically located in the plasma membrane (Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615 (2001)). Based on structural characteristics and substrate specificity, PI3K is classified into three classes. Class IA PI3K is a heterodimer composed of the p110 catalytic subunit and the p85 regulatory subunit. In mammals, there are three genes: PIK3CA, PIK3CB, and PIK3CD, encoding the p110 catalytic isoforms: p110α, p110β, and p110δ, respectively. Additionally, there are three genes: PIK3R1, PIK3R2, and PIK3R3, encoding the p85α (and its splice variants p55α and p50α), p85β, and p55γ regulatory subunits, collectively referred to as p85. The modular domain of the p85 / 55 / 50 subunit contains a Src homology (SH2) domain, which can bind to phosphotyrosine residues in the background sequence of the activating receptor and cytoplasmic tyrosine kinase, thereby activating and localizing class IA PI3K. Class IB PI3K is a heterodimer composed of the catalytic subunit p110γ and the regulatory subunit p101. p110γ is primarily expressed in leukocytes and can be directly activated by GPCRs. Class II PI3Ks are monomers containing only a single catalytic subunit. Class III PI3Ks consist of a single catalytic subunit, Vps34 (a homolog of yeast vacuole protein sorting defect 34). The phospholipid products of Class I PI3Ks associate upstream receptors with downstream cellular activities, including proliferation, survival, chemotaxis, cell transport, motility, metabolism, inflammation and allergic responses, transcription, and translation (Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)). There is currently interest and need for binding and modulating PI3Ks to treat a variety of diseases.

[0004] This disclosure addresses these and other unmet needs. Summary of the Invention

[0005] This invention includes pharmaceutical compositions for immediate release or methods of use thereof, the pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof that forms a covalent bond with a kinase or pseudokinase, and at least one pharmaceutically acceptable excipient. In one specific embodiment, the kinase is PI3-kinase (PI3K).

[0006] In another embodiment, the compound that forms a covalent bond with the kinase or pseudokinase is a compound having the following formula:

[0007] (FCB)a-(L)b-(CLM)c,

[0008] Or its pharmaceutically acceptable salt, wherein:

[0009] CLM stands for covalent connection mode;

[0010] L stands for connector;

[0011] a and c are each independent integers between 1 and 5; b is an integer between 0 and 5; and FCB contains:

[0012] .

[0013] In a specific implementation plan, the FCB has the following structure:

[0014] ,

[0015] R1 is selected from the following groups:

[0016] , , and .

[0017] In another specific embodiment, the compound is compound I:

[0018] Compound I.

[0019] Compound I is disclosed in PCT application publication WO 2021 / 055747 and PCT application PCT / CN2023 / 083760, the entire contents of which are incorporated herein by reference. In some embodiments, compound I is a phosphoinositol 3-kinase (PI3K) inhibitor. In some embodiments, compound I is an irreversible inhibitor of PI3K. In some embodiments, compound I is an irreversible inhibitor of PI3Kα. In other embodiments, compound I may form a covalent bond with an amino acid of PI3K. In other specific embodiments, compound I may form a covalent bond with a cysteine ​​residue in PI3K, such as PI3Kα (e.g., via the Michael reaction).

[0020] The present invention also includes administering the pharmaceutical composition described herein to a subject. In some embodiments, the method may include treating cancer, neurodegenerative diseases, autoimmune diseases, or aging in a subject in need. In other specific embodiments, the method may include treating or inhibiting cancer in a subject. In yet another specific embodiment, the method may include treating or improving cell proliferation disorders in a subject, the method comprising administering to a subject in need a therapeutically effective amount of a compound covalently bonded to a kinase or pseudokinase, or a pharmaceutically acceptable salt thereof, before, during, or after the subject has been administered a compound covalently bonded to a kinase or pseudokinase. In a specific embodiment, the kinase is PI3-kinase (PI3K), and preferably PI3Kα.

[0021] In another embodiment of treating or improving a subject's cell proliferation disorder, the cell proliferation disorder is cancer. In some embodiments, the cancer is selected from one or more of the following groups: leukemia, brain tumors, (small cell and non-small cell) lung cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, and cancers in tissues including intestinal tissue, pancreatic tissue, liver, kidney, prostate, ovary, lung, bone marrow, or breast tissue. In specific embodiments, the cancer is selected from the following groups: blood cancers, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, lung cancer, liver cancer, colon cancer, pancreatic cancer, lymph node cancer, colon cancer, small bowel cancer, prostate cancer, brain cancer, bile duct cancer, gallbladder cancer, head and neck cancer, bone cancer, Ewing sarcoma, skin cancer, kidney cancer, and heart cancer. In another embodiment, the cancer is selected from the following groups: breast cancer, ovarian cancer, pancreatic cancer, colorectal cancer, colon cancer, small bowel cancer, and lung cancer. In some embodiments, the cancer is associated with a mutation in the PIK3CA gene. In another embodiment of the invention, the subject is a human. In some implementations, the subjects have cancer with a mutation in the PIK3CA gene. Attached Figure Description

[0022] Figure 1 A flowchart outlining the process for manufacturing a pharmaceutical tablet comprising compound I of the present disclosure is provided.

[0023] Figure 2 The dissolution profile of 5 mg Compound I tablets (batch 1) in 900 mL of 0.01 M HCl at 37 °C was shown using apparatus 1I (paddle method) at 75 rpm.

[0024] Figure 3 The dissolution profile of 50 mg Compound I tablets (batch 1) in 900 mL of 0.01 M HCl at 37 °C was shown using apparatus 1I (paddle method) at 100 rpm.

[0025] Figure 4 The dissolution profile of 1 mg Compound I tablets (batch 2) in 900 mL of 0.01 M HCl at 37 °C was shown using apparatus 1I (paddle method) at 75 rpm.

[0026] Figure 5 The dissolution profile of 5 mg Compound I tablets (batch 2) in 900 mL of 0.01 M HCl at 37 °C was shown using apparatus 1I (paddle method) at 100 rpm.

[0027] Figure 6 The dissolution profile of 1 mg Compound I tablets (batch 3) in 900 mL of 0.01 M HCl at 37 °C was shown using apparatus 1I (paddle method) at 75 rpm.

[0028] Figure 7 The dissolution profile of compound I (batch 3) in 5 mg specification is shown in 900 mL of 0.01 M HCl at 37 °C using apparatus 1I (paddle method) at 100 rpm.

[0029] Figure 8 The dissolution profile of 1 mg Compound I tablets (batch 4) in 900 mL of 0.01 M HCl at 37 °C was shown using apparatus 1I (paddle method) at 75 rpm.

[0030] Figure 9 The dissolution profile of 5 mg Compound I tablets (batch 4) in 900 mL of 0.01 M HCl at 37 °C was shown using apparatus 1I (paddle method) at 100 rpm. Detailed Implementation

[0031] definition

[0032] For convenience, certain terms used in the specification, embodiments, and claims have been compiled herein. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0033] Throughout this specification, the terms “about” and / or “approximately” may be used in conjunction with numerical values ​​and / or ranges. The term “about” should be understood as referring to values ​​that are close to the stated numerical value. Furthermore, the phrases “less than about [a value]” or “greater than about [a value]” should be understood in conjunction with the definition of the term “about” provided herein. The terms “about” and “approximately” are used interchangeably.

[0034] Throughout this specification, numerical ranges are provided for certain quantities. It should be understood that these ranges encompass all subranges within them. Therefore, the range “50 to 80” includes all possible ranges within it (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range can be considered as endpoints of the ranges it covers (e.g., the range 50-80 includes ranges with endpoints of 55-80, 50-75, etc.).

[0035] Throughout this specification, the terms “composition” and “formulation” are used interchangeably and may refer to a mixture of materials.

[0036] The terms “an” or “a” refer to one or more of the entities; for example, “an inhibitor of PI3-kinase (PI3K)” refers to one or more PI3-kinase (PI3K) regulators or at least one PI3-kinase (PI3K) regulator. In some embodiments, the PI3-kinase (PI3K) regulator is a PI3Ka regulator. Therefore, the terms “an” (or “a”), “one or more”, and “at least one” are used interchangeably herein. Furthermore, reference to “an inhibitor” by the indefinite article “an” or “a” does not exclude the possibility that more than one inhibitor may exist, unless the context explicitly requires that only one inhibitor may exist.

[0037] As used herein, the verb "comprising" and its variants are used in a non-limiting sense in this specification and claims, meaning that the item following the word is included, but not excluded. The invention may suitably "comprise," "consist of," or "consist substantially of" the steps, elements, and / or reagents described in the claims.

[0038] It should also be noted that claims can be drafted to exclude any optional elements. Therefore, this statement is intended as a preliminary basis for using exclusive terms such as “only” or “only” in conjunction with the description of the claim elements, or for using a “negative” restriction.

[0039] Throughout this application, the terms “excipient,” “carrier,” and “medium” are used interchangeably to refer to substances administered in conjunction with the compounds of the present invention. The terms “excipient,” “carrier,” and “medium” refer to materials, compositions, or media that involve carrying or transporting a pharmaceutical agent from one organ or part of the body to another organ or part, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials.

[0040] As used herein, the phrase “pharmaceutically acceptable” means, to a reasonable extent of medical judgment, that a compound, material, composition, and / or dosage form is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio.

[0041] As used herein, the term "salt" includes pharmaceutically acceptable salts commonly used to form free base addition salts. The properties of the salt are not critical, provided it is pharmaceutically acceptable. The term "salt" also includes solvates (e.g., hydrates) of addition salts and polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids.

[0042] The term "pharmaceutically acceptable salt" includes salts obtained by reacting an alkalizing active compound with an inorganic or organic acid to form a salt, such as 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetaminobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L-form), aspartic acid (L-form), benzenesulfonic acid, benzoic acid, camphoric acid (+-form), camphor-10-sulfonic acid (+-form), decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexane, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, and galactopyric acid. Salts of gentianic acid, glucoheponic acid (D-type), gluconic acid (D-type), glucuronic acid (D-type), glutamic acid, glutamate, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL-type), lactobionic acid, lauric acid, maleic acid, malic acid (-L-type), malonic acid, mandelic acid (DL-type), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L-type), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L-type), thiocyanate, (p)toluenesulfonic acid, and undecenoic acid. Those skilled in the art will further appreciate that acid addition salts can be prepared by reacting the said compounds with suitable inorganic or organic acids via any of a variety of known methods.

[0043] As used herein, the phrase “a disease characterized by cell proliferation” or “a condition characterized by cell proliferation” includes, but is not limited to, cancer, benign tumors, and malignant tumors. Examples of cancer and tumors include, but are not limited to, cancers or tumor growths (e.g., leukemia, lymphoma, carcinoma) of the colorectal, breast, lung, liver, pancreas, lymph nodes, colon, prostate, brain, head and neck, skin, kidney, blood, and heart.

[0044] The term "treatment" means to relieve, reduce, delay, decrease, improve, or control one or more of at least one symptom of a subject's condition. The term "treatment" may also mean to prevent, delay the onset (i.e., the stage before the clinical manifestation of the condition) or reduce the risk of the condition developing or worsening.

[0045] As used herein, the terms “inhibit” or “reduce” cell proliferation mean, when compared with proliferating cells of methods, compositions and combinations not accepted by this application, the amount of cell proliferation that is slowed, reduced or, for example, prevented, is measured using methods known to those skilled in the art, and the reduction is, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%.

[0046] "Effective amount" means the amount of the formulation of the present invention sufficient to achieve such treatment when administered to a patient to treat a certain state, condition or ailment. "Effective amount" will vary depending on the active ingredient, the state, condition or ailment to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.

[0047] "Therapeutic effective amount" refers to the amount of a compound or therapeutic active agent that, when administered to a patient to treat a disease or other adverse medical condition, is sufficient to produce a beneficial effect on said disease or condition. Therapeutic effective amount will vary depending on the type of compound or therapeutic active agent selected, the disease or condition and its severity, and the age, weight, etc., of the patient to be treated. Determining the therapeutic effective amount of a given compound or therapeutic active agent is within the capabilities of a person skilled in the art and can be accomplished through routine experiments.

[0048] The term “therapeuticly effective” when applied to dosage or amount means that the amount of a compound or pharmaceutical preparation is sufficient to produce the desired clinical benefit when administered to a patient in need.

[0049] As used herein, "subject" can be a human, a non-human primate, a mammal, a rat, a mouse, a cow, a horse, a pig, a sheep, a goat, a dog, a cat, etc. In some embodiments, the subject is a human. In some embodiments, the subject may be suspected of having cancer or being at risk of developing cancer. The terms "subject" and "patient" are used interchangeably throughout this application.

[0050] “Mammals” include humans and domesticated animals (such as laboratory animals (such as mice, rats, monkeys, dogs, etc.) and domestic pets (such as cats, dogs, pigs, cattle, sheep, goats, horses, rabbits)), as well as non-domesticated animals (such as wild animals).

[0051] Unless otherwise stated, all weight percentages (i.e., “weight %”, “wt.%”, w / w and “% wt”) mentioned herein are measured relative to the total weight of the pharmaceutical composition.

[0052] As used herein, “substantially” or “basically” refers to the extent or degree of completeness or near-completeness of an action, feature, property, state, structure, item, or result. For example, an object “substantially” enclosed means that the object is either completely enclosed or nearly completely enclosed. In some cases, the exact degree of permissible deviation from absolute completeness may depend on the specific context. But in general, a closeness to completion will result in the same overall result as achieving absolute completeness. “Substantially” also applies when used in a negative sense to refer to the complete or near-complete absence of an action, feature, property, state, structure, item, or result. For example, a composition “substantially free of” other active agents either contains no other active agents or contains nearly no other active agents, such that its effect is the same as that of having no other active agents at all. In other words, a composition “substantially free of” a component, element, or other active agent may still contain such a substance, as long as its effect is not measurable.

[0053] As used herein, “D90” refers to the 90% value of the particle diameter as determined by sieving (i.e., the percentage of drug particles retained on a sieve during sieving with a specific mesh size). For example, if D90 = 100 μm, then 90% of the drug particles are retained on a 100 μm sieve during sieving. Similarly, “D80” refers to the 80% value of the particle diameter, “D70” to the 70% value, “D60” to the 60% value, “D50” to the 50% value, “D40” to the 40% value, “D30” to the 30% value, “D20” to the 20% value, and “D10” to the 10% value.

[0054] Compounds that form covalent bonds with PI3-kinase (PI3K)

[0055] The compound, for example, a compound having the following formula:

[0056] (FCB)a-(L)b-(CLM)c,

[0057] Its pharmaceutically acceptable salts, and / or subclasses thereof, or Compound I disclosed herein, or its salts, solvates, esters and / or prodrugs, may be used in the pharmaceutical compositions disclosed herein.

[0058] In another embodiment, the compound that forms a covalent bond with the kinase or pseudokinase is a compound having the following formula:

[0059] (FCB)a-(L)b-(CLM)c,

[0060] Or its pharmaceutically acceptable salt, wherein:

[0061] CLM stands for covalent connection mode;

[0062] L stands for connector;

[0063] a and c are each independent integers between 1 and 5; b is an integer between 0 and 5; and FCB contains:

[0064] .

[0065] In a specific implementation plan, the FCB has the following structure:

[0066] ,

[0067] R1 is selected from the following groups:

[0068] , , and .

[0069] In some embodiments, the compound that forms a covalent bond with a kinase or pseudokinase (e.g., PI3-kinase (PI3K)) is compound I. In some embodiments, the compound of formula (FCB)a-(L)b-(CLM)c is compound I.

[0070] In some embodiments, compound I is a crystalline form of compound I, or a pharmaceutically acceptable salt or solvation of compound I. In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of: phosphates, hydrochlorides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates, fumarates, maleates, L-tartrates, citrates, and succinates of compound I, or solvations thereof.

[0071] Compound I.

[0072] In specific embodiments, compound I is a salt, including a phosphate. In some embodiments, the compound that forms a covalent bond with PI3-kinase (PI3K) is referred to as a PI3K compound.

[0073] As used herein, the term "CLM" refers to any covalently binding mode capable of forming a covalent bond with a biological target. A CLM can be linked to an FCB via a bond or a linker. A CLM may include one or more chemical moieties capable of forming a covalent bond with the biological target. These chemical moieties can be electrophilic or nucleophilic groups.

[0074] As used herein, the term "biological target" refers to any target to which FCB non-covalently binds to produce a therapeutic effect. CLM covalently binds to the biological target. In some embodiments, the biological target is a protein. Non-limiting examples of biological targets include kinases, such as, but not limited to, phosphoinositol 3-kinase (PI3K) and pseudokinases.

[0075] The term "alkyl" refers to a saturated aliphatic group, including straight-chain alkyl, branched alkyl, cycloalkyl (alicyclic) group, alkyl-substituted cycloalkyl, and cycloalkyl-substituted alkyl.

[0076] In some embodiments, the straight-chain or branched alkyl group has 30 or fewer carbon atoms in its backbone (e.g., for a straight-chain C1-C1 alkyl group). 30 For C3-C branches 30 ), 20 or fewer, 12 or fewer, or 7 or fewer. Similarly, in some embodiments, the cycloalkyl group has 3 to 10 carbon atoms in its ring structure, for example, 5, 6, or 7 carbon atoms in the ring structure. As used throughout this specification, examples, and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having one or more substituents that replace hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogens, hydroxyl groups, carbonyl groups (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (such as thioesters, thioacetic esters, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate esters, phosphonates, phosphonites, amino groups, amide groups, amidine, imine, cyano, nitro, azide, mercapto, alkylthio, sulfate esters, sulfonates, aminosulfonyl, sulfonamide, sulfonyl, heterocyclic groups, aralkyl, or aromatic or heteroaromatic moieties.

[0077] Unless the number of carbons is otherwise specified, as used herein, "lower alkyl" means an alkyl group as defined above but having one to ten carbon atoms or one to six carbon atoms in its main chain structure. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl groups. In some embodiments, the substituents designated as alkyl groups herein are lower alkyl groups.

[0078] Those skilled in the art will understand that, where appropriate, the substituted portion of the hydrocarbon chain can itself be substituted. For example, the substituents of the substituted alkyl group can include halogens, hydroxyl groups, nitro groups, thiols, amino groups, azides, imino groups, amide groups, phosphoryl groups (including phosphonates and hypophosphonates), sulfonyl groups (including sulfates, sulfonamides, aminosulfonyl groups, and sulfonates), and silyl groups, as well as ethers, alkyl sulfides, carbonyl groups (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, etc. Cycloalkyl groups can be substituted in the same manner.

[0079] As used herein, “heteroalkyl” means a straight or branched chain containing at least one heteroatom, or a free radical containing a cyclic carbon, or a combination thereof. Suitable heteroatoms include, but are not limited to, O, N, Si, P, Se, B, and S, wherein phosphorus and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. Heteroalkyl can be substituted as defined above for alkyl.

[0080] The term "alkithioyl" refers to an alkyl group having a sulfur radical attached thereto as defined above. In some embodiments, the "alkithioyl" moiety is represented by one of -S-alkyl, -S-alkenyl, and -S-ynyl. Representative alkithioyl groups include methylthioyl and ethylthioyl. The term "alkithioyl" also covers cycloalkyl, alkenyl, and cycloalkenyl groups, as well as ynyl groups. "Arylthioyl" refers to an aryl or heteroaryl group. Alkithioyl groups can be substituted as defined above for alkyl groups.

[0081] The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groups that are similar in length and possible substitution to the alkyl groups described above, but each contains at least one double or triple bond.

[0082] As used herein, the term "alkoxy" or "alkoxy group" refers to an alkyl group having an oxygen group attached to it as defined above. Representative alkoxy groups include methoxy, ethoxy, propoxy, and tert-butoxy. An "ether" is two hydrocarbons covalently linked by oxygen. Accordingly, the substituent of the alkyl group that makes it an ether is or similar to an alkoxy group, as can be represented by one of -O-alkyl, -O-alkenyl, and -O-ynyl. Aryloxy groups can be represented by -O-aryl or O-heteroaryl, where aryl and heteroaryl are defined as follows. Alkoxy and aryloxy groups can be substituted as described above for alkyl groups.

[0083] The terms "amine" and "amino" are recognized in the art and refer to unsubstituted and substituted amines, for example, portions that can be represented by the following general formula: or Among them, R9 and R 10 and R' 10 Each can independently represent hydrogen, alkyl, alkenyl, or -(CH2). m -R8 or R9 and R 10 Together with the N atoms they are attached to, they complete a heterocycle having 4 to 8 atoms in the ring structure; R8 represents aryl, cycloalkyl, cycloalkenyl, heterocyclic, or polycyclic; and m is zero or an integer in the range of 1 to 8. In some embodiments, R9 or R 10 Only one of them can be a carbonyl group, for example, R9, R 10 It does not form an imide with nitrogen. In other embodiments, the term "amine" does not cover amides, for example, where R9 and R 10 One of them represents a carbonyl group. In some embodiments, R9 and R10 (and optional R') 10 Each of these groups independently represents hydrogen, alkyl or cycloalkyl, alkenyl or cycloalkenyl or ynyl. Therefore, as used herein, the term "alkylamine" means, as defined above, a substituted (as described above for alkyl groups) or unsubstituted alkyl group (i.e., R9 and R) connected thereto. 10 At least one of them is an alkyl group (an amino group).

[0084] The term "amide group" is generally understood in the art to refer to an amino-substituted carbonyl group and includes a portion that can be represented by the following general formula: Among them, R9 and R 10 As defined above.

[0085] As used in this article, "aryl" refers to C5-C 10 - Monocyclic aromatics, heterocyclics, fused aromatics, fused heterocyclics, diaromatics, or diheterocyclic ring systems. Broadly defined, as used herein, the term "aryl" includes 5-, 6-, 7-, 8-, 9-, and 10-membered monocyclic aromatic groups, which may contain zero to four heteroatoms, such as benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl groups with heteroatoms in their ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring may be substituted at one or more ring positions by one or more substituents (including, but not limited to, halogens, azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino (or quaternized amino), nitro, mercapto, imino, amide, phosphonate, hypophosphonate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN; and combinations thereof).

[0086] The term "aryl" also includes polycyclic cyclic systems having two or more cyclic rings, wherein two or more carbons are common to two adjacent rings (i.e., "fused rings"), wherein at least one of the rings is aromatic, for example, other cyclic rings or rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl and / or heterocyclic. Examples of heterocycles include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophene, benzooxazolyl, benzooxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazoleyl, benzoisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazolyl, 4aHcarbazolyl, carbaolinyl, chromanyl, chromenyl, cinnamyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3b]tetrahydrofuran, furanyl, furanyl Imidazolyl, imidazolinyl, imidazolyl, 1H-indazolyl, indoleyl, dihydroindoleyl, indazinyl, indoleyl, 3H-indoleyl, isoindoleyl, isobenzofuranyl, isoindazolyl, isoindolelinyl, isoindoleyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthidyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl 1,3,4-Oxadiazolyl, oxazolyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridine, phenanthrolinel, phenazinyl, phenothiazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinyl, 4-piperidinyl, piperinyl, pteridinyl, purine, pyranyl, pyrazinyl, pyrazolylalkyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridinyl, pyrimidinyl, pyrrolylalkyl, pyrrololinyl 2H-pyrrole, pyrrole, quinazolinyl, quinolinyl, 4H-quinolinyl, quinoxalinyl, quinolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, and xanthonyl. One or more of the rings may be substituted with "aryl" as defined above.

[0087] As used herein, the term "aralkyl" refers to an alkyl group that has been substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

[0088] As used in this article, the term "carbon ring" refers to an aromatic or non-aromatic ring in which every atom of the ring is carbon.

[0089] As used herein, "heterocyclic" or "heterocyclic" refers to a cyclic group of atoms linked by a monocyclic or bicyclic ring of carbon or nitrogen, the monocyclic or bicyclic ring containing 3 to 10 ring atoms and preferably 5 to 6 ring atoms, consisting of carbon and one to four heteroatoms, each selected from the group consisting of non-peroxide oxygen, sulfur, and N (Y), wherein Y is absent or H, O, (Cl-C) 10 Alkyl, phenyl, or benzyl groups, optionally containing one to three double bonds and optionally substituted with one or more substituents. Examples of heterocycles include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenel, benzooxazolyl, benzooxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbalinyl, chromanyl, chromenyl, cinnamyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]tetrahydrofuran, furanyl, furanyl, imidyl Alzolyl, imidazolinyl, imidazolyl, 1H-indazole, indoleyl, dihydroindoleyl, indazinyl, indoleyl, 3H-indoleyl, isoindoleyl, isobenzofuranyl, isoindazoleyl, isoindolelinyl, isoindoleyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthidyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl Azolyl, oxazolyl, oxazolyl, oxazolidinyl, oxazolidinyl, oxindolyl, pyrimidinyl, phenanthridine, phenanthrololinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinyl, 4-piperidinyl, piperidinyl, pteridinyl, purine, pyranyl, pyrazinyl, pyrazolylalkyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridinyl, pyrrolylalkyl, pyrrololinyl 2H-pyrrole, pyrrole, quinazolinyl, quinolinyl, 4H-quinolinyl, quinoxalinyl, quinolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl and xanthonyl. The heterocyclic group may optionally be substituted at one or more positions with one or more substituents of alkyl and aryl groups as defined above (e.g., halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, mercapto, imino, amide, phosphate, phosphonate, hypophosphonate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3 and -CN).

[0090] The term "carbonyl" is recognized in the art and includes such a portion that can be represented by the following general formula: or Where X is a bond or represents oxygen or sulfur, and R 11 R' indicates hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, or ynyl. 11 This indicates hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, or alkynyl. Where X is oxygen and R... 11 or R' 11 In the absence of hydrogen, the formula represents "ester". Where X is oxygen and R... 11 As defined above, the part is referred to herein as a carboxyl group, and specifically when R... 11 When X is hydrogen, the formula represents "carboxylic acid". When X is oxygen and R' 11 In the case of hydrogen, the formula represents "formate ester". Typically, in the case where the oxygen atom in the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. Where X is sulfur and R... 11 or R' 11 In the case that X is not hydrogen, the formula represents "thioester". Where X is sulfur and R... 11 In the case where X is hydrogen, the formula represents "thiocarboxylic acid". Where X is sulfur and R' 11 In the case where X is hydrogen, the formula represents "thiocarbamate". On the other hand, when X is a bond and R... 11 If it is not hydrogen, the above formula represents a "ketone" group. Where X is a bond and R... 11 In the case of hydrogen, the above formula represents an "aldehyde" group.

[0091] As used herein, the term "monoester" refers to an analogue of a dicarboxylic acid, wherein one of the carboxylic acids is functionalized into an ester, and the other carboxylic acid is a free carboxylic acid or a salt of a carboxylic acid. Examples of monoesters include, but are not limited to, monoesters of succinic acid, glutaric acid, adipic acid, octanoic acid, sebacic acid, azelaic acid, oxalic acid, and maleic acid.

[0092] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Examples of heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur, and selenium. Other heteroatoms include silicon and arsenic.

[0093] As used herein, the term “nitro” means -NO2; the term “halogen” specifies -F, -Cl, -Br or -I; the term “thiol” means -SH; the term “hydroxyl” means -OH; and the term “sulfonyl” means -SO2-.

[0094] As used herein, the term "substituted" refers to all permissible substituents in the compounds described herein. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic group containing any number of carbon atoms, preferably one to fourteen carbon atoms, and optionally containing one or more heteroatoms such as oxygen, sulfur, or nitrogen groups in a linear, branched, or cyclic configuration. Representative substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halogen, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aryloxy, substituted aryloxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amide, substituted amide, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C3-C 20 cyclic, substituted C3-C 20 Cyclic, heterocyclic, substituted heterocyclic amino acids, peptide groups, and polypeptide groups.

[0095] Heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents in the organic compounds described herein, which will satisfy the valence of the heteroatom. It should be understood that “substitution” or “substituted” includes the implied condition that such substitution is based on the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, i.e., that the compound does not spontaneously undergo transformations such as by rearrangement, cyclization, or elimination.

[0096] In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein. For a suitable organic compound, there may be one or more permissible substituents, and they may be the same or different. Heteroatoms such as nitrogen may have hydrogen substituents of the organic compounds described herein and / or any permissible substituents that will satisfy the valence of the heteroatom.

[0097] In various embodiments, the substituents are selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, aralkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thione, each of which is optionally substituted by one or more suitable substituents. In some embodiments, the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, aralkyl, carbamate, carboxyl, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclic, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thione, wherein each of the alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclic, ketone, phosphate ester, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thione may be further substituted by one or more suitable substituents.

[0098] Examples of substituents include, but are not limited to, halogens, azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, mercapto, imino, amide, phosphonate, hypophosphonate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, thion, ester, heterocyclic, –CN, aryl, aryloxy, perhaloalkoxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, azide, alkylthio, oxo, acylalkyl, carboxyl ester, formamide, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylalkylamino, alkylsulfonyl, formamidealkylaryl, formamidearyl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxyl, carbamoylaminoalkyl, cyano, alkoxyalkyl, perhaloalkyl, arylalkoxyalkyl, etc. In some implementations, the substituents are selected from cyano, halogen, hydroxyl, and nitro groups.

[0099] The terms “polypeptide,” “peptide,” and “protein” generally refer to polymers of amino acid residues. As used herein, the terms also apply to amino acid polymers in which one or more amino acids are chemical analogs or modified derivatives of naturally occurring amino acids. As commonly used herein, the term “protein” refers to an amino acid polymer linked together by peptide bonds to form a chain length sufficient to produce a polypeptide with tertiary and / or quaternary structures. By definition, the term “protein” excludes small peptides, which lack the higher-order structures considered essential for proteins.

[0100] As used herein, the term "substantially free" means that it contains no therapeutically effective amount of the compound when administered at the recommended dose, but may contain trace amounts of the compound that are not therapeutically effective. For compositions of the invention that are "substantially free" of reducing sugars (e.g., lactose) and / or sugar alcohols (e.g., mannitol), trace amounts of said reducing sugars (e.g., lactose) and / or mannitol may be present, for example, less than about 10%, less than about 9%, less than about 8%, less than 7%, less than 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, including all ranges and subranges therebetween.

[0101] This disclosure relates to pharmaceutical compositions comprising an inhibitor of phosphoinositol 3-kinase (PI3K) (e.g., compound I, or a pharmaceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof).

[0102]

[0103] (Compound I).

[0104] The present invention also includes using compound I or a pharmaceutically acceptable salt thereof as a compound in combination with other therapeutically active agents for any combination therapy or method of use or treatment.

[0105] CLM

[0106] The compounds disclosed herein may comprise one or more CLMs. A CLM can be any covalently binding mode capable of forming a covalent bond with a biological target. A CLM may include one or more chemical moieties, one or more of which are capable of forming a covalent bond with a biological target. In some embodiments, a CLM may include internal linkers or spacers. Internal linkers or spacers may combine two parts of a CLM or may be attached to a CLM.

[0107] In some embodiments, the CLM comprises at least one substituted or unsubstituted alkyne. In some embodiments, the CLM comprises at least one substituted or unsubstituted acrylamide. In some embodiments, the CLM comprises at least one substituted or unsubstituted vinylsulfonamide. In some embodiments, the CLM comprises at least one substituted or unsubstituted vinyl sulfone. In some embodiments, the CLM comprises at least one substituted or unsubstituted fumarate. In some embodiments, the CLM comprises at least one substituted or unsubstituted acrylate. In some embodiments, the CLM comprises at least one substituted or unsubstituted isothiocyanate. In some embodiments, the CLM comprises at least one substituted or unsubstituted sulfonyl fluoride. In some embodiments, the CLM comprises at least one substituted or unsubstituted fluorosulfate. In some embodiments, the CLM comprises at least one substituted or unsubstituted formylphenylboronic acid. In some embodiments, the CLM comprises at least one substituted or unsubstituted boric acid. In some embodiments, the CLM comprises at least one activated ester. In some embodiments, the CLM comprises at least one substituted or unsubstituted thioester. In some embodiments, the CLM comprises at least one sulfonyl group. In some embodiments, the CLM comprises at least one nitro group. In some embodiments, the CLM comprises at least one substituted or unsubstituted epoxide. In some embodiments, the CLM comprises at least one substituted or unsubstituted formylphenylboronic acid. In some embodiments, the CLM comprises at least one substituted or unsubstituted aryl halide. In some embodiments, the CLM comprises at least one substituted or unsubstituted aldehyde. In some embodiments, the CLM comprises at least one substituted or unsubstituted triazine. In some embodiments, the CLM comprises at least one substituted or unsubstituted cyanoacrylamide. In some embodiments, the CLM comprises at least one substituted or unsubstituted chloroacetamide.

[0108] An exemplary CLM includes, but is not limited to:

[0109]

[0110]

[0111]

[0112]

[0113] , A, B, C, and D are independently selected from the following groups each time they appear: H, halogen, CF3, -OH, -NH2, -SH, -SCH3, -CN, -NO2, -CH2(NH2), -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(O)CH3, NHC(O)-C 1-6 Alkyl, N(C) 1-3 Alkyl)C(O)-C 1-6 Alkyl, OC(O)NH2, OC(O)NH(CH3), OC(O)N(CH3)2, imidazole, pyrazol, methylimidazol, methylpyrazol, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-6 Cycloalkyl, optionally substituted 5-10 membered heterocycles, optionally substituted aryl, and optionally substituted 5-10 membered heteroaryl, wherein the optional substituents of A, B, C, and D are 1-3 independently selected from the group consisting of: halogen, OH, NH2, CH3, CF3, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -CH2NH2, -C(O)CH3, SH, -S-CH3, optionally substituted C 1-3Alkyl groups and optionally substituted C3-6 cycloalkyl groups. A1, A2, A3, A4, A5, and A6 are each independently selected from the group consisting of: H, halogen, CF3, -OH, -NH2, -SH, -SCH3, -CN, -NO2, -CH2(NH2), -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(O)CH3, NHC(O)-C1-6 alkyl, N(C1-3 alkyl)C(O)-C1-6 alkyl, OC(O)NH2, OC(O)NH(CH3), OC(O)N(CH3)2, imidazolyl, pyrazolyl, methylimidazolyl, methylpyrazolyl, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 ynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 5-10 heterocyclic, optionally substituted aryl, and optionally substituted 5-10 heteroaryl. The optional substituents of A1, A2, A3, A4, A5, and A6 are 1 to 3 substituents independently selected from the group consisting of: halogen, OH, NH2, CH3, CF3, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -CH2NH2, -C(O)CH3, SH, -S-CH3, optional substituted C1-3 alkyl and optional substituted C3-6 cycloalkyl, wherein the optional substituents of the C1-3 alkyl and C3-6 cycloalkyl are 1 to 2 substituents independently selected from the group consisting of: halogen, OH, NH2, CH3, CF3, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -CH2NH2, -C(O)CH3, SH, and -S-CH3, or fragments, derivatives, or analogs thereof.

[0114] In some implementations, the CLM is selected from the following group: , , , , , , , , , , and .

[0115] connector

[0116] The compounds in the pharmaceutical compositions disclosed herein may include one or more optional linkers connecting the FCB to the CLM. The linker L may be attached to any site on the FCB and CLM, provided that the efficacy of the FCB and the binding of the CLM are not significantly affected. In some embodiments, the CLM includes an optional internal linker.

[0117] In some embodiments, the linker (including the internal linker of the CLM) is a small molecule. In some embodiments, the linker (including the internal linker of the CLM) is selected from, but not limited to, substituted and unsubstituted C1-C30 alkyl, substituted and unsubstituted C2-C30 alkenyl, substituted and unsubstituted C2-C30 alkynyl, substituted and unsubstituted C3-C30 cycloalkyl, substituted and unsubstituted C1-C30 heterocyclic alkyl, substituted and unsubstituted C3-C30 cycloalkenyl, substituted and unsubstituted C1-C30 heterocyclic alkenyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl.

[0118] In some embodiments, the linker (including the internal linker of the CLM) may be selected from C1-C10 straight-chain alkyl, C1-C10 straight-chain O-alkyl, C1-C10 straight-chain substituted alkyl, C1-C10 straight-chain substituted O-alkyl, C4-C13 branched alkyl, C4-C13 branched O-alkyl, C2-C12 straight-chain alkenyl, C2-C12 straight-chain O-alkenyl, C3-C 12 Straight-chain substituted alkenyl groups, C3-C 12 Straight-chain substituted O-alkenyl groups, polyethylene glycol, polylactic acid, polyglycolic acid, poly(lactide-co-glycolic acid), polycaprolactone, polycyanoacrylate, ketones, aryl groups, heterocyclic compounds, succinates, amino acids, aromatic groups, ethers, crown ethers, ureas, thioureas, amides, purines, pyrimidines, bipyridines, indole derivatives used as crosslinking agents, chelating agents, aldehydes, ketones, diamines, diols, heterocyclic structures, nitrogen-containing heterocyclic propylenes, disulfides, thioethers, hydrazones, and combinations thereof. For example, the linker can be a C3 straight-chain alkyl group or a ketone. The alkyl chain of the linker can be substituted by one or more substituents or heteroatoms. In some embodiments, the linker contains one or more atoms or groups selected from –O-, -C(=O)-, -NR, -OC(=O)-NR-, -S-, -SS-. The linker can be a dicarboxylic acid derivative selected from succinic acid, glutaric acid, or diglycolic acid.

[0119] In some embodiments, the alkyl chain of the linker may optionally be interrupted by one or more atoms or groups selected from –O-, -C(=O)-, -NR, -OC(=O)-NR-, -S-, -SS-. The linker may be selected from dicarboxylic acid derivatives of succinic acid, glutaric acid, or diethanolic acid.

[0120] In some embodiments, the linker may be non-cleavable. In some embodiments, the linker may be cleavable. In some embodiments, the linker may be cleaved by an enzyme.

[0121] Non-limiting examples of connectors include

[0122]

[0123] D1, D2, D3, D4, D5, and D6 are independently selected from groups consisting of N, C, O, or S each time they appear. The condition is that if D1-6 are N, the corresponding position is trivalent; if D1-6 are O or S, the corresponding position is divalent. B1, B2, B3, B4, B5, and B6... The following groups are either absent or independently selected each time they appear: H, halogen, CF3, -OH, -CH3, -NH2, -SH, -SCH3, -CN, -NO2, -CH2(NH2), -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(O)CH3, NHC(O)-C1-6 alkyl, N(C1-3 alkyl)C(O)-C1-6 alkyl, OC(O)NH2, OC(O)NH(CH3), OC(O)N(CH3)2, imidazole, pyrazol, methylimidazol, methylpyrazol, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 ynyl, optionally substituted C3-6 Cycloalkyl, optionally substituted 5-10 membered heterocycles, optionally substituted aryl and optionally substituted 5-10 membered heteroaryl, wherein the optional substituents of B1, B2, B3 and B4 are 1-3 substituents, said substituents being independently selected from the group consisting of: halogens, OH, NH2, CH3, CF3, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -CH2NH2, -C(O)CH3, SH, -S-CH3, optionally substituted C1-3 alkyl and optionally substituted C3-6 cycloalkyl, wherein the optional substituents of C1-3 alkyl and C3-6 cycloalkyl are 1-2 substituents, said substituents being independently selected from the group consisting of: halogens, OH, NH2, CH3, CF3, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -CH2NH2, -C(O)CH3, SH and -S-CH3 or any fragment or analogue thereof.

[0124] In some implementations, the connection sub-selection is free. and A group is formed in which any end can be connected to the CLM. In some implementations, the choice is free. and The connector of the group is connected to the CLM, which is selected from the following groups: , , , , , , , , , , and .

[0125] In some embodiments, the kinase is a PI3-kinase (PI3K). The therapeutic conjugate may have the structure (FCB)a-(L)b-(CLM)c, wherein a and c are independently integers between 1 and 5, b is an integer between 0 and 5, and wherein the FCB portion comprises a PI3K inhibitor or a fragment, analogue, or derivative thereof.

[0126] The FCB, L (connector), and CLM sections have been discussed in the preceding sections. In a non-limiting example, the FCB includes... .

[0127] In some implementations, the FCB is a structure Compounds in which R1 is selected from the group consisting of: , , and .

[0128] Pharmaceutical Composition

[0129] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (FCB)a-(L)b-(CLM)c disclosed herein, and / or its subclass, or compound I, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof as an active ingredient, which is combined with a pharmaceutically acceptable excipient or carrier:

[0130]

[0131] (Compound I)

[0132] In a specific implementation, the pharmaceutical composition allows for the immediate release of compound I.

[0133] In some embodiments, compound I is a crystalline form of compound I, or a pharmaceutically acceptable salt or solvation of compound I. In some embodiments, a pharmaceutically acceptable salt of compound I is selected from the group consisting of phosphates, hydrochlorides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates, fumarates, maleates, L-tartrates, citrates, and succinates, or solvations thereof. In some embodiments, compound I is anhydrous or non-solventized. In another embodiment, the crystalline form is a phosphate of compound I or a solvation thereof. In a specific embodiment, the crystalline form is a hydrate. In another embodiment, the invention may be an amorphous form of compound I.

[0134] In the specific implementation, the form of compound I in the pharmaceutical composition described herein is derived from PCT application PCT / CN2023 / 083760, which is incorporated herein by reference in its entirety.

[0135] Pharmaceutical excipients can be added to pharmaceutical compositions or formulations to achieve a variety of purposes, including achieving immediate release of the compound after oral administration to a patient.

[0136] In some embodiments, the pharmaceutical composition herein may be in tablet form. In some embodiments, the tablets herein have a weight range of about 20 mg to about 500 mg, or about 50 mg to about 400 mg, or about 70 mg to about 250 mg, or about 80 mg to about 150 mg. In some embodiments, the tablets herein have a weight of about 100 mg. In some embodiments, the tablet diameter is less than about 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, or 4 mm. In some embodiments, the tablet is a coated tablet. In some embodiments, when compressed using a 6 mm tableting die, the tablet hardness is greater than about 0.5 Kp, about 0.7 Kp, about 1.0 Kp, about 1.2 Kp, about 1.5 Kp, or about 2.0 Kp. In some embodiments, the tablet friability is less than 3%, less than 2%, or less than 1%.

[0137] In some embodiments, the amount of the compound covalently bonded to the kinase or pseudokinase, a compound of formula (FCB)a-(L)b-(CLM)c, and / or its subclasses, or compound I, or its pharmaceutically acceptable salts, esters, or solvates, is about 0.1% to about 50% by weight, or 1% to about 40% by weight, or about 3% to about 20% by weight, or about 4% to about 10% by weight, relative to the total weight of the composition or tablet. In some embodiments, the amount of the compound covalently bonded to the kinase or pseudokinase, a compound of formula (FCB)a-(L)b-(CLM)c, and / or its subclasses, or compound I, or its pharmaceutically acceptable salts, esters, or solvates, is about 5% by weight.

[0138] In some embodiments, the amount of the compound covalently bonded to the kinase or pseudokinase, a compound of formula (FCB)a-(L)b-(CLM)c, and / or its subclasses, or compound I, or a pharmaceutically acceptable salt, ester, or solvate thereof, is about 0.1 mg to about 30 mg per tablet, or about 1 mg to about 20 mg per tablet, or about 3 mg to about 7 mg per tablet, or about 5 mg to about 6 mg per tablet. In some embodiments, the amount of the compound covalently bonded to the kinase or pseudokinase, a compound of formula (FCB)a-(L)b-(CLM)c, and / or its subclasses, or compound I, or a pharmaceutically acceptable salt, ester, or solvate thereof, is 5 mg per tablet.

[0139] In some embodiments, suitable pharmaceutical excipients may include fillers, binders, disintegrants, flow aids, lubricants, coatings, or any combination thereof.

[0140] In some embodiments, the filler includes materials such as silica, titanium dioxide, alumina, talc, kaolin, powdered cellulose, microcrystalline cellulose, urea, sodium chloride, and sugars, or combinations thereof. Any suitable sugar may be used in the compositions of this disclosure. As used herein, "sugar" includes sugar alcohols, monosaccharides, disaccharides, and oligosaccharides. Exemplary sugar alcohols include, but are not limited to, xylitol, mannitol, sorbitol, erythritol, lactitol, pentitol, and hexitol. Exemplary monosaccharides include, but are not limited to, glucose, fructose, aldose, and ketose. Exemplary disaccharides include, but are not limited to, sucrose, isomaltulose, lactose, trehalose, and maltose. Exemplary oligosaccharides include, but are not limited to, fructooligosaccharides, inulin, galactooligosaccharides, and mannosaccharides. In some embodiments, the sugar is sorbitol, mannitol, or xylitol. In some embodiments, the sugar is sorbitol. In some embodiments, the sugar is sucrose.

[0141] In some implementations, a suitable pharmaceutically acceptable filler may be selected from microcrystalline cellulose, silicified microcrystalline cellulose, mannitol EZ, pregelatinized starch, dicalcium phosphate dihydrate, lactose monohydrate, or any combination thereof.

[0142] In some embodiments, the amount of filler used in this disclosure is from about 10% to about 95% by weight, 10% to about 80% by weight, or about 20% to about 70% by weight, or about 30% to about 60% by weight, or about 40% to about 60% by weight, or about 40% to about 50% by weight, or about 42% to 46% by weight of the total weight of the composition or tablet. In some embodiments, the amount of filler used herein is from about 30% to about 60% by weight. In some embodiments, the amount of filler used herein is about 30% by weight. In some embodiments, the amount of filler used herein is from about 40% to about 50% by weight of the total weight of the composition or tablet. In some embodiments, the amount of filler used herein is from about 45% to about 60% by weight of the total weight of the composition or tablet. In some embodiments, the amount of filler used herein is from about 70% to about 90% by weight of the total weight of the composition or tablet.

[0143] In some embodiments, the amount of filler used herein is about 10 mg to about 80 mg per tablet, or about 20 mg to about 70 mg per tablet, or about 30 mg to about 60 mg per tablet, or about 40 mg to about 50 mg per tablet, or about 42 mg to about 46 mg per tablet. In some embodiments, the amount of filler used herein is 30 mg per tablet. In some embodiments, the amount of filler used herein is 42.5 mg per tablet.

[0144] In some embodiments, the amount of filler used herein is about 100 mg to about 800 mg per tablet, or about 200 mg to about 700 mg per tablet, or about 300 mg to about 600 mg per tablet, or about 400 mg to about 500 mg per tablet, or about 420 mg to about 460 mg per tablet. In some embodiments, the amount of filler used herein is 300 mg per tablet. In some embodiments, the amount of filler used herein is about 200 mg to about 300 mg per tablet.

[0145] In the specific implementation scheme, the filler comprises microcrystalline cellulose in accordance with the ratio and amount of filler described herein.

[0146] Binders can be used to impart cohesive properties to tablets, thereby ensuring that the tablet or tablet layer remains intact after compression. Suitable binder materials include, but are not limited to, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, polyvinyl alcohol, waxes, and natural and synthetic gums such as gum arabic sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, ethylcellulose, hydroxyethylcellulose, etc.), and magnesium aluminum silicate, as well as combinations thereof. Examples of polyvinylpyrrolidone include povidone, copovidone, and cross-linked povidone.

[0147] Solid pharmaceutical compositions compacted into dosage forms such as tablets may contain excipients, which serve to facilitate the binding of the active ingredient with other excipients after compaction. Binders used in solid pharmaceutical compositions and / or combinations include gum arabic, alginate, carbomer (e.g., carbopol), sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, tragacanth gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methylcellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polymethyl methacrylate, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.

[0148] In some implementations, a suitable pharmaceutically acceptable binder may be selected from povidone K29 / 32, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or any combination thereof.

[0149] In some embodiments, the amount of the binder used in this disclosure is from about 0.1% to about 10% by weight, or about 1% to about 10% by weight, or about 2% to about 8% by weight, or about 2% to about 6% by weight, or about 2% to 5% by weight, or about 3% to about 4% by weight of the total weight of the composition or tablet.

[0150] In some embodiments, the amount of adhesive used herein is about 0.1 mg to about 10 mg per tablet, or about 1 mg to about 10 mg per tablet, or about 2 mg to about 8 mg per tablet, or about 2 mg to about 6 mg per tablet, or about 2 mg to 5 mg per tablet, or about 3 mg to 4 mg per tablet.

[0151] In the specific implementation scheme, the adhesive comprises hydroxypropyl cellulose according to the ratio and amount of adhesive described herein.

[0152] Disintegrants can be used to promote the disintegration of the tablets, thereby increasing the erosion rate relative to the dissolution rate. Disintegrants are typically starches, clays, celluloses, alginates, gums, or cross-linked polymers (e.g., croscarmellose). Other non-limiting examples of suitable disintegrants include, for example, mildly cross-linked polyvinylpyrrolidone, corn starch, potato starch, cassava starch and modified starches, croscarmellose sodium, croscarmellose, sodium carboxymethyl starch, and combinations and mixtures thereof.

[0153] In some implementations, the pharmaceutically acceptable disintegrant may be selected from croscarmellose sodium, croscarmellose XL, or any combination thereof.

[0154] In some embodiments, the amount of the disintegrant used herein is from about 0.1% to about 10% by weight, or about 1% to about 10% by weight, or about 2% to about 8% by weight, or about 2% to about 6% by weight, or about 2% to 5% by weight, or about 3% to 4% by weight. In some embodiments, the amount of the disintegrant used herein is from about 0.1 mg to about 10 mg per tablet, or about 1 mg to about 10 mg per tablet, or about 2 mg to about 8 mg per tablet, or about 2 mg to about 6 mg per tablet, or about 2 mg to 5 mg per tablet, or about 3 mg to 4 mg per tablet, or about 1 mg to 2 mg per tablet, or about 8 mg to 10 mg per tablet.

[0155] In the specific implementation scheme, the disintegrant comprises crospovidone XL in accordance with the ratio and amount of disintegrant described herein.

[0156] Gliding agents can be added to improve the flowability of uncompacted solid compositions and enhance the accuracy of drug administration. Excipients that can be used as gliding agents include, for example, colloidal silica, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate.

[0157] In some implementations, a suitable pharmaceutically acceptable gliding agent may be selected from colloidal silica, talc, or any combination thereof.

[0158] In some embodiments, the amount of the gliding agent is from about 0.01% to about 10% by weight, or from about 0.1% to about 5% by weight, or from about 0.1% to about 3% by weight, or from about 0.2% to about 2% by weight, or from about 0.3% to 1% by weight, or from about 0.3% to 0.6% by weight, or from about 1% to 5% by weight, or from about 2% to 3% by weight, or from about 0.4% to about 0.5% by weight. In some embodiments, the amount of the gliding agent used herein is from about 0.01 mg to about 10 mg per tablet, or from about 0.1 mg to about 5 mg per tablet, or from about 0.1 mg to about 3 mg per tablet, or from about 0.2 mg to about 2 mg per tablet, or from about 0.3 mg to 1 mg per tablet, or from about 0.3 mg to 0.6 mg per tablet, or from about 0.4 mg to about 0.5 mg per tablet, or from about 6 mg to about 10 mg per tablet, or from about 7 mg to about 9 mg per tablet.

[0159] In the specific implementation scheme, the flow aid comprises colloidal silica, in accordance with the ratio and amount of flow aid described herein.

[0160] Lubricants can be used to facilitate tablet production, improve powder flowability, and prevent particle breakage (e.g., particle fragmentation) during pressure release. Available lubricants include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, talc, colloidal silica (e.g., Aerosil™ 200), mineral oil (soluble in PEG), hydrogenated vegetable oils (e.g., composed of hydrogenated and refined stearic acid and palmitic acid triglycerides), and combinations thereof.

[0161] When preparing dosage forms such as tablets by compacting powdered compositions and / or assemblies, the composition is subjected to pressure from a punch and a die. Some excipients and active ingredients tend to adhere to the surfaces of the punch and die, which can lead to pitting and other surface irregularities in the product. Lubricants can be added to the composition to reduce adhesion and facilitate product release from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitoyl stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearate fumarate, stearic acid, talc, and zinc stearate.

[0162] In some implementations, a suitable pharmaceutically acceptable lubricant may be selected from (e.g., plant-derived) magnesium stearate, sodium stearate fumarate, glyceryl behenate, or any combination thereof.

[0163] In some embodiments, the amount of lubricant used herein is from about 0.01% to about 10% by weight, or from about 0.1% to about 5% by weight, or from about 0.1% to about 3% by weight, or from about 0.2% to about 2% by weight, or from about 0.3% to 1% by weight, or from about 0.3% to 0.6% by weight, or from about 0.5% to 1.5% by weight, or from about 0.7% to 1.2% by weight, or from about 0.4% to 0.5% by weight.

[0164] In some embodiments, the amount of lubricant used herein is from about 0.01 mg to about 10 mg per tablet, or from about 0.1 mg to about 5 mg per tablet, or from about 0.1 mg to about 3 mg per tablet, or from about 0.2 mg to about 2 mg per tablet, or from about 0.3 mg to 1 mg per tablet, or from about 1 mg to about 3 mg per tablet, or from about 2 mg to about 3 mg per tablet, or from about 0.3 mg to 0.6 mg per tablet, or from about 0.4 mg to 0.5 mg per tablet.

[0165] In the specific implementation scheme, the lubricant comprises magnesium stearate in accordance with the ratio and amount of lubricant described herein.

[0166] In some embodiments, a suitable pharmaceutically acceptable coating may be selected from a water-soluble polymer. In some embodiments, a suitable pharmaceutically acceptable coating may be selected from Opadry II White (PVA), Opadry II White (HPMC), or any combination thereof.

[0167] In some embodiments, the amount of coating used herein is from about 0.1% to about 10% by weight, or about 1% to about 10% by weight, or about 2% to about 8% by weight, or about 2% to about 6% by weight, or about 2% to 5% by weight, or about 3% to 4% by weight of the composition or tablet.

[0168] In some embodiments, the coating used herein is applied to the tablet such that, based on the total weight of the tablet, the weight gain is about 1% to about 20% by weight. In some embodiments, the coating used herein is applied to the tablet such that, based on the total weight of the tablet, the weight gain is about 10% by weight, or about 7% by weight, or about 5% by weight, or about 3% by weight, or about 1% by weight.

[0169] In some embodiments, the amount of coating used herein is about 0.1 mg to about 10 mg per tablet, or about 1 mg to about 10 mg per tablet, or about 2 mg to about 8 mg per tablet, or about 2 mg to about 6 mg per tablet, or about 2 mg to 5 mg per tablet, or about 3 mg to 4 mg per tablet.

[0170] In some embodiments, the pharmaceutical excipients used herein are selected from microcrystalline cellulose (Avicel PH 101®), lactose monohydrate (Fast Flo®), hydroxypropyl cellulose (Klucel EXF®), croscarmellose sodium (Ac-di-sol®), colloidal silica (Cab-O-Sil®), plant-derived magnesium stearate, or any combination thereof.

[0171] In some embodiments, the pharmaceutical excipients used herein are selected from microcrystalline cellulose, crospovidone XL, colloidal silica (Cab-O-Sil®), plant-derived magnesium stearate, hydroxypropyl cellulose, or any combination thereof.

[0172] In one specific embodiment, the pharmaceutical composition comprises microcrystalline cellulose, hydroxypropyl cellulose, crospovidone XL, colloidal silica (Cab-O-Sil®), and plant-derived magnesium stearate. In another specific embodiment, the pharmaceutical composition or formulation is a tablet. In another specific embodiment, the tablet is an oral tablet. In another specific embodiment, the oral tablet is an immediate-release oral tablet. In specific embodiments, the pharmaceutical composition and formulation include a tablet coating. In a specific embodiment, the tablet is coated with Opadry II White.

[0173] In another embodiment, the pharmaceutical composition and formulation may be prepared according to the methods described in the examples herein. In specific embodiments, the pharmaceutical composition and formulation may be as described in Tables 2, 3, 5, 9, 12, or 15 herein.

[0174] In a specific embodiment, the pharmaceutical composition and formulation are tablets having a specific dissolution and disintegration profile. In a specific embodiment, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the drug (e.g., compound I) is released within about 10 minutes. In another specific embodiment, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of compound I is released within about 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute.

[0175] In another specific embodiment, the dissolution of the drug in the tablet is determined using 900 mL of 0.01 M HCl at 37.0 °C via device II (paddle method) at 75 rpm or 100 rpm.

[0176] In another specific embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound covalently bonded to a kinase or pseudokinase, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient, wherein the pharmaceutical composition allows for the immediate release of the compound, and the pharmaceutical composition is substantially free of impurities associated with said compound. In a specific embodiment, the compound is compound I, or a pharmaceutically acceptable salt or solvation thereof, and the impurity is associated with compound I, i.e., it is an analogue or a reaction product of compound I with the excipient in the composition.

[0177] In another embodiment, the pharmaceutical composition is substantially free of any reducing sugars, i.e., sugars having free aldehyde or free ketone groups. In another embodiment, the pharmaceutical composition is substantially free of lactose, galactose, glucose, maltose, fructose, ribose, and / or xylose. In another embodiment, the pharmaceutical composition is substantially free of lactose. In a specific embodiment, the lactose is anhydrous lactose. In a specific embodiment, the compositions of the present invention are substantially free of lactose isomers, such as sucrose, trehalose, maltose, isomaltose, maltulose, isomaltulose, menobiose, and cellobiose. In another embodiment, the compositions of the present invention are substantially free of mannitol isomers, such as sorbitol, and compounds closely related to mannitol, such as xylitol, erythritol, lactitol, and maltitol. In another specific embodiment, the compound is compound I or a pharmaceutically acceptable salt or solvation thereof. In a specific embodiment, compound I is in the form of a salt. In another specific embodiment, the salt is a phosphate.

[0178] The pharmaceutical formulations disclosed herein can be prepared by methods known to those skilled in the art (e.g., mixing, dissolving, granulating, preparing sugar-coated pellets, homogenizing, emulsifying, encapsulating, embedding, or lyophilizing processes). As described above, the pharmaceutical compositions of this disclosure may contain one or more pharmaceutically acceptable carriers, such as excipients and adjuvants that facilitate the processing of active molecules into pharmaceutical preparations.

[0179] In some embodiments, the pharmaceutical compositions of this disclosure are prepared as oral formulations. For oral administration, the compounds can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers enable the pharmaceutically active ingredient to be formulated into tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, pastes, suspensions, etc., for oral ingestion by a subject. Oral pharmaceutical compositions can be obtained by obtaining a solid excipient, optionally grinding the resulting mixture, and, if necessary, adding a suitable adjuvant, processing the granular mixture to obtain tablets or sugar-coated pill cores. Such oral pharmaceutical compositions can also be prepared by grinding or melt extrusion. Suitable excipients can be any of those disclosed herein, particularly fillers, such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP) preparations. In addition, disintegrants such as croscarmellose, agar, or alginate or its salts, such as sodium alginate, can be used. Wetting agents such as sodium dodecyl sulfate can also be added.

[0180] In some embodiments of this disclosure, the pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In some such embodiments, the pharmaceutical composition comprises a carrier and is formulated in an aqueous solution, such as water or a physiologically compatible buffer, such as Hanks' solution, Ringer's solution, or saline buffer. In some embodiments, other components are included (e.g., components that aid dissolution or act as preservatives). In some embodiments, an injectable suspension is prepared using a suitable liquid carrier, suspending agent, etc. Some injectable pharmaceutical compositions are provided in unit dosage forms, such as in ampoules or in multi-dose containers. Some injectable pharmaceutical compositions are suspensions, solutions, or emulsions in oily or aqueous carriers and may contain formulation adjuvants, such as suspending agents, stabilizers, and / or dispersants. Certain solvents suitable for injectable pharmaceutical compositions include, but are not limited to, lipophilic solvents and fatty oils, such as vegetable oils (e.g., sesame oil), and synthetic fatty acid esters, such as ethyl oleate or triglycerides. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the drug to allow for the preparation of high-concentration solutions.

[0181] Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol, or prepared as lyophilized powders. Acceptable carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils are commonly used as solvents or suspension media. For this purpose, any mild fixative oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectables. Formulations for intravenous administration may be contained in a solution in a sterile isotonic aqueous buffer. If necessary, the formulation may also contain a solubilizer and a local anesthetic to reduce pain at the injection site. Typically, the components are provided either individually or in unit dosage forms, such as as dry lyophilized powders or anhydrous concentrates, contained in hermetically sealed containers, such as ampoules or pouches, indicating the content of the active agent. In cases where the compound is administered by infusion, it can be dispensed using a formulation containing sterile pharmaceutical-grade water, saline, or glucose / water in an infusion bottle. In cases where the compound is administered by injection, ampoules of sterile water for injection or saline solution may be provided, allowing the ingredients to be mixed prior to administration.

[0182] Suitable formulations also include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostatic agents, bactericidal antibiotics, and solutes that make the formulation isotonic with the body fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. Liposome suspensions containing liposomes targeting tissues may be present in suitable formulations.

[0183] Parenteral administration of the formulations of this invention includes intravenous, subcutaneous, and intramuscular administration of the pharmaceutical compositions described herein. Preparations for parenteral administration include ready-to-use sterile injections, sterile dried soluble products (including subcutaneous tablets) to be combined with a solvent immediately before use, ready-to-use sterile injectable suspensions, sterile dried insoluble products to be combined with a carrier immediately before use, and sterile emulsions. Solutions may be aqueous or non-aqueous. Pharmaceutically acceptable carriers used in parenteral preparations include aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, thickeners, emulsifiers, chelating agents, and other pharmaceutically acceptable substances. Liposome suspensions are also suitable as pharmaceutically acceptable carriers.

[0184] In some embodiments of this disclosure, the pharmaceutical composition is formulated as a reservoir preparation. Such reservoir preparations typically have a longer duration of action than non-reservoir preparations. In some embodiments, such preparations are administered parenterally (e.g., by injection or implantation). For example, subcutaneous or intramuscular injection of a reservoir injection containing a sterile solution of a compound of formula (FCB)a-(L)b-(CLM)c and / or its subclasses, or compound I, or a pharmaceutically acceptable salt thereof, is an effective mode of administration. In some embodiments, the reservoir preparation is prepared using a suitable polymer or hydrophobic material (e.g., an emulsion in an acceptable oil) or ion exchange resin, or is prepared as a microsoluble derivative, such as a microsoluble salt. Thus, for example, the pharmaceutical composition may be formulated with a suitable polymer or hydrophobic material (e.g., an emulsion in an acceptable oil) or ion exchange resin, or formulated as a microsoluble derivative, such as a microsoluble salt. In some embodiments, the reservoir preparation provides a 1-day, 7-day, or 30-day reservoir release profile. In some embodiments, such preparations are administered according to a once-daily, once-weekly, or once-monthly injection regimen.

[0185] The concentration of the pharmaceutically active compound can be adjusted so that injection provides an effective amount to produce the desired pharmacological effect. The exact dosage depends on the patient's or animal's age, weight, and condition, as is known in the art. In some embodiments, a unit dose of the parenteral preparation is packaged in an ampoule or a syringe with a needle. All preparations intended for parenteral administration must be sterile, as is known and practiced in the art. Exemplarily, intravenous or intra-arterial infusion of a sterile aqueous solution containing a compound of formula (FCB)a-(L)b-(CLM)c and / or its subclasses, or compound I, or a pharmaceutically acceptable salt thereof, is an effective mode of administration.

[0186] In some embodiments, suitable pharmaceutically acceptable carriers may also include, but are not limited to, diluents and sterile aqueous or organic solutions. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, aqueous and non-aqueous solutions. Pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents suitable for this application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Aqueous carriers suitable for this application include, but are not limited to, water, ethanol, alcohol / aqueous solutions, glycerol, emulsions, or suspensions, including saline and buffer media.

[0187] Diluents may be added to the formulations described herein. Diluents can increase the volume of solid pharmaceutical compositions and / or combinations and can make pharmaceutical dosage forms containing compositions and / or combinations easier for patients and caregivers to handle. In several embodiments, diluents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL), fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, glucose binders, dextrin, dextran, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, and polymethyl methacrylates (e.g., EUDRAGIT). ® Microcrystalline cellulose includes potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc, and / or mixtures of any of the foregoing substances. Specific examples of microcrystalline cellulose include those sold under the trademark Avicel (FMC Corp., Philadelphia, Pa.), such as Avicel™ pH101, Avicel™ pH102, and Avicel™ pH112; lactose includes lactose monohydrate, anhydrous lactose, and Pharmatose DCL21; and dicalcium phosphate includes Emcompress.

[0188] Liquid carriers suitable for this application include, but are not limited to, water (partially containing additives, such as cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, such as diols) and their derivatives, and oils (such as fractionated coconut oil and peanut oil).

[0189] The liquid carriers applicable to this application can be used to prepare solutions, suspensions, emulsions, syrups, elixirs, and pressurized compositions. In some embodiments, the active ingredient is dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, a mixture of the two, or a pharmaceutically acceptable oil or fat. In some embodiments, the liquid carrier contains other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, or osmotic pressure modifiers.

[0190] Solid carriers suitable for use in this application include, but are not limited to, inactive substances such as lactose, starch, glucose, methylcellulose, magnesium stearate, calcium hydrogen phosphate, mannitol, etc. Solid carriers may also contain one or more substances used as flavoring agents, lubricants, solubilizers, suspending agents, fillers, flow aids, tableting aids, binders, or tablet disintegrants; they may also be encapsulating materials. In powders, the carrier may be a finely ground solid mixed with a finely ground active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in a suitable proportion and compacted into the desired shape and size. Powders and tablets may contain up to 99% active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone, low-melting-point waxes, and ion exchange resins. Tablets may be prepared by compression or molding, optionally with one or more excipients. Tablets can be prepared by compressing an active ingredient in free-flowing form (e.g., powder or granules) in a suitable machine. The active ingredient may optionally be mixed with a binder (e.g., povidone, gelatin, hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium carboxymethyl starch, crospovidone, crospovidone), surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored and may be formulated to provide delayed or controlled release of the active ingredient, for example, by using different proportions of hydroxypropyl methylcellulose to provide a desired release profile. Tablets may optionally be provided with an enteric coating for release in the intestinal tract, excluding the stomach.

[0191] The carriers suitable for use in this application can be mixed with disintegrants, diluents, granulators, lubricants, binders, etc., as needed using conventional techniques known in the art. The carriers can also be sterilized using methods that will not cause harmful reactions with the compounds, such as those commonly known in the art.

[0192] The pharmaceutical formulations disclosed herein can be prepared by methods known to those skilled in the art (e.g., mixing, dissolving, granulating, preparing sugar-coated pellets, homogenizing, emulsifying, encapsulating, embedding, or lyophilizing processes). As described above, the pharmaceutical compositions of this disclosure may contain one or more pharmaceutically acceptable carriers, such as excipients and adjuvants that facilitate the processing of active molecules into pharmaceutical preparations.

[0193] The dissolution rate of compacted solid pharmaceutical compositions in a patient's stomach can be increased by adding a disintegrant to the composition and / or the combination. Disintegrants include alginate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silica, croscarmellose sodium carboxymethyl cellulose, croscarmellose (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, potassium polycrylene, powdered cellulose, pregelatinized starch, sodium alginate, sodium carboxymethyl starch (e.g., EXPLOTAB), potato starch, and starch.

[0194] Flavoring agents and flavor enhancers make the dosage form more palatable to patients. Flavoring agents and flavor enhancers for pharmaceutical products that may be included in the compositions of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0195] Solid and liquid compositions and / or combinations may also be stained with any pharmaceutically acceptable coloring agent to improve their appearance and / or facilitate patient identification of the product and unit dose levels.

[0196] Liquid pharmaceutical compositions and / or combinations may be prepared using excipients, wherein the components are dissolved or suspended in a liquid carrier, such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0197] Liquid pharmaceutical compositions and / or combinations may contain emulsifiers to uniformly disperse active ingredients or other excipients insoluble in the liquid carrier throughout the composition. Emulsifiers that can be used in the liquid compositions and / or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, gum arabic, tragacanth, carrageenan, pectin, methylcellulose, carbomer, cetearyl alcohol, and cetyl alcohol.

[0198] Liquid pharmaceutical compositions and / or combinations may also contain viscosity enhancers to improve the palatability of the product and / or coat the lining of the gastrointestinal tract. Such agents include gum arabic, bentonite alginate, carbomer, calcium or sodium carboxymethyl cellulose, cetearyl alcohol, methylcellulose, ethylcellulose, guar gum gelatin, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium carboxymethyl starch, starch tragacanth gum, and xanthan gum.

[0199] Sweeteners such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0200] Preservatives and chelating agents, such as alcohols, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and EDTA, can be added at safe levels to improve storage stability.

[0201] Liquid compositions may also contain buffers such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. The selection and amount of excipients can be readily determined by the formulation scientist based on experience and consideration of standard procedures and references in the field.

[0202] The solid compositions of the present invention may include powders, granules, aggregates, and compacted compositions and / or combinations thereof. Dosage includes doses suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ocular administration. Although the most suitable route of administration in any given situation will depend on the nature and severity of the condition being treated, oral administration is the most preferred route of administration according to the present invention. Dosages can be conveniently presented in unit dosage forms and can be prepared by any method known in the pharmaceutical industry.

[0203] Dosage forms include solid dosage forms, such as tablets, powders, capsules, suppositories, sachets, lozenges, and lozenges, as well as liquid syrups, suspensions, aerosols, and elixirs.

[0204] The dosage form of the present invention may be a capsule containing the composition and / or combination thereof within a hard or soft shell, preferably the powdered or granular solid composition of the present invention. The shell may be made of gelatin and optionally contains plasticizers such as glycerin and sorbitol, as well as opacifiers or colorants.

[0205] Compositions for tablet or capsule filling can be prepared by wet granulation. In wet granulation, the active ingredient and excipients, in partial or complete powder form, are blended and then further blended in the presence of a liquid (usually water), which causes the powder to agglomerate into granules. The granules are dried and then sieved and / or ground to the desired particle size. The granules can be tableted, or other excipients, such as glidants and / or lubricants, can be added prior to tableting.

[0206] Compositions for tableting can be conventionally prepared by dry granulation. For example, a blend of active ingredient and excipient can be compacted into blocks or sheets, and then pulverized into compacted granules. The compacted granules can then be compressed into tablets.

[0207] Compositions for tableting can be conventionally prepared by melt granulation. For example, a blend of active ingredients and excipients can be granulated into particles using a melt-forming binder. The particles can then be compressed into tablets.

[0208] In some embodiments, the pharmaceutical composition, such as a tableting composition, comprises drug particles or drug-containing particles.

[0209] As an alternative to dry granulation, the blended composition can be directly compressed into a compacted dosage form using direct compression technology. Direct compression yields more uniform tablets free of particles. Excipients particularly suitable for direct compression tableting include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The appropriate use of these and other excipients in direct compression tableting is known to those skilled in the art with experience and skills related to the specific formulation challenges of direct compression tableting.

[0210] In some embodiments, the drug-containing particles or microparticles include a binder, filler, disintegrant, and / or lubricant. In some embodiments, the drug-containing particles are processed by rolling, for example, using the manufacturing parameters disclosed herein. In another specific embodiment, the drug-containing particles or microparticles may be additionally compressed after compaction. In a specific embodiment, the drug-containing particles or microparticles may be compressed into tablets. In a specific embodiment, the tablets contain compound I or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0211] In some embodiments, this disclosure provides pharmaceutical tablets prepared by the following steps:

[0212] (a) Blending a mixture of compound I or a pharmaceutically acceptable salt thereof with input materials, such as binders, fillers, disintegrants and / or lubricants of the first part;

[0213] (b) Compact or blend the blend mixture from step (a) using a roller compactor to form a compacted material;

[0214] (c) The roller-compacted material, i.e. the drug-containing particles or microparticles of step (b), is blended with the blending material of the second part, such as disintegrants, lubricants and / or binders, to obtain the final blend.

[0215] (e) Compress the final blend from step (c) into tablets; and

[0216] (f) Optionally, the tablets may be coated using the coating method described herein.

[0217] In another specific implementation plan, the pharmaceutical tablets are prepared according to... Figure 1 Prepared as shown.

[0218] In another embodiment, the roller compaction process can be adjusted to adjust the particle size or particle size distribution of the drug-containing particles or microparticles before compaction. In a specific embodiment, the particle size distribution of the drug-containing particles or microparticles can be adjusted according to the desired composition (i.e., the composition for immediate release). In a specific embodiment, the particle size distribution is determined by sieve analysis.

[0219] In one embodiment, approximately 2% to approximately 10% of the drug particles are trapped on a 20-mesh sieve (841 µm). In another embodiment, approximately 3% to approximately 8% of the drug particles are trapped on a 20-mesh sieve (841 µm). In yet another embodiment, approximately 3% to approximately 6% of the drug particles are trapped on a 20-mesh sieve (841 µm).

[0220] In one embodiment, approximately 10% to approximately 35% of the drug particles are retained on a 30-mesh sieve (595 µm). In another embodiment, approximately 20% to approximately 30% of the drug particles are retained on a 30-mesh sieve (595 µm). In yet another embodiment, approximately 25% to approximately 30% of the drug particles are retained on a 30-mesh sieve (595 µm).

[0221] In one embodiment, approximately 10% to approximately 20% of the drug particles are retained on a 40-mesh sieve (420 µm). In another embodiment, approximately 12% to approximately 18% of the drug particles are retained on a 40-mesh sieve (420 µm). In yet another embodiment, approximately 13% to approximately 16% of the drug particles are retained on a 40-mesh sieve (420 µm).

[0222] In one embodiment, approximately 0.2% to approximately 10% of the drug particles are retained on a 60-mesh sieve (250 µm). In another embodiment, approximately 1.0% to approximately 7% of the drug particles are retained on a 60-mesh sieve (250 µm). In yet another embodiment, approximately 3.0% to approximately 6.0% of the drug particles are retained on a 60-mesh sieve (250 µm).

[0223] In one embodiment, approximately 12% to approximately 25% of the drug particles are retained on a 100-mesh sieve (140 µm). In another embodiment, approximately 15% to approximately 23% of the drug particles are retained on a 100-mesh sieve (140 µm). In yet another embodiment, approximately 15% to approximately 20% of the drug particles are retained on a 100-mesh sieve (140 µm).

[0224] In one embodiment, approximately 10% to approximately 30% of the drug particles are retained on a 230-mesh sieve (63 µm). In another embodiment, approximately 12% to approximately 25% of the drug particles are retained on a 230-mesh sieve (63 µm). In yet another embodiment, approximately 15% to approximately 20% of the drug particles are retained on a 230-mesh sieve (63 µm).

[0225] In another embodiment, the D85 value of the drug particles is from about 50 µm to about 100 µm. In another embodiment, the D85 value of the drug particles is from about 60 µm to about 80 µm. In another embodiment, the D85 value of the drug particles is about 63 µm.

[0226] In another embodiment, the D85 value of the drug particles is greater than about 50 µm, about 60 µm, about 70 µm, about 80 µm, about 90 µm, or about 100 µm.

[0227] In another embodiment, the D65 value of the drug particles is from about 100 µm to about 200 µm. In another embodiment, the D65 value of the drug particles is from about 120 µm to about 160 µm. In another embodiment, the D65 value of the drug particles is about 140 µm. In another embodiment, the D65 value of the drug particles is greater than about 120 µm, about 130 µm, about 140 µm, about 150 µm, about 160 µm, or about 180 µm.

[0228] In another embodiment, the D45 value of the drug particles is from about 300 µm to about 500 µm. In another embodiment, the D45 value of the drug particles is from about 350 µm to about 450 µm. In another embodiment, the D45 value of the drug particles is about 420 µm. In another embodiment, the D55 value of the drug particles is greater than about 340 µm, about 360 µm, about 380 µm, about 420 µm, about 440 µm, or about 480 µm. In another embodiment, the drug particles have characteristics substantially similar to those shown in Table 1. In another embodiment, the aforementioned drug particles are drug particles before roller compaction. In another embodiment, the aforementioned drug particles are drug particles after roller compaction.

[0229] The capsule filler of the present invention may contain any of the blends and particles described above for tablet preparation; however, it does not undergo a final tablet preparation step.

[0230] The active ingredients and excipients can be formulated into compositions and / or combinations and dosage forms according to methods known in the art.

[0231] In some embodiments, the pharmaceutical compositions of this disclosure consist of compounds of formula (FCB)a-(L)b-(CLM)c and / or their subclasses, or compound I, or its pharmaceutically acceptable salts, esters, solvates, and / or prodrugs, and are stable compositions. In some embodiments of the pharmaceutical topical formulations disclosed herein, the total impurity content of the composition, as determined by HPLC, is less than 20% after 4 weeks at 40°C / 75%RH. In some embodiments, the total impurity content of the composition of this disclosure, as determined by HPLC, is less than 19% after 4 weeks at 40°C / 75%RH. In some embodiments, the total impurity content of the composition of this disclosure, as determined by HPLC, is less than 18% after 4 weeks at 40°C / 75%RH. In some embodiments, the total impurity content of the composition of this disclosure, as determined by HPLC, is less than 17% after 4 weeks at 40°C / 75%RH. In some embodiments, the total impurity content of the composition of this disclosure, as determined by HPLC, is less than 16% after 4 weeks at 40°C / 75%RH. In some embodiments, the total impurity content of the compositions of this disclosure is less than 15% as determined by HPLC after 4 weeks at 40°C / 75%RH. In some embodiments, the total impurity content of the compositions of this disclosure is less than 14% as determined by HPLC after 4 weeks at 40°C / 75%RH. In some embodiments, the total impurity content of the compositions of this disclosure is less than 13% as determined by HPLC after 4 weeks at 40°C / 75%RH. In some embodiments, the total impurity content of the compositions of this disclosure is less than 12% as determined by HPLC after 4 weeks at 40°C / 75%RH.

[0232] Therapeutic uses

[0233] The compounds and pharmaceutical compositions disclosed herein can be used in a variety of methods. For example, in some embodiments, the pharmaceutical compositions can be used in a method of modulating phosphoinositol 3-kinase (PI3K). In some embodiments, the modulation of phosphoinositol 3-kinase (PI3K) activity is performed in mammalian cells. In some embodiments, the modulation of phosphoinositol 3-kinase (PI3K) can be performed in a subject in need (e.g., a mammalian subject) and is used to treat the conditions or diseases described herein, including diseases or conditions for which irreversible inhibition of PI3K can provide therapeutic benefit to a subject suffering from said diseases or conditions.

[0234] In some embodiments, this disclosure provides a method for modulating the activity of a kinase or pseudokinase, the method comprising administering any of the pharmaceutical compositions disclosed herein to a subject in need. In some embodiments, the method inhibits the activity of the kinase or pseudokinase.

[0235] In some embodiments, this disclosure provides a method for modulating PI3K activity, the method comprising administering any of the pharmaceutical compositions disclosed herein to a subject in need.

[0236] In some embodiments, this disclosure provides a method for treating cancer, neurodegenerative disease, autoimmune disease, or aging in a subject of need, the method comprising administering a pharmaceutical composition disclosed herein to the subject of need. In some embodiments, this disclosure provides a method for treating cancer, the method comprising administering a pharmaceutical composition disclosed herein to a subject of need. In some embodiments, the cancer is selected from one or more of the group consisting of: leukemia, brain tumors, (small cell and non-small cell) lung cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, and cancers in tissues including intestinal tissue, pancreatic tissue, liver, kidney, prostate, ovary, lung, bone marrow, or breast tissue. In some embodiments, the subject has cancer with a mutation in the PIK3CA gene.

[0237] In embodiments of this disclosure, a method for reducing, inhibiting, or improving cell proliferation in patients in need is provided. In some embodiments, the reduction, inhibition, or improvement in the methods disclosed herein is performed in vivo. In another embodiment, the reduction, inhibition, or improvement is performed in vitro. In some embodiments, the cells in the methods disclosed herein are cancer cells. In embodiments of this disclosure, a method for reducing or preventing tumor growth is provided, the method comprising contacting tumor cells with the compounds or pharmaceutical compositions disclosed herein. In one embodiment, reducing or preventing tumor growth includes a reduction in tumor volume. In one embodiment, reducing or preventing tumor growth includes complete elimination of the tumor. In one embodiment, reducing or preventing tumor growth includes stopping or halting the growth of an existing tumor. In one embodiment, reducing or preventing tumor growth includes a reduction in the tumor growth rate.

[0238] The present invention also provides treatments for conditions associated with cell proliferation. In one embodiment, the method includes contacting cancer and / or tumor cells with a pharmaceutical composition disclosed herein, the pharmaceutical composition comprising a compound of formula (FCB)a-(L)b-(CLM)c and / or its subclasses, or compound I, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof.

[0239] In some embodiments, the compound that forms a covalent bond with the kinase or pseudokinase is Compound I. In some embodiments, the compound of formula (FCB)a-(L)b-(CLM)c is Compound I. In some embodiments, Compound I is a crystal form of Compound I, or a pharmaceutically acceptable salt or solvation of Compound I. In some embodiments, a pharmaceutically acceptable salt of Compound I is selected from the group consisting of phosphates, hydrochlorides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates, fumarates, maleates, L-tartrates, citrates, and succinates, or solvations thereof.

[0240] In another embodiment of the treatment or improvement of a subject's cell proliferation disorder, the cell proliferation disorder is cancer. In a specific embodiment, the cancer is selected from the group consisting of: hematologic malignancies, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, lung cancer, liver cancer, colon cancer, pancreatic cancer, lymph node cancer, colon cancer, small bowel cancer, prostate cancer, brain cancer, bile duct cancer, gallbladder cancer, head and neck cancer, bone cancer, Ewing sarcoma, skin cancer, kidney cancer, and heart cancer. In another embodiment, the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, colorectal cancer, colon cancer, small bowel cancer, and lung cancer. In another embodiment of the invention, the subject is a human being.

[0241] In one embodiment, the present invention provides a method for reducing or inhibiting cell proliferation, and / or a method for treating cancer, said method comprising co-administering a pharmaceutical composition to a patient in need, said pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (FCB)a-(L)b-(CLM)c, and / or its subclass, or compound I, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof. The present invention also provides methods for treating, preventing, improving, and / or slowing the progression of a disorder or condition characterized by cell proliferation in a subject. More specifically, said method of the present invention comprises administering to a subject an effective amount of the quinolone compound described herein to treat a disorder or condition characterized by cell proliferation.

[0242] As used herein, administration can be achieved or performed using any of a variety of methods known to those skilled in the art. Pharmaceutical compositions comprising compounds of formula (FCB)a-(L)b-(CLM)c, and / or their subclasses, or compound I, or its pharmaceutically acceptable salts, esters, solvates, and / or prodrugs, can be administered, for example, via subcutaneous, intravenous, parenteral, intraperitoneal, intradermal, intramuscular, local, enteric (e.g., oral), rectal, nasal, buccal, sublingual, vaginal routes, via inhalation spray, drug pump, or via an implanted reservoir, in dosage forms containing conventionally nontoxic, physiologically acceptable carriers or excipients.

[0243] Furthermore, pharmaceutical compositions comprising compounds of formula (FCB)a-(L)b-(CLM)c, and / or their subclasses, or compound I, or its pharmaceutically acceptable salts, esters, solvates, and / or prodrugs, may be applied to the local area requiring treatment. This may be achieved, for example, by, but not limited to, local infusion during surgery, topical application, transdermal patches, injection, catheters, suppositories, or via implants (which may optionally be porous, non-porous, or gel-like materials), including membranes such as silicone rubber membranes or fibers.

[0244] The administration form (e.g., syrup, elixir, capsule, tablet, foam, emulsion, gel, etc.) of compounds of formula (FCB)a-(L)b-(CLM)c, and / or their subclasses, or compound I, or its pharmaceutically acceptable salts, esters, solvates, and / or prodrugs, will depend in part on their route of administration. For example, for administration to mucous membranes (e.g., oral mucosa, rectal mucosa, intestinal mucosa, bronchial mucosa), nasal drops, aerosols, inhalers, nebulizers, eye drops, or suppositories may be used. The compounds of formula (FCB)a-(L)b-(CLM)c disclosed herein, and / or their subclasses, or compound I, or its pharmaceutically acceptable salts, esters, solvates, and / or prodrugs, may be administered with other bioactive agents, such as anticancer agents, analgesics, anti-inflammatory agents, anesthetics, and other agents that can control one or more symptoms or causes of a disorder or condition characterized by cell proliferation.

[0245] In one embodiment, a compound of formula (FCB)a-(L)b-(CLM)c, and / or its subclass, or compound I, or its pharmaceutically acceptable salt, ester, solvate, and / or prodrug, may be administered together with one or more second therapeutic agents.

[0246] Furthermore, administration may include administering multiple doses to the subject over an appropriate period of time. Such administration regimens can be determined using conventional methods after reviewing this disclosure.

[0247] In cases of progressive disorders or conditions characterized by cell proliferation, compounds of formula (FCB)a-(L)b-(CLM)c, and / or their subclasses, or compound I, or its pharmaceutically acceptable salts, esters, solvates, and / or prodrugs, are typically administered continuously. In some cases, administration of compounds of formula (FCB)a-(L)b-(CLM)c, and / or their subclasses, or compound I, or its pharmaceutically acceptable salts, esters, solvates, and / or prodrugs, may be initiated before the onset of disease symptoms as part of a strategy to delay or prevent the disease. In other cases, compounds of formula (FCB)a-(L)b-(CLM)c, and / or their subclasses, or compound I, or its pharmaceutically acceptable salts, esters, solvates, and / or prodrugs, are administered after the onset of disease symptoms as part of a strategy to slow or reverse disease progression, and / or as part of a strategy to improve cellular function and alleviate symptoms.

[0248] Those skilled in the art will understand that the dosage range will depend on the specific compound of formula (FCB)a-(L)b-(CLM)c, and / or its subclass, or compound I, or its pharmaceutically acceptable salt, ester, solvate, and / or prodrug and its potency. The dosage range should be understood to be sufficiently large to produce the intended effect of improvement in neurodegenerative disorders or other disorders and their associated symptoms, and / or to achieve cell survival, but not so large as to cause uncontrollable adverse side effects. However, it should be understood that the specific dosage level for any particular patient depends on a variety of factors, including the individual's age, weight, general health condition, sex, and diet; the time and route of administration; the rate of excretion; other previously administered medications; and the severity of the specific disease being treated, as is well known to those skilled in the art. In the event of any complications, the dosage may also be adjusted by the individual physician. When compound I disclosed herein is used in accordance with this application, no unacceptable toxicological effects are expected.

[0249] The effective amounts of compounds of formula (FCB)a-(L)b-(CLM)c, and / or their subclasses, or compound I, or its pharmaceutically acceptable salts, esters, solvates, and / or prodrugs, disclosed herein comprise an amount sufficient to produce a measurable biological response. The actual dose level of the active ingredient in this application may be varied to administer an amount of compounds of formula (FCB)a-(L)b-(CLM)c, and / or their subclasses, or compound I, or its pharmaceutically acceptable salts, esters, solvates, and / or prodrugs, that effectively achieve the expected therapeutic response for a particular subject and / or application. Preferably, a minimum dose is administered, and the dose is escalated to the lowest effective amount in the absence of dose-limiting toxicity. The determination and adjustment of the therapeutically effective dose, and the assessment of when and how to make such adjustments, are known to those skilled in the art.

[0250] Throughout this disclosure, numerous patents, patent applications, and publications are cited. The entire disclosure of these patents, patent applications, and publications is incorporated herein by reference in its entirety for all purposes to more fully describe the level of prior art known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail. The following examples further illustrate the invention but should not be construed as limiting its scope in any way.

[0251] Example

[0252] This disclosure has been generally described and can be more readily understood by referring to the following embodiments, which are only used to illustrate certain aspects and embodiments of the invention and are not intended to limit the invention.

[0253] The following examples are intended to be illustrative, and every effort has been made to ensure the accuracy of the numerical values ​​used (e.g., quantities, temperatures, etc.), but some experimental errors and deviations should be considered within the knowledge of those skilled in the art. Unless otherwise stated, temperatures are in degrees Celsius. Reagents are purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and unless otherwise stated, no further purification is required for use.

[0254] Example 1: Synthesis and characterization of methyl carbamate (5-(6-((4-(acryloylglycyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Compound I)

[0255] Synthesis of ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (1).

[0256]

[0257] Diethyl 1-amino-1H-pyrrole-2,4-dicarboxylate. Diethyl 1H-pyrrole-2,4-dicarboxylate (1002 g, 1 equivalent, 4.507 mol) and NMP (7.8 L) were added to a 20 L reaction vessel. Then potassium tert-butoxide (557.3 g, 1.1 equivalent, 4.967 mol) was added; the mixture turned pink at 37 °C. The mixture was stirred until all potassium tert-butoxide dissolved and cooled to 21 °C. Subsequently, O-(4-nitrobenzoyl)hydroxylamine (839.6 g, 1.02 equivalent, 4.610 mol) was added in portions (exothermic, temperature reached 36 °C). The reaction mixture became a deep purple suspension. The reaction mixture was stirred overnight at 45 °C (the temperature slowly decreased, and the mixture turned orange). After 18 hours, a sample was taken, diluted with ACN / water, and used for HPLC analysis. Then, a 2.5 L solution of sodium dithionite (478.6 g, 0.6 equivalent, 2.749 mol) in water was slowly added, maintaining the temperature below 30 °C. The reaction mixture was transferred to a 50 L separatory funnel. Toluene (15 L) and water (5 L) were added to separate the phases. The aqueous phase was extracted with toluene (3 × 1 L). The combined organic phases were washed with water (5 × 1 L) and a saturated solution. Sodium bicarbonate (5 × 1 L) and brine (1 L) were dried over sodium sulfate, filtered, and concentrated to give diethyl 1-amino-1H-pyrrole-2,4-dicarboxylate (1077 g, 3.90 mol, yield 86%) as an orange oil (QNMR purity 81%), which was allowed to stand to solidify. 1 ¹H NMR (299 MHz, DMSO-d⁶) δ 7.52 (d, J = 2.1 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.51 (d, J = 1.8 Hz, 2H), 4.34 – 4.06 (m, 4H), 1.38 – 1.14 (m, 6H). LCMS (ESI): Measured value 227.0 [M+H] + (Calculated value 227.1 [M+H]) + ).

[0258] Lithium 1-amino-4-(ethoxycarbonyl)-1H-pyrrole-2-carboxylate. Diethyl 1-amino-1H-pyrrole-2,4-dicarboxylate (1077 g, 1 equivalent, 3.90 mol), ethanol (3.8 L), and water (1.9 L) were added to a 10 L reaction vessel. Lithium hydroxide monohydrate (163.9 g, 56 wt%, 0.99 equivalent, 3.831 mol) was added, and the mixture was stirred at 60 °C. The conversion was monitored by LCMS analysis. The reaction was stopped after 6 hours and cooled to room temperature. The mixture was diluted with 2 L of toluene, and the layers were separated. The aqueous phase was washed with toluene (3 × 750 ml) and then concentrated at 60 °C on a rotary evaporator. The resulting solid was suspended in TBME (2 L), filtered, and washed with TBME (1 L). Lithium 1-amino-4-(ethoxycarbonyl)-1H-pyrrole-2-carboxylate was obtained (853.1 g, 3.50 mol, yield 90%) as a pale yellow solid (QNMR purity 83%). 1 ¹H NMR (400 MHz, DMSO-D6) δ 7.37 (s, 2H), 7.09 (d, J = 2.2 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). LCMS (ESI): Measured value 199.0 [M-Li+2H] + (Calculated value 199.1 [M-Li+2H]) + ).

[0259] Ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (1). Ammonium carbonate (2939 g, 9.00 equivalent, 30.59 mol) was added to a suspension of lithium 1-amino-4-(ethoxycarbonyl)-1H-pyrrole-2-carboxylate (835.8 g, 1 equivalent, 3.399 mmol) in a mixture of DMF (3.4 L) / MeTHF (8.5 mL), followed by HOBt (1041 g, 2.0 equivalent, 6.797 mol), EDCI HCl (1303 g, 2.0 equivalent, 6.797 mol), and DIPEA (2.96 L, 5 equivalent, 16.99 mol). The addition of these reagents produced an endothermic effect. The flask was stirred (suspension) at room temperature for 3 days. The conversion was monitored by LCMS analysis. The solid was removed by filtration and washed with MeTHF (2 L). The filtrate was concentrated at 60 °C. The crude product (2 kg) was redissolved in MeTHF (10 L) and washed with saturated sodium bicarbonate solution (2 × 2 L). Three phases were formed. The top phase (product fraction) was separated, dried over sodium sulfate, filtered, and concentrated to dryness. The resulting crude product (908 g) was recrystallized from EtOH (1.8 L). The solid was filtered, washed with EtOH (200 mL), and dried to give the first batch of ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (67 g) as a white solid. The mother liquor (794 g) was concentrated and purified by column chromatography (2 kg silica gel, gradient: DCM to 5% MeOH). The purified product (505 g) was recrystallized from EtOH (750 mL) and washed with EtOH (100 mL) to give a second batch of ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (68 g). The concentrated mother liquor (435 g) was purified again by column chromatography (6 kg silica gel, gradient: DCM to 5% MeOH). The product fraction was recrystallized to give an additional batch of 61 g of ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate. All batches were combined to give ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (1) (195.7 g, 992.4 mmol, yield 29%) as a white solid. 1¹H NMR (299 MHz, DMSO-d⁶) δ 7.96 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.31 (s, 1H), 7.13 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 1.8 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H). LCMS (ESI): Measured value 198.0 [M+H] + (Calculated value 198.1 [M+H]) + ).

[0260] Synthesis of 6-amino-4-(trifluoromethyl)nicotinaldehyde

[0261]

[0262] 6-Amino-4-(trifluoromethyl)nicotinaldehyde (2). 5-Bromo-4-(trifluoromethyl)-2-pyridinamide (200.0 g, 1 equivalent, 829.8 mmol) and anhydrous THF (2000 mL) were added to a 5 L three-necked flask equipped with a thermometer and under nitrogen atmosphere. The solution was cooled to -70 °C. A hexane solution of 2.5 Mn-butyllithium (995.8 mL, 3.00 equivalent, 2.49 mol) was added dropwise over 90 minutes, maintaining the temperature below -60 °C. The mixture was stirred at -70 °C for 15 minutes. Subsequently, DMF (160.6 mL, 2.50 equivalent, 2.074 mol) was added dropwise over 45 minutes, maintaining the temperature below -60 °C. The mixture was stirred at -70 °C for 30 minutes. The mixture was heated to -40°C and carefully quenched with water (74.8 mL, 5 equivalents, 4.149 mol). The resulting solution was heated to room temperature and stirred overnight. The mixture was further diluted with water / ethyl acetate (1 L / 1 L) and transferred to a separatory funnel. The organic layer was washed with water (5 × 300 mL). The combined aqueous phases were extracted with ethyl acetate (3 × 300 mL). The combined organic phases were washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated until a small amount of solvent remained and a solid was formed. The mixture was cooled to room temperature and diluted with heptane (300 mL). The mixture was filtered, the solid was washed with heptane, and dried to give 6-amino-4-(trifluoromethyl)nicotinaldehyde (2) (51.5 g, 271 mmol, 33% yield) as an orange solid. 1¹H NMR (299 MHz, DMSO-d⁶) δ 9.80 (q, J = 1.7 Hz, 1H), 8.63 (d, J = 2.1 Hz, 1H), 7.73 (s, 2H), 6.84 (d, J = 2.0 Hz, 1H). LCMS (ESI): Measured value 191.0 [M+H] + (Calculated value 191.0 [M+H]) + ).

[0263] Step 1: Synthesis of ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (3).

[0264]

[0265] A solution of ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (1) (195.7 g, 1.00 equivalent, 962.7 mmol) and 6-amino-4-(trifluoromethyl)nicotinaldehyde (2) (192.7 g, 1.00 equivalent, 962.7 mmol) in DMSO (1.9 L) was added to a 3 L three-necked flask equipped with a condenser, temperature probe, and mechanical stirrer. Copper chloride dihydrate (213.4 g, 1.30 equivalent, 633.4 mmol) was then added, and the mixture was stirred at 100 °C for 18 hours. The mixture was cooled to room temperature and poured into ice water (10 L), causing the product to precipitate. The suspension was stirred for 30 minutes and then filtered (using a Buchner funnel). The light brown filter cake was washed with water (3 × 1 L) and TBME (3 × 1 L). The solid was stripped with toluene (3 × 1 L) on a rotary evaporator to remove residual water. Ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (3) (340.6 g, 760.0 mmol, yield 79%) was obtained as a solid. 1 ¹H NMR (299 MHz, DMSO-d⁶) δ 12.20 (s, 1H), 8.08 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 1.8 Hz, 1H), 7.05 (s, 1H), 6.87 (s, 1H), 4.26 (q, J = 6.9 Hz, 2H), 1.29 (t, J = 7.1, 3H). LCMS (ESI): Measured value 368.0 [M+H] + (Calculated value 368.1 [M+H])+ 366.0 [MH] - (Calculated value: 366.1 [MH]) - ).

[0266] Step 2: Synthesis of ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (4).

[0267]

[0268] To a 5 L three-necked flask under nitrogen atmosphere and equipped with a thermometer, add ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (3) (335.6 g, 1 equivalent, 749.2 mmol), DMF (2.5 L), and morpholine (400 mL, 6.2 equivalent, 2.580 mol). Then, add PyBOP (606.9 g, 1.55 equivalent, 1.166 mol) in multiple portions, maintaining the temperature at approximately 15 °C (exothermic reaction). Stir the mixture at room temperature for 48 hours. Transfer the reaction mixture to a 20 L container and slowly add water (12.5 L). Filter the suspension through a Buchner funnel and wash with water (3 × 5 L) and TBME (2 × 5 L). The remaining clayey material was redissolved in ethyl acetate under reflux. The hot suspension was filtered through a glass funnel lined with diatomaceous earth to remove copper, and the filtrate was concentrated. The remaining solid was suspended in ethyl acetate (1 L) at 60 °C. The suspension was centrifuged at 3000 rpm. The resulting solution was decanted and concentrated. The residue was treated three more times with warm ethyl acetate. All organic phases were concentrated, the resulting solid was filtered, washed with TBME, and dried under vacuum at 60 °C. The solid was stripped with toluene (2 × 1 L) to give ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (4) (206.5 g, 473.2 mmol, yield 63%), a pale yellow solid with a QNMR purity of 91%. 1¹H NMR (300 MHz, cdCl₃) δ 8.56 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 6.81 (s, 1H), 4.88 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 4.08 (t, J = 4.8 Hz, 4H), 3.84 (t, J = 4.8 Hz, 4H), 1.39 (t, J = 7.1 Hz, 3H). LCMS (ESI): Measured value 437.2 [M+H] + (Calculated value 437.2 [M+H]) + ).

[0269] Step 3: Synthesis of tert-butyl 4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carbonyl)piperazine-1-carboxylate (5)

[0270]

[0271] To a 3 L three-necked flask under nitrogen atmosphere, ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (4) (206.5 g, 91 wt%, 1 equivalent, 473.2 mmol) and THF (2 L) were added. Subsequently, tert-butyl piperazine-1-carboxylate (440.7 g, 5.0 equivalent, 2.366 mol) and TBD (65.87 g, 1.0 equivalent, 473.2 mmol) were added, and the solution was stirred at 65 °C for 2 days. The transformation was monitored by LCMS and NMR analysis. The reaction mixture was concentrated at 50 °C to remove most of the THF. The material was dissolved in ethyl acetate (1 L) and washed with 1 M potassium hydrogen sulfate solution (2 × 500 mL), water (3 × 500 mL, diluted with brine to promote separation), and brine (250 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated at 50 °C (a foamy brown oil). The brown foam was stripped with toluene (1.5 L) to remove trace amounts of ethyl acetate, yielding tert-butyl 4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carbonyl)piperazine-1-carboxylate (5) (382.0 g, 464 mmol, yield 98%), as a brown foam with a QNMR purity of 70%. 1¹H NMR (300 MHz, cdcl₃) δ 8.52 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 6.98 (d, J = 1.7 Hz, 1H), 6.80 (s, 1H), 4.06 (t, J = 4.9 Hz, 4H), 3.82 (t, J = 4.9 Hz, 4H), 3.77 – 3.66 (m, overlapping with the THF signal, but 4H is obtained after subtracting the other THF signal), 3.48 (t, J = 5.0 Hz, 4H), 1.47 (m, 27H). LCMS (ESI): Measured value 577.2 [M+H] + (Calculated value 577.3 [M+H]) + ).

[0272] Step 4: 4-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (6).

[0273]

[0274] To a 5 L three-necked flask under nitrogen atmosphere, add tert-butyl 4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carbonyl)piperazine-1-carboxylate (5) (271.0 g, 1 equivalent, 470.0 mmol) and anhydrous THF (2 L). Cool the resulting solution to 0 °C and add a solution of TMS-Cl (107.0 n mL, 1.80 equivalent, 846.0 mmol) in anhydrous THF (100 mL) (the mixture forms a brown suspension). Further cool the mixture to -20 °C and add a 2.4 M LiAlH4 THF solution (294.0 mL, 1.50 equivalent, 705.0 mmol) over 80 minutes. Stir the reaction mixture at -20 °C for 60 minutes. 2 M Rochelle salt solution (1 L) was slowly added between -20°C and -10°C (the initial stage was very exothermic, with gas release) (after adding 100 ml, the mixture became very viscous and formed a solid. The solid dissolved slowly at -8°C and became easy to stir again). The mixture was warmed to room temperature overnight. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (6 kg silica gel; eluent: DCM / 3.5 M NH3 in MeOH solution) to give 4-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (6) (172.2 g, 306.1 mmol, yield 65%) as a white, fluffy solid. 1 ¹H NMR (299 MHz, cdcl₃) δ 8.53 (s, 1H), 7.58 (d, J = 1.5 Hz, 1H), 6.80 (s, 1H), 6.67 (d, J = 1.6 Hz, 1H), 4.82 (s, 2H), 4.14 – 3.95 (m, 4H), 3.82 (t, J = 4.8 Hz, 4H), 3.58 (s, 2H), 3.44 (t, J = 5.3 Hz, 4H), 2.43 (t, J = 5.1 Hz, 4H), 1.45 (d, J = 1.4 Hz, 9H). LCMS (ESI): Measured value 563.3 [M+H] + (Calculated value 563.3 [M+H]) + ); 561.2 [MH] - (Calculated value: 561.3 [MH]) - ).

[0275] Step 5: 4-((2-(6-((methoxycarbonyl)amino)-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (7).

[0276]

[0277] To a 3 L three-necked flask, tert-butyl 4-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazine-1-carboxylate (6) (172.2 g, 1 equivalent, 306.1 mmol), DCM (1.4 L), and pyridine (74 mL, 3.0 equivalent, 918.2 mmol) were added, and the solution was cooled to 0 °C. Methyl chloroformate (26.1 mL, 1.10 equivalent, 336.7 mmol) was added to the reaction mixture over 30 min. The mixture was slowly heated to room temperature and stirred overnight. HPLC analysis showed approximately 90% conversion. Additional methyl chloroformate (2.4 mL, 0.10 equivalent, 30.6 mmol) was added dropwise over 5 min, and the mixture was stirred at room temperature. After 4 hours, HPLC analysis showed complete conversion. The reaction mixture was poured into cold water (500 mL) and then transferred to a separatory funnel. The organic layer was collected, washed with water (3 × 500 mL) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was stripped with toluene to give solid tert-butyl 4-((2-(6-((methoxycarbonyl)amino)-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazine-1-carboxylate (7) (174.1 g, 280.5 mmol, 92% yield). 1 ¹H NMR (299 MHz, cdcl₃) δ 8.87 (s, 1H), 8.74 (s, 1H), 8.43 (s, 1H), 7.59 (d, J = 1.5 Hz, 1H), 6.69 (d, J = 1.6 Hz, 1H), 4.05 (t, J = 4.8 Hz, 4H), 3.84 (d, J = 7.1 Hz, 7H), 3.59 (s, 2H), 3.45 (t, J = 5.1 Hz, 4H), 2.44 (t, J = 4.9 Hz, 4H), 1.45 (s, 9H). LCMS (ESI): Measured value 621.3 [M+H] + (Calculated value: 621.8 [M+H]) +); 619.2 [MH] - (Calculated value: 619.3 [MH]) - ).

[0278] Step 6: (5-(4-morpholino-6-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate hydrochloride (8).

[0279]

[0280] Under nitrogen atmosphere, tert-butyl 4-((2-(6-((methoxycarbonyl)amino)-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazine-1-carboxylate (7) (172.1 g, 1 equivalent, 277.3 mmol) and CPME (1.0 L) (white suspension) were added to a flask, and the mixture was cooled to 6 °C. A solution of CPME in HCl (1.5 L, 3.0 mol / L, 16.2 equivalent, 4.50 mol) (slightly exothermic) was added over 30 minutes, and the mixture was stirred at room temperature (a yellow precipitate formed immediately) overnight. HPLC analysis showed complete conversion. The mixture was filtered, and the solid was washed with 250 mL of CPME and 500 mL of TBME. The solid was transferred to a flask, but due to its high viscosity (and potential hygroscopicity), MeOH was used for transfer. The mixture was concentrated on a rotary evaporator, and the solid was dried to give 198 g of crude product. The material was stripped with toluene (2 × 1 L) before recrystallization. The crude material (191 g) was recrystallized from MeOH (300 mL). The solid was collected by filtration, washed with cold MeOH (50 mL), and dried to give solid (5-(4-morpholino-6-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate dihydrochloride (8) (88.8 g, 150 mmol, yield 54%). 1¹H NMR (400 MHz, DMSO-D6) δ 12.13 (s, 1H), 10.92 (s, 1H), 9.59 (s, 2H), 8.73 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.38 (s, 1H), 4.41 (s, 2H), 4.02 (t, J = 4.9 Hz, 4H), 3.80 – 3.69 (m, 8H), 3.69 – 3.33 (m, 13H), 3.16 (s, 3H). LCMS (ESI): Measured value 521.2 [M+H] + (Calculated value 521.2 [M+H]) + ).

[0281] Step 7: (5-(6-((4-(acryloylglycyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (compound 1).

[0282]

[0283] Acryloylglycine. Add glycine (200 g, 1.0 equivalent, 2.66 mol), deionized water (88 mL), and sodium hydroxide (710 mL, 30 wt%, 2.0 equivalent, 5.32 mol) to a 2 L RBF (round bottom flask). Cool the mixture to -5°C, then add acryloyl chloride (225 mL, 96 wt%, 1.0 equivalent, 2.66 mol) while maintaining the temperature at approximately 0°C. Stir the mixture at 0°C for 1 hour. After 1 hour, acidify the mixture to pH 2 with HCl (310 mL, 12 mol / L, 1.4 equivalent, 3.72 mol). Saturate the mixture with sodium sulfate (approximately 100 g) and dilute with warm MeTHF (300 mL). Separate the phases, and extract the aqueous phase with MeTHF (3 × 250 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, and concentrated. When the volume was approximately 500 mL, a solvent exchange was performed with ethyl acetate (500 mL added). After removing 500 mL of ethyl acetate, the solvent exchange was repeated twice. The resulting slurry was stirred at room temperature for 1 hour, and the solid was collected, washed with ethyl acetate (2 × 60 mL), dried under vacuum, and further dried on a rotary evaporator to give acryloylglycine (76.00 g, 588.6 mmol, yield 22%) as a white solid. 1¹H NMR (299 MHz, DMSO-d⁶) δ 12.58 (s, 1H), 8.42 (t, J = 6.0 Hz, 1H), 6.30 (ddd, J = 17.1, 10.1, 0.8 Hz, 1H), 6.10 (ddd, J = 17.2, 2.3, 0.8 Hz, 1H), 5.62 (ddd, J = 10.1, 2.3, 0.8 Hz, 1H), 3.84 (dd, J = 6.0, 0.8 Hz, 2H). LCMS (ESI): Measured value 130.1 [M+H] + (Calculated value 130.1 [M+H]) + ).

[0284] DIPEA (100 mL, 4.7 mmol) was added to a suspension of (73.2 g, 1 equivalent, 123 mmol) in THF (750 mL). The mixture gradually became a solution, then became cloudy again. Acryloylglycine (23.9 g, 1.5 equivalent, 185 mmol) was added, followed by HATU (93.8 g, 2 equivalent, 247 mmol). The mixture (yellow) was stirred at room temperature. After 20 minutes, the mixture became a black suspension. The reaction was complete after 1 hour. The solution was diluted with 600 mL of ethyl acetate and quenched with 600 mL of saturated sodium bicarbonate solution. The organic phase was separated and washed with saturated sodium bicarbonate solution (600 mL) and brine (2 × 400 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give 147.2 g of a red, viscous, oily crude material. The crude material was dissolved in NMP (600 mL) at room temperature, and water (1.5 L) was added dropwise. The mixture was stirred at room temperature for 1 hour and then filtered. The residue was thoroughly washed with water and TBME to remove most of the NMP. The resulting solid was dissolved in DMSO (470 mL) and precipitated by adding water (900 mL). The residue was again thoroughly washed with water and TBME to remove most of the NMP and DMSO. The material was dried overnight at 40°C in a circulating oven to obtain solid methyl (5-(6-((4-(acryloylglycyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (compound I) (57.7 g, 91.4 mmol, yield 74%). 1H NMR (400 MHz, DMSO-D6) δ 10.89 (s, 1H), 8.72 (s, 1H), 8.30 (s, 1H), 8.20 (t, J = 5.5 Hz, 1H), 7.75 (d, J = 1.5 Hz, 1H), 6.97 (d, J= 1.6 Hz, 1H), 6.37 (dd, J = 17.1, 10.2 Hz, 1H), 6.09 (dd, J = 17.1, 2.2 Hz, 1H), 5.59 (dd, J = 10.2, 2.2 Hz, 1H), 4.02 (d, J = 5.5 Hz, 2H), 3.98 (t, J =4.9 Hz, 4H), 3.74 (d, J = 4.4 Hz, 7H), 3.57 (s, 2H), 3.52 – 3.37 (m, 4H), 2.39 (dt, J = 17.8, 4.9 Hz, 4H). LCMS (ESI): Measured value 632.4 [M+H] + (Calculated value: 632.3 [M+H]) + 630.2 [MH] - (Calculated value: 630.2 [MH]) - ).

[0285] Example 2: Transfection protocol and readings for NanoBRET screening

[0286] Human embryonic kidney 293-H (HEK 293, Gibco 293-H, #11631017) cell lines were cultured in high-glucose pyruvate Dulbecco modified Eagle medium (DMEM, Gibco, #11995065) supplemented with 10% fetal bovine serum (FBS, Gibco, #10082147) and 1× penicillin-streptomycin (100× solution, Gibco, #15140148). Cells were trypsinized using 0.05% or 0.25% trypsin-EDTA solution (trypsin-EDTA containing phenol red, Gibco, #25200056 (0.25%) or #25300054). Cells were cultured overnight in Opti-MEM medium supplemented with 10% fetal bovine serum (Opti-MEM I serum-depleted medium without phenol red, Gibco, #11058021) for NanoBRET reading experiments.

[0287] HEK293 cells were cultured appropriately before assay. The culture medium was removed from the cell flask by aspiration, and the cells were washed once with PBS and then aspirated for trypsin digestion to detach the cells. The trypsin was neutralized with growth medium, and the cells were pelleted by centrifugation at 200×g for 5 minutes. The culture medium was then aspirated, and the cells were resuspended in Opti-MEM I supplemented with 10% FBS to form a single-cell suspension. The cell density in the Opti-MEM I supplemented with 10% FBS was adjusted to 2×10⁶ cells / mL in sterile conical tubes. 5 Cells / mL. After transfection, cells are directly aliquoted into 96-well plates for NanoBRET assays the following day; therefore, cells are cultured overnight in Opti-MEM. Alternatively, cells can be transfected in batches and aliquoted into 96-well plates, allowing them to adhere overnight for elution studies.

[0288] The lipid:DNA complex was prepared as follows:

[0289] Prepare a 10 μg / mL DNA solution in serum-free Opti-MEM. This solution contains vector DNA and DNA encoding NanoLuc fusion with the target at the following ratio. A serial dilution step may be required to accurately dilute the NanoLuc fusion DNA. Add the following reagents to a sterile polystyrene tube in the following order: 1 mL phenol red-free Opti-MEM; 9.0 μg / mL vector DNA; 1.0 μg / mL NanoLuc fusion DNA (smaller amounts for some targets). Mix the reagents thoroughly. Add 30 μL of FuGENE HD to each mL of the DNA mixture to form a lipid:DNA complex. Avoid letting FuGENE HD touch the plastic side of the tube; pipette directly into the liquid in the tube. Mix by pipetting up and down 5–10 times and incubate at room temperature for 20 minutes to form the complex. Mix 1 part (e.g., 1 mL) of the lipid:DNA complex with 20 parts (e.g., 20 mL) of a 2 × 10⁻⁶ ppm solution. 5Mix HEK293 cell suspensions at 100 cells / mL in a sterile conical tube, gently mixing by pipetting up and down 5 times. Use this ratio to scale up or down for larger or smaller batch transfections accordingly. Dispense 100 µL of cell + lipid:DNA complex into sterile 96-well plates prepared with tissue culture (20,000 cells / well) and incubate for at least 16 hours to achieve expression. Then incubate the cells at 37°C, 5% CO2 for at least 16 hours. Prepare a serially diluted 100× final concentration of Compound I in 100% DMSO. Prepare a stock solution of serially diluted Compound I in PCR plates. Add 1 μL of the 100× serially diluted inhibitor / compound to each well of the transiently transfected overnight 96-well plate and mix by tapping the plate. Incubate the plate at 37°C, 5% CO2 overnight. Prepare a 1× concentration substrate mixture (500× stock solution) and an appropriate concentration of tracer solution in Opti-Mem. Cells in 96-well plates were washed five times with PBS (pH 7.4), 200 µL of PBS added each time. Cells were incubated at 37°C for 2 hours. 100 µL of 1× substrate-tracer solution was added, and the plates were gently tapped to mix. The signal was read hourly on a microplate reader over the next 6 hours. The results showed that compound I inhibited the PI3K target by more than 80%.

[0290] Example 3: Cell proliferation assay

[0291] The aim of this study was to investigate the effect of compound I treatment for 3 days on cell proliferation in 13 cell lines and to determine the IC50 of compound I in each cell line. The cell lines tested included: UM-UC-3 (bladder), KYSE-410 (HN / esophagus), SW1463 (rectum), Calu-1 (lung), NCI-H358 (lung), SW837 (rectum), SW756 (cervix), NCI-H2122 (lung), NCI-H1373 (lung), NCI-H1792 (lung), NCI-H23 (lung), MIA PaCa-2 (pancreas), and HC44.

[0292] Cells were resuscitated and cultured in a suitable medium. Cells were harvested during the logarithmic growth phase. Cells were then resuspended and counted using a Vi cell counter (cell viability was measured using a trypan blue rejection assay). Cells were then diluted, and 90 µL of cell suspension was added to each well of a 96-well plate according to the plate layout to achieve the final cell density. Two replicate plates were set up. One was used for the day 0 reading (T0), and the other was incubated overnight in a humidified incubator at 37°C and 5% CO2.

[0293] On day 0, 10 µL of culture medium was added to each well for T0 reading. Then, 50 µL of CellTiter-Glo® reagent was added to each well. The contents were then mixed on a track shaker for 2 minutes to promote cell lysis. The plate was then incubated at room temperature for 10 minutes to stabilize the luminescence signal. The luminescence values ​​were then recorded using an EnVision multi-label reader. The test compound, Compound I, and the control, cisplatin, were then diluted from 10 mM stock solution to different concentrations. Compound I was diluted by adding 10 µL of 10× Compound I working solution at various concentrations, ranging from 10 µM to approximately 0.005 µM. Cisplatin was diluted to approximately 3.33 mM to approximately 150 nM. The screening plate was then returned to the incubator for the appropriate treatment time (3 days).

[0294] For the endpoint CTG reading, 50 μL of CellTiter-Glo® reagent was added to each well. The contents were then mixed on a track shaker for 2 minutes to promote cell lysis. The plate was incubated at room temperature for 10 minutes to allow the luminescence signal to stabilize. The luminescence values ​​were then recorded using an EnVision multilabel reader. The IC50 values ​​for each cell line were determined. These measurements showed that compound I had inhibitory effects in a variety of cancer cell lines, with a significant inhibitory effect on NCI-H358 (see Table A).

[0295] Table A: IC50 proliferation assay

[0296]

[0297] Example 4: Immediate-release tablets containing compound I

[0298] Compound I was formulated into oral tablets for immediate release after administration to the patient. Compound I was used as an additive, according to... Figure 1 The weighing, compaction, blending, and tableting processes were completed as shown. Compaction tests were also conducted on the drug particles using different roller pressing process parameters (see Table 1), and for each process defined by the roller pressing parameters, the bulk density, tap density, particle size distribution obtained through sieve analysis, Hausner's ratio, and compressibility index were determined.

[0299] Table 1: Particle analysis of pharmaceutical products after roller pressing test

[0300]

[0301] Example 5: Stability study of formulations containing compound I

[0302] Stability studies were also conducted on various formulations of immediate-release compositions prepared according to the details in Tables 2 and 3 using different manufacturing methods (e.g., direct blending and granulation).

[0303] The stability of formulations 1 and 2 (see Tables 2 and 3) was evaluated by storing them in open containers at 40°C / 75%RH and 50°C for 4 weeks. Samples under the worst-case open container conditions were tested.

[0304] Apart from some assay variations related to sample preparation and sampling, no significant increase in degradation products was observed, indicating that the formulation is stable.

[0305] Table 2: Formulation 1 (direct blending) used for compatibility assessment

[0306]

[0307] Table 3: Formulation 2 (wet granulation) used for compatibility assessment of compound I

[0308]

[0309] Excipient compatibility studies were also conducted by mixing compound I with 18 individual commonly used excipients. Samples were weighed and mixed in amber vials, then stored capped or uncovered under two stability conditions (40°C / 75%RH and 50°C). The samples were evaluated at T0, 2 weeks, and 4 weeks. The results confirmed the compatibility of compound I with the excipients listed in the table below.

[0310] Table 4: Excipients

[0311]

[0312] Example 6: Compound I 5 mg and 50 mg oral tablets – Batch 1

[0313] 5 mg and 50 mg oral tablets were prepared using a dry granulation process, designated as "Batch 1". The formulations for each tablet are provided in Table 5 below.

[0314] Table 5: Compound I tablets, 5 mg and 50 mg – Batch 1

[0315]

[0316] The tablets in Table 5 were manufactured as follows. Colloidal silica (Cab-O-Sil) and crospovidone XL, NF were combined and passed through a 20-mesh sieve. In a Gemco double cone mixer (0.5 cubic feet), the following were added: Compound I, lactose monohydrate, NF (Fast Flo), the sieved colloidal silica (Cab-O-Sil), crospovidone XL, and microcrystalline cellulose NF (AvicelPH 102). The components were mixed for 10 minutes without unloading. A portion of magnesium stearate from Compound I was passed through a 30-mesh sieve. The sieved magnesium stearate was added to the blend, and the mixture was further mixed for 3 minutes. The initial blend was compacted using different parameters to assess particle size distribution and tableting feasibility. The compacted material was then ground using a granulator located below the rollers, passing sequentially through a 3.15 mm coarse sieve and a 1.0 mm fine sieve.

[0317] The weight of excipients was adjusted according to the yield of the ground particles. Hydroxypropyl cellulose (Klucel EXF), colloidal silica, NF (Cab-O-Sil), and crospovidone were sieved through a 20-mesh sieve. Magnesium stearate was sieved through a 30-mesh sieve. In a Gemco double cone blender (0.5 cubic feet): approximately half of the ground particles, colloidal silica (Cab-O-Sil), crospovidone, and sieved hydroxypropyl cellulose (Klucel EXF) were added sequentially, followed by the remaining ground particles. The mixture was blended at 23.5 rpm for five (5) minutes. The sieved magnesium stearate was then added to the blend, and the mixture was further blended at 23.5 rpm for an additional three (3) minutes. Table 6 shows the particle size distribution of the ground particles and the analysis results of the final blend.

[0318] Table 6: Analysis of ground particles and final blend – Batch 1

[0319]

[0320] The final blend was then divided into two portions for tableting: one for the 5 mg tablet and the other for the 50 mg tablet. The blend was tableted using a Globe Pharma tablet press, and weight (n=10), hardness (n=10), thickness (n=10), and friability were subsequently measured. Data for the 5 mg and 50 mg tablets are summarized in Tables 7 and 8, respectively. The batches showed uniform compression, with consistent weight, hardness, and thickness across the entire batch.

[0321] Table 7: Compressed tablet data for Compound I 5 mg – Batch 1

[0322]

[0323] Table 8: Compressed tablet data for Compound I 50 mg – Batch 1

[0324]

[0325] The tablets were then loaded into an O'Hara coating pan and coated with Opadry II White (85F18422) film coating solution, with a theoretical coating weight gain of 3%. The film coating solution was prepared by adding the required amount of purified water and stirring continuously for at least 45 minutes. Dissolution tests were performed on 5 mg tablets of Compound I coated with 0.01 M HCl at 37.0 °C using apparatus II (paddle method) at 75 rpm. Dissolution data are shown below. Figure 2 middle.

[0326] Dissolution testing of batch 1 showed that over 75% of the drug was released within 20 minutes, and complete drug release was achieved within 70 minutes. Disintegration testing of the coated tablets showed complete disintegration within 30 minutes.

[0327] Dissolution of 50 mg coated tablets from batch 1 was performed using 900 mL of 0.01 M HCl at 37.0 °C via apparatus II (paddle method) at 100 rpm. Dissolution data are shown below. Figure 3 The dissolution profile of the 50 mg tablets showed complete drug release within 10 minutes, confirming compliance with assay and dissolution specifications. However, chromatographic analysis detected unknown impurities in both the 5 mg and 50 mg formulations.

[0328] Example 7: Compound I 1 mg and 5 mg oral tablets – Batch 2

[0329] Batch 2 was manufactured to prepare new tablets in 1 mg and 5 mg strengths. Additionally, a low-moisture grade of material was used to evaluate its effect on unknown impurities. Tablets were prepared using the same method as the previous batches, with the 1 mg and 5 mg dosage strengths obtained using a co-blend. The formulations are described in Table 9.

[0330] Table 9: Compound I Oral Tablets 1 mg and 5 mg – Batch 2

[0331]

[0332] Batch 2 was prepared to produce new tablets in 1 mg and 5 mg strengths. Additionally, a low-moisture grade of material was used to assess its impact on unknown impurities. Tablets were prepared using the same method as previous batches, with dosage-proportioned strengths obtained using a co-blend.

[0333] The manufacturing process for batch 2 is as follows: Compound I, microcrystalline cellulose NF (Avicel PH112) (part IA), and Cab-O-Sil (part I) are combined and sieved through a 30-mesh stainless steel (SS) sieve into appropriately labeled double-layered polyethylene-lined containers. Half of the microcrystalline cellulose (Avicel PH112) (part IB) is added to a 0.5 cubic foot Gemco double cone mixer. The sieved material is then added. The remaining microcrystalline cellulose (Avicel PH112) (part IB) is then added. The mixture is blended for 10 minutes without starting the agitator.

[0334] The blend is then discharged into appropriately labeled double-layered polyethylene-lined containers and sieved through a 30-mesh SS sieve into another appropriately labeled double-layered polyethylene-lined container. In the same 0.5 cubic foot Gemco double cone blender:

[0335] Add half of the anhydrous lactose (part I).

[0336] Add crospovidone (part I).

[0337] Add the aforementioned sieved blend.

[0338] Add the remaining anhydrous lactose (part I).

[0339] Mix the mixture for 10 minutes without using a stirring rod.

[0340] The magnesium stearate was then weighed and sieved through a 30-mesh SS sieve into a double-layered polyethylene-lined container with an appropriate label.

[0341] In a 0.5 cubic foot Gemco double cone mixer: add about half of the ground particles; add colloidal silica NF (Cab-O-Sil) and crosslinked polyvinyl chloride; add sieved hydroxypropyl cellulose (Klucel EXF); and add the remaining ground particles.

[0342] The blend was mixed at 23.5 rpm for 5 minutes.

[0343] The sieved magnesium stearate was then added to the contents of the mixer. The mixture was further blended at 23.5 rpm for 3 minutes. 25 g composite samples were collected from both the initial blend (before compaction) and the ground particles (after compaction). The sieve analysis and density results of the particles before and after compaction are recorded in Table 10.

[0344] The initial blend was compacted using an Alexanderwerk WP 120 roller compactor at a target pressure of 60 bar. The screw feeder speed was automatically adjusted to maintain a 2.0 mm roller gap. The compacted material was then ground sequentially through a 3.15 mm coarse sieve and a 1.0 mm fine sieve using a pellet mill located below the rollers. The ground particles were then used for final blending.

[0345] Before weighing, adjust the weight of the excipients for the particles according to the yield of the ground particles. Hydroxypropyl cellulose (Klucel EXF), colloidal silica NF (Cab-O-Sil), and crospovidone are sieved through a 20-mesh sieve. Magnesium stearate is sieved through a 30-mesh sieve.

[0346] In a 0.5 cubic foot Gemco double cone mixer: add half of the ground particles; add colloidal silica NF (Cab-O-Sil), crospovidone, and sieved hydroxypropyl cellulose (Klucel EXF); add the remaining ground particles; and mix the mixture at 23.5 rpm for 5 minutes. Then add sieved magnesium stearate and mix for another 3 minutes at 23.5 rpm.

[0347] Table 10: Analysis of grinding particles and final blend of batch 2

[0348]

[0349] The final blend was then divided into two portions for tableting: one for the 1 mg formulation and the other for the 5 mg formulation. The blends were tableted using a Globe Pharma tablet press, and weight (n=10), hardness (n=10), thickness (n=10), and friability were subsequently measured. The data are summarized in Table 11. The batches showed uniform tableting, with consistent weight, hardness, and thickness across the entire batch.

[0350] Table 11: Compressed tablet data for Compound I 1 mg tablets – Batch 2

[0351]

[0352] The tablets were loaded into an O'Hara coating pan and coated with Opadry II White (85F18422) film coating solution, with a theoretical coating weight gain of 3%. The film coating solution was prepared by adding the required amount of purified water and stirring continuously for at least 45 minutes. The coating solution was continuously stirred throughout the coating process.

[0353] Dissolution of 1 mg of Compound I tablets was performed using 900 mL of 0.01 M HCl at 37.0 °C via apparatus II (paddle method) at 75 rpm. Dissolution data are shown below. Figure 4 The dissolution rate was 10 minutes. Disintegration of the coated tablets was 30 minutes, indicating complete disintegration.

[0354] Dissolution of 5 mg of Compound I tablets was performed using 900 mL of 0.01 M HCl at 37.0 °C via apparatus II (paddle method) at 100 rpm. Dissolution data are shown below. Figure 5 The dissolution profile of the 5 mg Compound I tablets showed complete release within 10 minutes, confirming compliance with assay and dissolution specifications. However, chromatographic analysis detected unknown impurities in both the 1 mg and 5 mg formulations.

[0355] Example 8: Dry granulation preparation of 1 mg and 5 mg oral tablets of compound I – batch 3

[0356] Batch 3 was reformulated by removing anhydrous lactose and using a dry granulation process to evaluate the effect of anhydrous lactose on unknown impurities. The formulation is shown in Table 12.

[0357] Table 12: Compound I Tablets – Co-blends – Batch 3

[0358]

[0359] The manufacturing method of batch 3 is as follows: Compound I, microcrystalline cellulose NF (Avicel PH112) (part IA) and Cab-O-Sil (part I) are combined and sieved through a 30-mesh stainless steel (SS) sieve into a double-layer polyethylene-lined container with an appropriate label.

[0360] In a 0.5 cubic foot Gemco double cone mixer: add half of the microcrystalline cellulose (Avicel PH112) (partial IB); then add the previously sieved material; then add the remaining microcrystalline cellulose (Avicel PH112) (partial IB); and mix for 10 minutes without using a stirring rod.

[0361] The blend is then discharged into a properly labeled double-layered polyethylene-lined container. The initial blend is then sieved through a 30-mesh SS sieve into another properly labeled double-layered polyethylene-lined container.

[0362] In a 0.5 cubic foot Gemco double cone mixer: add half of the sieved blend; add crosslinked polyvinyl chloride (part I); add the remaining sieved blend; then mix for 10 minutes without using a stirring rod.

[0363] The blend is then discharged into appropriately labeled double-layered polyethylene-lined containers. The initial blend is then sieved through a 30-mesh SS sieve into another appropriately labeled double-layered polyethylene-lined container, followed by the weighed magnesium stearate, which is then sieved through a 30-mesh SS sieve into the same container. In a 0.5 cubic foot Gemco double cone mixer: half of the sieved blend is added; the sieved magnesium stearate is added; the remaining sieved blend is added; and the mixture is then blended for 3 minutes without using a stirring rod.

[0364] The blend is then discharged into a double-layered polyethylene-lined container with appropriate labeling.

[0365] The initial blend was then compacted using an Alexanderwerk WP 120 roller compactor.

[0366] The blend is pressed into sheets / ribbons under a target pressure of 60 bar. The screw feeder speed is automatically adjusted to maintain a 2.0 mm roller gap. The compacted material is then ground sequentially through a 3.15 mm coarse sieve and a 1.0 mm fine sieve using a pellet mill located below the rollers.

[0367] In a 0.5 cubic foot Gemco double cone mixer: approximately half of the ground particles were added; colloidal silica NF (Cab-O-Sil) and crospovidone were added; sieved hydroxypropyl cellulose (Klucel EXF) was added; the remaining ground particles were added; and the mixture was blended at 23.5 rpm for 5 minutes. Subsequently, sieved magnesium stearate was added to the mixer contents, and the mixture was blended again at 23.5 rpm for 3 minutes. The sieve analysis and density results of the particles before and after compaction are shown in Table 13.

[0368] Table 13: Analysis of Grinding Particles and Final Blend – Batch 3

[0369]

[0370] The final blend was divided into two portions for tableting: one portion for preparing 1 mg tablets and the other for preparing 5 mg tablets. The blends were tableted using a Globe Pharma tablet compressor, and then weight (n=10), hardness (n=10), thickness (n=10), and friability were measured. The data are summarized in Table 14. The batches showed uniform compression, with consistent weight, hardness, and thickness across the entire batch.

[0371] Table 14: Compressed tablet data for Compound I 1 mg tablets – Batch 3

[0372]

[0373] The tablets were loaded into an O'Hara coating pan and coated with Opadry II White (85F18422) film coating solution, with a theoretical coating weight gain of 3%. The film coating solution was prepared by adding the required amount of purified water and stirring continuously for at least 45 minutes. The coating solution was continuously stirred throughout the coating process.

[0374] Batch 3 dissolved completely within 10 minutes. Disintegration testing of the coated tablets showed complete disintegration within 30 minutes.

[0375] The 1 mg coated tablet of Compound 1 was dissolved in 900 mL of 0.01 M HCl at 37.0 °C using apparatus II (paddle method) at 75 rpm. Dissolution data for the 1 mg specification are shown below. Figure 6 Dissolution data for 5 mg tablets are shown in [the table / document / etc.]. Figure 7 middle.

[0376] The dissolution profile of 5 mg tablets of compound I, batch 3, showed complete release within 10 minutes, confirming compliance with assay and dissolution specifications. By removing anhydrous lactose from the formulation and analyzing its effect on the unknown impurity, we observed that the impurity was no longer present. Therefore, we conclude that the unknown impurity was caused by the presence of lactose.

[0377] Example 9: Preparation of Compound I 1 mg and 5 mg oral tablets by wet granulation – Batch 4

[0378] This batch was reformulated by removing anhydrous lactose and using a wet granulation process to evaluate the impact of anhydrous lactose on unknown impurities. Table 15 shows the formulation.

[0379] Table 15: Compound I 1 mg and 5 mg blend tablets

[0380]

[0381] The preparation process for batch 4 is as follows: Raw materials are weighed into suitable containers, including containers lined with double-layer polyethylene and high-density polyethylene (HDPE). Compound I is combined with microcrystalline cellulose and NF (Avicel PH112) (partial IA) and sieved through a 30-mesh stainless steel sieve into appropriately labeled double-layer polyethylene-lined containers. The following materials are then transferred to a 0.5 cubic foot blender:

[0382] 50% microcrystalline cellulose (Avicel PH112) - IB fraction

[0383] Material from step 2 (screened)

[0384] Hydroxypropyl cellulose (Klucel EXF)

[0385] The remaining portion of microcrystalline cellulose (Avicel PH112) - IB fraction

[0386] The components were then blended for 5 minutes and discharged into a stainless steel hopper. Granulation was then initiated, with water added manually in a controlled manner. After granulation, the granules were dried in an oven at a set temperature of 60°C, and the loss on drying (LOD) was measured. The dried granules were then sieved through an 18-mesh sieve, and the particle size distribution (PSD) was tested. A composite sample of 25 grams of the initially sieved granules was collected.

[0387] Before weighing, the weight of the excipients was adjusted according to the yield of granulated particles. Colloidal silica, NF (Cab-O-Sil), and crospovidone were sieved through a 20-mesh sieve. Magnesium stearate was sieved through a 30-mesh sieve. Approximately 50% of the sieved particles were added to a 0.5 cubic foot Gemco double cone mixer. Then, colloidal silica, NF (Cab-O-Sil), and crospovidone were added. The remaining sieved particles were added, and the mixture was blended at 23.5 rpm for 5 minutes. The sieved magnesium stearate was then added to the material in the mixer, and blending continued at 23.5 rpm for 3 minutes. A composite sample of 25 g of the final blend was then collected. The sieve analysis and density results of the final blend particles are shown in Table 16.

[0388] Table 16: Analysis of Granulated Particles and Final Blend – Batch 4

[0389]

[0390] The final blend was divided into two portions for tableting: one portion for preparing 1 mg tablets and the other for preparing 5 mg tablets. The blends were tableted using a Globe Pharma tablet press, and then weight (n=10), hardness (n=10), thickness (n=10), and friability were measured. The data are summarized in Table 17. The batches showed uniform tableting, with consistent weight, hardness, and thickness across the entire batch.

[0391] Table 17: Compound I 1 mg tablet data – Batch 4

[0392]

[0393] The tablets were loaded into an O'Hara coating pan and coated with Opadry II White (85F18422) film coating solution, with a theoretical coating weight gain of 3%. The film coating solution was prepared by adding the required amount of purified water and stirring continuously for at least 45 minutes. The coating solution was continuously stirred throughout the coating process.

[0394] Dissolution of 1 mg of Compound I tablets was performed using 500 mL of 0.01 M HCl at 37.0 °C via apparatus II (paddle method) at 75 rpm. Dissolution data are shown below. Figure 8 In the first batch, the 1 mg tablets of batch 4 dissolved completely within 10 minutes. Disintegration of the coated tablets was tested, and they completely disintegrated within 30 minutes.

[0395] Dissolution of 5 mg of Compound I tablets was performed using 500 mL of 0.01 M HCl at 37.0 °C via apparatus II (paddle method) at 75 rpm. Dissolution data are shown below. Figure 9 middle.

[0396] The dissolution profile of the 5 mg Compound I tablets showed complete release within 10 minutes, confirming compliance with assay and dissolution specifications.

[0397] Example 10: Clinical study evaluating the safety, tolerability, and efficacy of compound I in selected adult patients with solid tumors.

[0398] The study was conducted in two parts: a dose escalation part, used to determine the maximum tolerated dose and the Phase 2 recommended dose (RP2D) when compound I in oral tablet form, as described in this paper, was administered at once-daily (QD) and twice-daily (BID) regimens; and a dose extension part, used to evaluate the safety and tolerability of compound I in specific tumor cohorts when administered at the Phase 2 recommended dose and regimen.

[0399] Intervention model description: Part 1 (multiple dose escalation, QD or BID): Selected patients with locally advanced, recurrent or metastatic solid tumors who have been assessed locally as having PIK3CA mutations; Part 2 (RP2D identified in Part 1): Selected patients with locally advanced, recurrent or metastatic solid tumors who have been assessed locally as having PIK3CA mutations will be included in the group defined by the protocol.

[0400] Compound I used in this study can be prepared as an oral immediate-release formulation according to tablet formulations 1 and 2 of Examples 5-8 above.

[0401] Adult subjects who are histologically diagnosed with colorectal cancer, gastric cancer, non-small cell lung cancer, human epidermal growth factor receptor 2 (HER2) negative breast cancer, head and neck squamous cell carcinoma, urothelial carcinoma, or selected gynecological cancers (ovarian cancer, cervical cancer, or endometrial cancer), and who are known to have PIK3CA mutations or amplifications (determined by a validated assay by a diagnostic laboratory certified by the American College of Pathologists / Clinical Laboratory Improvement Amendments [CAP / CLIA] or equivalent accreditation), and who meet all inclusion criteria will be included in the Phase 1 portion of the study.

[0402] In the dose escalation portion of the study, compound I will be evaluated as a monotherapy at multiple dose levels, administered orally until disease progression, unacceptable toxicity, or other prescribed discontinuation criteria are met.

[0403] Final dose studies have shown that immediate-release tablet compositions containing compound I are safe and effective in treating a variety of cancers, including colorectal cancer and breast cancer.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof that forms a covalent bond with a kinase or pseudokinase, and at least one pharmaceutical excipient, wherein the pharmaceutical composition allows for the immediate release of the compound.

2. The pharmaceutical composition according to claim 1, wherein the kinase is PI3-kinase (PI3K).

3. The pharmaceutical composition according to claim 1, wherein the compound forming a covalent bond with the kinase or pseudokinase is a compound having the following formula: (FCB)a-(L)b-(CLM)c, Or its pharmaceutically acceptable salt, wherein: CLM stands for covalent connection mode; L stands for connector; a and c are each independent integers between 1 and 5; b is an integer between 0 and 5; and FCB contains: .

4. The pharmaceutical composition according to claim 3, wherein the FCB has the following structure: , R1 is selected from the following groups: , , and .

5. The pharmaceutical composition according to any one of claims 1-4, wherein the compound is compound I: Compound I or a pharmaceutically acceptable salt or solvation thereof.

6. The pharmaceutical composition according to claim 5, wherein compound I is a crystal form of compound I, or a pharmaceutically acceptable salt or solvation of compound I.

7. The pharmaceutical composition according to claim 5, wherein compound I is an amorphous form of compound I or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutically acceptable salt of compound I is selected from the group consisting of phosphates, hydrochlorides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates, fumarates, maleates, L-tartrates, citrates, and succinates, or solvates thereof.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical excipient is selected from fillers, binders, disintegrants, flow aids, lubricants, coatings, or any combination thereof.

10. The pharmaceutical composition according to claim 9, wherein the filler is selected from microcrystalline cellulose, silicified microcrystalline cellulose, mannitol EZ, pregelatinized starch, calcium hydrogen phosphate dihydrate, lactose monohydrate, or any combination thereof.

11. The pharmaceutical composition according to claim 9, wherein the binder is selected from povidone K29 / 32, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or any combination thereof.

12. The pharmaceutical composition according to claim 9, wherein the disintegrant is selected from croscarmellose sodium, croscarmellose XL, carboxymethyl starch sodium, or any combination thereof.

13. The pharmaceutical composition according to claim 9, wherein the gliding agent is selected from colloidal silica, talc, or any combination thereof.

14. The pharmaceutical composition according to claim 9, wherein the lubricant is selected from plant-derived magnesium stearate, sodium stearate fumarate, glyceryl behenate, stearic acid, or any combination thereof.

15. The pharmaceutical composition of claim 9, wherein the coating is a water-soluble polymer selected from film-coated polymers based on polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose (HPMC).

16. The pharmaceutical composition of claim 9, wherein the coating is selected from Opadry II White (PVA), Opadry II White (HPMC), or any combination thereof.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the content of the compound or a pharmaceutically acceptable salt thereof that forms a covalent bond with a kinase or pseudokinase is greater than 50% by weight.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the content of the compound or its pharmaceutically acceptable salt that forms a covalent bond with the kinase or pseudokinase is from about 0.1% to about 50% by weight, or 1% to about 30% by weight, or about 1% to about 20% by weight, or about 1% to about 10% by weight, or about 1% to about 4% by weight, or about 4% to about 3% by weight, or about 5% to about 6% by weight, relative to the total core weight of the composition, i.e., the weight before coating.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the content of the compound or a pharmaceutically acceptable salt thereof that forms a covalent bond with a kinase or pseudokinase is about 2% by weight of the total core weight of the composition.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the filler content is about 10% to about 95% by weight, or about 20% to about 90% by weight, or about 30% to about 85% by weight, or about 40% to about 80% by weight, or about 40% to about 50% by weight, or about 42% to about 46% by weight of the total core weight of the composition.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the filler content is about 70% to about 90% by weight of the total core weight of the composition.

22. The pharmaceutical composition according to any one of claims 1 to 20, wherein the filler content is about 85% by weight of the total core weight of the composition.

23. The pharmaceutical composition according to any one of claims 1 to 20, wherein the filler content is about 86% by weight of the total core weight of the composition.

24. The pharmaceutical composition according to any one of claims 1 to 20, wherein the filler content is about 87% by weight of the total core weight of the composition.

25. The pharmaceutical composition according to any one of claims 1 to 20, wherein the filler content is about 88% by weight of the total core weight of the composition.

26. The pharmaceutical composition according to any one of claims 1 to 25, wherein the binder is present in a content of about 0.1% to about 10% of the total core weight of the composition, or about 1% to about 10% of the total core weight, or about 2% to about 8% of the total core weight, or about 2% to about 6% of the total core weight, or about 2% to about 5% of the total core weight, or about 2% to about 4% of the total core weight, or about 3% to about 4% of the total core weight.

27. The pharmaceutical composition according to any one of claims 1 to 26, wherein the binder content is about 3% by weight of the total core weight of the composition.

28. The pharmaceutical composition according to any one of claims 1 to 27, wherein the disintegrant is present in an amount of about 0.1% to about 10% by weight, or about 1% to about 10% by weight, or about 2% to about 8% by weight, or about 2% to about 6% by weight, or about 2% to 5% by weight, or about 3% to 4% by weight of the total core weight of the composition.

29. The pharmaceutical composition according to any one of claims 1 to 28, wherein the content of the disintegrant is about 3% by weight or about 3.5% by weight of the total core weight of the composition.

30. The pharmaceutical composition according to any one of claims 1 to 29, wherein the content of the gliding agent is from about 0.01% to about 10% by weight, or from about 0.1% to about 5% by weight, or from about 0.1% to about 3% by weight, or from about 0.2% to about 2% by weight, or from about 0.3% to 1% by weight, or from about 0.3% to 0.6% by weight, or from about 0.4% to 0.5% by weight.

31. The pharmaceutical composition according to any one of claims 1 to 30, wherein the content of the gliding agent is about 0.5% by weight or about 2.5% by weight of the total core weight of the composition.

32. The pharmaceutical composition according to any one of claims 1 to 31, wherein the lubricant is present in an amount of about 0.01% to about 10% by weight, or about 0.1% to about 5% by weight, or about 0.1% to about 3% by weight, or about 0.2% to about 2% by weight, or about 0.3% to 1% by weight, or about 0.3% to 0.6% by weight, or about 0.4% to 0.5% by weight, of the total core weight of the composition.

33. The pharmaceutical composition according to any one of claims 1 to 32, wherein the lubricant content is about 0.5% by weight or about 1% by weight of the total core weight of the composition.

34. The pharmaceutical composition according to any one of claims 1 to 33, wherein the coating content is about 0.1% to about 10% by weight, or about 1% to about 10% by weight, or about 2% to about 8% by weight, or about 2% to about 6% by weight, or about 2% to 5% by weight, or about 3% to 4% by weight.

35. The pharmaceutical composition according to any one of claims 9 to 31, wherein the coating content is about 3% by weight of the total weight of the composition.

36. The pharmaceutical composition according to any one of claims 9 to 35, wherein the pharmaceutical composition is a solid dosage form selected from tablets, powders, capsules, suppositories, sacs, lozenges and tablets.

37. The pharmaceutical composition according to any one of claims 1 to 36, wherein the pharmaceutical composition is in tablet form.

38. The pharmaceutical composition of claim 37, wherein the D85 value of the pharmaceutical particles before compression into the tablet is about 50 µm to about 100 µm, about 60 µm to about 80 µm, or about 63 µm.

39. The pharmaceutical composition of claim 37, wherein the D85 value of the pharmaceutical particles before tableting is greater than about 50 µm, about 60 µm, about 70 µm, about 80 µm, about 90 µm or about 100 µm.

40. The pharmaceutical composition of claim 37, wherein the D65 value of the pharmaceutical particles before compression into the tablet is about 100 µm to about 200 µm, about 120 µm to about 160 µm, or about 140 µm.

41. The pharmaceutical composition of claim 37, wherein the drug microparticles prior to compression into the tablet have a D65 value greater than about 120 µm, about 130 µm, about 140 µm, about 150 µm, about 160 µm, or about 180 µm.

42. The pharmaceutical composition of claim 37, wherein the D45 value of the pharmaceutical particles before compression into the tablet is about 300 µm to about 500 µm, about 350 µm to about 450 µm, or about 420 µm.

43. The pharmaceutical composition of claim 37, wherein the D50 value of the pharmaceutical particles before compression into the tablet is greater than about 340 µm, about 360 µm, about 380 µm, about 420 µm, about 440 µm, or about 480 µm.

44. A method for modulating the activity of a kinase or pseudokinase, comprising administering to a subject in need any of the pharmaceutical compositions of any one of claims 1 to 43.

45. The method of claim 44, wherein the activity of the kinase or pseudokinase is inhibited.

46. ​​The method of claim 44 or 45, wherein the kinase is PI3K.

47. A method for treating a subject in need of cancer, neurodegenerative disease, autoimmune disease, or aging, comprising administering to the subject in need the pharmaceutical composition of any one of claims 1 to 43.

48. The method of claim 47, wherein the subject has cancer.

49. The method of claim 47 or 48, wherein the cancer is selected from one or more of the group consisting of: leukemia, brain tumor, (small cell and non-small cell) lung cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, and cancers in tissues including intestinal tissue, pancreatic tissue, liver, kidney, prostate, ovary, lung, bone marrow, or breast tissue.

50. The method according to any one of claims 47 to 49, wherein the subject has cancer with a mutation in the PIK3CA gene.

51. The pharmaceutical composition according to any one of claims 1 to 43, wherein the pharmaceutical composition allows for the immediate release of the compound, and the pharmaceutical composition is substantially lactose-free.

52. The pharmaceutical composition according to claim 51, wherein the compound is compound I.

53. The pharmaceutical composition according to claim 51 or 52, wherein the lactose is anhydrous lactose.

54. The pharmaceutical composition according to any one of claims 1 to 43 or 51 to 53, wherein the pharmaceutical composition allows for the immediate release of the compound, and the pharmaceutical composition is substantially free of any reducing sugars.

55. The pharmaceutical composition according to claim 54, wherein the reducing sugar is lactose, galactose, glucose, maltose, fructose, ribose, and / or xylose.

56. The pharmaceutical composition according to claim 54 or 55, wherein the compound is compound I.

57. The pharmaceutical composition according to any one of claims 51 to 56, wherein the pharmaceutical excipient is selected from microcrystalline cellulose, crospovidone XL, colloidal silica (Cab-O-Sil®), hydroxypropyl cellulose, plant-derived magnesium stearate, or any combination thereof.

58. The pharmaceutical composition according to any one of claims 51 to 57, wherein the tablet is an oral tablet.

59. The pharmaceutical composition according to claim 58, wherein the oral tablet is an immediate-release oral tablet.

60. The pharmaceutical composition according to any one of claims 1 to 43 or 51 to 59, wherein the composition is as described in Tables 2, 3, 5, 9, 12 or 15 herein.

61. The pharmaceutical composition of claim 60, wherein, by the dissolution study described herein, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the compound is released within about 10 minutes.

62. The pharmaceutical composition according to claim 61, wherein at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of compound I is released within about 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute.

63. The pharmaceutical composition according to claim 61 or 62, wherein the dissolution of the compound in the tablet is determined using 900 mL of 0.01 M HCl at 37.0 °C via device II (paddle method) at 75 rpm or 100 rpm.

64. The pharmaceutical composition according to any one of claims 1 to 43 or claims 51 to 63, wherein compound I is in the form of a salt.

65. A method for modulating the activity of a kinase or pseudokinase, comprising administering to a subject in need any of the pharmaceutical compositions of any one of claims 51 to 64.

66. The method of claim 65, wherein the activity of the kinase or pseudokinase is inhibited.

67. The method of claim 65 or 66, wherein the kinase is PI3K.

68. A method for treating a subject in need of cancer, neurodegenerative disease, autoimmune disease, or aging, comprising administering to the subject in need the pharmaceutical composition of any one of claims 51 to 64.

69. The method of claim 68, wherein the subject has cancer.

70. The method of claim 69, wherein the cancer is selected from one or more of the group consisting of: leukemia, brain tumor, (small cell and non-small cell) lung cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, and cancers in tissues including intestinal tissue, pancreatic tissue, liver, kidney, prostate, ovary, lung, bone marrow, or breast tissue.

71. The method according to any one of claims 68 to 70, wherein the subject has cancer with a mutation in the PIK3CA gene.

Images