JP7129973B2 - Bromodomain inhibitor - Google Patents

Description

[Related Application]
No. 62/410,756 (filed October 20, 2016) and U.S. Provisional Patent Application No. 62, each of which is fully incorporated herein by reference for all purposes. No. 15/136,761 (filed April 22, 2016) claiming priority benefit of US patent application Ser. No. 15/136,761 (filed April 22, 2016).

[field]
This embodiment provides compounds and pharmaceutical compositions useful for the treatment of cancer, such as, for example, 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one. I will provide a.

[background]
There is a need in the art for effective treatment of cancer and neoplastic disease.

[Overview]
This embodiment includes bromodomain inhibitors, compound 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl, including crystalline forms, amorphous forms, solvates and hydrates thereof. Isoquinolin-1-one (“Compound 1”); and pharmaceutical compositions comprising this compound are provided.

At least one embodiment provides a pharmaceutical composition comprising crystalline Form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-isoquinolin-1-one. In specific embodiments, crystalline Form A of 4-[2-(cyclopropyl-methoxy)-5-methylsulfonylphenyl]-2-methyliso-quinolin-1-one is 7.8, 9.0, 15 X-ray powder diffraction (XRPD) 2-theta (2-theta) reflection peaks at .7, 18.0, 21.1, 22.0, 23.6 and 24.5 2-theta.

At least one embodiment provides a pharmaceutical composition comprising amorphous 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one.

In at least one embodiment, the pharmaceutical composition comprises 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one and at least one solid matrix polymer. A related embodiment has a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer of from about 1:1 to about 1:9 A pharmaceutical composition is provided. Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:1 . Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropyl-methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:2 do. Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:3 . Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyliso-quinolin-1-one to solid matrix polymer is 1:4 do. Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:5 . Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:6 . Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:7 . Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonyl-phenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:8 do. Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:9 .

At least one embodiment provides a solid matrix comprising a polyvinylpyrrolidone derivative. At least one embodiment provides a solid matrix comprising a cellulose derivative. The cellulose derivative may be at least one of hydroxypropylmethycellulose, hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate or hydroxypropylmethylcellulose acetate succinate. Another embodiment provides a pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethicellulose. Another embodiment provides a pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethycellulose phthalate. Another embodiment provides a pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethylcellulose acetate stearate. Another embodiment provides a pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethylcellulose acetate succinate.

In at least one embodiment, the pharmaceutical composition comprises amorphous 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one and a solid polymer matrix.

In some embodiments, the pharmaceutical composition comprises a spray-dried dispersion of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, optionally Optionally, it further comprises a solid polymer matrix. In some embodiments, the pharmaceutical composition comprises micronized 4-[2-(cyclopropylmethoxy)-5-methyl-sulfonylphenyl]-2-methylisoquinolin-1-one and optionally further solid Contains a polymer matrix.

At least one embodiment is a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, wherein 4-[2-(cyclopropyl A pharmaceutical composition is provided wherein methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is prepared by a process comprising spray drying.

At least one embodiment is a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, wherein 4-[2-(cyclopropyl A pharmaceutical composition is provided wherein methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is prepared by a process comprising rapid expansion of supercritical CO ₂ solution (RESS) micronization.

At least one embodiment is a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one and a solid matrix polymer, wherein 4-[2 A pharmaceutical composition is provided wherein -(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-isoquinolin-1-one has been processed by spray drying and the solid matrix polymer is a polyvinylpyrrolidone derivative .

At least one embodiment is a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one and a solid matrix polymer, wherein 4-[2 A pharmaceutical composition is provided wherein -(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one has been processed by spray drying and the solid matrix polymer is a cellulose derivative.

At least one embodiment is a medicament for the treatment of cancer, the pharmaceutical composition comprising 4-[2-(cyclopropyl-methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one wherein the pharmaceutical composition comprises a spray-dried dispersion of 4-[2-(cyclopropylmethoxy)-5-methyl-sulfonylphenyl]-2-methylisoquinolin-1-one, optionally with a solid matrix polymer , to provide medicines. At least one embodiment is a medicament for the treatment of cancer, the pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methyl-sulfonylphenyl]-2-methylisoquinolin-1-one wherein the pharmaceutical composition is prepared by a process comprising spray drying dispersion, optionally with a solid matrix polymer. The cancer may be nuclear protein in the testis (NUT) midline carcinoma (NMC), prostate cancer, breast cancer, bladder cancer, lung cancer or melanoma. The cancer may be Burkitt's lymphoma. The cancer may be glioblastoma (GBM), basal cell carcinoma, pancreatic, multiple myeloma or acute myelogenous leukemia (AML).

At least one embodiment comprises administering to a subject a pharmaceutical composition comprising 4-[2-(cyclopropyl-methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, Provided is a method of treating cancer in a subject in need thereof, wherein the pharmaceutical composition is prepared by a process comprising spray drying dispersion. In certain embodiments, the cancer is NMC, prostate cancer, breast cancer, bladder cancer, lung cancer or melanoma. In another embodiment, the cancer is Burkitt's Lymphoma. In other embodiments, the cancer is GBM, basal cell carcinoma, pancreatic, multiple myeloma or AML.

[Brief description of the drawing]
FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline Form A of compound 1. FIG. FIG. 2 shows the XRPD pattern of amorphous Compound 1. FIG. FIG. 3 is from a differential scanning calorimetry (DSC) experiment for crystalline Form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one (Compound 1). showing the data. 4 shows data from a gravimetric vapor sorption (GVS)/(DVS) isothermal plot experiment for crystalline Form A of Compound 1. FIG. ◆ Cycle 1 adsorption; ■ Cycle 1 desorption; ▲ Cycle 2 adsorption; □ Cycle 2 desorption; ■ Cycle 3 adsorption 5 is a bar graph of AUG 0-20 hours (hr ng/mL) from a full rat pharmacokinetic (PK) study of crystalline Form A of Compound 1. FIG. Dosing was PO at 10 mg/kg, 30 mg/kg, 100 mg/kg or 300 mg/kg. Figure 6 shows data from a 6 hour mouse PK study in which Compound 1 was treated as a spray dried dispersion (SDD) in four different formulations containing Compound 1 and polymer. FIG. 7 illustrates the XRPD pattern of amorphous Compound 1 in SDD. Figure 8a illustrates a rat PK study using SDD with compound 1, AUC 0-24 hours (hr ^* ng/mL); dosing by oral administration (PO) of Figure 8b illustrates a canine PK study using SDD with compound 1, AUC 0-24 hours (hr ^* ng/mL); showing. Figure 9 illustrates plasma exposure levels of Compound 1 in rats following oral administration of various SDD preparations.

[Detailed description]
It is to be understood that this invention is not limited to the particular methods, protocols and reagents, etc., described herein, as such may vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined solely by the claims.

All patents and other publications identified are referenced for the purposes of describing and disclosing, for example, the methods described in such publications, which may be used in connection with the present invention. are incorporated herein by, but are not intended to provide definitions of terms that contradict those presented herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this connection should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to dates or representations as to the contents of these documents are based on the information available to applicants and do not constitute any admission as to the accuracy of the dates or contents of these documents.

As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Throughout this specification, unless otherwise indicated, the terms "comprise," "comprises," and "comprising" refer to one or more of the stated integer or group of integers. It is used inclusively rather than exclusively, as may include other unstated integers or groups of integers. The term "or" is inclusive unless modified, for example, by "either." Thus, unless the context clearly indicates otherwise, the word "or" means any one member of a specific list and includes any combination of members of the list. Except as indicated in the working examples or otherwise, all numbers expressing quantities of ingredients or reaction conditions used herein are to be understood as being modified in all instances by the term "about." should.

Headings are provided for convenience only and are not to be construed as limiting the invention in any way. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined solely by the claims. Certain terms are first defined so that this disclosure may be more readily understood. Additional definitions appear throughout the detailed description.

The bromodomain inhibitor compounds (ie, compound 1) described herein are bromodomain 4 (BRD4) inhibitors. In preliminary in vitro studies, BRD4 inhibition was demonstrated in several different cell lines (Raji, human Burkitt's lymphoma cells; HL-60, human proleukemia cells; and NCI-H460, human non-small cell lung cancer cells). Observed in addition to other cancer-related inhibitory activities. See US patent application Ser. No. 14/517,705.

"Compound 1" or "4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one" "the compound" or any other suitable name Refers to a compound having the structure:

In the context of this embodiment, 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one or Compound 1, etc. are referred to as the context specific (e.g., "Form A") crystalline forms, amorphous forms, solvates, hydrates and pharmaceutically acceptable salts thereof; and pharmaceutical compositions containing the compounds, unless required. Unless otherwise stated, structures depicted herein are implied by the presence of one or more isotopically enriched atoms or atomic isotopes at one or more of the atoms that constitute such compounds. It is intended to include compounds that differ only in unnatural proportions of .

Thus, as described herein, Compound 1 may be prepared in various solid forms including, but not limited to, amorphous phases, crystalline forms, ground forms, micronized forms, nanoparticulate forms. In some embodiments, Compound 1 is amorphous. In some embodiments, compound 1 is amorphous and anhydrous. In some embodiments, Compound 1 is crystalline. In some embodiments, Compound 1 is crystalline and anhydrous. In some embodiments, Compound 1 is crystalline and milled. In some embodiments, Compound 1 is crystalline and in micronized form. In some embodiments, Compound 1 is amorphous and in micronized form. In some embodiments, Compound 1 is crystalline and in nanoparticulate form. In some embodiments, Compound 1 is amorphous and dispersed with additional organic materials. In some embodiments, Compound 1 is amorphous and combined with polymeric matrix excipients. In some embodiments, compound 1 is amorphous and has been processed by spray drying dispersion.

Accordingly, as described herein, compound 1 may be in the form of solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and can be dissolved in water, ethanol, methanol, during the drug substance synthesis or isolation, or drug product formulation or isolation process. , methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), It may be formed using pharmaceutically acceptable solvents such as dioxane, heptane, toluene, anisole, acetonitrile. In one aspect, solvates are formed using, but not limited to, Class 3 solvent(s). Classification of solvents is defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Impurities: Guidelines for Residual Solvents, Q3C(R5) (February 2011). In some embodiments, the solvate of Compound 1 is an anhydrate. Hydrates are special solvates formed when the solvent is water; alcoholates are formed when the solvent is alcohol. In some embodiments, the solvate of compound 1 is a hydrate. In some embodiments, Compound 1 exists in an unsolvated form.

[Amorphous compound 1]
In some embodiments, Compound 1 is amorphous. In some embodiments, Amorphous Compound 1 has an X-ray powder diffraction (XRPD) pattern that indicates a lack of crystallinity. FIG. 2 illustrates the XRPD pattern of amorphous Compound 1. FIG. One embodiment provides a pharmaceutical composition comprising amorphous 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one.

[Form A Compound 1]
In some embodiments, Compound 1 is crystalline. In some embodiments, Compound 1 is crystalline Form A. FIG. 1 demonstrates the XRPD pattern of crystalline Form A of Compound 1. FIG. Some embodiments thereby provide pharmaceutical compositions comprising crystalline Form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one.

An embodiment exhibits at least one XRPD reflection peak selected from 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6 and 24.5 2-theta. A pharmaceutical composition comprising crystalline Form A of -[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is provided. One embodiment exhibits at least two XRPD reflection peaks selected from 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6 and 24.5 2-theta. A pharmaceutical composition comprising crystalline Form A of -[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is provided. One embodiment exhibits at least three XRPD reflection peaks selected from 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6 and 24.5 2-theta A pharmaceutical composition comprising crystalline Form A of -[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is provided. One embodiment exhibits at least four XRPD reflection peaks selected from 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6 and 24.5 2-theta. A pharmaceutical composition comprising crystalline Form A of -[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is provided. One embodiment is a 4-[2-(cyclo A pharmaceutical composition comprising crystalline Form A of propylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is provided. One embodiment provides a pharmaceutical composition comprising crystalline Form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one exhibiting the XRPD pattern of FIG. .

[Preparation of crystal form]
In some embodiments, a crystalline form of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is prepared as outlined in the examples. It is noted that the solvents, temperatures and other reaction conditions presented herein may vary.

[Suitable solvent]
A therapeutic agent to be administered to a mammal, such as a human, must be prepared according to regulatory guidelines. Such government regulatory guidelines are referred to as Good Manufacturing Practice (GMP). GMP guidelines outline acceptable contamination levels for active therapeutic agents, such as the amount of residual solvent in the final product. This is in line with the concerns of Classification of solvents is defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Humna Use (ICH), Impurities: Guidelines for Residual Solvents, Q3C(R5), (February 2011).

Solvents fall into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents of limited use in the manufacture of therapeutic agents. Class 3 solvents are solvents with low toxicity potential and low risk to human health. Data for class 3 solvents show low toxicity in acute and short term studies and negative genotoxicity studies.

Examples of Class 1 solvents, of which measurable amounts are avoided in drug products, include benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene and 1,1,1-trichloroethane.

Examples of class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane. , 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene and xylene.

Examples of Class 3 solvents with low toxicity include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, Ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2 - propanol, propyl acetate and tetrahydrofuran.

Residual solvent in an active pharmaceutical ingredient (API) originates from the manufacture of the API. In some cases the solvent is not completely removed by the actual manufacturing technique. Appropriate selection of solvents for synthesis of APIs can enhance yield or may determine characteristics such as crystal form, purity and solubility. Solvent is therefore an important parameter in the synthetic process. The amount of residual solvent carried over from the API to the final drug product may also be considered.

In some embodiments, compositions comprising Compound 1 comprise organic solvent(s). In some embodiments, compositions comprising compound 1 comprise residual or trace amounts of organic solvent(s). In some embodiments, the composition comprising Compound 1 comprises a residual amount of Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent. In some embodiments, Class 3 solvents are acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethylsulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate , formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol , propyl acetate and tetrahydrofuran. In some embodiments, Class 3 solvents are selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol and ethanol.

[Specific term]
The term "acceptable" or "pharmaceutically acceptable", with respect to a pharmaceutical composition, formulation or ingredient, means having no lasting adverse effects on the general health of the subject being treated; It does not inhibit the physical activity or properties of the compound and is considered relatively non-toxic.

As used herein, "amelioration" of symptoms of a specific disease, disorder or condition by administration of a specific compound or pharmaceutical composition may be permanent or temporary, persistent or transient It refers to any reduction in severity, delay in onset, slowing of progression, or reduction in duration, regardless of whether or not it may result from or be related to administration of a compound or composition.

"Bioavailability" refers to the percentage of API (eg, Compound 1) in the dose that is delivered to the systemic circulation of the animal or human being studied. The total exposure (AUC _(0-∞) ) of a drug when administered intravenously is commonly defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which an API (eg Compound 1) is absorbed into the systemic circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.

"Blood plasma concentration" refers to the concentration of Compound 1 in the plasma constituents of a subject's blood. It is understood that plasma concentrations of Compound 1 may vary significantly between subjects due to metabolic variations and/or possible interactions with other therapeutic agents. According to one embodiment disclosed herein, the Blood plasma concentration of Compound 1 may vary from subject to subject. Similarly, values such as maximum plasma concentration (C _max ) or time to reach maximum plasma concentration (T _max ) or total area under the plasma concentration time curve (AUC _(0-∞) ) can vary from subject to subject. Because of this variability, the amount necessary to establish a "therapeutically effective amount" of Compound 1 may vary from subject to subject.

As used herein, the terms "effective amount" or "therapeutically effective amount" refer to an administered sufficient amount of an agent or compound to alleviate to some extent one or more of the symptoms of the disease or condition being treated. . The result may be a reduction and/or alleviation of a sign, symptom or cause of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is a composition comprising a compound disclosed herein necessary to provide a clinically significant reduction in disease symptoms without adverse side effects. is the amount of An appropriate "effective amount" in any individual case may be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, prophylactically effective amounts. An "effective amount" of a compound disclosed herein is an amount effective to achieve the desired pharmacological effect or therapeutic improvement without adverse side effects. An "effective amount" or "therapeutically effective amount" varies from subject to subject due to variations in the metabolism of Compound 1, the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated and the judgment of the prescribing physician. It is understood that there are cases where By way of example only, a therapeutically effective amount may be determined by routine experimentation, including, but not limited to, dose escalation clinical trials.

The terms "enhance" or "enhancing" mean to increase or prolong either the intensity or duration of a desired effect. By way of example, "potentiating" the effect of a therapeutic agent refers to the ability to increase or prolong either in intensity or duration the effect of a therapeutic agent in treating a disease, disorder, or condition. As used herein, an "enhancing effective amount" refers to an amount adequate to enhance the efficacy of a therapeutic agent in treating a disease, disorder or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health and response to drugs and the judgment of the treating physician. .

As used herein, the term "modulate" includes, by way of example only, enhancing target activity, inhibiting target activity, limiting target activity, or modulating target activity. It means interacting with a target, either directly or indirectly, so as to alter the activity of the target, including enhancing activity.

As used herein, the term "modulator" refers to a compound that alters the activity of a molecule. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of activity in the absence of the modulator. In certain embodiments, modulators are inhibitors that reduce the magnitude of one or more activities of the molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator that increases the magnitude of at least one activity of a molecule. In certain embodiments, the presence of a modulator results in an activity that does not occur in the absence of the modulator.

"optional" or "optionally" means that the event or circumstance being described may or may not occur and the description includes the cases where the event or circumstance does and does not occur .

"Pharmaceutically acceptable salt" includes both acid and base addition salts. The pharmaceutically acceptable salts of any one of the Substituted Heterocyclic Derivative Compounds described herein are intended to include any pharmaceutically suitable salt forms. Pharmaceutically acceptable salts of Compound 1 are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

As used herein, the term "prophylactically effective amount" refers to that amount of the composition applied to the patient that alleviates to some extent one or more symptoms of the disease, condition or disorder being treated. For such prophylactic applications, such amounts may depend on the patient's state of health, weight, and the like. It is considered well within the skill of the art for determination of such prophylactically effective amounts by routine experimentation, including, but not limited to, dose escalation clinical trials.

As used herein, the term "subject" refers to an animal that is the object of treatment, observation or experimentation. A subject may be an animal, such as a mammal, including, by way of example only and not limitation, a human or non-human primate. The terms patient and subject may be used interchangeably.

As used herein, the term "target activity" refers to a biological activity that can be modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signaling, enzymatic activity, tumor growth, amelioration of one or more symptoms associated with inflammation or inflammation-related processes and diseases or conditions. be done.

As used herein, the terms "treat", "treating" or "treatment" mean alleviating, alleviating or ameliorating symptoms of a disease or condition, additionally preventing symptoms, ameliorating or preventing underlying metabolic causes of symptoms, inhibiting disease or condition, e.g. halting progression of disease or condition, ameliorating disease or condition, disease or to reverse the condition, to alleviate the condition caused by the disease or condition, or to stop the symptoms of the disease or condition. The terms "treat", "treating" or "treatment" include, but are not limited to, prophylactic and/or curative treatment.

[Pharmaceutical composition/formulation]
Pharmaceutical compositions are prepared in a conventional manner using one or more physiologically acceptable carriers including excipients and adjuvants that facilitate processing of the active compounds into preparations that can be used pharmaceutically. may be formulated in Proper formulation is dependent on the route of administration chosen. Any of the well-known techniques, carriers and excipients understood to be pharmaceutically acceptable may be used as appropriate and as understood in the art. Pharmaceutically acceptable excipients and formulations are well known in the art. REMINGTON: SCIENCE & PRACTICE OF PHARMACY, 19th Ed. (Mack Publishing Co., Easton, PA, 1995); PHARMACEUTICAL DOSAGE FORMS (Liberman & Lachman, eds., Marcel Decker, New York, NY, 1980); PHARMACEUTICAL DOSAGE See FORMS & DRUG DELIVERY SYSTEMS, 7th Ed. (Lippincott Williams & Wilkins, 1999).

As used herein, a pharmaceutical composition or formulation comprises Compound 1 and other excipients such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents or maintaining release agents. refers to mixtures with means for controlling or controlling. A pharmaceutical composition can facilitate administration of Compound 1 to a subject, such as a mammal. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of Compound 1 is generally administered in a pharmaceutical composition to a subject having the disease, disorder or condition to be treated. A subject may be a mammal, such as a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the strength of the compound used and other factors. Compound 1 may be used singly or in combination with one or more therapeutic agents as components of mixtures. Compound 1 may be used as the sole therapeutic treatment or in combination with one or more therapeutic agents or treatment modalities in the treatment of disease states.

In some embodiments, pharmaceutical compositions comprising crystalline Compound 1 are formulated for solid oral administration. In other embodiments, pharmaceutical compositions comprising crystalline Compound 1 are formulated for other than oral administration. Pharmaceutical compositions described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, tablets, capsules, pills, Immediate release formulation, fast melt formulation, sustained release formulation, controlled release formulation, delayed release formulation, sustained release formulation, pulsatile release formulation, multiparticulate formulation or mixed immediate and controlled release formulations and formulations containing Accordingly, the pharmaceutical compositions described herein may be administered by, but not limited to, oral, parenteral (eg, intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal or transdermal administration. Subjects can be administered by multiple routes of administration, including routes.

Pharmaceutical compositions comprising Compound 1 can be prepared by, by way of example only, conventional mixing, micronizing, spray drying dispersion, nanoparticle forming, dissolving, granulating, dragee making, grinding, emulsifying, encapsulating, entrapping or compressing processes. may be manufactured in a conventional manner, such as by means of

The pharmaceutical compositions described herein include, but are not limited to, oral, parenteral (eg, intravenous, subcutaneous or intramuscular), buccal, intranasal, intrarectal or transdermal routes of administration. It may be formulated for administration to a subject (eg, mammal) via any conventional means.

Accordingly, one embodiment is a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, wherein 4-[2-(cyclopropyl Methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is processed by spray drying to provide a pharmaceutical composition wherein the solid matrix polymer is a polyvinylpyrrolidone derivative.

One embodiment is a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, wherein 4-[2-(cyclopropyl-methoxy )-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is processed by spray drying to provide a pharmaceutical composition wherein the solid matrix polymer is a cellulose derivative.

In another embodiment, the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is from about 1:1 to about 1:9. Certain pharmaceutical compositions are provided. Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methyl-sulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:1 do. Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methyl-sulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:2 do. Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropyl-methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:3 do. Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropyl-methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:4 do. Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclo-propylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:5 do. Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:6 . Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:7 . Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:8 . Another embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is 1:9 .

Another embodiment provides a pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethycellulose. Another embodiment provides a pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethycellulose phthalate. Another embodiment provides a pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethylcellulose acetate stearate. Another embodiment provides a pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethylcellulose acetate succinate. Another embodiment provides a pharmaceutical composition wherein 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is amorphous and the composition is prepared by SDD do.

[Dosage form]
Pharmaceutical compositions comprising Compound 1 described herein include, but are not limited to, solid oral dosage forms, controlled-release formulations, fast-dissolving formulations, effervescent formulations, tablets, powders, pills, capsules, delayed-release formulations. It can be formulated in any suitable dosage form, including formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations and mixed immediate and controlled release formulations.

Dosage forms for oral use are prepared by mixing at least one suitable solid excipient with at least Compound 1 and optionally grinding the resulting mixture to form granules, optionally tablets or sugar-coated. It can be obtained by processing a mixture of granules after adding suitable auxiliaries to obtain a shaped core. Suitable excipients include, for example, sugars including lactose, sucrose, mannitol or sorbitol; maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxy-methylcellulose. or pharmaceutically acceptable fillers such as polyvinylpyrrolidone (PVP or povidone) or other excipients such as calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Pharmaceutical preparations for oral use also include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules contain the active ingredients, i.e. Compound 1, in admixture with filler such as fillers such as lactose; binders such as starches; or lubricants such as talc or magnesium stearate; and, optionally, stabilizers. can be contained. In soft capsules, the active compound(s) may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Additionally, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

In some embodiments, the solid dosage forms disclosed herein are tablets (suspension tablets, fast-dissolving tablets, bite-disintegration tablets, rapid-disintegration tablets, effervescent tablets). tablets or caplets), pills, powders (including sterile packaged powders, dispensable powders, or effervescent powders), capsules (including both soft or hard capsules, e.g. from animal-derived gelatin or vegetable-derived HPMC). manufactured capsules, or "sprinkle capsules"), solid dispersions, solid solutions, bioerodible dosage forms, sustained release dosage forms, controlled release dosage forms, pulsatile release dosage forms, multiparticulate dosage forms or It may be in the form of pellets or granules, or it may be in the form of an aerosol. In other embodiments, the dosage form is a powder. In still other embodiments, the dosage form is in the form of a tablet, including, but not limited to, quick-dissolve tablets. Additionally, the dosage forms described herein may be administered as a single capsule or in multiple capsule dosage forms. In some embodiments, the dosage form is administered as 2 or 3 or 4 capsules or tablets.

In some embodiments, solid dosage forms such as tablets, effervescent tablets and capsules are prepared by mixing particles of Compound 1 with at least one pharmaceutical excipient to form a bulk blend composition. be done. When we refer to these bulk blend compositions as homogenous, it means that the particles of Compound 1 are evenly dispersed throughout the composition so that the composition is equally effective, such as tablets, pills and capsules. It means that it can be easily divided into unit dosage forms of Individual dosage forms also include film coatings that disintegrate upon ingestion or on contact with a diluent. These dosage forms can be manufactured by conventional pharmacological techniques.

Conventional pharmacological techniques include, for example: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation or (6) fusion. One or a combination of methods are included. See, for example, Lachman et al., THEORY & PRACTICE OF INDUS. PHARM. (Lea & Febiger, 1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluid bed spray drying or coating (e.g., wurster coating), tangential coating. ), top spray, tableting, extrusion, and the like.

Drug absorption is a complex process driven by numerous physicochemical factors. For example, particle size may play a major role in the absorption of slowly dissolving drugs. The dissolution rate of solid particles is often proportional to surface area, which is directly related to particle size. Dosage forms for oral use may be obtained by milling or other physical means to reduce the particle size of the API, excipients, or mixtures thereof. Atomization is the process of reducing the diameter of the particle size of a solid material. In at least one embodiment, Compound 1 is micronized. In some embodiments, micronized compound 1 is obtained by physical means such as milling or grinding. In other embodiments, atomized compound 1 is atomized via the Rapid Expansion of Supercritical _CO2 Solution (RESS) process. In some embodiments, micronized Compound 1 has particles of about 200 nm to about 600 nm, about 600 nm to about 1,000 nm, about 1,000 nm to about 1,400 nm, or about 1400 nm to about 1,800 nm. It has a size distribution. In some embodiments, Micronized Compound 1 is in crystalline Form A. In some embodiments, Micronized Compound 1 is amorphous.

At least one embodiment is a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, wherein 4-[2-(cyclopropyl A pharmaceutical composition is provided wherein methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is processed by spray drying.

One embodiment is a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, wherein 4-[2-(cyclopropylmethoxy) A pharmaceutical composition is provided wherein -5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is micronized by a RESS process.

Formulations for oral use may also be obtained by the use of spray drying, melt extrusion or thermodynamic mixing techniques. Typically, materials resulting from the use of spray drying techniques are dispersions of amorphous API within a solid matrix. The resulting solid dispersions exhibit increased drug surface area, reduced drug crystallinity, and can provide improved API stability during storage. Solid matrices are typically water-soluble or water-miscible organic or inorganic polymers.

Suitable matrix polymers include lactose, glucose, sucrose (e.g. Dipac®), dextrose, dextrin, molasses, mannitol, sorbitol, xylitol (e.g. Xylitab®), polysaccharide acids, microcrystalline glucose. cellulose preparations such as starch, corn starch, wheat starch, rice starch, pregelatinized starch potato starch, microcrystalline cellulose (e.g. Avicel®), larch arabogalactan; proteins such as gelatin natural or synthetic gums such as gum arabic, ghatti gum, mucus of isapol husks, gum tragacanth; methylcellulose, microcrystalline cellulose, croscarmellose, croscarmellose sodium, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, Ethylcellulose, Hydroxypropylcellulose (e.g. Klucel®), Ethylcellulose (e.g. Ethocel®), Hydroxypropylmethycellulose (HPMC), Hydroxypropylmethycellulose phthalate, Hydroxypropylmethylcellulose acetate stearate (HPMCAS), Crosslinked carboxymethylcellulose, methylcellulose (e.g. Methocel®), hydroxypropylmethylcellulose (e.g. hypromellose or Pharmacoat®), hydroxypropylmethylcellulose acetate stearate (HS-LF and HS), hydroxypropylmethylcellulose acetate Organic polymers such as succinate (AquaSolve (registered trademark), HPMC-AS), HPMCAS-L, HMPCAS-M, HPMCAS-H; polyvinyl acetate (PVA), polyvinyl acetate phthalate (PVAP), crospovidone (crosslinked polyvinyl N- pyrrolidone), polyvinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone (PVP, such as Povidone® CL, Kollidone® CL, Polyplasdone® XL-10, Povidone® K-12 ), synthetic polymers such as polyethylene glycol; or magnesium aluminum silicate (e.g. Veegum® standard) or from clays such as bentonite (absorbent aluminum phyllosilicate clay).

Processing steps such as feed solution preparation, feed solution atomization and spray drying inlet and outlet temperatures are optimized as is well known in the art. See, for example, REMINGTON'S PHARM. SCI., 20TH ED. (2000). In some embodiments, the pharmaceutical solid dosage forms described herein comprise Compound 1 processed by spray drying. In some embodiments, the dosage forms described herein comprise a solid matrix comprising Compound 1 incorporated into the solid matrix via spray drying dispersion.

The pharmaceutical solid dosage forms described herein comprise Compound 1 and compatible carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, humectants, antifoam agents, antioxidants, preservatives, or one or more thereof at least one pharmaceutically acceptable excipient such as a combination of In still other embodiments, a film coating is provided around the formulation of Compound 1 using standard coating procedures (eg, such as those described in REMINGTON'S, 2000). In one embodiment, some or all of the particles of Compound 1 are coated. In another embodiment, some or all of the particles of Compound 1 are microencapsulated. In yet another embodiment, none of the particles of Compound 1 are microencapsulated or coated.

Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate. , Sodium Caseinate, Soy Lecithin, Sodium Chloride, Tricalcium Phosphate, Dipotassium Phosphate, Sodium Stearoyl Lactylate, Carrageenan, Monoglycerides, Diglycerides, Pregelatinized Starch, Hydroxypropyl Methylcellulose, Hydroxypropyl Methylcellulose Acetate Stearate, Sucrose, Crystals. cellulose, lactose, mannitol and the like.

Suitable fillers for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, glucose, dextrate, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl-methycellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and the like.

In order to release the API from the solid dosage form matrix as efficiently as possible, disintegrants are often used in formulations, especially when the dosage form is compressed with a binder. Disintegrants help break up the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, native starches such as corn or potato starch, pregelatinized starches such as National 1551 or Amijel®. or sodium starch glycolate such as Promogel® or Explotab®, wood products, methyl microcrystalline cellulose, e.g. Avicel®, Avicel® PH101, Avicel® PH102, Avicel® ® PH105, Elcema ® P100, Emcocel ® , Vivacel ® , Ming Tia ® and Solka-Floc ® , methyl cellulose, cellulose such as croscarmellose, or Crosslinked sodium carboxymethylcellulose (Ac-Di-Sol (registered trademark)), crosslinked cellulose such as crosslinked carboxymethylcellulose or crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymer such as crospovidone and crosslinked polyvinylpyrrolidone, alginic acid alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum (registered trademark) HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin or tragacanth, sodium starch glycolate, bentonite , natural sponge, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like. In some embodiments provided herein, the disintegrant is native starch, pregelatinized starch, sodium starch, methyl microcrystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, cross-linked carboxymethylcellulose sodium, cross-linked carboxy It is selected from the group consisting of methyl cellulose, cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clays or gums. In some embodiments provided herein, the disintegrant is croscarmellose sodium.

Binders provide cohesiveness to a solid oral dosage form formulation. For example, in powder-filled capsule formulations, binders help form a plug that can be filled into a soft or hard shell capsule; Helps ensure blend uniformity prior to the filling step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., hypromellose). USP Pharmacoat-603, Hydroxypropyl Methylcellulose Acetate Stearate (Aqoate HS-LF and HS), Hydroxypropyl Methylcellulose Acetate Succinate (HPMC-AS), Hydroxyethylcellulose, Hydroxypropylcellulose (e.g. Klucel®), Ethylcellulose ( Ethocel (R)) and microcrystalline cellulose (e.g. Avicel (R)), microcrystalline glucose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonite, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, cloth Povidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars such as sucrose (e.g. Dipac®), glucose, glucose, molasses, mannitol, sorbitol, xylitol (e.g. Xylitab®), Natural or synthetic gums such as lactose, gum arabic, tragacanth, gum ghatti, issapol peel mucilage, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10 and Povidone (registered trademark) K-12), larch arabogalactan, Veegum (registered trademark), polyethylene glycol, wax, sodium alginate, and the like.

Generally, binder levels of 20% to 70% can be used in powder-filled gelatin capsule formulations. Binder usage levels in tablet formulations vary depending on the application, direct compression, wet granulation, roller compaction, or the use of other excipients such as fillers, which can act as moderate binders. Formulators in the art can determine binder levels for formulations, but binder levels of up to 70% are common in tablet formulations.

Suitable lubricants or glidants for use in the solid dosage forms described herein include stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, aluminum, calcium, magnesium Alkali metal and alkaline earth metal salts such as zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine , Carbowax (trademark), PEG4000, PEG5000, PEG6000 and other polyethylene glycols or methoxypolyethylene glycols, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, etc. . In some embodiments provided herein, the lubricant is stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate and selected from the group consisting of waxes; In some embodiments, the lubricant is magnesium stearate.

Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose and glucose), polysaccharides (including dextrates and maltodextrins), Polyols (including mannitol, xylitol and sorbitol), cyclodextrins and the like. In some embodiments provided herein, the diluent is lactose, sucrose, glucose, dextrate, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, crystalline Selected from the group consisting of cellulose, microcellulose and talc. In some embodiments provided herein the diluent is microcrystalline cellulose.

The term "water-insoluble diluent" includes calcium phosphate, calcium sulfate, starch, modified starch and microcrystalline and microcellulose (e.g. Avicel, powdered cellulose, having a density of about 0.45 g/ ^cm3 ) and talc and the like. , typically represent compounds used in pharmaceutical composition formulations and dosage forms.

Wetting agents suitable for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monolaurate. oleates, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (eg Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, doxate sodium, triacetin, vitamin E TPGS, and the like.

Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, Glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic (registered trademark) (BASF), and the like. In some embodiments provided herein, the surfactant is sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, polaxomers, bile salts, glyceryl monostearate, ethylene oxide and propylene oxide. is selected from the group consisting of copolymers with In some embodiments provided herein the surfactant is sodium lauryl sulfate.

Suitable suspending agents for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinyl-pyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, Polyethylene glycol, such as polyethylene glycol, which may have a molecular weight of about 300 to about 6000 or about 3350 to about 4000 or about 7000 to about 5400, vinylpyrrolidone/vinylacetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropyl Methylcellulose, polysorbate-80, hydroxyethylcellulose, hydroxypropylmethylcellulose acetate succinate (HPMCAS), sodium alginate, gums such as tragacanth gum and gum arabic, guar gum, xanthan such as xanthan gum, sugars such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose , hydroxypropylmethylcellulose, hydroxyethylcellulose, etc., polysorbate-80, sodium alginate, polyethoxylate sorbitan monolaurate, polyethoxylate sorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, tocopherols or tocotrienols.

It should be understood that there is considerable overlap in the excipients used in the solid dosage forms described herein. As such, the above-listed additives should be considered merely illustrative, and not limiting of the types of additives that may be included in the solid dosage forms described herein. The amounts of such additives can be readily determined by those skilled in the art depending on the specific properties desired.

In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, plasticizers are generally high boiling solids or liquids. Suitable plasticizers may be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate. and castor oil.

Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth include one or more flavoring agents. In other embodiments, compressed tablets include a film (ie, film coating) that encloses the final compressed tablet. In some embodiments, film coating can provide delayed release of Compound 1 from the formulation. In other embodiments, film coatings aid patient compliance (eg, Opadry® coatings or sugar coatings to facilitate oral administration). Film coatings typically include Opadry® in the range of about 1% to about 3% by weight of the tablet. As noted, in some embodiments compressed tablets comprise one or more additional excipients.

Capsules may be prepared, for example, by placing a bulk blend of a formulation of Compound 1 within a capsule. In some embodiments, formulations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules, such as capsules containing HPMC. In other embodiments, the formulation may be placed in sprinkle capsules, where the capsule may be swallowed whole, or the capsule may be opened and the contents sprinkled onto food prior to ingestion. In some embodiments, the therapeutic dose is divided into multiple (eg, 2, 3, or 4) capsules. In some embodiments, the entire dose of formulation is delivered in capsule form.

In various embodiments, particles of Compound 1 and one or more excipients are dry blended and substantially disintegrate within a predetermined time frame following oral administration, thereby: less than about 30 minutes, about 35 minutes hardness sufficient to provide a pharmaceutical composition that releases the formulation into gastrointestinal fluids in less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, etc. is compressed into a mass such as a tablet having a

In another aspect, the dosage form may comprise a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulated material. Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, defoamers, antioxidants, flavoring agents, as well as binders, suspending agents, disintegrants, fillers, surfactants, carrier materials such as agents, solubilizers, stabilizers, lubricants, wetting agents and diluents. Materials useful for microencapsulation include materials compatible with Compound 1 that sufficiently isolate Compound 1 from other incompatible excipients or formulation components.

Materials that are compatible with Compound 1 microencapsulation include those that delay the in vivo release of Compound 1. Exemplary microencapsulation materials useful for delaying release of formulations containing compounds described herein include, but are not limited to, Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers Hydroxypropyl cellulose ethers (HPC) such as (L-HPC), Seppifilm-LC, Pharmacoat®, Metrorose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843. Methylcellulose polymers such as Hydroxypropyl methylcellulose ether (HPMC), Methocel®-A, Hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Metolose®, E461, Ethocel ®, Aqualon®-EC, Surelease® and mixtures thereof, polyvinyl alcohols (PVA) such as Opadry AMB, hydroxyethyl-celluloses such as Natrosol®. , carboxymethylcellulose and salts of carboxymethylcellulose (CMC) such as Aqualon®-CMC, polyvinyl alcohols and polyethylenes such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starches Glycol Copolymer, Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100 , Eudragit RD100, Eudragit E100, Eudragit L12.5, Eudragit S12.5, Eudragit NE30D and Eudragit NE40D and mixtures of acrylic polymers and cellulose ethers, cellulose acetate phthalate, Sepifilm such as mixtures of HPMC and stearic acid, cyclodextrin, if and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols such as PEG300, PEG400, PEG600, PEG1450, PEG3350 and PEG800, stearic acid, propylene glycol, oleic acid and triacetin are incorporated into the microencapsulation material. In other embodiments, microencapsulation materials useful for delaying release of pharmaceutical compositions are those from the USP or National Formulary (NF). In still yet other embodiments, the microencapsulation material is Klucel™ hydroxypropylcellulose. In still other embodiments, the microencapsulation material is Methocel™ cellulose ether.

Microencapsulated compound 1 can be formulated by methods well known to those skilled in the art. Such well-known methods include, for example, spray drying processes, rotating disk solvent processes, hot melt processes, spray cooling methods, fluidized beds, electrostatic deposition, centrifugal extrusion, rotary suspension separation, liquid-gas or solid-gas interfaces. polymerization, pressure extrusion or spray solvent extraction. In addition to these, several chemical techniques such as complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid medium, in situ polymerization, drying in liquid and desolvation in liquid medium. may also be used. Other methods such as roller compaction, extrusion/spheronization, coacervation or nanoparticle coating may also be used.

In one embodiment, the particles of Compound 1 are microencapsulated prior to formulation into one of the forms described above. In yet another embodiment, some or most of the particles are coated prior to further formulation using standard coating procedures such as those described in REMINGTON'S, 2000).

In other embodiments, the solid dosage formulation of Compound 1 is coated with one or more layers. Illustratively, plasticizers are generally high boiling solids or liquids. Suitable plasticizers may be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate. and castor oil.

In other embodiments, powders containing formulations comprising Compound 1 may be formulated to include one or more pharmaceutical excipients and flavoring agents. Such powders may be prepared, for example, by mixing the formulation with optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include suspending and/or wetting agents. This bulk blend is evenly divided into unit dose packages or multi-dose package units.

In some embodiments, a pharmaceutical formulation is provided comprising particles of Compound 1 and at least one dispersion or suspension agent for oral administration to a subject. The formulations may be powders or granules for suspension, which on admixture with water gives a substantially uniform suspension.

Because a given additive is often classified differently by different practitioners in the art, or commonly used for any of several different functions, the aqueous dispersions described herein It is understood that there is overlap between the above-listed additives used in substances or suspensions. Accordingly, the additives listed above should be understood as merely exemplary, rather than limiting, of the types of additives that may be included in the formulations described herein. The amounts of such additives can be readily determined by those skilled in the art according to the specific properties desired.

[Bromodomain inhibitor]
Chromatin is a complex of DNA and proteins that make up the chromosomes. Histones are the major protein components of chromatin and act as spools around which DNA winds. Changes in chromatin structure are affected by covalent modifications of histone proteins and by non-histone binding proteins. Several classes of enzymes are known to modify histones at various sites.

Epigenetics is the study of genetic changes in gene expression caused by mechanisms other than the underlying DNA sequence. Molecular mechanisms that play a role in epigenetic regulation include DNA methylation and chromatin/histone modifications.

Eukaryotic genomes are highly organized within the nucleus of the cell. An extraordinary compaction is required to package the 3 billion nucleotides of the human genome into the cell nucleus where chromosomes reside in complexes of nucleic acids and proteins called chromatin. Histones are the most important protein components of chromatin. There are a total of six classes of histones (H1, H2A, H2B, H3, H4 and H5) divided into two classes: core histones (H2A, H2B, H3 and H4) and linker histones (H1 and H5). The basic unit of chromatin is the nucleosome, which contains approximately 147 base pairs of DNA wrapped around a core histone octamer containing two copies each of core histones: H2A, H2B, H3 and H4. These nucleosome units are then further organized and compacted by aggregation and folding of nucleosomes to form a highly condensed chromatin structure. A variety of different states of compaction are possible, with chromatin structural rigidity varying during the cell cycle and being most compact during the process of cell division.

Chromatin structure therefore plays an important role in the regulation of gene transcription, and gene transcription cannot occur efficiently in highly condensed chromatin. Chromatin structure is regulated by a series of post-translational modifications into histone proteins, particularly histones H3 and H4, most commonly into the 'histone tail' that extends from the core nucleosome structure. These post-translational modifications include acetylation, methylation, phosphorylation, ribosylation-sumoylation, ubiquitination, citrullination, deimination and biotinylation. The histone tails as well as the core of histones H2A and H3 can be modified. Considering the function of histones in chromatin, histone modifications are essential for diverse biological processes such as gene expression, DNA replication, DNA repair and chromosome condensation.

[Histone acetylation and bromodomains]
Histone acetylation is generally associated with the activation of gene transcription, as it is well known that by altering the electrostatic state the modification abolishes the interaction of DNA with histone octamers. In addition to this physical change, certain proteins are known to bind to acetylated lysine residues within histones in order to function according to the epigenetic code. Bromodomains are small (approximately 110 amino acids) distinct domains within proteins that commonly, but not exclusively, bind acetylated lysine residues in the context of histones. Approximately 50 proteins are known to contain bromodomains, which have various functions within the cell.

The BET family of bromodomain-containing proteins consists of four proteins (BRD2, BRD3, BRD4 and BRD-t). Bromodomain-containing proteins (such as BET and non-BET proteins) that recognize acetylated lysines on histones have been implicated in proliferative diseases. For example, homozygous BRD4 knockout mice are impaired in their ability to maintain the inner cell mass and die shortly after embryo transfer, while heterozygous BRD4 knockout mice are prenatal and postnatal with reduced proliferation rate. indicate growth failure. BRD4 regulates genes expressed during M/Gl, including proliferation-related genes, and remains bound to chromatin throughout the cell cycle. Dey, et al., 20 Mol. Biol. Cell 4899 (2009). BRD4 also physically associates with mediators and P-TEFb (a heterodimer of cyclin-dependent kinase 9 [CDK9], cyclin K, cyclin T or cyclin T2a or T2b) to promote transcriptional elongation. . Yang et al., 24 Oncogene 1653 (2005); Yang et al., 19 Mol. Cell 535 (2005). CDK9 is associated with c-Myc-dependent transcription and is thereby a validated target in chronic lymphocytic leukemia (CLL). Phelps et al., 113 Blood 2637 (2009); Rahl et al., 141 Cell 432 (2010).

Furthermore, BRD4 is translocated to a nuclear protein (NUT protein) in the testis in patients with lethal midline carcinoma, an invasive form of human squamous cell carcinoma. French et al., 159 Am. J. Pathol. 1987 (2001). In vitro analysis using RNAi supports that BRD4 plays a causative role in the recurrent chromosomal transition t(15;19)(q13;p13.1) that defines lethal midline carcinoma. there is French et al., 63 Cancer Res. 304 (2003). Similarly, inhibition of the BRD4 bromodomain has been found to result in growth arrest/differentiation of BRD4-NUT cell lines in vitro and in vivo. Filippakopoulos et al., Selective Inhibition of BET Bromodomains, 468 Nature 1067 (2010).

Bromodomain-containing proteins (such as BET proteins) are also associated with inflammatory diseases. BET proteins (eg, BRD2, BRD3, BRD4 and BRDT) control the assembly of histone acetylation-dependent chromatin complexes that regulate inflammatory gene expression. Hargreaves et al., 138 Cell 129 (2009); LeRoy et al., 30 Molec. Cell 51 (2008); Jang et al., 19 Molec. Cell 523 (2005); (2005). Key inflammatory genes (secondary response genes) are downregulated upon bromodomain inhibition of the BET subfamily, and non-responsive genes (temporary response genes) remain transcriptionally primed. BET bromodomain inhibition prevents LPS-induced endotoxic shock and bacteria-induced sepsis in vivo. Nicodeme et al., Suppression of Inflammation by a Synthetic Histone Mimic, 468 Nature 1119 (2010).

Bromodomain-containing proteins (such as BET proteins) have also been found to play a role in viral infections. For example, BRD4 is associated with the onset and duration of basal epithelial human papillomavirus (HPV) infection, and BRD4 binding maintains the viral genome as an extrachromosomal episome. In some strains of HPV, BRD4 binding to the HPV transcriptional activator protein, E2 (early protein 2), tethers the viral genome to infected cell chromosomes. BRD4-E2 binding is important both for transactivating E2 and for repressing transcription of two HPV oncoproteins, early protein 6 [E6] and early protein 7 [E7]. Disruption of BRD4 or BRD4-E2 interactions blocks E2-dependent gene activation. BRD4 also functions to tether other classes of viral genomes (eg, herpesvirus, Epstein-Barr virus) to the chromatin of infected cells. Kurg, in DNA REPLICATION - CURRENT ADVANCES 613 (Seligmann, ed., InTech, Rijeka, Croatia, 2011).

Bromodomain-containing proteins have also been found to bind to acetylated lysine residues on proteins other than histones. For example, the bromodomain of CREB-binding protein transcriptional coactivator (CBP) allows recognition of p53 with acetylated Lys382. Interaction between the bromodomain and acetyl-p53 promotes p53-induced transcriptional activation of the CDK inhibitor p21 and cell cycle arrest following DNA damage.

Another novel bromodomain-containing protein is BAZ2B, whose biological functions are believed to function similarly to ACF1, the Drosophila BAZ2B orthologue. The ACF complex plays a role in establishing constant nucleosome spacing during chromatin assembly and influencing different remodeling outcomes at target loci.

One embodiment provides a method of regulating gene transcription in a cell comprising contacting a bromodomain-containing protein with a compound of Compound 1. Another embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyllysine region of a protein comprising contacting the bromodomain with a compound of Compound 1.

[Pharmaceuticals and methods of treatment]
Compositions described herein are generally useful for inhibiting the activity of one or more proteins involved in epigenetic regulation. Thus, at least one embodiment provides a bromodomain (e.g., BET proteins such as BRD2, BRD3, BRD4 or BRDT, and CBP, ATAD2A, GCN5L) by contacting a cell or intracellular chromatin with Compound 1. , BAZ2B, FALZ, TAF1 or BRPF1) or variants thereof, which are known to modulate epigenetic regulation mediated by one or more proteins containing an acetyl-lysine recognition motif. offer. In at least one embodiment, bromodomains (e.g., BET proteins such as BRD2, BRD3, BRD4 or BRDT and CBP, ATAD2A, GCN5L, BAZ2B, FALZ, Methods are provided for modulating epigenetic regulation mediated by one or more proteins containing an acetyl-lysine recognition motif, also known as non-BET proteins such as TAF1 or BRPF1) or variants thereof. In some embodiments, the bromodomain-containing protein is a BET protein. In some embodiments, the BET protein is BRD4.

In some embodiments, BET proteins (BRD2, BRD3, BRD4 or BRDT), non-BET proteins (CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1), by contacting a cell or chromatin within a cell with Compound 1. or BRPF1, etc.) or mutants thereof. Some embodiments comprise administering to the subject a pharmaceutical composition comprising Compound 1. , TAF1 or BRPF1) or mutants thereof. In some embodiments, the bromodomain-containing protein is a BET protein. In some embodiments, the BET protein is BRD4.

In some embodiments, BET proteins (BRD2, BRD3, BRD4 or BRDT), non-BET proteins (CBP, ATAD2A, GCN5L, Methods of inhibiting the activity of bromodomain-containing proteins such as BAZ2B, FALZ, TAF1 or BRPF1) or variants thereof are provided. In some embodiments, the bromodomain-containing protein is a BET protein. In some embodiments, the BET protein is BRD4.

Diseases and conditions treatable by the methods of the invention include cancer, neoplastic diseases and other proliferative disorders. Accordingly, one aspect is a method of treating a subject with cancer, neoplastic disease, and other proliferative disorders, the method comprising administering a pharmaceutical composition comprising Compound 1 to the subject. In one embodiment, a human patient is treated with a pharmaceutical composition comprising Compound 1 described herein, wherein Compound 1 is active in the subject with a bromodomain-containing protein activity (BRD2, BRD3, BRD4 or BRDT). etc.) is present in an amount that is effective to measurably inhibit.

The invention further provides methods of treating a subject, such as a human, suffering from cancer, neoplastic disease, or other proliferative disorder. methods by inhibiting bromodomains (e.g., BRD4) and generally modulating gene expression thereby inducing various cellular effects, specifically induction or suppression of gene expression, cell growth arrest; administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising compound 1 described herein that functions by inducing cell differentiation or inducing apoptosis.

The present invention provides treatment for cancer, neoplasia by administering an effective amount of a pharmaceutical composition comprising Compound 1 described herein to a mammal, specifically a human, in need of such treatment. It further relates to methods for treating or ameliorating a disease or another proliferative disorder. In some aspects of the invention, the disease treated by the methods of the invention is cancer.

One embodiment involves administering to a patient a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one requiring A method of treating cancer in a patient is provided, wherein the pharmaceutical composition is prepared by a process comprising spray drying dispersion.

At least one embodiment provides a medicament for treating cancer, neoplastic disease or other proliferative disorders, the medicament comprising Compound 1 as described herein. A medicament may comprise a pharmaceutical composition comprising Compound 1 and a polymer matrix. The medicament may comprise a pharmaceutical composition wherein Compound 1 is Amorphous Compound 1 or Form A Compound 1. A medicament may comprise a pharmaceutical composition in which Compound 1 is micronized.

In some embodiments, the cancer treated by a medicament comprising Compound 1 is NUT midline cancer, prostate cancer, breast cancer, bladder cancer, lung cancer or melanoma. In some embodiments, the cancer is Burkitt's lymphoma. In some embodiments, the cancer is glioblastoma (GBM), basal cell carcinoma, pancreatic cancer, multiple myeloma, or acute myelogenous leukemia (AML).

[Example]
The following components, formulations, processes and procedures for practicing the methods disclosed herein correspond to those described above. Other embodiments and uses will be apparent to those skilled in the art in light of this disclosure. The examples that follow are provided merely as illustrations of various embodiments and should not be construed as limiting the invention in any way.

[Example 1]
Synthesis of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one (Compound 1) Unless otherwise noted, reagents and solvents were obtained from Acros Organics ( Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall , UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals ( Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany) ), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD) and Wako Chemicals USA, Inc. (Richmond, VA). obtained from and used.

Methods well known to those skilled in the art are revealed through various reference books and databases. Suitable reference books and treatises provide references to articles detailing the synthesis or describing the preparation of reactants useful in the preparation of the compounds described herein. For example, SYNTHETIC ORGANIC CHEM. (John Wiley & Sons, Inc., NY); Sandler et al., ORGANIC FUNCTIONAL GROUP PREPARATIONS (2nd Ed., Acad. Press, NY, 1983); HOUSE, MODERN SYNTHETIC REACTIONS (2nd Ed. Benjamin, Inc., Menlo Park, CA, 1972); Gilchrist, HETEROCYCLIC CHEM. (2nd Ed., John Wiley & Sons, NY, 1992); March, ADV. ORGANIC CHEM.: REACTIONS, MECH. & STRUCTURE ( 4th Ed., Wiley-Intersci., NY, 1992). Additional suitable reference books and treatises detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide references to articles describing such preparations. For example, Fuhrhop & Penzlin, ORGANIC SYNTHESIS: CONCEPTS, METHODS, STARTING MATERIALS: SECOND, REVISED & ENLARGED ED. (John Wiley & Sons ISBN: 3-527-29074-5, 1994); Hoffman, ORGANIC CHEM., AN INTERMEDIATE TEXT (Oxford Univ. Press, ISBN 0-19-509618-5, 1996); Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS: GUIDE TO FUNCTIONAL GROUP PREPARATIONS (2nd Ed., Wiley-VCH, ISBN: 0-471-19031-4, 1999) ；Otera (Ed.), MODERN CARBONYL CHEM. (Wiley-VCH, ISBN: 3-527-29871-1, 2000)；Patai, PATAI'S 1992 GUIDE TO THE CHEM. OF FUNCTIONAL GROUPS (Intersci. ISBN: 0-471- 93022-9, 1992); Solomons, ORGANIC CHEM. (7th Ed., John Wiley & Sons, ISBN: 0-471-19095-0, 2000); Stowell, INTERMEDIATE ORGANIC CHEM. ORGANIC CHEM.: STARTING MATS. & INTERMEDIATES: AN ULLMANN'S ENCYCLO. (John Wiley & Sons, ISBN: 3-527-29645-X, 1999), in 8 vols.; ORGANIC REACTIONS (John Wiley & Sons, 1942-2000), in over 55 volumes; CHEM. OF FUNCTIONAL GROUPS (John Wiley & Sons), in 73 volumes.

Specific and analogous reactants are available in most public and university libraries and through online databases (for further details contact the American Chemical Society, Washington, DC) the Chemical Abstract Service of the American Chemical It is also revealed through an index of well-known chemicals produced by the Society. Chemicals that are well known but not commercially available in catalogs can be prepared by custom chemical synthesis companies where a number of standard chemical suppliers (eg, those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the substituted heterocyclic derivative compounds described herein is Stahl & Wermuth, HANDBOOK OF PHARMACEUTICAL SALTS (Verlag Helvetica Chimica Acta, Zurich, 2002).

本明細書において開示される置換複素環誘導体化合物の合成のための追加的方法は、当業者に容易に利用可能である。 General methods for the synthesis of substituted heterocyclic derivatives include, but are not limited to, the following references: WO 2009/158396; WO 2005/63768; WO 2006/112666; Briet et. al., 58 Tetrahedron 5761 ( WO 2002); WO 2008/77550; WO 2008/77551; WO 2008/77556; WO 2007/12421; WO 2007/12422; 3860 (1999); WO 2004/29051; and US 2009/0054434. Further examples of the synthesis of substituted heterocyclic derivatives are found in the following references.

Additional methods for synthesizing the substituted heterocyclic derivative compounds disclosed herein are readily available to those of ordinary skill in the art.

For the synthesis of compound 1, anhydrous solvents and oven-dried glassware were used for moisture or oxygen sensitive synthetic transformations. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise stated. Spectra are given in ppm (δ) and coupling constants (J) are reported in Hertz. The solvent peak was used as the reference peak for the ¹ H NMR spectra.

Step 1: 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one

4-bromo-2-methylisoquinolin-1-one (100 mg, 0.42 mmol), bis(pinacolato)diboron (214 mg, 0.84 mmol), Pd(dppf)Cl ₂ (31 mg) in dioxane (2 mL) under nitrogen. , 0.04 mmol) and potassium acetate (104 mg, 1.05 mmol) was heated to 90° C. for 135 minutes. The mixture was then cooled to room temperature (RT) and diluted with ethyl acetate (8 mL). The mixture was washed with an aqueous saturated solution of NaHCO ₃ (8 mL) and brine (8 mL). The organic phase was separated, _dried over _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (10%-90% EtOAc/hexanes) to give the title compound (44 mg, 37%).
1H NMR (CDCl3, 400 MHz) δ 8.43 (d, J=7.9 Hz, 1H), 8.40 (dd, J=8.2 Hz, 0.9 Hz, 1H), 7.68 (s, 1H), 7.65 (ddd, J=8.2 , 8.2, 1.1 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 3.63 (s, 3H), 1.38 (s, 12H). LCMS: 286 (M+H)+

Step 2: 4-[2-(Cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one in dioxane (1.15 mL) under N ₂ for about 3 min. (51 mg, 0.14 mmol), 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene (30 mg, 0.13 mmol), 1 M K ₃ PO ₄ (0.3 mL) in water and Pd(dppf)Cl ₂ (10 mg, 0.013 mmol), then microwaved at 100° C. for 1 h, then filtered through a plug of anhydrous Na ₂ SO ₄ using ethyl acetate for transfer and rinse. Purification by silica gel chromatography, eluting with 5% to 50% EA in hexanes over 4 minutes and continuing with 50% isocratic EA gave the title compound.
¹ H NMR (DMSO-d6, 400 MHz) δ 0.09 (m, 2H), 0.29 (m, 1H), 0.35 (m, 1H), 0.94 (m, 1H), 3.22 (s, 3H), 3.57 (s , 3H), 3.95 (m, 2H), 7.16 (d, J=7.9 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.53 (m, 2H), 7.65 (t, J=7.6 Hz , 1H), 7.81 (d, J=2.4 Hz, 1H), 7.97 (dd, J=8.8, 2.4 Hz, 1H), 8.30 (d, J=8.1 Hz, 1H). LCMS: 384 (M+H) ⁺

Alternatively, 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one can be prepared as follows.
Step 1: 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one

4-bromo-2-methylisoquinolin-1-one (8.0 g, 33.6 mmol), bis(pinacolato)diboron (17.1 g, 67.2 mmol), KOAc (6.6 g, 67.2 mmol), Pd ₂ (dba) ₃ (3.1 g, 3.36 mmol) and X-Phos (1.6 g, 3.36 mmol) was stirred at 60° C. for 12 hours. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (PE:EA=15:1) to give the title compound (6.0 g, 62%) as a solid.

Step 2: 4-[2-(Cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound from step 1 (5.0 g, 17.5 mmol), 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene (6.4 g, 21 mmol), K ₃ PO ₄ (9.3 g, 43.9 mmol) and Pd(dppf)Cl ₂ (1.4 g, 1.75 mmol) were stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EA:DCM=1:4). Appropriate fractions were combined and concentrated under reduced pressure. The solid obtained was recrystallized from DCM/MTBE (1:1, 50 mL) to give the title compound (4.0 g, 60%) as a white solid.
1H NMR: (CDCl3, 400 MHz) δ 8.51 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 7.98 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.86 (d, J= 2.4 Hz, 1H), 7.53 (m, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.10 (m, 2H), 3.88 (m, 2H), 3.66 (s, 3H), 3.09 (s, 3H), 1.02-0.98 (m, 1H), 0.44-0.38 (m, 2H), 0.11-0.09 (m, 2H). LCMS: 384.1 (M+H)+.
See also US patent application Ser. No. 14/517,705.

Example 2 In Vitro Enzyme Inhibition Assay An _IC50 determination for the heterocyclic derivative BRD4 inhibitor Compound 1 was performed as follows. His-tagged BRD4 was cloned, expressed and purified to homogeneity. Filipakopoulos et al., 468 Nature 1067-73 (2010). Monitoring BRD4 binding and inhibition of biotinylated H4-tetraacetyl peptide (AnaSpec, H4K5/8/12/16(Ac), biotin-labeled) interaction with target using AlphaScreen technology (Life Technologies) evaluated by BRD4 (BD1) (2 nM final) in 384-well ProxiPlates in 50 mM HEPES (pH 7.3), 10 mM NaCl, 0.25 mM TCEP, 0.1% (w/v) BSA and 0.005% (w/v) Brij Peptides (15 nM final) were combined in -35 in the presence of either DMSO (0.4% DMSO final) or a dilution series of compound 1 in DMSO. After incubation for 20 minutes at RT, alpha-streptavidin donor beads and nickel chelate acceptor beads were added to a final concentration of 5 μg/mL. After 2 hours of equilibration, plates were read on the Envision instrument and _IC50s were calculated using a 4-parameter non-linear curve fit. The ability of compound 1 to inhibit BRD4 activity was quantified and relative _IC50 values were determined. For comparison, a related compound, 2-methyl-4-phenylisoquinolin-1-one, had an IC ₅₀ of 2.782 μM in this assay. Compound 1, as shown in Table 1, exhibited IC ₅₀ values of ≦0.5 μM in this assay.

Example 3 In Vitro Cell-Based Assay A colorimetric cell proliferation assay (cellular MTS assay) was performed for the heterocyclic derivative BRD4 inhibitors disclosed herein to affect the proliferation of established cancer cell lines. Conducted to assess performance.

Assay principle:
The cellular MTS assay is a 7-day plate-based colorimetric assay that quantifies the amount of newly generated NADH in the presence or absence of test compounds. NADH levels are used for quantification of cancer cell proliferation.

Assay method:
Established cancer cell lines with different driving mutations were obtained from the American Type Culture Collection (ATCC) and routinely passaged according to ATCC protocols. For routine assays, these cells were seeded at a density that allowed approximately 90% confluence after 7 days of culture. Raji, human Burkitt's lymphoma cells (cMYC) were seeded at 15,000 cells per 96 wells. HL-60, human pro-leukemic cells (NRAS, p16, p53, c-Myc amplification) were seeded at 5,000 cells per 96 wells. NCI-H460, human non-small cell lung cancer cells (KRAS, PIK3CA, STLK11, p16) were seeded at 3,000 cells per 96 wells. Plated cells were incubated for 24 hours, after which cells received 11-point dilutions of Compound 1 at final concentrations ranging from 100 μM to 2.0 nM. Cells were incubated in the presence of drugs for 168 hours at 37°C, 5% _CO2 . At the end of this incubation period, 80 μL of medium was removed and 20 μL of CellTiter96® AQueous Non-Radioactive Cell Proliferation Assay assay solution (Promega) was added. Cells were incubated until OD ₄₉₀ >0.6 was reached. _IC50 values were calculated using the IDBS XLfit software package, including background-subtracted _OD490 values and normalization to DMSO control. Cell proliferation IC ₅₀ values were uploaded and recorded using the Chem Biography Platform. Table 1 provides the results of in vitro enzyme inhibition assay experiments and in vitro cell-based assay experiments performed with Compound 1.

Example 4 Preparation of Crystalline Form A Compound 1 A pure fraction was collected from silica gel column chromatography purification of Compound 1 (60:40 Hex/EtOAc to 100% EtOAc), filtered through a polish filter, Concentrate to about 800 mL-1000 mL. The resulting slurry was filtered and washed with a mixture of Hex/EtOAc (50:50, 2x200 mL). The sputum yellow solid was dried under vacuum at room temperature to give 128.6 g of purified Compound 1.

Compound 1 (140.6 g) in filtered THF (840 mL) was placed in a 3-liter, 3-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, heating mantle and nitrogen inlet. The slurry was heated to 40-45°C and held for 1 hour. The slurry was then filtered and the solids washed twice with THF (100 and 50 mL). The solid was dried in vacuum at 30-35° C. to give 128.4 g of crystalline Compound 1.

Example 5a XRPD Studies of Compound 1 The XRPD patterns were also obtained from Bruker using CuKα radiation (40 kV, 40 mA), θ-2θ goniometer and V4 divergence and receiving slits, Ge monochromator and Lynxeye detector. Collected on an AXS D8 Advance diffractometer. The software used for data collection was Diffrac Plus XRD Commander v2.6.1 and data were analyzed and presented using Diffrac Plus EVA v15.0.0.0.

Samples were run under ambient conditions as flat plate specimens using the powder as received. The sample was gently packed into a recess cut into a polished zero-background (510) silicon wafer. The sample was rotated in its own plane during analysis. Data collection details are: angular range: 2 2-theta to 42 degrees 2-theta; step size: 0.05 degrees 2-theta; collection time: 0.5 sec/step. FIG. 1 shows the XRPD diffractogram of Form A Compound 1. FIG. Significant XRPD reflection peaks at, but not limited to, 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6 and 24.5 peak.

Example 5b XRPD Study of Amorphous Compound 1 Crystalline Compound 1 (516 mg) was dissolved in dichloromethane (11 mL). Solvent was removed under vacuum (40° C., 30 mbar). The residual solid was further dried under vacuum (25° C., 0 mbar) for 30 minutes and analyzed by XRPD. The XRPD diffractogram shows no diffraction peaks. 2 shows the XRPD diffractogram of amorphous Compound 1. FIG.

Example 6 Differential Scanning Calorimetry (DSC) Studies of Form A Compound 1 DSC data were collected on a Mettler DSC 823E equipped with a 34-position autosampler. The instrument was calibrated for energy and temperature using certified indium. Typically, 0.5 mg to 5 mg (eg, 4.877 mg) of each sample was heated from 25° C. to 350° C. at 10° C./min in a pinhole aluminum pan. A nitrogen purge at 50 mL/min was maintained across the sample. Instrument management and data analysis software is STARe v12.1. Wg ⁻¹ , Integral −599.85 mJ normalized −122.99 Jg ⁻¹ . Onset is shown at 224.33° C.; a sharp endotherm due to melting of the sample is seen at 224.95° C. and illustrated in FIG.

Example 7 Gravimetric Vapor Sorption (GVS) Studies of Form A Compound 1 Sorption isotherms were controlled by DVS Intrinsic Control software v1.0.1.2 (or v1.0.1.3). were obtained using an SMS DVS Intrinsic moisture sorption analyzer. The sample temperature was maintained at 25°C by instrument control. Humidity was controlled by mixed flows of dry and wet nitrogen at a total flow rate of 200 mL/min. Relative humidity was measured by a calibrated Rotronic probe (dynamic range 1.0% RH to 100% RH) positioned near the sample. Sample weight change (mass relaxation) as a function of %RH was constantly monitored by a microbalance (accuracy ±0.005 mg).

Typically 5-20 mg of sample was placed in a tared mesh stainless steel basket at ambient conditions. Samples were loaded and removed at 40% RH and 25°C (typical room conditions). Standard isotherms were performed at 25° C., 10% RH, intervals spanning the range 0% RH to 90% RH. Data analysis was performed using Microsoft Excel using the DVS Analysis Suite v6.2 (or 6.1 or 6.0). FIG. 4 illustrates a graph of adsorption isotherm data.

Example 8 Aqueous Solubility Study of Form A Compound 1 Using the kinetic shake flask method, the solubility of Compound 1 Form A in 50 mM phosphate buffer, pH=7.4 was determined. determined to be between 2.6 μg/mL and 3.7 μg/mL.

Example 9 Pharmacokinetic Study to Determine Dose Proportionality in Rats Following Oral Administration of Crystalline Form A of Compound 1 It produced non-linear exposure levels (AUC 0-24 hours) when administered orally to female Sprague Dawley rats at 10 mg/kg, 30 mg/kg, 100 mg/kg or 300 mg/kg as a suspension in 5% HPMC. An overview of this research is illustrated in Fig. 5.

Example 10 Preparation of Spray-Dried Dispersion of Compound 1 A spray-dried dispersion (SDD) was prepared by adding a solution of compound 1 in dichloromethane to polyvinylpyrrolidone (PVP K12 PF) or hydroxypropylmethylcellulose (Methocel E5 LV). either with either a 1:1 or 1:3 ratio of compound 1:polymer, resulting in four unique combinations, and then each preparation was run through a lab-scale Buchi Spray Dryer (Buchi B290). outlet T° 57°C; aspirator 100%; nozzle air 30 mm; pump speed 25%; set-up: open loop).

Example 11 PK Study to Determine Plasma Exposure Levels in Mice 6 Hours After Oral Administration of Various SDD Preparations of Compound 1 Determining Plasma Exposure Levels of Four SDDs Prepared as Described Above For this purpose, each preparation was orally administered as a suspension in 0.5% MC to female CD-1 mice. FIG. 6 illustrates the results of this experiment. wrap up:
In compositions containing PVP polymer at a compound 1:polymer ratio of 1:1, compound 1 had an average AUC of 0-6 hours, 7,193 hr ng/mL.
In compositions containing PVP polymer at a compound 1:polymer ratio of 1:3, compound 1 had a mean AUC of 0-6 hours, 8,872 hr ng/mL.
In compositions containing HPMC polymer at a Compound 1:polymer ratio of 1:1, Compound 1 had an average AUC of 0-6 hours, 10,484 hr ng/mL.
In compositions containing HPMC polymer at a Compound 1:polymer ratio of 1:3, Compound 1 had an average AUC of 0-6 hours, 24,430 hr ng/mL.

Example 12 Preparation of SDD of Compound 1 Containing HPMC in a Compound 1:polymer Ratio of 1:3 Prepared by mixing in a 1:3 compound 1:polymer ratio, stirring the mixture overnight and then spray drying using a lab-scale Buchi spray dryer.

Example 13 XRPD Study of Compound 1 as SDD with HPMC FIG. 7.

Example 14 PK Study to Determine Dose Proportionality in Rats or Dogs After Oral Administration of Compound 1 SDD Compound 1 prepared as 25% Compound 1:HPMC SDD as described in Example 12 was , showed approximate dose proportionality through the dose range 10 mg/kg to 300 mg/kg when administered as an oral dosage form (0.5% methylcellulose (MC) suspension) to female Sprague Dawley rats. The results are shown in Figure 8a. Approximate dose proportionality was administered to male beagle dogs as an oral dosage form (0.5% MC suspension) with Compound 1 prepared as 25% Compound 1:HPMC SDD as described in Example 12. Cases have been demonstrated over a dose range of 1 mg/kg to 10 mg/kg. The results are shown in Figure 8b.

Example 15 Preparation of SDD of Compound 1 Using Various Grades of HPMCAS A Spray Dried Dispersion (SDD) was prepared by mixing a solution of Compound 1 in (90:10) acetone:water with hydroxypropyl methylcellulose acetate succinate M or H. (HPMCAS-M or HPMCAS-H) at either a 1:9 or 1:3 compound 1:polymer ratio, and each preparation was then run through a custom bench-scale Lab Spray Dryer (BLD-35; process Parameters: inlet T° 93-109°C; outlet T° 42-43°C; atomization pressure 110 psi; feed rate 29 g/min; glass flow rate 450 g/min).

Example 16 PK Study to Determine Plasma Exposure Levels in Rats Following Oral Administration of Various SDD Preparations of Compound 1 To determine plasma exposure levels of the three SDDs prepared as described above , each of them at 10 mg/kg (based on compound 1) to female Sprague Dawley rats as a suspension in 0.5% MC for 10% HPMCAS-M SDD or 25% HPMCAS-M and 25% HPMCAS -H SDD was administered orally as a suspension in 0.5% Methocel A4M/0.5% HPMCAS-HF/20 mM Tris, pH 7.4. FIG. 9 illustrates the results of this experiment. In compositions containing HPMCAS-M polymer at a Compound 1:polymer ratio of 1:9, Compound 1 had a mean AUC of 0-24 hours, 28,069 hr ^* ng/mL. In compositions containing HPMCAS-M polymer at a Compound 1:polymer ratio of 1:3, Compound 1 had a mean AUC of 0-24 hours, 24,558 hr ^* ng/mL. In compositions containing HPMCAS-H polymer at a Compound 1:polymer ratio of 1:3, Compound 1 had a mean AUC of 0-24 hours, 27,469 hr ^* ng/mL.

Example 17 Preparation of Spray-Dried Dispersion of Compound 1 Containing HPMCAS-H A spray-dried dispersion (SDD) was prepared by mixing a solution of Compound 1 in (90:10) acetone:water with hydroxypropyl methylcellulose acetate succinate (HPMCAS-H). HG) at a compound 1:polymer ratio of either 1:1, 1:2.85 or 1:3, then each preparation was run through a custom bench-scale Lab Spray Dryer (Bend Research BLD-35; Process parameters: inlet T 84-94° C.; outlet T 40-42° C.; atomization pressure 120 psi; nozzle-pressure rotation/Schlick 2.0; solution spray rate 25 g/min; It was prepared by spray drying using

Example 18 Immediate Release Tablets Containing 10 mg of Compound 1 Immediate release tablets containing 10 mg of Compound 1 were generally prepared as follows. The ingredients listed in Table 2 (below) were blended, sieved, and blended again prior to granulation. The blended ingredients were granulated using a dry granulation process. The dry granulated material was then blended with the extragranular material. The blended material was compressed into tablets using a 6mm SRC (standard round concave) tooling.

Example 19 Immediate Release Tablets Containing 100 mg of Compound 1 One version of immediate release tablets containing 100 mg of Compound 1 was prepared generally as follows. The ingredients listed in Table 3 (below) were blended, sieved and blended again prior to granulation. The blended ingredients were granulated using a dry granulation process. The dry granulated material was then blended with the extragranular material. The blended materials were compressed into tablets using a concave modified oval tool (9.1 mm x 18.1 mm).

Example 20 Immediate Release Tablets Containing 200 mg of Compound 1 One version of immediate release tablets containing 200 mg of Compound 1 is prepared as follows. The ingredients listed in Table 4 (below) were blended, sieved and blended again prior to granulation. The blended ingredients are granulated using a dry granulation process. The dry granulated material is then blended with the extragranular material. The blended materials are then compressed into tablets.

Claims (15)

A 4- A pharmaceutical composition comprising a micronized form of [2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one. 2. The pharmaceutical composition of Claim 1 , wherein the pharmaceutical composition comprises at least one solid matrix polymer. 3. The pharmaceutical composition according to claim 2 , wherein the solid matrix polymer is polyvinylpyrrolidone or a polyvinylpyrrolidone derivative. 3. A pharmaceutical composition according to claim 2 , wherein the solid matrix polymer is a cellulose derivative. 5. The pharmaceutical composition according to claim 4 , wherein the cellulose derivative is hydroxypropylmethicellulose. 5. The pharmaceutical composition according to claim 4 , wherein the cellulose derivative is hydroxypropylmethycellulose phthalate. 5. The pharmaceutical composition according to claim 4 , wherein the cellulose derivative is hydroxypropylmethylcellulose acetate stearate. 5. The pharmaceutical composition according to claim 4 , wherein the cellulose derivative is hydroxypropylmethylcellulose acetate succinate. A pharmaceutical composition according to any one of claims 1 to 8 , wherein the pharmaceutical composition has been processed by spray drying. 3. A method according to claim 2 , wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is from 1:1 to 1:9. pharmaceutical composition. Ratios of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer of 1:1, 1:2, 1:3, 1:4, 1 3. The pharmaceutical composition according to claim 2 , which is selected from: :5, 1:6, 1:7, 1:8 or 1:9. Use of a pharmaceutical composition according to any one of claims 1-11 for the preparation of a medicament for the treatment of cancer or other neoplastic diseases. 13. Use of the pharmaceutical composition according to claim 12 , wherein the cancer is nuclear protein in testicular (NUT) midline carcinoma (NMC), prostate cancer, breast cancer, bladder cancer, lung cancer, or melanoma. 13. Use of the pharmaceutical composition according to claim 12 , wherein the cancer is Burkitt's lymphoma. 13. Use of the pharmaceutical composition according to claim 12 , wherein the cancer is glial basal cell tumor (GBM), basal cell carcinoma, pancreatic cancer, multiple myeloma, or acute myelogenous leukemia (AML).

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