TW201316989A - Compositions and methods for treating polycythemia vera and essential thrombocythemia - Google Patents

Abstract

Provided herein are compositions and methods for treating polycythemia vera (PV) and/or essential thrombocythemia (ET) in a subject. The methods comprise administering to the subject an effective amount of compound which is which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt or a hydrate thereof.

Description

Composition and method for treating true plethremia and primary thrombocytosis

Provided herein are compositions and methods for treating plethora of dysplasia and/or essential thrombocytopenia. The compositions and methods provided herein are directed to the treatment of true plethora and/or essential thrombocytopenia with a compound that inhibits JAK2, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

Cross-reference to related applications

This application claims the application of the United States Provisional Application No. 61/510,406, filed on July 21, 2011, and the US Provisional Application No. 61/510,409, filed on July 27, 2011, and the application filed on February 27, 2012 The priority rights of the French application No. 1251749, filed on Feb. 27, 2012, the content of each of which is hereby incorporated by reference in its entirety.

True plethora ("PV") is a selective stem cell disease that belongs to three typical BCR-ABL-negative myeloproliferative sputum with myelofibrosis ("MF") and essential thrombocytopenia ("ET"). Tumor ("MPN"). True plethora affects the proliferation of red blood cell line, bone marrow cell line and megakaryocyte cell line, mainly leading to increased blood volume ratio, increased white blood cells and increased thrombocytosis. In addition, patients with PV suffer from splenomegaly and disease-related symptoms such as itching, night sweats, fatigue and bone pain. If PV is still progressive under standard therapy, it can lead to increased risk of thromboembolism, hemorrhage, and progression to MF or even acute myeloid leukemia. The JAK2 kinase mutation (JAK2V617F) can be found in BCR-ABL negative typical MPN. Levine RL et al., Cancer Cell. 2005, 7(4): 387- 97. This mutation is present in more than 90% of patients with PV. This genetic aberration and other MPN-associated mutations directly (eg, MPL mutations) or indirectly (eg, LNK or CBL) cause the above-mentioned disease-related symptoms. Pardanani AD et al, Blood. 2006, 108: 3472-3476; Scott LM et al, N Engl J Med. 2007, 356: 459-468.

Standard therapies for PV include bloodletting and low-dose aspirin. Hydroxyurea therapy can also be considered for high risk PV. Barbui T et al, J Clin Oncol 2011, 29(6): 761-70. PV patients treated with hydroxyurea may become intolerant of hydroxyurea or become a person with resistance to hydroxyurea. Patients with high-risk PV and intolerance to hydroxyurea or PV with resistance to hydroxyurea have therapeutic needs.

Primary thrombocytopenia ("ET") is a selective stem cell disease that belongs to three typical BCR-ABL-negative myeloproliferative tendons as well as myelofibrosis ("MF") and true plethora ("PV"). Tumor ("MPN"). Primary thrombocytopenia is characterized by megakaryocyte proliferation and continuous thrombocytosis. In addition, patients with ET suffer from splenomegaly and disease-related symptoms (such as itching, night sweats, fatigue, and bone pain). If ET is still progressive under standard therapy, it can lead to increased risk of thromboembolism, hemorrhage, and progression to MF or even acute myeloid leukemia. JAK2 kinase (JAK2V617F) mutations can be found in BCR-ABL negative typical MPN. Levine RL et al, Cancer Cell. 2005, 7(4): 387-97. This mutation is present in almost half of patients with ET. This genetic aberration and other MPN-associated mutations directly (eg, MPL mutations) or indirectly (eg, LNK or CBL) cause the above-mentioned disease-related symptoms. Pardanani AD et al, Blood. 2006, 108: 3472-3476; Scott LM et al, N Engl J Med. 2007, 356: 459-468.

Standard therapies for ET include the use of hydroxyurea in high-risk ETs. Low dose aspirin therapy can also be considered for ET. Barbui T et al, J Clin Oncol 2011, 29(6): 761-70. ET patients treated with hydroxyurea may become intolerant to hydroxyurea or resistant to hydroxyurea. Patients with ET who are intolerant of hydroxyurea or have hydroxyurea-resistant ET have therapeutic needs.

All references, including patent applications and publications, cited herein are hereby incorporated by reference in their entirety.

Provided herein is a method of treating a true plethora (PV) in a subject, the method comprising administering to the individual an effective amount of the compound N-t-butyl-3-[(5-methyl-2-{[4-(2) - pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein the individual has PV , wherein an effective amount of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine-4- The hydrazinium sulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is from about 50 mg to about 400 mg per day, and the weight specified therein is the free base portion weight of the compound. In some embodiments, the dose is administered orally.

In some embodiments, the individual has a PV that is resistant to hydroxyurea or a patient is intolerant to hydroxyurea treatment. In some embodiments, the individual has PV, and there is no myelofibrosis (MF) or acute myeloid leukemia (AML). In some embodiments, the individual has an increased risk of developing MF. Example In particular, an individual may have one or more risk factors selected from the group consisting of: 1) having PV for at least 15 years, 2) having a homozygous JAK2 V617F mutant dual gene, and 3) having elevated serum lactate dehydrogenation Enzyme content, and 4) have endogenous megakaryocyte community formation. In some embodiments, the individual has been previously treated with another JAK2 inhibitor, such as Ruxolitinib. In some embodiments, the individual is selected for treatment based on one or more of the following criteria: (i) the individual has PV resistant to hydroxyurea or the patient is intolerant to hydroxyurea treatment; (ii) the individual suffers There is PV, there is no myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the individual has been previously treated with another JAK2 inhibitor (such as rosolinib); and (iv) the individual has increased Risk of developing MF, for example, an individual may have one or more risk factors selected from the group consisting of: 1) having PV for at least 15 years, 2) having a homozygous JAK2 V617F mutant dual gene, and 3) having Elevated serum lactate dehydrogenase content, and 4) endogenous megakaryocyte community formation. In some embodiments, the methods described herein can further comprise the step of determining whether the individual satisfies one or more of the above criteria prior to treatment.

In some embodiments, the methods described herein further comprise monitoring a JAK2V617F mutant dual gene in a blood cell of an individual. In some embodiments, the blood cells are granulocytes. In some embodiments, the JAK2V617F mutation in the granulocytes of the individual is monitored. In some embodiments, the methods further comprise monitoring the degree of STAT3 phosphorylation in the blood cells.

In some embodiments, the dose or amount administered (such as a dose or amount administered orally) is about 50 mg per day, 100 mg per day, 200 mg per day or per dose. Any of the days 400 mg. In some embodiments, the compound is administered over a period of at least 32 weeks. In some embodiments, the compound is provided in a capsule comprising the following: (i) the compound N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidine)- 1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or hydrate thereof, (ii) microcrystalline cellulose, and Iii) Sodium stearyl fumarate wherein the hybrid is contained in a capsule. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base portion weight of the compound.

In some embodiments, the methods further comprise directing the individual to fasting up an effective amount of the compound. In some embodiments, the methods further comprise directing the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP3A4. In some embodiments, the methods further comprise directing the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP2C19.

Also provided herein is a method of treating essential thrombocytopenia (ET) in a subject, the method comprising administering to the individual an effective amount of the compound N-t-butyl-3-[(5-methyl-2-{[4 -(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the individual Having ET, wherein an effective amount of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine The 4-amino)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is from about 50 mg to about 400 mg per day, and the weight specified therein is the free base portion weight of the compound. In some embodiments, the compound is administered orally.

In some embodiments, the individual is resistant to treatment with hydroxyurea ET or individual intolerance to hydroxyurea treatment. In some embodiments, the individual has ET and there is no myelofibrosis (MF) or acute myeloid leukemia (AML). In some embodiments, the individual has an increased risk of developing MF. In some embodiments, the individual has been previously treated with another JAK2 inhibitor, such as rosolinib. In some embodiments, the individual is selected for treatment based on one or more of the following criteria: (i) the individual has ET or individual intolerance to hydroxyurea treatment; (ii) the individual With ET, there is no myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the individual has an increased risk of developing MF; and (iv) the individual has previously been treated with another JAK2 inhibitor (such as Russo Litini) is treated. In some embodiments, the methods described herein can further comprise the step of determining whether the individual satisfies one or more of the above criteria prior to treatment.

In some embodiments, the methods described herein further comprise monitoring a JAK2V617F mutant dual gene in a blood cell of an individual. In some embodiments, the blood cells are granulocytes. In some embodiments, the methods further comprise monitoring the degree of STAT3 phosphorylation in the blood cells.

In some embodiments, the dose or amount administered (such as an orally administered dose or amount) is about 50 mg per day, 100 mg per day, 200 mg per day, or 400 mg per day. In some embodiments, the compound is administered over a period of at least 32 weeks. In some embodiments, the compound is provided in a capsule comprising the following: (i) the compound N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidine)- 1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or hydrate thereof, (ii) microcrystalline cellulose, and Iii) Sodium stearyl fumarate, wherein the mixture is contained in a capsule in. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base portion weight of the compound.

In some embodiments, the methods further comprise directing the individual to fasting up an effective amount of the compound. In some embodiments, the methods further comprise directing the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP3A4. In some embodiments, the methods comprise directing the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP2C19.

Also provided herein is a kit or article comprising (a) a compound N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)benzene) Amino]pyrimidin-4-yl)amino]benzenesulfonamide, a pharmaceutically acceptable salt thereof or hydrate thereof, and (b) a package insert or label indicating i) a compound suitable for use in therapy An individual having a true plethora and ii) orally administering to the individual a dose of from about 50 mg to about 400 mg per day, wherein the indicated weight is the free base portion weight of the compound.

In some embodiments, the package insert or label indicates a dose of 50 mg per day, 100 mg per day, 200 mg per day, or 400 mg per day. In some embodiments, the package insert or label indicates administration of the compound over a period of at least 32 weeks. In some embodiments, the compound is in a capsule comprising the following hybrid: (i) compound N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidine-1) -ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or hydrate thereof, (ii) microcrystalline cellulose, and (iii a stearin sodium fumarate in which the hybrid is contained in a capsule. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base portion weight of the compound.

In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual having a PV resistant to hydroxyurea treatment, or the compound is suitable for treating an individual having PV, wherein the individual is intolerant to hydroxyurea treatment . In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual having PV, no MF or AML. In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual at increased risk of developing MF. In some embodiments, the individual has at least one risk factor selected from the group consisting of: 1) having PV for at least 15 years, 2) having a homozygous JAK2 V617F mutant dual gene, and 3) having elevated serum lactate dehydrogenation Enzyme content, and 4) have endogenous megakaryocyte community formation. In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual who has been previously treated with another JAK2 inhibitor, such as rosolinib.

In some embodiments, the package insert or label directs the individual to take an effective amount of the compound on an empty stomach. In some embodiments, the package insert or label directs the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP3A4. In some embodiments, the methods further comprise directing the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP2C19.

Also provided herein is a kit or article comprising (a) a compound N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)benzene) Amino]pyrimidin-4-yl)amino]benzenesulfonamide, a pharmaceutically acceptable salt thereof or hydrate thereof, and (b) a package insert or label indicating i) a compound suitable for use in therapy The individual having primary thrombocytopenia and ii) orally administering the compound to the individual at a dose of from about 50 mg to about 400 mg per day, wherein the indicated weight is the free base portion weight of the compound.

In some embodiments, the package insert or label indicates a dose of 50 mg per day, 100 mg per day, 200 mg per day, or 400 mg per day. In some embodiments, the package insert or label indicates administration of the compound over a period of at least 32 weeks. In some embodiments, the compound is in a capsule comprising the following hybrid: (i) compound N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidine-1) -ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or hydrate thereof, (ii) microcrystalline cellulose, and (iii a stearin sodium fumarate in which the hybrid is contained in a capsule. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base portion weight of the compound.

In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual having an ET that is resistant to hydroxyurea treatment or for treating an individual who is intolerant to hydroxyurea treatment. In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual having ET, no MF or AML. In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual at increased risk of developing MF. In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual who has been previously treated with another JAK2 inhibitor, such as rosolinib.

In some embodiments, the package insert or label directs the individual to take an effective amount of the compound on an empty stomach. In some embodiments, the package insert or label directs the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP3A4. In some embodiments, the package insert or label directs the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP2C19.

Also provided herein is the use of a compound for the manufacture of a medicament for treating plethora (PV) in a subject, wherein the compound is N-t-butyl-3-[(5-methyl-2-{[4- (2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the individual has PV, wherein the compound is administered to the subject in an amount of from about 50 mg to about 400 mg per day, and wherein the weight specified is the weight of the free base portion of the compound. In some embodiments, the use is in accordance with any of the methods of treating PV provided herein. For example, in some embodiments, the compounds are for oral administration. In some embodiments, the individual has a PV that is resistant to hydroxyurea treatment. In some embodiments, the individual is intolerant to hydroxyurea treatment. In some embodiments, the individual has an increased risk of developing myelofibrosis. In some embodiments, the individual has at least one risk factor selected from the group consisting of: 1) having PV for at least 15 years, 2) having homozygous binding to the JAK2 V617F mutant dual gene, and 3) having elevated serum lactate Dehydrogenase content, and 4) have endogenous megakaryocyte community formation. In some embodiments, the individual has been previously treated with another JAK2 inhibitor, such as rosolinib. In some embodiments, the treating further comprises monitoring the JAK2V617F mutant dual gene in the granulocytes of the individual. In some embodiments, the treating further comprises monitoring the degree of STAT3 phosphorylation in the blood cells. In some embodiments, the blood cells are granulocytes. In some embodiments, the compound is administered orally in a dose or amount of about 50 mg, 100 mg, 200 mg, or 400 mg per day. In some embodiments, the compound is administered orally for a period of at least 32 weeks. In some embodiments, the compound, such as when administered for administration, is in a capsule comprising the following hybrid: (i) compound N-t-butyl-3-[(5-methyl-2-{[ 4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii Microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the hybrid is contained in a capsule. In some embodiments, the capsules contain about 50 mg or about 100 mg of the compound, wherein the specified weight is the free base portion weight of the compound. In some embodiments, the treating further comprises directing the individual to fasting up an effective amount of the compound. In some embodiments, the treating further comprises directing the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP3A4. In some embodiments, the treating further comprises directing the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP2C19. In some embodiments, the individual has PV, and there is no myelofibrosis (MF) or acute myeloid leukemia (AML). In some embodiments, the compound is in a pharmaceutical composition, for example, comprising N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy). A pharmaceutical composition of phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof and a pharmaceutically acceptable carrier. In some embodiments, the compound is N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine 4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

Also provided herein is the use of a compound for the manufacture of a medicament for treating essential thrombocytopenia (ET) in a subject, wherein the compound is N-t-butyl-3-[(5-methyl-2-{[ 4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the individual Having ET wherein the compound is administered to the subject in an amount from about 50 mg to about 400 mg per day, and wherein the weight specified is the weight of the free base portion of the compound. In some embodiments, the use is in accordance with any of the methods of treating ET provided herein. For example, in some embodiments, the compounds are for oral administration. In some embodiments, the individual has an ET that is resistant to hydroxyurea treatment. In some embodiments, the individual is intolerant to hydroxyurea treatment. In some embodiments, the individual has an increased risk of developing myelofibrosis. In some embodiments, the individual has been previously treated with another JAK2 inhibitor, such as rosolinib. In some embodiments, the treating further comprises monitoring the JAK2V617F mutant dual gene in the granulocytes of the individual. In some embodiments, the treating further comprises monitoring the degree of STAT3 phosphorylation in blood cells of the individual. In some embodiments, the blood cells are granulocytes. In some embodiments, the compound is administered orally in a dose or amount of any of about 50 mg, 100 mg, 200 mg, or 400 mg per day. In some embodiments, the compound is administered orally for a period of at least 32 weeks. In some embodiments, the compound, such as when administered for administration, is in a capsule comprising the following hybrid: (i) compound N-t-butyl-3-[(5-methyl-2-{[ 4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii Microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the hybrid is contained in a capsule. In some embodiments, the capsules contain about 50 mg or about 100 mg of the compound, wherein the specified weight is the free base portion weight of the compound. In some embodiments, the treating further comprises directing the individual to fasting up an effective amount of the compound. In some embodiments, the treating further comprises directing the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP3A4. In some embodiments, the treating further comprises directing the individual to avoid ingesting an agent that is at least a moderately inducing agent or inhibitor of CYP2C19. In some embodiments, the individual has ET, no myelofibrosis (MF) or acute myeloid leukemia. In some embodiments, the compound is in a pharmaceutical composition, for example, comprising N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy). A pharmaceutical composition of phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof and a pharmaceutically acceptable carrier. In some embodiments, the compound is N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine 4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

Also provided herein are compounds for the treatment of true plethora (PV) in an individual wherein the compound is N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidine-)- 1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein the individual has PV, wherein the compound is in a daily An individual is administered to an individual in an amount from about 50 mg to about 400 mg, and wherein the weight specified is the weight of the free base portion of the compound. In some embodiments, the use is in accordance with any of the methods of treating PV provided herein. In some embodiments, the compounds are for oral administration. In some embodiments, the compound is N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine 4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

Also provided herein are compounds for the treatment of essential thrombocytopenia (ET) in an individual wherein the compound is N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrole) a pyridin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the individual has ET, wherein the compound The individual is administered in an amount of from about 50 mg to about 400 mg per day, and the weight specified therein is the free base portion weight of the compound. In some embodiments, the use is in accordance with any of the methods of treating ET provided herein. In some embodiments, the compounds are for oral administration. In some embodiments, the compound is N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine 4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

It will be appreciated that one, some or all of the properties of the various embodiments described herein can be combined to form other embodiments of the compositions and methods provided herein. These and other aspects of the compositions and methods provided herein will become apparent to those skilled in the art.

I. Definition

As used herein, "treatment" or "treating" is a method of obtaining beneficial results or desired results, including clinical outcomes. The beneficial or desired clinical outcome may include, but is not limited to, one or more of the following: reducing the symptoms caused by the disease, improving the quality of life of the patient suffering from the disease, reducing the dosage of other drugs needed to treat the disease, and delaying the progression of the disease, And/or prolong the survival of the individual.

As used herein, "delaying the onset of a disease" means deferring, hindering, slowing, retarding, stabilizing, and/or delaying the occurrence of a disease or disease symptom. This delay may vary for a length of time depending on the medical history and/or the individual being treated. As is apparent to those skilled in the art, a full or significant delay may actually encompass prevention, wherein the individual is not ill.

As used herein, an "effective amount" or "effective amount" of a pharmaceutical, compound or pharmaceutical composition is an amount sufficient to achieve a beneficial result or desired result. For prophylactic use, beneficial results or desired results can include, for example, one or more of the following results: such as elimination or reduction of the disease (including biochemical symptoms of the disease, histological and/or behavioral symptoms, complications thereof, and presentation during the onset of the disease) The intermediate pathological phenotype) risks reducing the severity of the disease or delaying the onset of the disease. For therapeutic use, beneficial results or desired results can include, for example, one or more of the following clinical outcomes: such as reducing one or more symptoms and pathological conditions caused by or associated with the disease, improving the quality of life of the patient suffering from the disease, reducing The dosage of other drugs needed to treat the disease, such as enhancing the effect of another drug via targeting, delaying disease progression, and/or prolonging survival. The effective dose can be administered in one or more administration forms. An effective amount of a drug, compound or pharmaceutical composition can be, for example, an amount sufficient to effect a prophylactic or therapeutic treatment, either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound or pharmaceutical composition can be achieved with or without the combination of another drug, compound or pharmaceutical composition. Thus, an "effective dose" can be considered in the case of administration of one or more therapeutic agents, and if the desired result is achieved or achieved in combination with one or more other agents, a single agent can be administered in an effective amount.

In some embodiments of treating PV, an effective dose results in a decrease in blood volume ratio. In some embodiments, the effective dose is such that after 8 treatment cycles are completed, the blood volume ratio is below 45% for at least 3 months in the absence of bleeding. In some embodiments, the effective dose results in a blood volume ratio of <45% in the absence of exsanguination, or a response of 3 or more of the other criteria. In some embodiments, the effective dose causes one or more of the following: i) a blood volume ratio of <45% in the absence of bleeding; ii) a platelet count 400 × 10 ⁹ / L; iii) white blood cell count 10 × 10 ⁹ / L; iv) normal spleen size during imaging; v) disease-related symptoms (such as microvascular disorders, itching, headache) are absent or reduced.

In some embodiments of treating ET, the effective dose is such that the platelet count is completed after 8 treatment cycles are completed. 400 × 10 ⁹ / L for a minimum of 3 months. In some embodiments, the effective dose causes one or more of the following reactions: i) platelet count 400×10 ⁹ /L; ii) disease-related symptoms (such as microvascular disorders, itching, headache) are absent or reduced; iii) normal spleen size during imaging; iv) white blood cell count 10 × 10 ⁹ / L.

As used herein, "combined" refers to performing another mode of treatment in addition to one mode of treatment. Thus, "joining" may refer to performing another mode of treatment before, during, or after performing a treatment mode on an individual.

As used herein, "patient" or "individual" refers to a mammal, including a human, a dog, a horse, a cow or a cat.

The term "pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and can be administered to the subject.

As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by the manufacture of its acid or base salt.

The singular forms "a", "the" and "the"

References herein to "about" values or parameters include (and describe) embodiments that are themselves directed to the value or parameter. For example, mention the description package "about X" Includes a description of the "X".

It is to be understood that the aspects and variations of the compositions and methods provided herein may include "consisting of the forms and variations" and/or "consisting essentially of the aspects and variations."

II. Compounds and pharmaceutical compositions

Provided herein is a compound N - tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl) Amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof. Also provided herein is a pharmaceutical composition comprising N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino} Pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable excipient or carrier. The compounds and pharmaceutical compositions described herein are useful for treating or delaying the onset of plethora (PV) and/or essential thrombocytopenia (ET) in an individual. N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino] Phenylsulfonamide has the following chemical structure:

The compounds provided herein can be formulated into the therapeutic compositions in either natural or salt form. Pharmaceutically acceptable non-toxic salts include base addition salts (formed with free carboxyl groups or other anionic groups) which can be derived from inorganic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, hydroxide Calcium or ferric hydroxide) and organic bases (such as isopropylamine, trimethylamine, 2-ethylamino) Ethanol, histidine, procaine and its analogs). The salts may also form an acid addition salt with any free cationic group and will typically be combined with a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid or an organic acid such as acetic acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid. Oxalic acid, tartaric acid, mandelic acid and the like are formed together.

Salts of the compounds provided herein may include amine salts formed by protonating an amine with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the compounds provided herein may also include amine salts formed by protonating an amine with a suitable organic acid such as p-toluenesulfonic acid, acetic acid, methanesulfonic acid, and the like. Other excipients intended to be used in the practice of the compositions and methods provided herein are excipients available to those of ordinary skill, such as United States Pharmacopeia, Volume XXII, and National Formulary, Section XVII. Excipients are disclosed in U.S. Patent No. Pharmacopeia Convention, Inc., Rockville, Md. (1989), the disclosure of which is incorporated herein by reference.

Furthermore, the compounds provided herein can include polymorphs. The compounds described herein may be in alternative forms. For example, the compounds described herein can include hydrated forms. As used herein, "hydrate" means a compound provided herein and the form of the molecular form of water (i.e., wherein the H-OH bond is not broken) associated, for example, and can be represented by the formula RH ₂ O, wherein R is herein The compound provided. A given compound may form more than one hydrate, including, for example, a monohydrate (RH ₂ O); or a polyhydrate (R.nH ₂ O, where n is an integer greater than 1), including, for example, a dihydrate (R.2H _{2 )} O), trihydrate (R.3H ₂ O) and analogs thereof; or fractional hydrates such as Rn/2H ₂ O, Rn/3H ₂ O, Rn/4H ₂ O and the like, wherein n is an integer .

The compounds described herein may also include the acid hydrate form. As used herein, "acid hydrate" means by association of a compound having one or more base moieties with at least one compound having one or more acid moieties or via having one or more acid moieties. a complex formed by association of a compound with at least one compound having one or more base moieties, the complex further associated with a water molecule to form a hydrate, wherein the hydrate is as previously defined and R represents The above complex.

In some embodiments, the compound is N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino} Pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate and has the following chemical structure:

Pharmaceutical compositions for administration of the compounds described herein, alone or in combination with other therapeutic agents, may be presented in unit dosage form and may be applied by the methods well known in the art of pharmacy and described in the PCT/ filed on Nov. 10, 2010. It is prepared by any of the methods of US2010/056280 (Publication No. WO 2012/060847) and Example 4 of US Patent No. 61/410,924, filed on Nov. 7, 2010. Such methods can include associating the active ingredient with a carrier which comprises one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and finely bringing the active ingredient to a liquid carrier or finely pulverizing the solid carrier or The two are associated, and then (if necessary) the product is shaped into the desired formulation for preparation. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of the disease. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, in the form of a hard capsule or a soft capsule.

Provided herein are capsules for oral administration comprising the following hybrids: (i) compound N - tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidine)- 1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) an excipient (for example, microcrystals) Cellulose), and (iii) a lubricant (such as stearin fumarate), wherein the hybrid is contained in a capsule. Capsules can be made using methods known in the art and described herein. See, for example, Example 3 herein, and Example 5 of PCT/US2010/056280 (Publication No. WO 2012/060847) filed on Nov. 10, 2010, and U.S. Patent No. 61/410,924, filed on Nov. 7, 2010. The capsules can also be made according to the method of Example 5 of PCT Application No. PCT/US2011/059643 (Publication No. WO 2012/061833), filed on Nov. 7, 2011. Microcrystalline cellulose can be used as a filler and/or diluent in the capsules provided herein. Sodium stearyl fumarate can be used as a lubricant in the capsules provided herein. In some embodiments, the microcrystalline cellulose is deuterated microcrystalline cellulose. For example, deuterated microcrystalline cellulose can be composed of microcrystalline cellulose and colloidal ceria particles. In some embodiments, the deuterated microcrystalline cellulose is a combination of 98% microcrystalline cellulose and 2% colloidal ceria.

In some embodiments, the capsules may contain from about 10 mg to 680 mg of the compound, wherein the specified weight is the free base portion weight of the compound. In some embodiments, the capsules contain from about 10 mg to about 650 mg. In some embodiments, the capsules contain from about 100 mg to about 600 mg. In some embodiments, the capsules contain from about 200 mg to about 550 mg. In some embodiments, the capsules contain from about 300 mg to about 500 mg. In some embodiments, the capsules contain about 10 mg, about 20 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400. Mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 650 mg of the compound. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the compound is N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine 4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

In some embodiments, the weight ratio of the compound in the capsule to the microcrystalline cellulose (such as deuterated microcrystalline cellulose) is between about 1:1.5 and about 1:15 (eg, between about 1:5 and about 1:10). Between about 1:5 to about 1:12, or between about 1:10 and about 1:15), wherein the weight of the compound is the weight of the free base portion of the compound. In some embodiments, the weight ratio of the compound in the capsule to the sodium stearyl fumarate is between about 5:1 and about 50:1 (eg, between about 5:1 and about 10:1, at Between about 5:1 and about 25:1, between about 5:1 and about 40:1, between about 7:1 and about 34:1, or between about 8:1 and about 34:1 Wherein the weight of the compound is the weight of the free base portion of the compound.

In some embodiments, the capsules comprise from about 5% to about 50% (eg, from about 5% to about 10% or from about 5% to about 35%) of the total weight of the compound of the compound, wherein the weight of the compound is the free base of the compound. Partial weight. In some implementations In one embodiment, the capsules comprise from about 40% to about 95% (eg, from about 50% to about 90% or from about 60% to about 90%) microcrystalline cellulose (such as deuterated microcrystalline cellulose) of the total fill weight of the capsule. In some embodiments, the capsules comprise from about 0.2% to about 5% (eg, from about 0.2% to about 2% or from about 0.5% to about 1.5%, or from about 0.5%, about 1%, or about 1.5%) of the total filling weight of the capsule. ) stearin bismuth sodium dibutoxide.

Also provided herein are unit dosage forms comprising the following hybrids: (i) 50 mg or 100 mg of the compound N -t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidine)- 1-ethylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the specified weight is the free base portion of the compound Weight, (ii) excipients (eg, microcrystalline cellulose) and (iii) lubricants (eg, stearin fumarate). In some embodiments, the unit dosage form is in the form of a capsule and the hybrid is contained in a capsule. In some embodiments, the compound is N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine 4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

In some embodiments, the weight ratio of the compound to the microcrystalline cellulose (such as deuterated microcrystalline cellulose) in a unit dosage form is between about 1:1.5 and about 1:15 (eg, between about 1:5 and about 1:10) Between about 1:5 to about 1:12, or between about 1:10 and about 1:15), wherein the weight of the compound is the weight of the free base portion of the compound. In some embodiments, the weight ratio of the compound to the stearin sodium fumarate in the unit dosage form is between about 5:1 and about 50:1 (eg, between about 5:1 and about 10:1, Between about 5:1 and about 25:1, between about 5:1 and about 40:1, between about 7:1 and about 34:1, or between about 8:1 and about 34:1 Between) wherein the weight of the compound is the weight of the free base portion of the compound.

In some embodiments, the capsules comprise from about 5% to about 50% (eg, from about 5% to about 10% or from about 5% to about 35%) of the total weight of the compound, wherein the weight of the compound is the free base of the compound. Partial weight. In some embodiments, the capsule contains from about 40% to about 95% (eg, from about 50% to about 90% or from about 60% to about 90%) microcrystalline cellulose (such as deuterated microcrystalline cellulose) based on the total weight of the hybrid. ). In some embodiments, the capsules comprise from about 0.2% to about 5%, such as from about 0.2% to about 2% or from about 0.5% to about 1.5%, or from about 0.5%, about 1%, or about 1.5%, by total weight of the hybrid. ) stearin bismuth sodium dibutoxide.

III. Methods for treating and preventing true plethora

Provided herein are methods for treating, delaying, and/or preventing PV in a subject, the method comprising administering to the subject an effective amount of a compound N -t-butyl-3-[(5-methyl-2-{[4 -(2-Pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof. In some embodiments, the individual has PV and has not progressed to MF or AML. In some embodiments, the individual has an increased risk of developing MF. In some embodiments, the individual has a PV that is resistant to or resistant to hydroxyurea. In some embodiments, the individual is a human individual. In some embodiments, an effective amount of N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino} Pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is from about 50 mg to about 400 mg per day, and the weight specified therein is the free base portion weight of the compound.

Methods for diagnosing various types of PV are known in the art. PV diagnosis can be based on revised World Health Organization (WHO) guidelines. See Vardiman et al, Blood 114: 937-51, 2009. PV diagnosis may require the existence of two primary criteria and one secondary criterion or the existence of a first primary criterion and two secondary criteria. The main criteria include: 1) hemoglobin is greater than 18.5 g/dL in men, greater than 16.5 g/dL in women, or other signs of increased red blood cell volume ((a) heme or blood volume ratio is greater than in terms of age, sex, residence The 99th percentile of the method-specific reference range for altitude; (b) if the baseline value of the person is recorded and continuously increased by at least 2 g/dL (which cannot be attributed to the correction of iron deficiency), blood red The prime is greater than 17 g/dL in men, greater than 15 g/dL in women; or (c) increased red blood cell volume is greater than 25% of the average normal predicted value; 2) JAK2 V617F or other functionally similar mutations are present ( Such as JAK2 exon 12 mutation). Secondary criteria include: 1) Bone marrow biopsies show hypercellularity in terms of age with trilineage growth (panmyelosis) of significant red blood cells, granulocytes and megakaryocyte proliferation; 2) The content of serum erythropoietin is lower than the normal reference range; 3) the formation of endogenous red blood cell community in vitro.

An individual suffering from true plethremia and absence of myelofibrosis may be an individual who does not have myelofibrosis after true plethora. The criteria required for MF after PV include: 1) Recording of a plethora of stimuli previously diagnosed as defined by the World Health Organization (WHO) guidelines. See Tefferi et al, Blood 110: 1092-1097, 2007; 2) Myelofibrosis, classified according to European classification 2 to 3 (on the 0 to 3 scale), diffuse, usually crude fiber, no collagen Signs (negative trichrome staining), or diffuse, coarse fibrous web, with collagenized areas (positive trichrome staining) (Thiele et al., Haematologica 90: 1128-1132, 2005); or classified as 3 to 4 according to criteria Grade (on the 0 to 4 scale), for diffuse and dense reticulin with extensive interphase, occasionally with only local collagen bundles and/or local osteosclerosis, or diffuse and cytosolic The increase is accompanied by extensive intersection, with a thick collagen bundle, usually associated with significant osteosclerosis (Manoharan et al, Br J Haematol 43: 185-190, 1979). Other criteria for post-PV MF (which requires two criteria) include: 1) anemia, below the reference range for appropriate age, sex (sex), gender (gender) and elevation considerations, or continued loss of bloodletting (in the absence of cytoreductive therapy) or cytoreductive treatment (in the case of increased red blood cells); 2) photo of peripheral blood of leukoerythroblastic; 3) increased splenomegaly, Defined as an increase in palpable splenomegaly greater than or equal to 5 cm (distance from the apex of the spleen to the left rib margin) or a new palpable splenomegaly; and 4) one or more of the following three systemic symptoms: Loss of more than 10% within 6 months, night sweats or unexplained fever (greater than 37.5 ° C).

In some embodiments, an individual with PV has an increased risk of progression to MF. Individuals with an increased risk of progression to myelofibrosis with PV may have one or more of the following risk factors: 1) duration of disease for PV lasts at least 10 years; 2) presence of JAK2 V617F mutation (eg, homozygous JAK2 V617F mutation) 3) elevated serum lactate dehydrogenase content; 4) endogenous megakaryocyte community formation. See Alvarez-Larran et al, Br J Haematol 146: 504-509, 2009.

If the individual with PV treated by hydroxyurea has a hematocrit greater than 45% or has been bled twice in the last six months and at least once in the last three months, the individual may have hydroxyurea Resistant or intolerant of hydroxy urea. See Barosi et al., Br . J. Haematol . 148:961-3, 2010.

In some embodiments, if the individual is a human, the individual has a point mutation (JAK2V617F) from lysine 617 to phenylalanine in Janus kinase 2 (JAK2 kinase); or if the individual is non-human lactating In animals, the individual has a point mutation corresponding to proline 617 to amphetamine in Janus kinase 2 (JAK2 kinase). In some embodiments, if the individual is a human, the individual is negative for a proline 617 to amphetamine mutation of JAK2; or if the individual is a non-human mammal, the individual corresponds to a Janus kinase 2 (JAK2) In the kinase), the mutation of proline 617 to phenylalanine was negative. Individuals that are positive or negative for JAK2V617F can be determined by polymerase chain reaction ("PCR") analysis using genomic DNA from bone marrow cells or blood cells (eg, white blood cells or granulocytes). PCR analysis can be either dual gene-specific PCR (eg, dual gene-specific quantitative PCR) or PCR sequencing. See Kittur J et al, Cancer 2007, 109(11): 2279-84 and McLornan D et al, Ulster Med J. 2006, 75(2): 112-9, each of which is incorporated by reference. It is expressly incorporated herein.

In some embodiments, the individual has a PV that is resistant to hydroxyurea or a patient is intolerant to hydroxyurea treatment. In some embodiments, the individual has PV, and there is no myelofibrosis (MF) or acute myeloid leukemia (AML). In some embodiments, the individual has been previously treated with another JAK2 inhibitor, such as rosolinib. In some embodiments, the individual has an increased risk of developing MF. For example, an individual may have one or more risk factors selected from the group consisting of: 1) having PV for at least 15 years, 2) having the same The type binds to the JAK2 V617F mutant dual gene, 3) has elevated serum lactate dehydrogenase content, and 4) has endogenous megakaryocyte community formation. In some embodiments, the individual is selected for treatment based on one or more of the following criteria: (i) the individual has a resistance to hydroxyurea or a patient is intolerant to hydroxyurea treatment; (ii) the individual has PV , absence of myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the individual has been previously treated with another JAK2 inhibitor (such as rosolinib); and (iv) the individual has an increased risk The risk of MF, for example, an individual may have one or more risk factors selected from the group consisting of: 1) having PV for at least 15 years, 2) having a homozygous JAK2 V617F mutant dual gene, and 3) having an elevation The serum lactate dehydrogenase content, and 4) have endogenous megakaryocyte community formation. In some embodiments, the methods described herein can further comprise the step of determining whether the individual satisfies one or more of the above criteria prior to treatment.

In some embodiments, an individual treated in a manner described herein has been previously treated with another JAK2 inhibitor. The prior therapy may be a JAK2 inhibitor (eg, INCB018424 or rosolinib (commercially available from Incyte), CEP-701 (lestaurtinib, available from Cephalon) or XL019 (available from Exelixis), CYT387 (available from YB Biosciences), SB1518 (available from SBio), and AZD1480 (available from AstraZeneca)) (see Verstovsek S., Hematology Am Soc Hematol Educ Program. 2009: 636-42). In some embodiments, the individual has been treated with another JAK2 inhibitor (eg, INCB018424 or rosolinib (available from Incyte)) and is treated with the JAK2 inhibitor (eg, INCB018424 or rosolibinib (available for purchase) Since Incyte)) is resistant. In some embodiments, the individual has accepted another JAK2 inhibitor treatment (e.g., INCB018424 or rosolinib (commercially available from Incyte)) and is intolerant to the JAK2 inhibitor treatment (e.g., INCB018424 or rosolidini (commercially available from Incyte)). In some embodiments, the individual has been treated with another JAK2 inhibitor (eg, INCB018424 or rosolidini (commercially available from Incyte)) and is not treated with the JAK2 inhibitor (eg, INCB018424 or rosolidinib (available for purchase) Reacts or partially reacts from Incyte)). In some embodiments, the individual has been treated with another JAK2 inhibitor (eg, INCB018424 or rosolinib (available from Incyte)) and is treated with the JAK2 inhibitor (eg, INCB018424 or rosolibinib (available for purchase) Since Incyte)) has inappropriate drug toxicity. In some embodiments, the individual has been treated with another JAK2 inhibitor (eg, INCB018424 or rosolinib (commercially available from Incyte)) and the JAK2 inhibitor treatment (eg, INCB018424 or rosolibinib (available from Incyte)) has failed. In some embodiments, an individual who is resistant or intolerant to PV, and is resistant to another JAK2 inhibitor (eg, INCB018424 or rosolinib (commercially available from Incyte)) has greater than 45% blood volume Ratio, or bloodletting twice in the last six months and at least once in the last three months. In some embodiments, the other JAK2 inhibitor is rosolinib. In some embodiments, the individual does not undergo splenectomy.

In some embodiments, the individual does not receive concomitant treatment with a pharmaceutical to herbal agent known as at least a moderate inhibitor or inducer of CYP3A4 or a drug known to be at least a moderate inhibitor or inducer of CYP3A4 to the herb Pharmacy. Based on in vitro evaluation, N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine-4 -amino)amino]benzamide is metabolized by human CYP3A4. Avoid increasing N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine-4- Amino] sulfinamide plasma concentration agent (ie, CYP3A4 inhibitor) or a decrease in N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidine) -1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide plasma concentration agent (also known as CYP3A4 inducer) (including herbal agents and foods (eg grapefruit/grape) Pomelo juice) appears in an individual treated as described herein. In addition, in vitro data indicate that N -t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine- 4-yl)amino]benzenesulfonamide inhibits CYP3A4 in a time-varying manner. Agents that are sensitive to the metabolism of CYP3A4 should be used with caution because of N -t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-yloxy)) Co-administration of phenyl)amino}pyrimidin-4-yl)amino]benzenesulfonamide results in a higher plasma concentration of the co-administered agent. A list of clinically relevant receptors for CYP3A4 includes alfentanil, cyclosporine, diergotamine, ethinyl estradiol, ergotamine, fen Fentanyl, pimozide, quinidine, sirolimus, tacrolimus, clarithromycin, erythromycin, Telithromycin, alprazolam, diazepam, midazolam, triazolam, indinavir, ritonavir ( Ritonavir), saquinavir, prokinetic, cisapride, astemizole, chlorpheniramine, amlodipine, diltiazem ( Diltiazem), felodipine, nifedipine, verapamil, atorvastatin, cerivastatin, lovastatin, simvastatin Statvastatin, aripiprazole, gleevec, fluphene Alcohol (halopericol), sildenafil (sildenafil), tamoxifen (tamoxifen), taxoid (taxane), trazodone (trazodone) and vincristine (Vincristine). The list of clinically relevant inducers for CYP3A4 includes carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, saint St. John's wort and troglitazone. The list of clinically relevant inhibitors of CYP3A4 includes indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone (nefazodone), erythromycin, grapefruit juice, verapamil, diltiazem, cimetidine, amiodarone, fluvoxamine, mibefradil and Troleandomycin. See the following reference: Flockhart et al., http://medicine.iupui.edu/clinpharm/ddis/clinicaltable.aspx., 2009.

In some embodiments, the individual does not receive concomitant treatment with a pharmaceutical to herbal agent known as at least a moderate inhibitor or inducer of CYP2C19 or a drug known to be at least a moderate inhibitor or inducer of CYP2C19 to the herb Pharmacy.

It can be administered by a dose of about 50 mg per day to 500 mg per day. Administration to treat an individual (such as a human) which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl) Amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the specified weight is the free base portion weight of the compound. In some embodiments, the compound is administered at a dose of 50 mg per day, 100 mg per day, 200 mg per day, 300 mg per day, or 400 mg per day. The compounds can be in the form of capsules and/or unit dosage forms as described herein. In some embodiments, the compound administered is mixed with microcrystalline cellulose and sodium stearyl fumarate, and the hybrid is in a capsule. In some embodiments, the compound is administered orally.

In some embodiments, the compound is administered to the individual for at least 1 cycle, at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 per day. A 28-day cycle of cycles. In some embodiments, the compound is administered to the individual daily for a 28-day cycle of at least 6 cycles, a 28-day cycle of at least 8 cycles, a 28-day cycle of at least 10 cycles, a 28-day cycle of at least 12 cycles, at least A 28-day cycle of 15 cycles, a 28-day cycle of at least 18 cycles, or a 28-day cycle of at least 24 cycles. In some embodiments, the compound is administered to the individual for at least 4 weeks, at least 8 weeks, at least 10 weeks, at least 20 weeks, at least 30 weeks, at least 32 weeks, at least 40 weeks, or at least 50 weeks. In some embodiments, the compound is administered to the individual daily for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least eight months, or at least one year . In some embodiments, the compound is administered once a day.

In some embodiments, the treatments provided herein improve one or more symptoms associated with PV in an individual. For example, the treatments described herein can produce one or more of the following: a reduced blood volume ratio (eg, a blood volume level below about 45% in the absence of bleeding, for a minimum of 3 months), and a decrease in platelet count ( E.g 400 × 10 ⁹ / L), white blood cell count is reduced (for example 10×10 ⁹ /L), the spleen size is reduced (for example, by imaging, the spleen size is normal or near normal, or the spleen size or spleen volume is reduced by at least about 10%, 15%, 20%, 25%) , 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90%), and other diseases related Symptoms such as microvascular disorders, itching and headaches improve. In some embodiments, the treatments described herein are effective to reduce thrombocytosis, reduce JAK2V617F dual gene load, reduce myelofibrosis, and/or reduce bone marrow cell viability. The reduction, reduction, improvement or improvement may be at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, compared to the level prior to the start of treatment with the compounds provided herein. 80% or 90%.

In some embodiments, the treatments provided herein produce a complete response. In some embodiments, the treatment provided herein produces a partial response. The criteria for complete and partial reactions can be based on any of the criteria known in the art, for example according to the European LeukemiaNet consensus guidelines.

Also provided herein is a method of monitoring PV treatment in an individual, the method comprising (a) administering to the individual an effective amount of the compound N -t-butyl-3-[(5-methyl-2-{[4-(2- Pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or hydrate thereof; (b) monitoring the individual's granules The degree of STAT3 phosphorylation in the blood cells of the JAG2V617F mutant dual gene and/or individual in the cell. In some embodiments, the methods can further comprise determining whether the individual should continue or stop treatment.

IV. Methods for treating and preventing primary thrombocytopenia

Provided herein are methods for treating, delaying, and/or preventing ET in a subject, the method comprising administering to the individual an effective amount of the compound N -t-butyl-3-[(5-methyl-2-{[4 -(2-Pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof. In some embodiments, the individual has ET and has not progressed to MF or AML. In some embodiments, the individual has an increased risk of developing MF. In some embodiments, the individual has an ET or an individual intolerant to hydroxyurea that is resistant to hydroxyurea treatment. In some embodiments, the individual is a human individual. In some embodiments, N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine-4 An effective amount of -amino)benzamide or a pharmaceutically acceptable salt thereof or hydrate thereof is orally administered from about 50 mg to about 400 mg per day, and wherein the weight is a free base of the compound Partial weight.

Methods for diagnosing various types of ET are known in the art. ET diagnosis can be based on revised World Health Organization (WHO) guidelines. See Vardiman et al, Blood 114: 937-51, 2009. ET diagnosis needs to meet four criteria. The criteria include: 1) the platelet count continues to be equal to or greater than 450 × 10 ⁹ /L during the course of treatment; 2) the bone marrow biopsy sample shows mainly megakaryocyte cell proliferation, expanding the number of mature megakaryocytes, and There was no significant increase in left ventricular shift in neutrophil granulocyte production or erythropoiesis; 3) WHO guidelines that did not meet true plethremia, primary myelofibrosis, BCR-ABL1-positive CML or myelodysplastic syndrome or other myeloma . Under guidelines 3) WHO guidelines that do not comply with true plethora, iron replacement therapy is required to increase the heme content to the true plethora of the serum with reduced serum ferritin. The exclusion of true plethora is based on hemoglobin and blood volume ratio, and does not require measurement of red blood cell mass. Under guidelines 3) WHO guidelines that do not meet primary myelofibrosis, there is no need for associated cytosolic fibrosis, collagen fibrosis, peripheral blood erythrocytosis, or significantly high cell bone marrow with primary bone marrow Typical megakaryocyte morphology of fibrosis (such as small megakaryocytes to large megakaryocytes with abnormal nuclear/cytoplasmic ratios and polychromatic spherical or irregularly folded nuclei and dense clusters). In the criteria 3) WHO guidelines that do not comply with BCR-ABL1 positive CML, BCR-ABL1 is not required. Under guidelines 3) WHO guidelines that do not meet myelodysplastic syndromes, there is no need for erythropoiesis abnormalities and abnormal granulocyte generation; 4) JAK2 V617F or other pure line markers, or absence of JAK2 V617F, signs of non-reactive thromboembolism . Under criteria 4), the causes of reactive thrombocytosis include iron deficiency, splenectomy, surgery, infection, inflammation, connective tissue disease, metastatic cancer, and lymphoproliferative disorders. However, if other criteria are met, there is a possibility that the condition associated with reactive thrombocytosis does not exclude ET.

An individual having ET but not progressing to MF may be an individual who does not have myelofibrosis after primary thrombocytopenia. The criteria required for myelofibrosis after primary thrombocytopenia include: 1) Recording a previous diagnosis of primary thrombocytopenia as defined by the World Health Organization (WHO) guidelines (see Tefferi et al., Blood 110: 1092-1097, 2007); 2) Myelofibrosis, classified according to European classification 2 to 3 (on a scale of 0 to 3), is diffuse, usually a crude fiber network, with no signs of collagenation (negative trichrome staining) ), or a diffuse, crude fiber network with a collagenized area (positive trichrome staining) (Thiele et al., Haematologica 90: 1128-1132, 2005); or classified as 3 to 4 according to the standard (from 0 to Level 4), diffuse and densely packed with cytoplasmic proteins with extensive intersections, occasionally with only local collagen bundles and/or local osteosclerosis, or diffuse and densely packed with retinoic proteins with extensive intersections and coarse Collagen bundles are often associated with significant osteosclerosis (Manoharan et al, Br J Haematol 43: 185-190, 1979). Other criteria for myelofibrosis after primary thrombocytopenia (which requires two criteria) include: 1) anemia, below the reference range for appropriate age, sex (sex), gender (gender), and elevation considerations And the decrease in hemoglobin content from baseline is greater than or equal to 2 mg/ml; 2) photo of peripheral red blood cells; 3) increased splenomegaly, defined as the increase in palpable splenomegaly greater than or equal to 5 cm (spleen tip to the left) The distance between the costal ribs) or the newly visible palpable splenomegaly; 4) elevated lactate dehydrogenase (LDH) is higher than the reference content; 5) one or more of the following three systemic symptoms: at 6 months The internal weight loss is more than 10%, night sweats or unexplained fever (greater than 37.5 ° C).

In some embodiments, an individual with ET has an increased risk of progression to MF.

If an individual suffering from ET treated with hydroxyurea has a platelet count greater than 600 x ¹⁰⁹ /L, the individual may be resistant to hydroxyurea or intolerant to hydroxyurea. See Barosi et al., Leukemia 21:277-80, 2007.

In some embodiments, if the individual is a human, the individual has a point mutation from glutamine 617 to phenylalanine in Jaynes kinase 2 (JAK2 kinase) (JAK2V617F); or if the individual is a non-human mammal, the individual There is a point mutation corresponding to proline 617 to amphetamine in Janus kinase 2 (JAK2 kinase). In some embodiments, if the individual is a human, the individual is negative for a proline 617 to amphetamine mutation of JAK2; or if the individual is a non-human mammal, the individual corresponds to a Janus kinase 2 (JAK2) In the kinase), the mutation of proline 617 to phenylalanine was negative. Whether the individual is positive or negative for JAK2V617F can be determined by polymerase chain reaction ("PCR") analysis using genomic DNA from bone marrow cells or blood cells (eg, whole blood leukocytes). PCR analysis can be either dual gene-specific PCR (eg, dual gene-specific quantitative PCR) or PCR sequencing. See Kittur J et al, Cancer 2007, 109(11): 2279-84 and McLornan D et al, Ulster Med J. 2006, 75(2): 112-9, each of which is incorporated by reference. It is expressly incorporated herein.

In some embodiments, the individual has an ET or an individual intolerant to hydroxyurea that is resistant to hydroxyurea treatment. In some embodiments, the individual has ET and there is no myelofibrosis (MF) or acute myeloid leukemia (AML). In some embodiments, the individual has an increased risk of developing MF. In some embodiments, the individual has been previously treated with another JAK2 inhibitor, such as rosolinib. In some embodiments, the individual is selected for treatment based on one or more of the following criteria: (i) the individual has ET or individual intolerance to hydroxyurea treatment; (ii) Have ET, no myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the individual has an increased risk of developing MF; and (iv) the individual has previously taken another JAK2 inhibitor (such as Lu Treatment with soritinib). In some embodiments, the methods described herein can further comprise the step of determining whether the individual satisfies one or more of the above criteria prior to treatment.

In some embodiments, an individual treated in a manner described herein has been previously treated with another JAK2 inhibitor. The prior therapy may be a JAK2 inhibitor (eg, INCB018424 or rosolinib (commercially available from Incyte), CEP-701 (toltinib, available from Cephalon) or XL019 (available from Exelixis) (see Verstovsek S) ., Hematology Am Soc Hematol Educ Program. 2009: 636-42). In some embodiments, the individual has been treated with another JAK2 inhibitor (eg, INCB018424 or rosolinib (available from Incyte)) and is treated with the JAK2 inhibitor (eg, INCB018424 or rosolibinib (available for purchase) Since Incyte)) is resistant. In some embodiments, the individual has been treated with another JAK2 inhibitor (eg, INCB018424 or rosolinib (commercially available from Incyte)) and is intolerant of the JAK2 inhibitor treatment (eg, INCB018424 or rosolibinib ( Available from Incyte)). In some embodiments, the individual has been treated with another JAK2 inhibitor (eg, INCB018424 or rosolidini (commercially available from Incyte)) and is not treated with the JAK2 inhibitor (eg, INCB018424 or rosolidinib (available for purchase) Reacts or partially reacts from Incyte)). In some embodiments, the individual has been treated with another JAK2 inhibitor (eg, INCB018424 or rosolinib (available from Incyte)) and is treated with the JAK2 inhibitor (eg, INCB018424 or rosolibinib (available for purchase) Since Incyte)) has inappropriate drug toxicity. In some embodiments, the individual has been treated with another JAK2 inhibitor (eg, INCB018424 or rosolinib (commercially available from Incyte)) and the JAK2 inhibitor treatment (eg, INCB018424 or rosolibinib (available from Incyte)) has failed. In some embodiments, an individual having ET, resistant to another JAK2 inhibitor treatment (eg, INCB018424 or rosolinib (commercially available from Incyte)) has more than 600 x ¹⁰⁹ /L platelet count. In some embodiments, the other JAK2 inhibitor is rosolinib. In some embodiments, the individual does not undergo splenectomy.

In some embodiments, the individual does not receive concomitant treatment with a pharmaceutical to herbal agent known as at least a moderate inhibitor or inducer of CYP3A4 or a drug known to be at least a moderate inhibitor or inducer of CYP3A4 to the herb Pharmacy. Based on in vitro evaluation, N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine-4- The amino) benzenesulfonamide dihydrochloride monohydrate is metabolized by human CYP3A4. Avoid increasing N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine-4- Plasma base concentration of phenylsulfonamide dihydrochloride monohydrate (also known as CYP3A4 inhibitor) or reduction of N -tert-butyl-3-[(5-methyl-2-{[4- (2-Pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate plasma concentration (ie CYP3A4 elicitor) (including herbal agents and foods (eg grapefruit/grapefruit juice)) appear in patients receiving this compound. In addition, in vitro data indicate that N -t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine- 4-yl)amino]benzenesulfonamide dihydrochloride monohydrate inhibits CYP3A4 in a time-varying manner. Agents that are sensitive to the metabolism of CYP3A4 should be used with caution because of N -t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-yloxy)) The co-administration of phenyl]amino]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate results in a higher plasma concentration of the co-administered agent. A list of clinically relevant receptors for CYP3A4 includes alfentanil, cyclosporine, diergotamine, ethinyl estradiol, ergotamine, fentanyl, piperazine, quinidine, sirolimus, Tacrolimus, clarithromycin, erythromycin, telithromycin, alprazolam, diazepam, midazolam, triazolam, indinavir, ritonavir, saquinavir, Prokinetics, cisapride, astemizole, chlorpheniramine, amlodipine, diltiazem, felodipine, nifedipine, verapamil, atorvastatin, cerivastatin, lovastatin Simvastatin, aripiprazole, gliclavir, haloperidol, sildenafil, tamoxifen, taxane, trazodone and vincristine. A list of clinically relevant inducers of CYP3A4 includes carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampicin, St. John's wort, and troglitazone. The list of clinically relevant inhibitors of CYP3A4 includes indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, erythromycin, grapefruit juice, Verapamil, diltiazem, cimetidine, amiodarone, fluvoxamine, mibefral and oleandomycin. See the following reference: Flockhart et al., http://medicine.iupui.edu/clinpharm/ddis/clinicaltable.aspx., 2009.

An individual (such as a human) can be treated by oral administration at a dose of from about 50 mg per day to 500 mg of the compound per day, which is N-t-butyl-3-[(5-methyl-2-{[ 4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, The weight specified therein is the weight of the free base portion of the compound. In some embodiments, the compound is administered at a dose of 50 mg per day, 100 mg per day, 200 mg per day, 300 mg per day, or 400 mg per day. The compounds can be in the form of capsules and/or unit dosage forms as described herein. In some embodiments, the compound administered is in admixture with microcrystalline cellulose and sodium stearyl fumarate, and the mixture is in a capsule. In some embodiments, the compound is administered orally.

In some embodiments, the compound is administered to the individual for at least 1 cycle, at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 per day. A 28-day cycle of cycles. In some embodiments, the compound is administered to the individual daily for a 28-day cycle of at least 6 cycles, a 28-day cycle of at least 8 cycles, a 28-day cycle of at least 10 cycles, a 28-day cycle of at least 12 cycles, at least A 28-day cycle of 15 cycles, a 28-day cycle of at least 18 cycles, or a 28-day cycle of at least 24 cycles. In some embodiments, the compound is administered to the individual for at least 4 weeks, at least 8 weeks, at least 10 weeks, at least 20 weeks, at least 30 weeks, at least 32 weeks, at least 40 weeks, or at least 50 weeks. In some embodiments, the compound is administered to the individual daily for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least eight months, or at least one year . In some embodiments, the compound is administered once a day.

In some embodiments, the treatments provided herein improve one or more symptoms associated with ET in an individual. For example, the treatments described herein can produce one or more of the following: reducing platelet counts (eg, platelet counts) 400 × 10 ⁹ / L or 600 × 10 ⁹ / L or > 50% reduction from baseline), white blood cell count (for example 10×10 ⁹ /L), reducing the size of the spleen (for example, by imaging, the spleen size is normal or close to normal, or the spleen size or spleen volume is reduced by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90%), and improvement Other disease-related symptoms (such as microvascular disorders, itching, and headache). In some embodiments, the treatments described herein are effective to reduce thrombocytosis, reduce JAK2V617F dual gene load, reduce myelofibrosis, and/or reduce bone marrow cell viability. The reduction, reduction, improvement or improvement may be at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, compared to the level prior to the start of treatment with the compounds provided herein. 80% or 90%.

In some embodiments, the treatments provided herein produce a complete response. In some embodiments, the treatment provided herein produces a partial response. The criteria for complete and partial reactions can be based on any of the criteria known in the art, for example according to the European LeukemiaNet consensus guidelines.

Also provided herein is a method of monitoring ET treatment in an individual comprising (a) administering to the individual an effective amount of the compound N -t-butyl-3-[(5-methyl-2-{[4-(2- Pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or hydrate thereof; (b) monitoring the individual's granules The degree of STAT3 phosphorylation in the blood cells of the JAG2V617F mutant dual gene and/or individual in the cell. In some embodiments, the methods can further comprise determining whether the individual should continue or stop treatment.

V. Products and kits

Also provided herein are articles or kits comprising the compound N - tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine) A pyrimidine-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof. In some embodiments, the article or kit further includes instructions for using the compounds described herein in the methods provided herein. In some embodiments, the article or kit further includes a label or package insert that provides an indication. In some embodiments, the compounds are in the form of capsules and/or unit dosage forms described herein.

In some embodiments, the article or kit can further comprise a container. Suitable containers include, for example, bottles, vials (e.g., dual chamber vials), syringes (such as single or dual chamber syringes), and test tubes. The container may be formed from a variety of materials, such as glass or plastic, and the container may hold a compound in the form of, for example, a formulation to be administered. The article or kit may further comprise a label or package insert on or associated with the container to indicate instructions for reconstitution and/or use of the compound. In some embodiments, the package insert or label is located at a location that is visible to the intended purchaser.

In some embodiments, the label or package insert can further indicate that the compound is suitable or contemplated for use in treating or preventing PV in an individual. In some embodiments, the package insert or label indicates that the compound is suitable for treating i) a compound suitable for treating an individual having PV and ii) orally administering a compound to the individual at a dose of from about 50 mg to about 400 mg per day, The weight specified therein is the weight of the free base portion of the compound. In some embodiments, the package insert or label indicates a dose of 50 mg, 100 mg, 200 mg, or 400 mg per day. In some embodiments, the compound is in a capsule comprising the following hybrid: (i) compound N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino a sulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the hybrid is contained in a capsule. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base portion weight of the compound. In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual having a PV that is resistant to treatment with hydroxyurea, or for treating an individual having PV, wherein the individual is intolerant to hydroxyurea treatment. In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual with an increased risk of developing MF. In some embodiments, the individual has at least one risk factor selected from the group consisting of: 1) having PV for at least 15 years, 2) having a homozygous JAK2 V617F mutant dual gene, and 3) having elevated serum lactate dehydrogenation Enzyme content, and 4) have endogenous megakaryocyte community formation. In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual who has been previously treated with another JAK2 inhibitor, such as rosolinib.

The label or package insert may further indicate that the compound is suitable or contemplated for use in treating or preventing ET in an individual. In some embodiments, the package insert or label indicates that the compound is suitable for treating i) a compound suitable for treating an individual ET and ii) orally administering a compound to the individual at a dose of from about 50 mg to about 400 mg per day, wherein The weight is the weight of the free base portion of the compound. In some embodiments, the package insert or label indicates a dose of 50 mg, 100 mg, 200 mg, or 400 mg per day. In some embodiments, the compound is in a capsule comprising the following hybrid: (i) compound N-t-butyl-3-[(5-A) Keto-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the hybrid is contained in a capsule. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base portion weight of the compound. In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual having an ET that is resistant to hydroxyurea treatment or for treating an individual who is intolerant to hydroxyurea treatment. In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual with an increased risk of developing MF. In some embodiments, the package insert or label indicates that the compound is suitable for treating an individual who has been previously treated with another JAK2 inhibitor, such as rosolinib.

The following are examples of the methods and compositions provided herein. It will be appreciated that in view of the general description provided above, various other embodiments may be practiced.

Instance Example 1

Oral administration of N-tert-butyl-3-[5 in patients with true plethora (PV) who are resistant to hydroxyurea treatment and in patients with PV and intolerance to hydroxyurea -methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate ( Random open label study of APIs. Individuals in this study were administered a capsule form of the drug substance as described in Example 3.

Research overview

The study was designed to study (1) 100 mg, 200 mg, and 400 mg oral doses of a daily dose of a drug that is resistant to hydroxyurea-treated PV and patients with PV, intolerance to hydroxyurea. The effect of inducing the absence of bloodletting and the blood volume ratio of less than 45% for at least 3 months; (2) the safety of the drug substance; (3) the daily dose of 100 mg, 200 mg and 400 mg The efficacy of the drug on inducing complete or partial clinical hematologic response; (4) the pharmacokinetics of the drug substance after a single and repeated dose; (5) the pharmacodynamics of the drug substance, such as in patients with the JAK2V617F mutation Measurement of changes in JAK2V617F dual gene load and/or STAT3 phosphorylation inhibition; (6) effects of drug substance on histological, cytogenetic, and molecular responses in bone marrow; (7) baseline myeloproliferative neoplasms ( MPN) changes in related symptoms and overall impact on quality of life are obtained through the continuous implementation of the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (see Scherber et al, Blood 116:4095, 2010); (8) Use EuroQol E Q-5D ^TM Questionnaire (see the EuroQol Group, EuroQol-a new facility of the measurement of health-related quality of life, Health Policy 16:199-208, 1990) for general health-related quality of life and value of use; (9 The effects of the drug substance on histological, cytogenetic and molecular responses in the bone marrow; (10) the effect of the drug substance on leukocyte increase and thrombocytosis; (11) the change in the formation of endogenous red blood cell community; (12) Replenishing iron (Fe/ferritin/transferrin/transferrin saturation %) in iron-deficient patients; (13) drug-metabolizing enzymes that may be associated with the JAK-STAT pathway or associated with myeloaplastic tumor (MPN) Gene genomic analysis of genes.

patient

Patients included in the study were diagnosed as having resistance to hydroxyurea-treated PV or patients with PV intolerance to hydroxyurea according to revised World Health Organization (WHO) guidelines (see Table 1) (according to LeukemiaNet consensus guidelines). PV resistant to hydroxyurea is defined as having a blood volume ratio of >45% for patients with hydroxyurea or two times for bleeding within the last 6 months and at least once for bleeding within the last 3 months (Barosi et al. Br J Haematol ., 148(6): 961-3, 2010).

Patients were randomly assigned to a 1:1:1 ratio to 1 of the following 3 drug dose groups: 100 mg, 200 mg, and 400 mg (free base) per day (approximately 10 patients per dose). Patients remained study treatment for a minimum of 8 cycles with no disease progression or unacceptable poisoning. Patients who have completed 8 treatment cycles, are tolerant of study treatment, and are clinically beneficial continue to be treated. For patients randomized to 100 mg per day or 200 mg per day, it is permissible to switch to a higher dose after the patient completes 8 therapy cycles.

method

The drug substance is supplied in the form of a hard capsule containing a drug substance in the form of 100 mg or 50 mg of the free base. The capsule contains a blend of a drug substance and microcrystalline cellulose, and a small amount of sodium stearyl fumarate is added as a lubricant to facilitate the manufacture. Capsules were self-administered on a daily basis from the first day of the study in the 28-day cycle and thereafter at approximately the same time each day in a single dose on an empty stomach (1 hour before meals or 2 hours after meals).

At the end of the 4th and 8th cycles or at the end of treatment (EOT), the clinical hematologic response to treatment with the drug substance was evaluated based on the European LeukemiaNet consensus guidelines and at 30 days of follow-up.

The following parameters were measured from baseline: spleen size by palpation at the end of each cycle, EOT, and follow-up at 30 days; at the end of the 4th and 8th cycles or EOT, by magnetic Resonance Imaging (MRI) is the spleen volume of patients who are palpable to the spleen at baseline; MPN-SAF at the end of the first, fourth, and eighth cycles or EOT and at 30 days of follow-up Reaction; and EQ-5D reaction at the end of the 8th cycle or EOT. At baseline and thereafter (a) in patients who have achieved a complete (clinical hematology) response, at the time of complete response and if they still have a complete response Bone marrow analysis (including cytogenetics, cellular and cellular components (eg blast cells) every 6 months in patients who have cytogenetic abnormalities or retinoic fibrosis at baseline after 6 months, and (b) at baseline Count) and net fibrin fibrosis).

The blood volume ratio was measured at the end of each cycle and the bleeding requirements during the study period were recorded. The JAK2V617F mutant dual gene in granulocytes was measured at baseline and at the end of the 4th and 8th cycles or at EOT. The dual gene load was also measured in patients with disease progression. Analysis before dosing on the first day of the first cycle and 2 hours and 6 hours after dosing and on the second and fifteenth day of the first cycle and on the first day of the second cycle STAT3 phosphorylation. STAT3 phosphorylation was also measured in patients with disease progression. Changes at baseline and at the end of the first, fourth, and eighth cycles or EOT at a single center: endogenous erythrocyte community formation and iron supplementation in iron-deficient patients (Fe/ Ferritin/transferrin/transferrin saturation %). Pharmacogenomic analysis of drug-metabolizing enzymes and genes that may be associated with the JAK-STAT pathway or associated with MPN prior to dosing on day 1 of the first cycle. Safety will be assessed based on the following: the incidence of sudden adverse events (TEAE) and clinical laboratory parameters, red blood cell infusion requirements, Eastern Cooperative Oncology Group (ECOG) performance status (PS) , signs of life and changes in body weight relative to baseline. The term "National Cancer Institute" (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be used to assess and report adverse events.

Example 2.

Oral administration of N-tert-butyl-3- in patients with primary thrombocytopenia (ET) who are resistant to hydroxyurea treatment or in patients with ET and intolerance to hydroxyurea [(5-Methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride Random open label study of hydrates (APIs). Individuals in this study were administered a capsule form of the drug substance as described in Example 3.

Research overview

This study was designed to study (1) daily doses of 50 mg, 100 mg, 200 mg, and 400 mg oral doses (given as free base) in patients with ET resistant to hydroxyurea treatment And reduce platelet counts in patients who are intolerant to hydroxyurea treatment 400 × 10 ⁹ / L for a minimum of 3 months; (2) 50 mg, 100 mg, 200 mg and 400 mg daily dose of the drug in patients with ET resistant to hydroxyurea treatment Or safety in patients who are not intolerant to hydroxyurea; (3) efficacy of oral, 50 mg, 100 mg, 200 mg, and 400 mg oral doses in inducing complete or partial clinical hematologic response; (4) Pharmacokinetics of the drug substance after single and repeated doses; (5) Pharmacodynamics of the drug substance, such as changes in JAK2V617F dual gene load and/or STAT3 phosphorylation inhibition in patients with JAK2V617F mutation Measurement; (6) the effect of the drug substance on histological, cytogenetic, and molecular responses in the bone marrow; (7) changes in baseline myeloid hyperplasia (MPN)-related symptoms and overall impact on quality of life, via Continuous implementation of the MPH Symptom Assessment Form (MPN-SAF) was obtained (Scherber et al, Blood 116:4095, 2010); (8) Using the EuroQol EQ-5D ^TM Questionnaire (The EuroQol Group, Health Policy , 16(3) :199-208,1990) General health-related quality of life and value of use (9) the drug on the leukocytosis and increased platelet action; and (10) on drug metabolizing enzymes and drug gene-related genes of the MPN may be related to JAK-STAT or path analysis.

patient

Patients included in the study were diagnosed with ET according to a revised WHO guidelines (see Table 2), wherein the ET was resistant to hydroxyurea treatment or where the patient was intolerant to hydroxyurea treatment (according to LeukemiaNet consensus guidelines). ETs that are resistant to hydroxyurea treatment are defined as patients with hydroxyurea having a platelet count of >600 x ¹⁰⁹ /L (Barosi et al, Leukemia , 21(2): 277-80, 2007).

The disease is based on hemoglobin and blood volume ratio, and does not need to measure the amount of red blood cells.

There is no need for cytoplasmic fibrosis, collagen fibrosis, peripheral blood erythrocytosis or significant high-cell bone marrow with typical megakaryocyte morphology (with abnormal nucleus/cytoplasmic ratio) Multi-color spherical or irregularly folded nuclei and dense clusters of small megakaryocytes to large megakaryocytes).

^§ There is no need for BCR-ABL1 .

^∥ There is no need for abnormal red blood cell formation and abnormal granulocyte production.

Causes of ^sputum reactive thrombocytosis include iron deficiency, splenectomy, surgery, infection, inflammation, connective tissue disease, metastatic cancer, and lymphoproliferative disorders. However, if other criteria are met, there is a possibility that the condition associated with reactive thrombocytosis does not exclude ET.

Patients were randomized to a 1:1:1 ratio to 1 of the following 3 dose groups: 100 mg, 200 mg, and 400 mg per day (approximately 10 patients per dose). Patients remained study treatment for a minimum of 8 cycles with no disease progression or unacceptable poisoning. Patients who have completed 8 treatment cycles, are tolerant of study treatment, and are clinically beneficial continue to be treated. For patients randomized to 100 mg per day or 200 mg per day, patients may be allowed to switch to higher doses after completing 8 treatment cycles.

method

The drug substance is supplied in the form of a hard capsule containing 100 mg or 50 mg of the free base. The capsule contains a blend of a drug substance and microcrystalline cellulose, and a small amount of sodium stearyl fumarate is added as a lubricant to facilitate the manufacture. In continuous The 28-day cycle was started on the first day of the study and thereafter, at approximately the same time every day, once a day on an empty stomach (1 hour before meals or 2 hours after meals), the capsules were orally administered.

The primary endpoint was a decrease in platelet count. Platelet counts were measured at the end of each cycle. Platelet count after completing 8 therapy cycles 400 × 10 ⁹ / L for a minimum of 3 months is considered a reaction.

At the end of the 4th and 8th cycles or at the end of treatment (EOT), the clinical hematologic response to treatment with the drug substance was evaluated based on the European LeukemiaNet consensus and at 30 days of follow-up. In addition, the following parameters were measured from baseline: spleen size by palpation at the end of each cycle, EOT and at 30 days of follow-up; at the end of the 4th and 8th cycles or EOT, borrow The spleen volume of patients who are palpable to the spleen at baseline by magnetic resonance imaging (MRI); MPN at the end of the first, fourth, and eighth cycles or EOT and at 30 days of follow-up - SAF (Mongoclastia Symptoms Symptom Assessment Form) response; and EQ-5D response at the end of the 8th cycle or EOT. At baseline and thereafter (a) in patients who achieved complete (clinical hematology) response, again at 6 months after complete response and if they still have complete response, and (b) cytogenetic at baseline Bone marrow analysis (including cytogenetics, cellular and cellular composition (eg, blast cell count), and retinoic fibrosis) was performed every 6 months in patients with abnormalities or reticular fibrosis. In a subset of patients positive for mutation, the JAK2V617F mutant pair of genes in granulocytes was measured at baseline and at the end of the 4th and 8th cycles or at EOT by a central laboratory. The dual gene load was also measured in patients with disease progression. Analysis before dosing on the first day of the first cycle and 2 hours and 6 hours after dosing and on the second and fifteenth day of the first cycle and on the first day of the second cycle STAT3 phosphorylation. STAT3 phosphorylation was also measured in patients with disease progression. Pharmacogenomic analysis of drug-metabolizing enzymes and genes that may be associated with the JAK-STAT pathway or associated with MPN prior to dosing on day 1 of the first cycle. Safety was assessed based on the following: incidence of therapeutic emergency adverse events (TEAE) and clinical laboratory parameters, red blood cell infusion requirements, Eastern Cooperative Oncology Group (ECOG) performance status (PS), vital signs, and body weight relative to baseline Variety. Adverse events are assessed and reported using the National Cancer Institute (NCI) - Common Terminology Guidelines for Adverse Events (CTCAE) version 4.03. Platelet counts were measured at the end of each cycle.

Example 3. N-Tertibutyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl) Capsule form and manufacturing process of amino] benzenesulfonamide dihydrochloride monohydrate

N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino] The benzenesulfonamide dihydrochloride monohydrate drug is provided in 50 mg and 100 mg capsule strengths, wherein the weight (unit amount) is for the active (ie free base) moiety ( N -tert-butyl-3- Designated by the amount of [(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide . The quantitative composition of the drug capsules of each strength is shown in Table 3.

For the manufacture of N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl) The process description of the amine] benzenesulfonamide dihydrochloride monohydrate capsule is as follows:

A. Dry granulation of the components (implemented for all three drug strengths): 1. Blending N -tert-butyl-3-[(5-methyl-2-{[] in a conical blender 4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate, stearic acid fumaric acid Sodium and about 50% deuterated microcrystalline cellulose for 5 minutes. 2. The blend is passed through a conical grinder equipped with a circular 18 mesh screen and a circular impeller. The blend is fed back into the conical blender. 3. The remaining 50% deuterated microcrystalline cellulose was sieved through a conical mill and added to the blender. The mixture was blended for 15 minutes. 4. Pass the final blend through a roller press. 5. The strip-shaped stream compacted by the roll is passed through a conical grinder equipped with a circular 16 mesh screen and a circular impeller. 6. Blend the ground material in a conical blender for 5 minutes to ensure homogeneity. 7. Use the sampler to remove the in-process inspection (IPC) sample from the conical blender. Perform a performance analysis on the sample.

B. Capsule filling (for all three drug strengths): 1. If the performance exceeds the 98% to 102% (w/w) nominal, then the capsule fill weight is adjusted. 2. Encapsulation of the material prepared using an automatic capsule filling machine. The prepared capsules are bottled and stored at 20 °F to 28 °F (68 °C to 82 °C) and ambient humidity.

The inclusion homogeneity and solubility were examined. The HPLC method was validated using an analyst, one design run per analyst, and met all required criteria for specificity, accuracy, accuracy, linearity, and sample stability.

The capsules can also be made according to the method described in Example 5 of PCT Application No. PCT/US2011/059643 (Publication No. WO 2012/061833), filed on Nov. 7, 2011.

While the foregoing examples have been described in detail by way of illustration and example

Claims (57)

A method of treating a true plethora (PV) in a subject, the method comprising orally administering to the individual an effective amount of the compound N-t-butyl-3-[(5-methyl-2-{[4-( 2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the individual suffers from PV, wherein N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl) An effective amount of the amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is from about 50 mg to about 400 mg per day, and wherein the weight is the free base portion weight of the compound. The method of claim 1, wherein the individual has a PV that is resistant to hydroxyurea treatment. The method of claim 1, wherein the individual is intolerant to hydroxyurea treatment. The method of any one of claims 1 to 3, wherein the individual has an increased risk of developing myelofibrosis. The method of claim 4, wherein the individual has at least one risk factor selected from the group consisting of: 1) having PV for at least 15 years, 2) having homozygous binding to the JAK2 V617F mutant dual gene, and 3) having elevated The serum lactate dehydrogenase content, and 4) have endogenous megakaryocyte community formation. The method of any one of claims 1 to 5, wherein the individual has been previously treated with rosolitinib. The method of any one of claims 1 to 6, further comprising monitoring a JAK2V617F mutant pair gene in the granulocyte of the individual. The method of any one of claims 1 to 7, further comprising monitoring the degree of STAT3 phosphorylation in the blood cell. The method of any one of claims 1 to 8, wherein the compound is administered orally at a dose of 50 mg per day. The method of any one of claims 1 to 8, wherein the compound is administered orally at a dose of 100 mg per day. The method of any one of claims 1 to 8, wherein the compound is administered orally at a dose of 200 mg per day. The method of any one of claims 1 to 8, wherein the compound is administered orally at a dose of 400 mg per day. The method of any one of claims 1 to 12, wherein the compound is administered for a period of at least 32 weeks. The method of any one of claims 1 to 13, wherein the compound is provided in a capsule comprising the following mixture: (i) the compound N-t-butyl-3-[(5-methyl-2-{ [4-(2-Pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, Ii) microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the mixture is contained in the capsule. The method of claim 14, wherein the capsule contains 50 mg or 100 mg of the compound, wherein the weight is the free base portion weight of the compound. The method of any one of claims 1 to 15, further comprising directing the individual to ingest the effective amount of the compound on an empty stomach. The method of any one of claims 1 to 16, further comprising directing the An agent that avoids taking up at least a moderate inducer or inhibitor of CYP3A4. The method of any one of claims 1 to 17, further comprising an agent that directs the individual to avoid ingesting at least a moderately inducing agent or inhibitor of CYP2C19. The method of any one of claims 1 to 18, wherein the individual has PV, and there is no myelofibrosis (MF) or acute myeloid leukemia. The method of any one of claims 1 to 19, wherein the compound is N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy) Phenyl]amino]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate. A kit comprising (a) a compound N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino) Pyrimidine-4-yl)amino]benzenesulfonamide, a pharmaceutically acceptable salt thereof or hydrate thereof, and (b) a package insert or label indicating i) that the compound is suitable for treating a patient The individual of the blood and ii) orally administering the compound to the individual at a dose of from about 50 mg to about 400 mg per day, wherein the weight is the free base portion weight of the compound. The kit of claim 21, wherein the package insert or the label indicates that the dose is 50 mg, 100 mg, 200 mg or 400 mg per day. The kit of claim 21 or 22, wherein the compound is in a capsule comprising a mixture of: (i) the compound N-t-butyl-3-[(5-methyl-2-{[4- (2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or hydrate thereof, (ii) micro Crystal cellulose, and (iii) sodium stearyl fumarate, wherein the mixture is contained in In the capsule. The kit of claim 23, wherein the capsule contains 50 mg or 100 mg of the compound, wherein the weight is the free base portion weight of the compound. The kit of any one of claims 21 to 24, wherein the package insert or the label indicates that the compound is suitable for treating an individual having a PV resistant to hydroxyurea treatment. The kit of any one of claims 21 to 24, wherein the package insert or the label indicates that the compound is suitable for treating an individual having PV, wherein the individual is intolerant to hydroxyurea treatment. The kit of any one of claims 21 to 26, wherein the package insert or the label indicates that the compound is suitable for treating an individual having an increased risk of developing myelofibrosis. The kit of claim 27, wherein the individual has at least one risk factor selected from the group consisting of: 1) having a plethora of at least 15 years, 2) having a homozygous binding to the JAK2 V617F mutant pair, 3 ) having elevated serum lactate dehydrogenase levels, and 4) having endogenous megakaryocyte community formation. The kit of any one of claims 21 to 28, wherein the package insert or the label indicates that the compound is suitable for treating an individual who has been previously treated with rosolizinib. The kit of any one of claims 21 to 29, wherein the compound is N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-yl) Oxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate. A method for treating essential thrombocytopenia (ET) in an individual, the method comprising orally administering to the individual an effective amount of the compound N-t-butyl-3-[(5-methyl-2-{[4 -(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the individual Having ET, wherein N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidine-4- An effective amount of the amino) benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is from about 50 mg to about 400 mg per day, and wherein the weight is the free base portion weight of the compound. The method of claim 31, wherein the individual has an ET that is resistant to hydroxyurea treatment. The method of claim 31, wherein the individual is intolerant to hydroxyurea treatment. The method of any one of claims 31 to 33, wherein the individual has an increased risk of developing myelofibrosis. The method of any one of claims 31 to 34, wherein the individual has been previously treated with rosolinib. The method of any one of claims 31 to 35, further comprising monitoring a JAK2V617F mutant pair gene in the granulocyte of the individual. The method of any one of claims 31 to 36, further comprising monitoring the degree of STAT3 phosphorylation in the blood of the individual. The method of any one of claims 31 to 37, wherein the compound is administered orally at a dose of 50 mg per day. The method of any one of claims 31 to 37, wherein the compound is administered orally at a dose of 100 mg per day. The method of any one of claims 31 to 37, wherein the compound is administered orally at a dose of 200 mg per day. The method of any one of claims 31 to 37, wherein the compound is administered orally at a dose of 400 mg per day. The method of any one of claims 31 to 41, wherein the compound is administered for a period of at least 32 weeks. The method of any one of claims 31 to 42, wherein the compound is provided in a capsule comprising a mixture of: (i) a compound N-t-butyl-3-[(5-methyl-2-{ [4-(2-Pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, Ii) microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the mixture is contained in the capsule. The method of claim 43, wherein the capsule contains 50 mg or 100 mg of the compound, wherein the weight is the free base portion weight of the compound. The method of any one of claims 31 to 44, further comprising directing the individual to ingest the effective amount of the compound on an empty stomach. The method of any one of claims 31 to 45, further comprising an agent that directs the individual to avoid ingesting at least a moderately inducing agent or inhibitor of CYP3A4. The method of any one of claims 31 to 46, further comprising an agent that directs the individual to avoid ingesting at least a moderately inducing agent or inhibitor of CYP2C19. The method of any one of clauses 31 to 47, wherein the individual has ET, There is no myelofibrosis (MF) or acute myeloid leukemia. The method of any one of claims 31 to 48, wherein the compound is N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy) Phenyl]amino]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate. A kit comprising (a) a compound N-t-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino) Pyrimidine-4-yl)amino] benzenesulfonamide, a pharmaceutically acceptable salt thereof or hydrate thereof, and (b) a package insert or label indicating i) that the compound is suitable for use in treating a primary The individual of sectocrombocytosis and ii) orally administering the compound to the individual at a dose of from about 50 mg to about 400 mg per day, wherein the weight is the free base portion weight of the compound. A kit of claim 50, wherein the package insert or the label indicates that the dose is 50 mg, 100 mg, 200 mg or 400 mg per day. A kit according to claim 50 or 51, wherein the compound is in a capsule comprising a mixture of: (i) compound N-t-butyl-3-[(5-methyl-2-{[4- (2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or hydrate thereof, (ii) micro Crystalline cellulose, and (iii) sodium stearyl fumarate, wherein the mixture is contained in the capsule. The kit of claim 52, wherein the capsule contains 50 mg or 100 mg of the compound, wherein the weight is the free base portion weight of the compound. The kit of any one of claims 50 to 53, wherein the package insert or the label indicates that the compound is suitable for treatment with a treatment of hydroxyurea Resistant ET or intolerant individuals. The kit of any one of claims 50 to 54, wherein the package insert or the label indicates that the compound is suitable for treating an individual having an increased risk of developing myelofibrosis. The kit of any one of claims 50 to 55, wherein the package insert or the label indicates that the compound is suitable for treating an individual who has been previously treated with rosolizinib. The kit of any one of claims 50 to 56, wherein the compound is N -tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-yl) Oxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.