JPWO2019232188A5 - - Google Patents

Description

In addition to those described herein, various modifications of the invention will be apparent to those skilled in the art from the above description. Such amendments are also intended to fall within the claims of the attachment. Each reference, including all patents, patent applications, and publications cited in this application, is incorporated herein by reference in its entirety.
The present application also includes the following aspects.
[Aspect 1]
A method of treating a patient's disease, wherein the disease is associated with aberrant expression or activity of PI3Kδ kinase, wherein the method is:
i) Administer the inhibitor of PI3Kδ to the patient at a first dosage of about 3 mg / day to about 50 mg / day over a first period of about 2 to about 12 weeks; and
ii) Less than the first dosage given to the patient at the end of the first period,
(A) Approximately 2.5 mg / day or less; or
(B) Approximately 50 mg / week or less,
Including the administration of a second dose of PI3Kδ inhibitor,
The method, wherein the second dosage is administered over a second period that occurs after the first period.
[Aspect 2]
The method according to aspect 1, wherein the first dosage is about 20 mg / day.
[Aspect 3]
The method according to aspect 1 or 2, wherein the first period is from about 8 weeks to about 12 weeks.
[Aspect 4]
The method according to aspect 1 or 2, wherein the first period is about 8 weeks.
[Aspect 5]
The method according to any one of aspects 1 to 4, wherein the first dosage is reduced during the first period.
[Aspect 6]
The method according to any one of aspects 1 to 5, wherein the second dosage is about 2.5 mg / day or less.
[Aspect 7]
The method according to any one of aspects 1 to 5, wherein the second dosage is about 2.5 mg / day.
[Aspect 8]
The method according to any one of aspects 1 to 5, wherein the second dosage is about 50 mg / week or less.
[Aspect 9]
The method according to any one of aspects 1 to 5, wherein the second dosage is about 20 mg / week.
[Aspect 10]
The method according to any one of aspects 1-9, wherein the second dosage is reduced during the second period.
[Aspect 11]
The method according to any one of aspects 1-10, wherein the patient has been identified as exhibiting one or more symptoms associated with an adverse event (TEAE) manifested under one or more treatments.
[Aspect 12]
Any of aspects 1-11, wherein the patient has been identified as exhibiting the one or more symptoms associated with an adverse event (TEAE) that occurred under one or more treatments during the first period. The method described in one.
[Aspect 13]
Aspects 1-12, wherein the first period ends when the patient is identified as exhibiting the one or more symptoms associated with an adverse event (TEAE) manifested under one or more treatments. The method according to any one of.
[Aspect 14]
The adverse events that occurred under one or more of the above treatments were diarrhea / colitis, nausea, fatigue, rash, neutrophilia, fever, hypotension, sepsis, dyspnea, pneumonia, pneumonia, hypertension, hypertension. Blood glucose, abdominal pain, bronchitis, dehydration, thrombocytopenia, cough, vomiting, loss of appetite, increased tearing, oral herpes, tachycardia, spinal cord compression, refractory pain, elevated alkaline phosphatase, elevated transaminase, hypertension Includes one or more of blood, hypercalcemia, diarrhea, alopecia, constipation, excess fluid, headache, hypopotassium, sleeping sweat, encephalopathy, atrial fibrillation, atrial fibrillation, and dyspnea. The method according to any one of aspects 1 to 13.
[Aspect 15]
The adverse events that occurred under one or more of the above treatments were diarrhea / colitis, chills, fatigue, rash, cough, vomiting, dizziness, fever, hypocytopenia, abdominal pain, constipation, loss of appetite, sleeping sweat, and itching. , A method according to any one of aspects 1 to 13, comprising one or more of back pain, chills, leukopenia, neutropenia, lymphopenia, thrombocytopenia, and anemia. ..
[Aspect 16]
The method of any one of embodiments 1-13, wherein the adverse event manifested under the one or more treatments comprises one or more of diarrhea / colitis and rash.
[Aspect 17]
In any one of embodiments 14-16, wherein the diarrhea / colitis comprises one or more of diarrhea, colitis, small bowel colitis, gastroenteritis, microscopic colitis, and cytomegalovirus colitis. The method described.
[Aspect 18]
The rash comprises one or more of exfoliative dermatitis, rash, erythema rash, mottled rash, mottled rash-like rash, pruritic rash, exfoliative rash, systemic rash, rash, and pustular rash. , The method according to any one of aspects 14 to 17.
[Aspect 19]
The method according to any one of aspects 14-18, wherein the neutropenia comprises febrile neutropenia.
[Aspect 20]
The method according to any one of aspects 14-19, wherein the increase in transaminase comprises an increase in alanine transaminase (ALT), an increase in aspartate transaminase (AST), or a combination thereof.
[Aspect 21]
The inhibitor of PI3Kδ is as follows:
4- {3- [1- (4-Amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl] -5-chloro-2-ethoxy-6-fluorophenyl} pyrrolidine -2-On; and
5- {3- [1- (4-Amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl] -5-chloro-2-ethoxy-6-fluorophenyl}- 1,3-Oxazolidine-2-one;
The method according to any one of aspects 1-20, which is selected from or is a pharmaceutically acceptable salt thereof.
[Aspect 22]
The inhibitor of PI3Kδ is 4-{3- [1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl] -5-chloro-2-ethoxy. The method according to any one of aspects 1-20, which is -6-fluorophenyl} pyrrolidine-2-one, or a pharmaceutically acceptable salt thereof.
[Aspect 23]
The inhibitor of PI3Kδ is (S) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl)). -5-Chloro-2-ethoxy-6-fluorophenyl) The method of embodiment 22, wherein pyrrolidine-2-one, or a pharmaceutically acceptable salt thereof.
[Aspect 24]
The inhibitor of PI3Kδ is (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl)). -5-Chloro-2-ethoxy-6-fluorophenyl) The method of embodiment 22, wherein pyrrolidine-2-one, or a pharmaceutically acceptable salt thereof.
[Aspect 25]
The inhibitor of PI3Kδ is (S) -4-(3-((R) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl)). -5-Chloro-2-ethoxy-6-fluorophenyl) The method of embodiment 22, wherein pyrrolidine-2-one, or a pharmaceutically acceptable salt thereof.
[Aspect 26]
The inhibitor of PI3Kδ is (R) -4-(3-((R) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl)). -5-Chloro-2-ethoxy-6-fluorophenyl) The method of embodiment 22, wherein pyrrolidine-2-one, or a pharmaceutically acceptable salt thereof.
[Aspect 27]
The inhibitor of PI3Kδ is 4-{3- [1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl] -5-chloro-2-ethoxy. The method according to aspect 22, which is a pharmaceutically acceptable salt of -6-fluorophenyl} pyrrolidine-2-one.
[Aspect 28]
The inhibitor of PI3Kδ is (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl)). -5-Chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride, according to aspect 27.
[Aspect 29]
The salt has a 1: 1 stoichiometric ratio of (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1). -Il) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one vs. hydrochloric acid, according to aspect 27.
[Aspect 30]
27. The method of aspect 27, wherein the salt is crystalline.
[Aspect 31]
The inhibitor of PI3Kδ is 5-{3- [1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl] -5-chloro-2-ethoxy. The method according to any one of aspects 1 to 20, which is -6-fluorophenyl} -1,3-oxazolidine-2-one, or a pharmaceutically acceptable salt thereof.
[Aspect 32]
The inhibitor of PI3Kδ is (R) -5-{3-[(R) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl]. -5-Chloro-2-ethoxy-6-fluorophenyl} -1,3-oxazolidine-2-one, or a pharmaceutically acceptable salt thereof, according to aspect 31.
[Aspect 33]
The inhibitor of PI3Kδ is (R) -5-{3-[(S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl]. -5-Chloro-2-ethoxy-6-fluorophenyl} -1,3-oxazolidine-2-one, or a pharmaceutically acceptable salt thereof, according to aspect 31.
[Aspect 34]
The inhibitor of PI3Kδ is (S) -5-{3-[(S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl]. -5-Chloro-2-ethoxy-6-fluorophenyl} -1,3-oxazolidine-2-one, or a pharmaceutically acceptable salt thereof, according to aspect 31.
[Aspect 35]
The inhibitor of PI3Kδ is (S) -5-{3-[(R) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl]. -5-Chloro-2-ethoxy-6-fluorophenyl} -1,3-oxazolidine-2-one, or a pharmaceutically acceptable salt thereof, according to aspect 31.
[Aspect 36]
The diseases include chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hodgkin lymphoma (HL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). , And Waldenström macroglobulinemia (WM), according to any one of aspects 1-35.
[Aspect 37]
36. The method of aspect 36, wherein the marginal zone lymphoma (MZL) is selected from extranodal MZL, nodal MZL, spleen MZL, and unknown MZL subtypes.
[Aspect 38]
36. The method of aspect 36, wherein the Hodgkin lymphoma (HL) is selected from classical Hodgkin lymphoma (HL) and nodular lymphocyte-predominant HL.
[Aspect 39]
The diffuse large B-cell lymphomas are activated B-cell-like (ABC) diffuse large B-cell lymphoma (ABC-DLBCL) and germinal center B-cell (GCB) diffuse large B-cell lymphoma (GCB). -The method of aspect 36, selected from DLBCL).
[Aspect 40]
A method of treating a patient's disease, the disease being chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) follicular lymphoma (FL) hodgkin lymphoma (HL), mantle cell lymphoma. (MCL), marginal zone lymphoma (MZL), and Waldenström macroglobulinemia (WM) are selected from the following methods:
i) In the patient, (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl)- 5-Chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride in a first dosage of about 20 mg / day to about 50 mg / day for a first period of about 8 to about 9 weeks Administer over; and
ii) For the patient, a second dosage of about 2.5 mg / day or less said (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo] [3. , 4-d] Pyrimidine-1-yl) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride to be administered over the second period that occurs after the first period. The above-mentioned method.
[Aspect 41]
A method of treating a patient's disease, the disease being chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) follicular lymphoma (FL) hodgkin lymphoma (HL), mantle cell lymphoma. (MCL), marginal zone lymphoma (MZL), and Waldenström macroglobulinemia (WM) are selected from the following methods:
i) In the patient, (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl)- 5-Chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride in a first dosage of about 20 mg / day to about 50 mg / day for a first period of about 8 to about 9 weeks Administer over; and
ii) For the patient, a second dosage of about 20 mg / week to about 50 mg / week, said (R) -4- (3-((S) -1- (4-amino-3-methyl-1H-pyrazolo). [3,4-d] Pyrimidine-1-yl) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride is administered over the second period that occurs after the first period. The method described above, comprising:
[Aspect 42]
A method of treating a patient's disease, the disease being chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) follicular lymphoma (FL) hodgkin lymphoma (HL), mantle cell lymphoma. (MCL), marginal zone lymphoma (MZL), and Waldenström macroglobulinemia (WM) are selected from the following methods:
i) In the patient, (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl)- 5-Chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride is administered at a first dose of about 20 mg / day over a first period of about 8 weeks; and
ii) For the patient, a second dosage of about 2.5 mg / day said (R) -4- (3-((S) -1- (4-amino-3-methyl-1H-pyrazolo] [3. 4-d] Pyrimidine-1-yl) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride to be administered over the second period that occurs after the first period. Included, said method.
[Aspect 43]
A method of treating a patient's disease, the disease being chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) follicular lymphoma (FL) hodgkin lymphoma (HL), mantle cell lymphoma. (MCL), marginal zone lymphoma (MZL), and Waldenström macroglobulinemia (WM) are selected from the following methods:
i) In the patient, (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl)- 5-Chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride is administered at a first dose of about 20 mg / day over a first period of about 8 weeks; and
ii) For the patient, a second dosage of about 20 mg / week, said (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo] [3,4- d] Pyrimidine-1-yl) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride comprising administration over a second period that occurs after the first period. The method.
[Aspect 44]
A method of treating a patient's disease, wherein the disease is associated with aberrant expression or activity of PI3Kδ kinase, wherein the method is:
i) Administer the inhibitor of PI3Kδ to the patient at a first dosage of about 3 mg / day to about 50 mg / day over a first period of about 2 to about 12 weeks; and
ii) The patient receives the inhibitor of PI3Kδ in a second dosage of about 2.5 mg / day to about 7.5 mg / day, which is less than the first dosage administered at the end of the first period. Including doing
The method, wherein the second dosage is administered over a second period that occurs after the first period.
[Aspect 45]
44. The method of aspect 44, wherein the second dosage is from about 3.0 mg / day to about 7.0 mg / day.
[Aspect 46]
44. The method of aspect 44, wherein the second dosage is from about 4.0 mg / day to about 6.0 mg / day.
[Aspect 47]
44. The method of aspect 44, wherein the second dosage is about 5.0 mg / day.
[Aspect 48]
The inhibitor of PI3Kδ is (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl)). The method according to any one of aspects 44-47, which is a 5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride.
[Aspect 49]
The diseases include chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hodgkin lymphoma (HL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). , And Waldenström macroglobulinemia (WM), according to any one of embodiments 44-48.
[Aspect 50]
49. The method of aspect 49, wherein the marginal zone lymphoma (MZL) is selected from extranodal MZL, nodal MZL, spleen MZL, and unknown MZL subtypes.
[Aspect 51]
49. The method of aspect 49, wherein the Hodgkin lymphoma (HL) is selected from classical Hodgkin lymphoma (HL) and nodular lymphocyte-predominant HL.
[Aspect 52]
The diffuse large B-cell lymphomas are activated B-cell-like (ABC) diffuse large B-cell lymphoma (ABC-DLBCL) and germinal center B-cell (GCB) diffuse large B-cell lymphoma (GCB). -The method of aspect 49, selected from DLBCL).

Claims (52)

A drug comprising a PI3Kδ inhibitor for treating a patient's disease, wherein the disease is associated with aberrant expression or activity of PI3Kδ kinase .
i ) The PI3K δ inhibitor is administered to the patient at a first dose of about 3 mg / day to about 50 mg / day over a first period of about 2 to about 12 weeks ;
ii) The PI3Kδ inhibitor is less than the first dosage given to the patient at the end of the first period.
(A) Approximately 2.5 mg / day or less; or (b) administered at a second dosage of approximately 50 mg / week or less.
Characterized by being used in
The medicine, characterized in that the said medicine is used such that the second dosage is administered over a second period that occurs after the first period. The medicine according to claim 1, wherein the first dosage is about 20 mg / day. The medicine according to claim 1 or 2, wherein the first period is about 8 to about 12 weeks. The medicine according to claim 1 or 2, wherein the first period is about 8 weeks. The medicine according to any one of claims 1 to 4, wherein the first dosage is reduced during the first period. The drug according to any one of claims 1 to 5, wherein the second dosage is about 2.5 mg / day or less. The drug according to any one of claims 1 to 5, wherein the second dosage is about 2.5 mg / day. The drug according to any one of claims 1 to 5, wherein the second dosage is about 50 mg / week or less. The drug according to any one of claims 1 to 5, wherein the second dosage is about 20 mg / week. The medicine according to any one of claims 1 to 9, wherein the second dosage is reduced during the second period. The pharmaceutical according to any one of claims 1 to 10, wherein the patient has been identified as exhibiting one or more symptoms associated with an adverse event (TEAE) manifested under one or more treatments. 1 _ The drug described in the section. 25 . The drug according to any one of the above. The adverse events that occurred under one or more of the above procedures were diarrhea / colitis, nausea, fatigue, rash, neutrophilia, fever, hypotension, sepsis, dyspnea, pneumonia, pneumonia, hypertension, hypertension. , Abdominal pain, bronchitis, dehydration, thrombocytopenia, cough, vomiting, loss of appetite, increased tearing, oral herpes, tachycardia, spinal cord compression, refractory pain, elevated alkaline phosphatase, elevated transaminase, hypertension Claims comprising one or more of illness, hypercalcemia, diarrhea, alopecia, constipation, excess fluid, headache, hypopotassium, sleeping sweat, encephalopathy, atrial fibrillation, atrial fibrillation, and dyspnea. The drug according to any one of 1 to 13. The adverse events that occurred under one or more of the above treatments were diarrhea / colitis, chills, fatigue, rash, cough, vomiting, dizziness, fever, hypopotassium, abdominal pain, constipation, loss of appetite, sleeping sweat, itching, The pharmaceutical according to any one of claims 1 to 13, which comprises one or more of back pain, chills, leukopenia, neutropenia, lymphopenia, thrombocytopenia, and anemia. The pharmaceutical according to any one of claims 1 to 13, wherein the adverse event manifested under the one or more treatments comprises one or more of diarrhea / colitis and rash. 13 . The listed medicine . The rash comprises one or more of exfoliative dermatitis, rash, erythema rash, mottled rash, mottled scaly rash, pruritic rash, exfoliative rash, systemic rash, rash, and pustular rash. The medicine according to any one of claims 14 to 17. The apparatus according to any one of claims 14 to 18, wherein the neutropenia comprises febrile neutropenia . The pharmaceutical according to any one of claims 14 to 19, wherein the increase in transaminase comprises an increase in alanine transaminase (ALT), an increase in aspartate transaminase (AST), or a combination thereof. The PI3K δ inhibitor is as follows:
4- {3- [1- (4-Amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl] -5-chloro-2-ethoxy-6-fluorophenyl} pyrrolidine -2-one; and 5- {3- [1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl] -5-chloro-2-ethoxy- 6-Fluorophenyl} -1,3-oxazolidine-2-one;
The medicine according to any one of claims 1 to 20, which is selected from the above or is a pharmaceutically acceptable salt thereof. The PI3K δ inhibitor is 4- {3- [1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl] -5-chloro-2-. The pharmaceutical according to any one of claims 1 to 20, which is ethoxy-6-fluorophenyl} pyrrolidine-2-one or a pharmaceutically acceptable salt thereof. The PI3K δ inhibitor is (S) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) ethyl. )-5-Chloro-2-ethoxy-6-fluorophenyl) The pharmaceutical according to claim 22, which is pyrrolidine-2-one, or a pharmaceutically acceptable salt thereof. The PI3K δ inhibitor is (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) ethyl. )-5-Chloro-2-ethoxy-6-fluorophenyl) The pharmaceutical according to claim 22, which is pyrrolidine-2-one, or a pharmaceutically acceptable salt thereof. The PI3K δ inhibitor is (S) -4-(3-((R) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) ethyl. )-5-Chloro-2-ethoxy-6-fluorophenyl) The pharmaceutical according to claim 22, which is pyrrolidine-2-one, or a pharmaceutically acceptable salt thereof. The PI3K δ inhibitor is (R) -4-(3-((R) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) ethyl. )-5-Chloro-2-ethoxy-6-fluorophenyl) The pharmaceutical according to claim 22, which is pyrrolidine-2-one, or a pharmaceutically acceptable salt thereof. The PI3K δ inhibitor is 4- {3- [1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl] -5-chloro-2-. 22. The pharmaceutical agent of claim 22, which is a pharmaceutically acceptable salt of ethoxy-6-fluorophenyl} pyrrolidine-2-one. The PI3K δ inhibitor is (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) ethyl. )-5-Chloro-2-ethoxy-6-fluorophenyl) The pharmaceutical according to claim 27, which is pyrrolidine-2-one hydrochloride. The salt is ( R) -4- (3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5. The pharmaceutical according to claim 27, wherein the chemical ratio of chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one to hydrochloric acid is 1: 1 . The pharmaceutical according to claim 27, wherein the salt is crystalline. The PI3K δ inhibitor is 5-{3- [1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl] -5-chloro-2-. The pharmaceutical according to any one of claims 1 to 20, which is ethoxy-6-fluorophenyl} -1,3-oxazolidine-2-one, or a pharmaceutically acceptable salt thereof. The PI3K δ inhibitor is (R) -5-{3-[(R) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl). ] -5-Chloro-2-ethoxy-6-fluorophenyl} -1,3-oxazolidine-2-one, or a pharmaceutically acceptable salt thereof, according to claim 31. The PI3K δ inhibitor is (R) -5-{3-[(S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl). ] -5-Chloro-2-ethoxy-6-fluorophenyl} -1,3-oxazolidine-2-one, or a pharmaceutically acceptable salt thereof, according to claim 31. The PI3K δ inhibitor is (S) -5-{3-[(S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl). ] -5-Chloro-2-ethoxy-6-fluorophenyl} -1,3-oxazolidine-2-one, or a pharmaceutically acceptable salt thereof, according to claim 31. The PI3K δ inhibitor is (S) -5-{3-[(R) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl). ] -5-Chloro-2-ethoxy-6-fluorophenyl} -1,3-oxazolidine-2-one, or a pharmaceutically acceptable salt thereof, according to claim 31. The diseases include chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hodgkin lymphoma (HL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). , And Waldenström macroglobulinemia (WM), according to any one of claims 1-35 . 36. The pharmaceutical according to claim 36, wherein the marginal zone lymphoma (MZL) is selected from extranodal MZL, nodal MZL, spleen MZL, and unknown MZL subtypes. The pharmaceutical according to claim 36, wherein the Hodgkin lymphoma (HL) is selected from classical Hodgkin lymphoma (HL) and nodular lymphocyte-predominant HL. The diffuse large B-cell lymphomas are activated B-cell-like (ABC) diffuse large B-cell lymphoma (ABC-DLBCL) and germinal center B-cell (GCB) diffuse large B-cell lymphoma (GCB). -The pharmaceutical according to claim 36, selected from DLBCL). (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl)) for treating the patient's disease It is a drug containing ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride , and the disease is chronic lymphocytic leukemia (CLL), diffuse large cell type B cell. Lymphoma (DLBCL) Follicular lymphoma (FL) Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), marginal zone lymphoma ( MZL ), and Waldenström macroglobulinemia (WM). ,
i ) ( R ) -4- (3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-chloro -2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride is given to the patient at a first dose of about 20 mg / day to about 50 mg / day for a first dose of about 8 to about 9 weeks. Administered over a period of time; then
ii) (R) -4- (3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-chloro -2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride is administered to the patient at a second dosage of about 2.5 mg / day or less over the second period that occurs after the first period. Be done
The above-mentioned medicine , which is characterized in that it is used as described above. (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl)) for treating the patient's disease It is a drug containing ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride , and the disease is chronic lymphocytic leukemia (CLL), diffuse large cell type B cell. Lymphoma (DLBCL) Follicular lymphoma (FL) Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), marginal zone lymphoma ( MZL ), and Waldenström macroglobulinemia (WM). ,
i ) ( R ) -4- (3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-chloro -2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride is given to the patient at a first dose of about 20 mg / day to about 50 mg / day for a first dose of about 8 to about 9 weeks. Administered over a period of time; then
ii) (R) -4- (3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-chloro A second period in which -2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride occurs in the patient at a second dosage of about 20 mg / week to about 50 mg / week after the first period. Administered over
The above-mentioned medicine , which is characterized in that it is used as described above. (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl)) for treating the patient's disease It is a drug containing ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride , and the disease is chronic lymphocytic leukemia (CLL), diffuse large cell type B cell. Lymphoma (DLBCL) Follicular lymphoma (FL) Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), marginal zone lymphoma ( MZL ), and Waldenström macroglobulinemia (WM). ,
i ) ( R ) -4- (3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-chloro -2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride was administered to the patient at a first dose of about 20 mg / day over a first period of about 8 weeks ;
ii) (R) -4- (3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-chloro -2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride is administered to the patient at a second dosage of about 2.5 mg / day over the second period that occurs after the first period. Ru
The above-mentioned medicine , which is characterized in that it is used as described above. (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl)) for treating the patient's disease It is a drug containing ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride , and the disease is chronic lymphocytic leukemia (CLL), diffuse large cell type B cell. Lymphoma (DLBCL) Follicular lymphoma (FL) Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), marginal zone lymphoma ( MZL ), and Waldenström macroglobulinemia (WM). ,
i ) ( R ) -4- (3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-chloro -2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride was administered to the patient at a first dose of about 20 mg / day over a first period of about 8 weeks ;
ii) (R) -4- (3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) -5-chloro -2-ethoxy-6-fluorophenyl) pyrrolidine-2-one hydrochloride is administered to the patient at a second dosage of about 20 mg / week over the second period that occurs after the first period.
The above-mentioned medicine , which is characterized in that it is used as described above. A drug comprising a PI3Kδ inhibitor for treating a patient's disease, wherein the disease is associated with aberrant expression or activity of PI3Kδ kinase .
i ) The PI3Kδ inhibitor is administered to the patient at a first dose of about 3 mg / day to about 50 mg / day over a first period of about 2 to about 12 weeks;
ii) The PI3Kδ inhibitor is less than the first dosage given to the patient at the end of the first period, at a second dosage of about 2.5 mg / day to about 7.5 mg / day. Be administered
Characterized by being used in
The drug , wherein the second dosage is used such that it is administered over a second period that occurs after the first period. The medicine according to claim 44, wherein the second dosage is from about 3.0 mg / day to about 7.0 mg / day. The medicine according to claim 44, wherein the second dosage is from about 4.0 mg / day to about 6.0 mg / day. The medicine according to claim 44, wherein the second dosage is about 5.0 mg / day. The PI3K δ inhibitor is (R) -4-(3-((S) -1- (4-amino-3-methyl-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) ethyl. )-5-Chloro-2-ethoxy-6-fluorophenyl) The pharmaceutical according to any one of claims 44 to 47, which is pyrrolidine-2-one hydrochloride. The diseases include chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hodgkin lymphoma (HL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). , And Waldenström macroglobulinemia (WM), according to any one of claims 44-48 . The pharmaceutical according to claim 49, wherein the marginal zone lymphoma (MZL) is selected from extranodal MZL, nodal MZL, spleen MZL, and unknown MZL subtypes. The pharmaceutical according to claim 49, wherein the Hodgkin lymphoma (HL) is selected from classical Hodgkin lymphoma (HL) and nodular lymphocyte-predominant HL. The diffuse large B-cell lymphomas are activated B-cell-like (ABC) diffuse large B-cell lymphoma (ABC-DLBCL) and germinal center B-cell (GCB) diffuse large B-cell lymphoma (GCB). -The pharmaceutical according to claim 49, selected from DLBCL).