Bruton's tyrosine kinase inhibitor dosing

Abstract

Provided are Bruton's tyrosine kinase (BTK) inhibitors that exhibit inhibitory activity against resistant mutants of BTK and a favorable tolerability profile, as well as methods for treating cancer (particularly lymphoma and leukemia) and autoimmune diseases using said inhibitors. The present invention provides a method for administering a dose of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.

Description

[Technical field]

[0001] The present invention relates to (S)-5-amino-3-amino-p-tolyl-p-tolyl esters for the treatment of conditions such as cancer and autoimmune diseases. -(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1 ,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide or a pharma- ceutically acceptable salt thereof. [Background technology]

[0002] Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase related to src. BTK is a member of the IL-1 c family. It is involved in the development of normal white blood cells known as B cells. It plays a key role in the B cell antigen receptor signaling pathway required for activation and survival. BTK also plays an important role in the proliferation and survival of various B cell malignancies. Thus, BTK inhibits, for example, the proliferation and proliferation of mature B-cell non-Hodgkin's Lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, Waldenstrom's macroglottis Globulinemia, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma A number of idiopathic leukemias, including idiopathic leukemia, B-cell prolymphocytic leukemia, hairy cell leukemia, and marginal zone lymphoma. It is a useful molecular target for the treatment of a range of B-cell leukemias and lymphomas.

[0003] B cells are a major cause of chronic graft-versus-host disease (CGVHD), a life-threatening complication of allogeneic stem cell transplantation. It has also been reported that it plays a prominent role in the development of cGVHD and is thought to be effective in preventing cGVHD. This has prompted research into B-cell targeted therapies for the treatment of rheumatoid arthritis and the associated inflammatory bowel disease. It has variable efficacy in refractory cGVHD and may help prevent its development. In addition, ibrutinib, a covalent BTK inhibitor, has shown efficacy in refractory cGVHD in 20 It was approved by the US FDA in 2017.

[0004] (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl (phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo BTK-I and its compounds The physiologically acceptable salts are disclosed in WO17 / 103611 and WO It is disclosed in 2020 / 028258.

[0005] Many patients treated with BTK inhibitors for cancer, especially BTK-mediated cancers, experience severe or are refractory or unable to undergo further treatment due to potentially life-threatening recurrence or adverse events For example, the BTK inhibitor ibrutinib has been shown to reduce the number of cases of refractory or intolerant cancers. Treated patients may become resistant and / or intolerant to further treatment. ato A.,et al.,“Toxicities and Outcomes o f 616 Ibrutinib-Treated Patients in the United States:A Real-World Analysis”,Hae matologica, 2018, 103(5), 874-879). In patients, increasing the dose of ibrutinib to overcome resistance may be necessary, as it may reduce neutropenia. , thrombocytopenia, diarrhea, anemia, musculoskeletal pain, rash, nausea, bruising, fatigue, bleeding, and vomiting. Toxicity associated with ibrutinib, including fever, may not be a viable option. do.

[0006] As described by Mato (2018), in the case of ibrutinib, toxicity was This was the most common reason for discontinuation in the setting, accounting for 63.1% of discontinuations in field use, and relapse. Toxicity accounted for 50.2% of discontinuations in both commercial and refractory (R / R) use. It was the most common reason for discontinuation in several settings, including commercial and clinical trial use. 50% of discontinuations in clinical trials, 77.7% of discontinuations in clinical trials, R / 52.5% of discontinuations in R commercial use and 3.5% of discontinuations in R / R clinical use Ibrutinib toxicities leading to dose interruptions and treatment discontinuation included joint pain and Symptoms include nausea, vomiting, atrial fibrillation, rash, cytopenias, infections, pneumonia, bleeding, and diarrhea. These toxicities may be due to on-target BTK inhibition and off-target inhibition of other kinases, such as Tec. Of note, discontinuation due to progressive disease (PD) was due to both vasopressin and vasopressin-dependent inhibition of vasopressin. The percentages were low at 15.8% in field settings and 20.9% in R / R use. Richter transformation to malignant large B-cell lymphoma or Hodgkin lymphoma is a common pathology in the field setting. This accounted for 5.3% of discontinuations in the primary setting and 5.0% in the R / R setting. The starting dose of nib (420 mg / day vs. <420 mg / day) was associated with a lower incidence of toxicity (51% vs. 50%) and Proportion of patients who discontinued ibrutinib due to progression or disease (19.6% vs. 21.4%) A retrospective analysis of the RESONATE trial showed that ibrutinib dose intensity Progression-free survival (PF) in R / R chronic lymphocytic leukemia patients with low dose interruption for more than 7 days S), which suggests that toxic treatment interruptions may adversely affect long-term outcomes. Preclinical studies suggest that it is more selective for off-target disease than ibrutinib. Acalabrutinib, a potent BTK inhibitor, has demonstrated some toxicity (e.g., cardiac toxicity) in clinical trials. Although it was associated with an overall reduction in the frequency of adverse events (e.g., atrial fibrillation, major bleeding), other toxicities (e.g., There was no association with cytopenia, upper respiratory tract infection, or diarrhea (Byrd, Furman et al.N Engl J Med(July 4,2013),369:32- 42, Byrd, Harrington et al. N Engl J Med(Ja Nuary 28,2016);374:323-332). Summary of the Invention

[0007] There remains a need to provide alternative therapeutic approaches to patients suffering from cancer and autoimmune diseases. In addition, there remains a need to provide alternative therapies for patients with cGVHD. There is a need for alternatives, particularly for patients who develop resistance or intolerance to current therapies. and provide an alternative therapeutic approach that is active against resistant mutants of BTK and has better efficacy. To provide an alternative BTK inhibitor with a favorable tolerability profile or to reduce adverse events An alternative that allows for maximal BTK inhibition with limited events and fewer interruptions or discontinuations There remains a need to provide treatment that can

[0008] During human clinical trials, administration of BTK-I has been shown to be effective in treating cancers with anti-cancer drugs such as ibrutinib and acalabrutinib. The severity of adverse events observed with other BTK inhibitors, e.g., severe leukopenia, Neutropenia, decreased platelet count, reticulocyte count, and red blood cell mass consistent with bone marrow suppression / toxicity In addition, it did not induce atrial fibrillation, bleeding, cytopenia, or arrhythmia. (Mato A., et al., “Toxicities and Outcomes of 616 I brutinib-Treated Patients in the United States:A Real-World Analysis”,Haematolog ica,2018,103(5),874-879. March 21, 2019 to March 202 Between September 27, 2000 and September 27, 323 patients received 25 mg to 300 mg once daily (QD). Across seven dose levels ranging from 0.01 to 0.25 QD, ≥10% of patients (n=323) The only treatment-emergent adverse event, regardless of attribute or grade, was fatigue (n=10). 65, 20%), diarrhea (n=55, 17%), and bruising (n=42, 13%). 121 patients with chronic lymphocytic leukemia (CLL) treated with efficacy-evaluable cBTKi In patients (median prior line = 4), the overall response rate (ORR) was 62% (95% CI: 53-99.9%). 71) and increased to 84% in patients followed up for 10 months. cBTKi resistance (67%, 53 / 79) and cBTKi intolerance (52%, 22 / 42) , BTK C481 mutant (71%, 17 / 24), and BTK wild-type (66%, 43 / 65) with chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SL L)) were similar in 52 efficacy-evaluable cBTKi-treated patients. In patients with MCL, the ORR was 52% (95% CI: 38-66). Of 117 CLL or MCL patients who responded, all but eight remained progression-free. Waldenström's macroglobulinemia (WM) (n=19, ORR 68%) and Responses were also observed in patients with follicular lymphoma (FL) (n=8, ORR 50%). , dose interruption, dose reduction, and permanent discontinuation due to drug-related adverse events (AEs), respectively. , observed in 8.0% (26 patients), 2.2% (7 patients), and 1.5% (5 patients) of patients. .

[0009] Atrial arrhythmias and bleeding are two serious adverse events associated with discontinuation of covalent BTK inhibitors. In the overall safety population of 323 patients, atrial fibrillation / flutter occurred in 2 patients (0.6%). Both events were grade 2 and were observed only in patients with atrial fibrillation. The pulmonary circulation was considered to be unrelated to BTK-I for various reasons. Only one patient had a persistent pulmonary embolism during a bicycle accident. In total, 18 patients experienced grade 3 bleeding, including cardiac arrest and subarachnoid hemorrhage. Previous BTK inhibitors were discontinued due to vascular toxicity (15 patients) or bleeding (3 patients). No TK-I patients experienced a recurrence of these events.

[0010] The present invention relates to a method for treating cancer or an autoimmune disease in a patient in need thereof. In one embodiment, the method comprises administering to the patient a compound that is BTK-I or a pharma- ceutical acceptable salt thereof. The method includes administering to the patient a daily dose of about 120 mg to about 600 mg of the salt. Typically, the daily dose is between about 125 mg and about 600 mg. Preferably, the method is for treating cancer. Preferably, the compound is BTK-I. Preferably, the patient is a patient with relapsed or refractory Preferably, the patient is treatment naive. Preferably, the patient is Prior anticancer therapy. Preferably, the patient is receiving at least one B have received at least one prior anticancer therapy, including a TK inhibitor-based therapy. Preferably, the patient has not received prior anti-cancer therapy including a BTK inhibitor. Patients have had one prior anti-cancer therapy. Preferably, patients have had two prior anti-cancer therapies. Preferably, the patient has undergone two or more prior anticancer therapies. , concomitant use of B-cell lymphoma type 2 (BCL-2) inhibitors and / or anti-CD20-based therapies Preferably, the anti-CD20 based therapy is administered in the first It is administered on day 1, or as a split dose on days 1 and 2 of a 28 day cycle. For example, anti-CD20-based therapy is administered at approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 or as split doses on days 1 and 2. Baseline therapy was administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. and then anti-CD20-based therapy is administered on day 1 or any subsequent day. Either not administered at all during each of the subsequent cycles. The 2 inhibitor is administered during the fourth 28-day cycle. Preferably, the anti-CD20 based therapy is , administered on day 1 or as a split dose on days 1 and 2 of the first 28-day cycle; Anti-CD20-based therapy is then administered on day 1 or on each of any subsequent cycles. The BCL-2 inhibitor was administered either in the fourth 28-day cycle or not at all in between. Preferably, BTK-I is administered daily starting on day 1, and anti-CD20 Baseline therapy was administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. and anti-CD20-based therapy is then administered on day 1 or any subsequent day. During each of the subsequent cycles, the BCL-2 inhibitor is either not administered at all or not at all. The BCL-2 inhibitor is preferably venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the BCL-2 inhibitor is an anti-CD20-based Preferably, the anti-CD20 based therapy is obinutuzumab. Preferably, the anti-CD20 based therapy is selected from the group consisting of rituximab, cyclophosphamide, and doxorubicin. xorubicin hydrochloride, vincristine sulfate, and prednisone (such therapy Rituximab is preferably administered daily for 1 day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is administered in one dose or as a split dose on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on days 1 ± 3 of an initial 28-day cycle. 2 in, Or as a split dose on days 1 and 2. Preferably, rituximab is administered Approximately 375 mg / m on day 1 of the first 28-day cycle 2 or for splitting on days 1 and 2 Rituximab is then administered at approximately 500 mg / m on day 1. 2 Administered at or not at all during each of any subsequent cycles. For the fourth 28-day cycle, venetoclax is administered at a dose of approximately 20 mg on days 1 to 7 of the cycle and 10 mg on days 1 to 7 of the cycle. Approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and approximately 200 mg on days 22-24 of the cycle. Approximately 200 mg is administered on day 28, followed by approximately 400 mg for any subsequent cycles. Preferably, rituximab is administered daily at about 375 mg / kg on day 1 of the first 28-day cycle. mg / m 2 or as split doses on days 1 and 2. Rituximab is Then, about 500 mg / m on day 1 2 or during each of any subsequent cycles. VENCLEXTA was administered circa 48-day cycles or not at all during the fourth 28-day cycle. Approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 15-21 of the cycle. Approximately 100 mg is administered on days 22-28 of the cycle, and approximately 200 mg on days 22-28 of the cycle. For each subsequent cycle, the BTK-I is dosed at about 400 mg daily. 00 mg daily, and rituximab is administered at approximately 375 mg / day on day 1 of the first 28-day cycle. m 2 or as split doses on days 1 and 2, and rituximab is then administered , approximately 500 mg / m on day 1 2 or during each of any subsequent cycles. VENCLEXTA was administered either once or twice daily during the fourth 28-day cycle. ~20 mg on day 7, ~50 mg on days 8-14 of the cycle, ~1 mg on days 15-21 of the cycle 00 mg on days 22-28 of the cycle, and approximately 200 mg on days 22-28 of the cycle, and then Subsequent cycles are also administered at approximately 400 mg daily.

[0011] The present invention also relates to methods for treating and / or preventing the proliferation and / or proliferation of activated B cells in patients with BTK-mediated cancers. or a method of inhibiting survival, comprising administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of BTK. -I, or a pharma- ceutical acceptable salt thereof, is administered to a subject who is suffering from BTK-mediated cancer progression or unacceptable toxicity. orally administering to the subject a therapeutically effective amount of the compound or or a salt thereof, at steady state in patients 24 hours after administration, is greater than 90 percent of the BTK In one embodiment, the method comprises administering to the subject a therapeutically effective amount of a medicament for use in a method for treating a chronic inflammatory disease, the method comprising administering to the subject a therapeutically effective amount of a medicament ... Preferably, the compound is BTK-I. Preferably, the patient is suffering from relapsed or refractory Preferably, the patient is treatment naive. Preferably, the patient has at least one Preferably, the patient has received at least one BTK inhibitor-based anticancer therapy. Preferably, the patient has received at least one prior anti-cancer therapy, including chemotherapy. Preferably, the patient has not received any prior anti-cancer therapy including an inhibitor. Preferably, the patient has undergone two prior anti-cancer therapies. In another embodiment, the method comprises administering to a patient suffering from B-cell lymphoma 2 ( Concurrent, separate, or sequential administration of BCL-2 inhibitors and / or anti-CD20-based therapies Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28 day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0012] The method also includes administering to a subject a therapeutically effective amount of BTK-mediated cancer, such as a BTK-mediated cancer, or a combination thereof. or a method of inhibiting survival, comprising administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of BTK. -I, or a pharma- ceutical acceptable salt thereof, is administered to a subject who is suffering from BTK-mediated cancer progression or unacceptable toxicity. orally administering in successive daily dose regimens until The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Preferably, the compound is BTK-I. Preferably, the patient is Preferably, the patient is treatment naïve. Preferably, the patient is: At least one prior anticancer therapy has been administered. Preferably, the patient has received at least one prior anticancer therapy. The patient has received at least one prior anti-cancer therapy, including a K inhibitor-based therapy. The patient has not received any prior anti-cancer therapy including a BTK inhibitor. Prior anti-cancer therapy. Preferably, the patient has received two prior anti-cancer therapies. In another embodiment, the method comprises administering to the patient a B cell Concurrent, separate, or concurrent use of BCL-2 inhibitors and / or anti-CD20-based therapies or continuous administration. Preferably, the anti-CD20 based therapy is administered for the first 28 days. The antibody is administered on day 1 of the treatment phase or as a split dose on days 1 and 2 of the treatment phase. CD20-based therapy is administered at approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 So, or as split doses on days 1 and 2. Preferably, the anti-CD20 based Therapy is administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. and then anti-CD20-based therapy is administered on day 1 or on day 2 of any subsequent cycles. Either not administered at all between each other. is administered during the fourth 28-day cycle. Preferably, the anti-CD20 based therapy is administered during the first Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, anti-CD2 0-based therapy may then be administered on day 1 or during each of any subsequent cycles. or not at all, and a BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, BTK-I is administered daily starting on day 1, and anti-CD20-based Therapy is administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. and anti-CD20-based therapy is then administered on day 1 or on day 2 of any subsequent cycle. Either not administered at all between each, and the BCL-2 inhibitor was administered in the fourth 28 The BCL-2 inhibitor is preferably venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20 based therapy is Preferably, the anti-CD20 based therapy is obinutuzumab. Preferably, the anti-CD20 based therapy is R-CHOP. , approximately 375 mg / m on day 1 of the first 28-day cycle 2 or split into days 1 and 2 Preferably, rituximab is administered on day 1 ± 3 of the first 28-day cycle. Approximately 375 mg / m 2The dose is administered in one dose, or as a split dose on days 1 and 2. Rituximab should be administered at a dose of approximately 375 mg / m on day 1 of the first 28-day cycle. 2 In or 1 Rituximab is then administered approximately 50 mg on day 1. 0 mg / m 2 or not at all during each of any subsequent cycles Preferably, venetoclax is administered during cycles 1 to 7 of a fourth 28-day cycle. Approximately 20 mg on the first day of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 100 mg on days 15-21 of the cycle. mg on days 22-28 of the cycle, and approximately 200 mg on days 22-28 of the cycle, followed by Rituximab is preferably administered at about 400 mg daily for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 Either or not administered at all during each of the subsequent cycles of During the fourth 28-day cycle, approximately 20 mg on days 1-7 of the cycle and approximately 50 mg on days 8-14 of the cycle. g, approximately 100 mg on days 15-21 of the cycle, and approximately 200 mg on days 22-28 of the cycle. At about 400 mg daily thereafter for any subsequent cycles. Alternatively, BTK-I is administered at approximately 200 mg daily, and rituximab is administered for the first 28-day cycle. Approximately 375 mg / m on day 1 2 or as split doses on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 Either administered at once or at any subsequent Either not administered during each of the four cycles or not administered at all. During the 28-day cycle, approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 10 mg on days 1-7 of the cycle. Approximately 100 mg is administered on days 15-21 of the cycle, and approximately 200 mg is administered on days 22-28 of the cycle. and then dosed at about 400 mg daily for any subsequent cycles.

[0013] The present invention also provides a compound that is a BTK-I for use in the treatment of cancer or an autoimmune disease. or a pharma- ceutically acceptable salt thereof, wherein the compound or salt is administered to a patient at a dose of about 120 mg to about 6 The compound or a pharma- ceutically acceptable salt thereof is preferably administered in a daily dose of 0.100 mg. Preferably, the dose is from about 125 mg to about 600 mg. It is.

[0014] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. and the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg. Also provided herein is a compound or a pharma- ceutically acceptable salt thereof. Preferably, the dose is about 1 25 mg to about 600 mg. Preferably, the compound is BTK-I.

[0015] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient at a daily dose of about 120 mg to about 600 mg; Simultaneous, separate, or sequential administration with CL-2 inhibitors and / or anti-CD20 based therapies Also provided herein is a compound or a pharma- ceutically acceptable salt thereof, which is administered Typically, the dose is about 125 mg to about 600 mg. is administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. Preferably, the anti-CD20 based therapy is administered for about 37 days on day 1±3 of the first 28 day cycle. 5 mg / m 2 or as a split dose on days 1 and 2. Anti-CD20-based therapy should be administered on day 1 or days 1 and 2 of the first 28-day cycle. as divided doses, followed by anti-CD20-based therapy on day 1 or Either not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 28 day cycle. The regimen is administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. and anti-CD20-based therapy is then administered on day 1 or any subsequent week. Either not administered at all during each of the four phases, and a BCL-2 inhibitor was not administered during the fourth phase. The BTK-I is administered daily, starting on day 1, during a 28 day cycle. Anti-CD20-based therapy should be administered on day 1 or days 1 and 2 of the first 28-day cycle. as divided doses, and anti-CD20-based therapy is then administered on day 1 or or not at all during each of any subsequent cycles, The inhibitor is administered during the fourth 28 day cycle. Preferably, the BCL-2 inhibitor is BCL2-I or a pharma- ceutical acceptable derivative thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the BCL-2 inhibitor is an anti-CD Preferably, the anti-CD20 based therapy is rituximab. Preferably, the anti-CD20 based therapy is obinutes. Preferably, the anti-CD20 based therapy is R-CHOP. Rituximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or Day 1 and as a split dose on days 2 and 3. Preferably, rituximab is administered on the first 28 days. Approximately 375 mg / m on days 1 ± 3 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg on day 1 of the first 28-day cycle. / m 2 Rituximab is administered in a single dose or as a split dose on days 1 and 2. Then, on the first day, about 500 mg / m 2 or administered simultaneously during each of any subsequent cycles. Preferably, venetoclax is administered at least once every four 28-day periods. During the period, about 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15- It is administered at approximately 100 mg on day 21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, about 400 mg is dosed daily for any subsequent cycles. Mab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the first and second days as divided doses on day 1, followed by rituximab at approximately 500 mg / m 2 Throw it or not at all during each of any subsequent cycles. Venetoclax is administered at approximately 20 mg on days 1 to 7 of the fourth 28-day cycle and at approximately 20 mg on days 8 to 10 of the fourth 28-day cycle. Approximately 50 mg on day 14, approximately 100 mg on days 15-21 of the cycle, and approximately 22-28 of the cycle. Approximately 200 mg is administered on day 1 of each cycle, followed by approximately 400 mg every day for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily and rituximab is administered at about , approximately 375 mg / m on day 1 of the first 28-day cycle 2 or split into days 1 and 2 Rituximab is then administered at a dose of approximately 500 mg / m on day 1. 2 Administered at or not at all during each of any subsequent cycles, Toclax is administered at approximately 20 mg on days 1-7 of the fourth 28-day cycle and 20 mg on days 8-14 of the cycle. Approximately 50 mg in the eyes, approximately 100 mg on days 15-21 of the cycle, and approximately 22-28 of the cycle Approximately 200 mg is administered, followed by approximately 400 mg daily for any subsequent cycles. will be done.

[0016] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, wherein Preferably, the dose is between about 125 mg and about 600 mg. The compound is BTK-I.

[0017] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, is relapsed or refractory, and the compound or salt is Compounds or agents thereof administered simultaneously, separately, or sequentially with D20-based therapy Also provided herein are physiologically acceptable salts. Preferably, the dose is from about 125 mg to about 60 mg. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28 day cycle at a dose of: or as split doses on days 1 and 2. Preferably, the anti-CD20 based The regimen is approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 On the first day and Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by Anti-CD20-based therapy may be administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered at least once every 4 to 8 weeks. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered on days 1 or as split doses on days 1 and 2, anti-CD20-based therapy is then administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Typically, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered daily starting on day 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, anti-CD2 0-based therapy may then be administered on day 1 or during each of any subsequent cycles. or not at all, and a BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The anti-CD20 based therapy is preferably rituximab. Preferably, the anti-CD20 based therapy is obinutuzumab. The D20-based regimen is R-CHOP. Preferably, rituximab is administered for the first 28 days. About 375 mg / m on day 1 of the cycle 2 or as a split dose on days 1 and 2 Preferably, rituximab is administered at about 375 mg on days 1±3 of an initial 28-day cycle. / m 2 or as a split dose on days 1 and 2. Cimab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the first and second days Rituximab is administered as divided doses to the eyes, approximately 500 mg / m on day 1, followed by 2 in or not at all during each of any subsequent cycles. Preferably, venetoclax is administered at a dose of about 20 mg on days 1 to 7 of a fourth 28-day cycle. g, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg was administered on days 22-28 of the first cycle, followed by approximately Rituximab is administered daily at 400 mg on day 1 of the first 28-day cycle. Approximately 375 mg / m 2 Administered in single doses or as split doses on days 1 and 2 Cimab was then administered at approximately 500 mg / m on day 1. 2 or each of the following cycles venetoclax was administered either in the fourth or 28-day follow-up. During the cycle, approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 15 mg on days 15-20 of the cycle. It is administered at approximately 100 mg on days 21 to 28 of the cycle and at approximately 200 mg on days 22 to 28 of the cycle. and then about 400 mg daily for any subsequent cycles. -I is administered at approximately 200 mg daily, and rituximab is administered at approximately 3 mg daily on day 1 of the first 28-day cycle. 75 mg / m 2 or as split doses on days 1 and 2, and rituximab Then, on the first day, approximately 500 mg / m 2 or during each of any subsequent cycles. During the fourth 28-day cycle, venetoclax was administered either once or twice a day. 20 mg on days 1-7 of the cycle, 50 mg on days 8-14 of the cycle, and 15-21 of the cycle. It is administered at approximately 100 mg on days 22-28 of the cycle, and approximately 200 mg on days 22-28 of the cycle, followed by Any subsequent cycles will be dosed at approximately 400 mg daily.

[0018] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, wherein the compound is treatment-naïve. Preferably, the dose is between about 125 mg and about 600 mg. It's TK-I.

[0019] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, The subject is treatment naïve and the compound or salt is administered in combination with a BCL-2 inhibitor and / or an anti-CD20 vector. The compound or its pharma- ceutical equivalents may be administered simultaneously, separately, or sequentially with the other therapeutic agents. Acceptable salts are also provided herein. Preferably, the dose is from about 125 mg to about 600 mg. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle or on day 1 of the first 28-day cycle. The anti-CD20 based therapy is administered as a split dose on days 1 and 2. , approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle 2 On or on the first and second days Preferably, the anti-CD20 based therapy is administered in divided doses over the first 28 days. Administered on day 1 of the phase or as split doses on days 1 and 2 of the phase, followed by anti-CD2 0-based therapy is administered on day 1 or not at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 28 day cycle or is not administered during the fourth 28 day cycle. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28 day cycle. or as split doses on days 1 and 2, and anti-CD20-based therapy is or not administered at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28-day cycle. TK-I was administered daily starting on day 1, and anti-CD20-based therapy was administered daily for the first 28 days. Administered as a split dose on days 1 or 1 and 2 of the phase I anti-CD20-based The therapy is then administered on day 1 or not at all during each of any subsequent cycles. or not, and a BCL-2 inhibitor is administered during a fourth 28 day cycle. Preferably, the BCL-2 inhibitor is venetoclax. is BCL2-I or a pharma- ceutically acceptable salt thereof. Preferably, the anti-CD20 based therapy is rituximab. Preferably, the anti-CD20 based therapy is obinutuzumab. The primary therapy is R-CHOP. Preferably, rituximab is administered once every 28 days of the first cycle. Approximately 375 mg / m on the first day 2 or as split doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on days 1 ± 3 of the first 28 day cycle. 2 in or as a split dose on days 1 and 2. Preferably, rituximab is , approximately 375 mg / m on day 1 of the first 28-day cycle 2 or split into days 1 and 2 Rituximab is then administered at a dose of approximately 500 mg / m on day 1. 2 Administered at or not at all during each of any subsequent cycles. Alternatively, venetoclax is administered at approximately 20 mg on days 1 to 7 of the fourth 28-day cycle, Approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and approximately 200 mg on days 22 of the cycle. Approximately 200 mg is administered on day 28, followed by approximately 400 mg for any subsequent cycles. g daily. Preferably, rituximab is administered at about 37 g daily on day 1 of the first 28-day cycle. 5 mg / m 2 or as split doses on days 1 and 2, and rituximab , then about 500 mg / m on day 1 2 or during each of any subsequent cycles. During the fourth 28-day cycle, venetoclax was administered either once or twice a day. Approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 15-21 of the cycle. Approximately 100 mg is administered in the first eye and approximately 200 mg on days 22-28 of the cycle, and then Any subsequent cycles are also dosed at about 400 mg daily. 200 mg daily, and rituximab is administered at approximately 375 mg on day 1 of the first 28-day cycle. / m 2 Rituximab is administered in a single dose or as a split dose on days 1 and 2. Then, on the first day, about 500 mg / m 2 or administered simultaneously during each of any subsequent cycles. VENCLEXTA is administered either intravenously or intramuscularly during the fourth 28-day cycle. Approximately 20 mg on days 1-7, approximately 50 mg on days 8-14 of the cycle, approximately 15-21 of the cycle It is administered at 100 mg, and at approximately 200 mg on days 22 to 28 of the cycle, and then Subsequent cycles are also dosed at approximately 400 mg daily.

[0020] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, The compound or a pharma- ceutical acceptable salt thereof may also be used in patients who have received at least one prior anticancer therapy. As provided herein, preferably, the dose is between about 125 mg and about 600 mg. Preferably, the compound is BTK-I.

[0021] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, has received at least one prior anticancer therapy, and the compound or salt is a BCL-2 inhibitor and / or administered simultaneously, separately, or sequentially with an anti-CD20-based therapy; Also provided herein is a compound or a pharma- ceutically acceptable salt thereof. Preferably, the dose is about 125 mg to about 600 mg. Preferably, the anti-CD20 based therapy is administered for the first 28 It is administered on day 1 of the daily cycle, or as a split dose on days 1 and 2. , anti-CD20-based therapy is approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 in or as a split dose on days 1 and 2. The regimen is administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. and then anti-CD20-based therapy is administered on day 1 or on any subsequent week. Either no BCL-2 inhibitors are administered during each of the phases. The anti-CD20 based therapy is administered during the fourth 28 day cycle. Administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle, anti-C D20-based therapy is then administered on day 1 or during each of any subsequent cycles. or not at all, and the BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, BTK-I is administered daily starting on day 1, and anti-CD20-based The regimen is administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. and anti-CD20-based therapy is then administered on day 1 or any subsequent week. Either not administered at all during each of the four phases, and a BCL-2 inhibitor was not administered during the fourth phase. It is administered during a 28 day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20 based therapy is rituximab. Preferably, the anti-CD20 based therapy is obinutuzumab. Preferably, the anti-CD20 based therapy is R-CHOP. Approximately 375 mg / m on day 1 of the first 28-day cycle. 2 or on the first and second days Preferably, rituximab is administered on day 1 of the first 28-day cycle ± About 375 mg / m every 3 days 2 or as split doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle. 2 And again is administered as split doses on days 1 and 2, with rituximab then administered approximately once a day on day 1. 500 mg / m 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered during the first 28-day cycle of the fourth cycle. ~20 mg on day 7, ~50 mg on days 8-14 of the cycle, ~1 mg on days 15-21 of the cycle 00 mg on days 22-28 of the cycle, and approximately 200 mg on days 22-28 of the cycle, and then Subsequent cycles are also dosed at about 400 mg daily. Preferably, rituximab is administered daily for the first About 375 mg / m on day 1 of a 28-day cycle 2 or as divided doses on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 It is administered either or not at all during each of the subsequent cycles, During the fourth 28-day cycle, approximately 20 mg was administered on days 1-7 of the cycle and approximately 5 mg was administered on days 8-14 of the cycle. 0 mg, approximately 100 mg on days 15-21 of the cycle, and approximately 200 mg on days 22-28 of the cycle. mg daily, followed by approximately 400 mg daily for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily and rituximab is administered at about 200 mg daily for the first 28 days. About 375 mg / m on day 1 of the cycle 2 or as a split dose on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 Either or not administered at all during each of the subsequent cycles, and venetoclax During the fourth 28-day cycle, approximately 20 mg on days 1-7 of the cycle and approximately 50 mg on days 8-14 of the cycle , about 100 mg on days 15-21 of the cycle, and about 200 mg on days 22-28 of the cycle. is administered at about 400 mg daily for any subsequent cycles.

[0022] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, at least one prior anticancer therapy, including at least one BTK inhibitor-based therapy Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which has been subjected to The dosage is between about 125 mg and about 600 mg. Preferably, the compound inhibits BTK-I. be.

[0023] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, at least one prior anticancer therapy, including at least one BTK inhibitor-based therapy The compound or salt is a BCL-2 inhibitor and / or an anti-CD20 based The compound or a pharma- ceutically acceptable salt thereof may be administered simultaneously, separately, or sequentially with the therapy. Also provided herein are salts thereof. Preferably, the dosage is from about 125 mg to about 600 mg. Preferably, the anti-CD20 based therapy is administered on day 1 or on day 1 and on day 2 of the first 28 day cycle. Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Approximately 375 mg / m on days 1 ± 3 of a 28-day cycle 2 or split into days 1 and 2 Preferably, the anti-CD20 based therapy is administered in doses of 100 mg / kg / day or 100 mg / kg / day of the first 28 day cycle. It is given on day 1 or as a split dose on days 1 and 2, followed by anti-CD20-based chemotherapy. The drug therapy may be administered on day 1 or not at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 28 day cycle. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28 day cycle, or The anti-CD20-based therapy is administered as split doses on days 1 and 2, followed by 1 either on day 1 of each subsequent cycle or not at all during each of the subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. I was administered daily starting on day 1, and anti-CD20-based therapy was administered on day 1 of the first 28-day cycle. Administered on days 1 or as split doses on days 1 and 2, anti-CD20-based therapy is then administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Preferably, the BCL-2 inhibitor is venetoclax. L2-I or a pharma- ceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BC L2-I. Preferably, the anti-CD20 based therapy is rituximab. Preferably, the anti-CD20 based therapy is obinutuzumab. The therapy is R-CHOP. Preferably, rituximab is administered on day 1 of the first 28-day cycle. Approximately 375mg / m 2 or as a split dose on days 1 and 2. Rituximab is administered at approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 And again is administered as split doses on days 1 and 2. Preferably, rituximab is administered initially Approximately 375 mg / m on day 1 of a 28-day cycle 2 or in split doses on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 It is administered at Either not administered at all during each of any subsequent cycles. Venetoclax is administered at approximately 20 mg on days 1 to 7 of the fourth 28-day cycle and at approximately 20 mg on days 8 to 10 of the fourth 28-day cycle. Approximately 50 mg on day 14, approximately 100 mg on days 15-21 of the cycle, and approximately 22-28 of the cycle. Approximately 200 mg is administered on day 1 of each cycle, followed by approximately 400 mg every day for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / day on day 1 of the first 28-day cycle. / m 2 Rituximab is administered in a single dose or as a split dose on days 1 and 2. Then, on the first day, about 500 mg / m 2 or administered simultaneously during each of any subsequent cycles. VENCLEXTA is administered either intravenously or intramuscularly during the fourth 28-day cycle. Approximately 20 mg on days 1-7, approximately 50 mg on days 8-14 of the cycle, approximately 15-21 of the cycle It is administered at 100 mg, and at approximately 200 mg on days 22 to 28 of the cycle, and then Subsequent cycles are also dosed at about 400 mg daily. Preferably, BTK-I is dosed at about 200 mg daily. mg daily, with rituximab administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 or as split doses on days 1 and 2, and rituximab is then administered Approximately 500 mg / m on the day 2 or not administered at all during each of any subsequent cycles. VENCLEXTA was administered or not administered during days 1-7 of the fourth 28-day cycle. Approximately 20 mg on the first day of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 100 mg on days 15-21 of the cycle. mg on days 22-28 of the cycle, and approximately 200 mg on days 22-28 of the cycle, followed by During the first phase, the drug is administered at approximately 400 mg daily.

[0024] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, have not received prior anticancer therapy involving a BTK inhibitor, Also provided herein are salts thereof. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, the compound is BTK-I.

[0025] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, have not received prior anticancer therapy, including a BTK inhibitor, and the compound or salt is Administered simultaneously, separately, or sequentially with inhibitors and / or anti-CD20-based therapies Also provided herein are compounds, or pharma- ceutically acceptable salts thereof, which are The amount is about 125 mg to about 600 mg. Preferably, the anti-CD20 based therapy is initially The dose is administered on day 1, or as a split dose on days 1 and 2 of a 28 day cycle. Alternatively, anti-CD20-based therapy should be administered at approximately 375 mg / kg on days 1 ± 3 of the first 28-day cycle. m 2 or as split doses on days 1 and 2. 0-based therapy is given in split doses on days 1 or 1 and 2 of the first 28-day cycle. as a first infusion, followed by an anti-CD20-based therapy on day 1 or During each of the subsequent cycles, either BCL The -2 inhibitor is administered during the fourth 28-day cycle. is administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. The anti-CD20 based therapy is then administered on day 1 or each of any subsequent cycles. The BCL-2 inhibitor was administered either during the fourth 28-day period or not at all during the fourth 28-day period. Preferably, BTK-I is administered daily starting on day 1, and anti-CD2 0-based therapy is given in split doses on days 1 or 1 and 2 of the first 28-day cycle. and anti-CD20-based therapy is then administered on day 1 or During each of the subsequent cycles, the BCL-2 inhibitor is either not administered at all or not at all. and during a fourth 28 day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the BCL-2 inhibitor is an anti-CD20 based Preferably, the anti-CD20 based therapy is rituximab. Preferably, the anti-CD20 based therapy is obinutuzumab. Preferably, the anti-CD20 based therapy is R-CHOP. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Preferably, rituximab is administered on the first 28-day cycle as a split dose on the first 28-day cycle. Approximately 375 mg / m on the first day ± 3 days 2 given in a single dose or as a split dose on days 1 and 2 Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle. 2 in or as split doses on days 1 and 2, with rituximab administered daily thereafter. About 500 mg / m2 in the eye 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered circadianally during the fourth 28 day cycle. Approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 15-21 of the cycle. Approximately 100 mg is administered on days 22-28 of the cycle, and approximately 200 mg on days 22-28 of the cycle. Each subsequent cycle is also dosed at about 400 mg daily. Approximately 375 mg / m on day 1 of the first 28-day cycle 2 or for splitting on days 1 and 2 Rituximab is then administered at approximately 500 mg / m on day 1. 2 Administered at or not at all during each of any subsequent cycles; Claxil is administered at approximately 20 mg on days 1-7 of the fourth 28-day cycle and 20 mg on days 8-14 of the cycle. about 50 mg on days 15-21 of the cycle, about 100 mg on days 22-28 of the cycle, and about 200 mg daily, then approximately 400 mg daily for any subsequent cycles. Preferably, the BTK-I is administered at about 200 mg daily and the rituximab is administered at about 200 mg daily. About 375 mg / m on day 1 of a 28-day cycle 2 or as divided doses on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 It is administered either or not at all during each of the subsequent cycles, During the fourth 28-day cycle, approximately 20 mg was administered on days 1-7 of the cycle and approximately 5 mg was administered on days 8-14 of the cycle. 0 mg, approximately 100 mg on days 15-21 of the cycle, and approximately 200 mg on days 22-28 of the cycle. mg daily, followed by approximately 400 mg daily for any subsequent cycles.

[0026] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, Also provided herein are compounds or pharma- ceutically acceptable salts thereof, in which the subject has received one prior anticancer therapy. Preferably, the dose is between about 125 mg and about 600 mg. This compound is BTK-I.

[0027] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, have received one prior anticancer therapy and the compound or salt is administered in combination with a BCL-2 inhibitor and / or or anti-CD20-based therapy, administered simultaneously, separately, or sequentially with the compound or Also provided herein are pharma- ceutically acceptable salts thereof. Preferably, the dose is about 125 mg. ~ about 600 mg. Preferably, the anti-CD20 based therapy is administered for one of the first 28 day cycles. Preferably, the anti-CD2 0-based regimen is approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 In or 1 The anti-CD20 based therapy is administered as a split dose on days 1 and 2. , administered on day 1 or as a split dose on days 1 and 2 of the first 28-day cycle; Thereafter, anti-CD20-based therapy is administered on day 1 or on each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered either in the first Preferably, the anti-CD20 based therapy is administered during the first 28 days of the cycle. Administered as a split dose on days 1 or 1 and 2 of the cycle, anti-CD20-based The drug regimen is then administered on day 1 or not at all during each of any subsequent cycles. or not administered, and a BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, BTK-I is administered daily starting on day 1 and anti-CD20-based therapy is administered daily starting on day 2. , administered on day 1 or as a split dose on days 1 and 2 of the first 28-day cycle; Anti-CD20-based therapy is then administered on day 1 or on each of any subsequent cycles. The BCL-2 inhibitor was administered either in the fourth 28-day cycle or not at all in between. Preferably, the BCL-2 inhibitor is venetoclax. The BCL-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20 based therapy is Preferably, the anti-CD20 based therapy is obinutuzumab. In the present case, the anti-CD20-based therapy is R-CHOP. Preferably, rituximab is administered first. Approximately 375 mg / m on day 1 of a 28-day cycle 2 or in split doses on days 1 and 2 Preferably, rituximab is administered about 3 times daily on days 1±3 of the first 28-day cycle. 75 mg / m 2 or as a split dose on days 1 and 2. Rituximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 Or on the first day Rituximab is then administered at approximately 500 mg on day 1 and 2 as divided doses. / m 2 either administered at once during each of the subsequent cycles or not administered at all during each of the subsequent cycles. Preferably, venetoclax is administered on cycle days 1 to 7 during a fourth 28-day cycle. Approximately 20 mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and approximately 200 mg on days 22-28 of the cycle, and then for any subsequent cycles. Rituximab is preferably administered at about 400 mg daily for the first 28 day cycle. Approximately 375 mg / m on day 1 2 or as split doses on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 Either administered at once or at any subsequent Either not administered during each of the four cycles or not administered at all. During the 28-day cycle, approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 10 mg on days 1-7 of the cycle. Approximately 100 mg is administered on days 15-21 of the cycle, and approximately 200 mg is administered on days 22-28 of the cycle. and then dosed at about 400 mg daily for any subsequent cycles. BTK-I was administered at approximately 200 mg daily, and rituximab was administered daily for the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, any subsequent cycles are dosed at approximately 400 mg daily.

[0028] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, The compound or a pharma- ceutically acceptable salt thereof is also described herein, wherein the patient has undergone two prior anticancer therapies. Preferably, the dose is between about 125 mg and about 600 mg. This compound is BTK-I.

[0029] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, The patient has received two prior anticancer therapies and the compound or salt is administered in combination with a BCL-2 inhibitor and / or or anti-CD20-based therapy, administered simultaneously, separately, or sequentially with the compound or Also provided herein are pharma- ceutically acceptable salts thereof. Preferably, the dose is about 125 mg. ~ about 600 mg. Preferably, the anti-CD20 based therapy is administered for one of the first 28 day cycles. Preferably, the anti-CD2 0-based regimen is approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 In or 1 The anti-CD20 based therapy is administered as a split dose on days 1 and 2. , administered on day 1 or as a split dose on days 1 and 2 of the first 28-day cycle; Thereafter, anti-CD20-based therapy is administered on day 1 or on each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered either in the first Preferably, the anti-CD20 based therapy is administered during the first 28 days of the cycle. Administered as a split dose on days 1 or 1 and 2 of the cycle, anti-CD20-based The drug regimen is then administered on day 1 or not at all during each of any subsequent cycles. or not administered, and a BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, BTK-I is administered daily starting on day 1 and anti-CD20-based therapy is administered daily starting on day 2. , administered on day 1 or as a split dose on days 1 and 2 of the first 28-day cycle; Anti-CD20-based therapy is then administered on day 1 or on each of any subsequent cycles. The BCL-2 inhibitor was administered either in the fourth 28-day cycle or not at all in between. Preferably, the BCL-2 inhibitor is venetoclax. The BCL-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20 based therapy is Preferably, the anti-CD20 based therapy is obinutuzumab. In the present case, the anti-CD20-based therapy is R-CHOP. Preferably, rituximab is administered first. Approximately 375 mg / m on day 1 of a 28-day cycle 2 or in split doses on days 1 and 2 Preferably, rituximab is administered about 3 times daily on days 1±3 of the first 28-day cycle. 75 mg / m 2 or as a split dose on days 1 and 2. Rituximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 Or on the first day Rituximab is then administered at approximately 500 mg on day 1 and 2 as divided doses. / m 2 either administered at once during each of the subsequent cycles or not administered at all during each of the subsequent cycles. Preferably, venetoclax is administered on cycle days 1 to 7 during a fourth 28-day cycle. Approximately 20 mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and approximately 200 mg on days 22-28 of the cycle, and then for any subsequent cycles. Rituximab is preferably administered at about 400 mg daily for the first 28 day cycle. Approximately 375 mg / m on day 1 2 or as split doses on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 Either administered at once or at any subsequent Either not administered during each of the four cycles or not administered at all. During the 28-day cycle, approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 10 mg on days 1-7 of the cycle. Approximately 100 mg is administered on days 15-21 of the cycle, and approximately 200 mg is administered on days 22-28 of the cycle. and then dosed at about 400 mg daily for any subsequent cycles. BTK-I was administered at approximately 200 mg daily, and rituximab was administered daily for the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, any subsequent cycles are dosed at approximately 400 mg daily.

[0030] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, Also disclosed herein are compounds or pharma- ceutically acceptable salts thereof, in which the patient has received more than two prior anticancer therapies. Preferably, the dose is between about 125 mg and about 600 mg. , this compound is BTK-I.

[0031] A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. wherein the compound or salt is administered to the patient in a daily dose of about 120 mg to about 600 mg, has received more than two prior anticancer therapies and the compound or salt is or a compound or combination thereof administered simultaneously, separately, or sequentially with an anti-CD20 based therapy. or a pharma- ceutically acceptable salt thereof are also provided herein. Preferably, the dose is about 125 mg. Preferably, the anti-CD20 based therapy is administered in the first 28 day cycle. It is administered on day 1 or as a split dose on days 1 and 2. Preferably, the anti-CD The 20-based regimen is approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 In, or It is administered as a split dose on days 1 and 2. Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. and then the anti-CD20-based therapy is administered on day 1 or each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during or at no time. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on days 1 or 1 and 2 of the daily cycle, anti-CD20 vector The therapy is then administered on day 1 or on any subsequent cycles. The BCL-2 inhibitor is administered during the fourth 28-day cycle or is not administered at all during the fourth 28-day cycle. Preferably, BTK-I is administered daily starting on day 1, and anti-CD20 based therapy is is administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. The anti-CD20 based therapy is then administered on day 1 or each of any subsequent cycles. The BCL-2 inhibitor was administered either during the fourth 28-day period or not at all during the fourth 28-day period. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20 based therapy is obinutuzumab. Typically, the anti-CD20 based therapy is R-CHOP. Preferably, rituximab is About 375 mg / m on day 1 of the first 28-day cycle 2 or in split doses on days 1 and 2 Preferably, rituximab is administered approximately daily on day 1 ± 3 of the first 28 day cycle. 375 mg / m 2 or as a split dose on days 1 and 2. Rituximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or Day 1 and rituximab was administered as a split dose on days 1 and 2, followed by approximately 500 mg of rituximab on day 1. g / m 2 or not at all during each of any subsequent cycles. Preferably, venetoclax is administered on days 1 to 7 of a fourth 28-day cycle. 20 mg on days 8-14 of the cycle, 50 mg on days 15-21 of the cycle, and 100 mg on days 16-22 of the cycle. and approximately 200 mg on days 22-28 of the cycle, and then in any subsequent cycles. Preferably, rituximab is administered at about 400 mg daily for the first 28 days. Approximately 375 mg / m on day 1 of the period 2 given in a single dose or as a split dose on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 Either at or after Either not administered during each of the subsequent cycles or not administered at all, and venetoclax During the 28-day cycle of 4, approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, Approximately 100 mg is administered on days 15-21 of the cycle, and approximately 200 mg is administered on days 22-28 of the cycle. and then about 400 mg daily for any subsequent cycles. In the study, BTK-I was administered at approximately 200 mg daily, and rituximab was administered once every 28 days during the first cycle. Approximately 375 mg / m on the first day 2 Administered in single doses or as split doses on days 1 and 2 Tuximab was then administered at approximately 500 mg / m on day 1. 2 or any subsequent cycle venetoclax was administered either between the fourth and fourth During an 8-day cycle, approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 100 mg on days 9-11 of the cycle. It is administered at approximately 100 mg on days 15-21 and approximately 200 mg on days 22-28 of the cycle. and then dosed at about 400 mg daily for any subsequent cycles.

[0032] The present invention also relates to methods for treating and / or preventing the proliferation and / or proliferation of activated B cells in patients with BTK-mediated cancers. or a compound or a pharmacopoeitic agent thereof for use in inhibiting survival of BTK-I. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt, Administered on a continuous daily dosing regimen until progression of BTK-mediated cancer or unacceptable toxicity. Oral administration, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. The present invention provides a compound or a pharma- ceutically acceptable salt thereof, which is capable of inhibiting the action of the agonist. It is BTK-I.

[0033] Inhibiting the proliferation and / or survival of activated B cells in patients with BTK-mediated cancers A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for use in inhibiting The present invention relates to a method for treating BTK-mediated cancer, the method comprising administering to a patient suffering from the cancer a therapeutically effective amount of a compound or salt. Administer orally in a continuous daily dosing regimen until progression or unacceptable toxicity. Including, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Harmed, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0034] Increased Activated B Cells in Patients with Relapsed or Refractory BTK-Mediated Cancers Compounds that are BTK-I or compounds thereof for use in inhibiting proliferation and / or survival and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or or salts are administered at successive daily dose levels until progression of BTK-mediated cancer or unacceptable toxicity occurs. Oral administration with dimen, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Also provided herein are compounds, or pharma- ceutically acceptable salts thereof, which are preferably , this compound is BTK-I.

[0035] Increased Activated B Cells in Patients with Relapsed or Refractory BTK-Mediated Cancers Compounds that are BTK-I or compounds thereof for use in inhibiting proliferation and / or survival and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or or salts are administered at successive daily dose levels until progression of BTK-mediated cancer or unacceptable toxicity occurs. Oral administration with dimen, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Harmed, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day,2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0036] Proliferation of activated B cells in patients with treatment-naïve BTK-mediated cancers and and / or a compound which is a BTK-I or a pharmaceutical agent thereof for use in inhibiting survival. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. , in a continuous daily dosing regimen until BTK-mediated cancer progression or unacceptable toxicity occurs. Oral administration, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Also provided herein are compounds, or pharma- ceutically acceptable salts thereof, which are preferably , this compound is BTK-I.

[0037] Proliferation of activated B cells in patients with treatment-naïve BTK-mediated cancers and and / or a compound which is a BTK-I or a pharmaceutical agent thereof for use in inhibiting survival. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. , in a continuous daily dosing regimen until BTK-mediated cancer progression or unacceptable toxicity occurs. Oral administration, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Harmed, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0038] Activated BTK-mediated cancer in patients with cancers who have received at least one prior anticancer therapy and for use in inhibiting proliferation and / or survival of isolated B cells. or a pharma- ceutical acceptable salt thereof, The compound or salt is administered in an effective amount until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administered in a continuous daily dosing regimen, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Also provided herein are compounds, or pharma- ceutically acceptable salts thereof, which are preferably , this compound is BTK-I.

[0039] Activated BTK-mediated cancer in patients with cancers who have received at least one prior anticancer therapy and for use in inhibiting proliferation and / or survival of isolated B cells. or a pharma- ceutical acceptable salt thereof, The compound or salt is administered in an effective amount until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administered in a continuous daily dosing regimen, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Harmed, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0040] At least one prior anticancer therapy, including at least one BTK inhibitor-based therapy Proliferation and / or survival of activated B cells in patients with BTK-mediated cancers A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for use in inhibiting and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. Administered orally in a continuous daily dosing regimen until progression of cancer or unacceptable toxicity. Including, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Also provided herein are compounds, or pharma- ceutically acceptable salts thereof, which are preferably , this compound is BTK-I.

[0041] At least one prior anticancer therapy, including at least one BTK inhibitor-based therapy Proliferation and / or survival of activated B cells in patients with BTK-mediated cancers A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for use in inhibiting and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. Administered orally in a continuous daily dosing regimen until progression of cancer or unacceptable toxicity. Including, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Harmed, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0042] In patients with BTK-mediated cancers who have not received prior anticancer therapy including a BTK inhibitor BTK-1 for use in inhibiting proliferation and / or survival of activated B cells or a pharma- ceutical acceptable salt thereof, and administering to the subject a therapeutically effective amount of the compound or salt such that progression of BTK-mediated cancer or unacceptable toxicity does not occur. orally administering the compound in a continuous daily dosage regimen until A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Also provided herein are compounds, or pharma- ceutically acceptable salts thereof, which are preferably , this compound is BTK-I.

[0043] In patients with BTK-mediated cancers who have not received prior anticancer therapy including a BTK inhibitor BTK-1 for use in inhibiting proliferation and / or survival of activated B cells or a pharma- ceutical acceptable salt thereof, and administering to the subject a therapeutically effective amount of the compound or salt such that progression of BTK-mediated cancer or unacceptable toxicity does not occur. orally administering the compound in a continuous daily dosage regimen until A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Harmed, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0044] Activated B cells in patients with BTK-mediated cancers who received one prior anticancer therapy or a compound which is a BTK-I for use in inhibiting proliferation and / or survival of a and a pharma- ceutical acceptable salt thereof, wherein the compound is administered to a patient suffering from a BTK-mediated cancer in a therapeutically effective amount. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Also provided herein are compounds, or pharma- ceutically acceptable salts thereof, which are preferably , this compound is BTK-I.

[0045] Activated B cells in patients with BTK-mediated cancers who received one prior anticancer therapy or a compound which is a BTK-I for use in inhibiting proliferation and / or survival of a and a pharma- ceutical acceptable salt thereof, wherein the compound is administered to a patient suffering from a BTK-mediated cancer in a therapeutically effective amount. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Harmed, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0046] Activated B cells in patients with BTK-mediated cancer who had received two prior anticancer therapies or a compound which is a BTK-I for use in inhibiting proliferation and / or survival of a and a pharma- ceutical acceptable salt thereof, wherein the compound is administered to a patient suffering from a BTK-mediated cancer in a therapeutically effective amount. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Also provided herein are compounds, or pharma- ceutically acceptable salts thereof, which are preferably , this compound is BTK-I.

[0047] Activated B cells in patients with BTK-mediated cancer who had received two prior anticancer therapies or a compound which is a BTK-I for use in inhibiting proliferation and / or survival of a and a pharma- ceutical acceptable salt thereof, wherein the compound is administered to a patient suffering from a BTK-mediated cancer in a therapeutically effective amount. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Harmed, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0048] Activated B-cell proliferation in patients with BTK-mediated cancers who had received more than two prior anticancer therapies Compounds that are BTK-I or BTK-II for use in inhibiting cell proliferation and / or survival. or a pharma- ceutical acceptable salt thereof, wherein a therapeutically effective amount of the compound is administered to a patient suffering from a BTK-mediated cancer. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the compound in a dosage regimen comprising: A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Also provided herein are compounds, or pharma- ceutically acceptable salts thereof, which are preferably , this compound is BTK-I.

[0049] Activated B-cell proliferation in patients with BTK-mediated cancers who had received more than two prior anticancer therapies Compounds that are BTK-I or BTK-II for use in inhibiting cell proliferation and / or survival. or a pharma- ceutical acceptable salt thereof, wherein a therapeutically effective amount of the compound is administered to a patient suffering from a BTK-mediated cancer. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the compound in a dosage regimen comprising: A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. An amount that results in greater than 90 percent inhibition, inhibiting the proliferation and survival of activated B cells. Harmed, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0050] The present invention also relates to methods for treating and / or preventing the proliferation and / or proliferation of activated B cells in patients with BTK-mediated cancers. or a compound or a pharmacopoeitic agent thereof for use in inhibiting survival of BTK-I. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt, Administered on a continuous daily dosing regimen until progression of BTK-mediated cancer or unacceptable toxicity. Oral administration, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Preferably, the compound is a BTK inhibitor, -I.

[0051] Inhibiting the proliferation and / or survival of activated B cells in patients with BTK-mediated cancers A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for use in inhibiting The present invention relates to a method for treating BTK-mediated cancer, the method comprising administering to a patient suffering from the cancer a therapeutically effective amount of a compound or salt. Administer orally in a continuous daily dosing regimen until progression or unacceptable toxicity. Including, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0052] Increased Activated B Cells in Patients with Relapsed or Refractory BTK-Mediated Cancers Compounds that are BTK-I or compounds thereof for use in inhibiting proliferation and / or survival and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or or salts are administered at successive daily dose levels until progression of BTK-mediated cancer or unacceptable toxicity occurs. Oral administration with dimen, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0053] Activated B-cell proliferation in patients with relapsed or refractory BTK-mediated cancers and / or a compound which is a BTK-I or for use in inhibiting survival A pharma- ceutical acceptable salt thereof is administered to a patient suffering from a BTK-mediated cancer in a therapeutically effective amount of the compound or The salts were administered in successive daily dose regimes until progression of BTK-mediated cancer or unacceptable toxicity occurred. Orally administering the compound in a dose of 100 mg / kg orally; The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0054] Proliferation of activated B cells in patients with treatment-naïve BTK-mediated cancers and and / or a compound which is a BTK-I or a pharmaceutical agent thereof for use in inhibiting survival. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. , in a continuous daily dosing regimen until BTK-mediated cancer progression or unacceptable toxicity occurs. Oral administration, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0055] Proliferation of activated B cells in patients with treatment-naïve BTK-mediated cancers and and / or a compound which is a BTK-I or a pharmaceutical agent thereof for use in inhibiting survival. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. , in a continuous daily dosing regimen until BTK-mediated cancer progression or unacceptable toxicity occurs. Oral administration, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day,2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0056] Activated BTK-mediated cancer in patients with cancers who have received at least one prior anticancer therapy and for use in inhibiting proliferation and / or survival of isolated B cells. or a pharma- ceutical acceptable salt thereof, The compound or salt is administered in an effective amount until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administered in a continuous daily dosing regimen, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0057] Activated BTK-mediated cancer in patients with cancers who have received at least one prior anticancer therapy and for use in inhibiting proliferation and / or survival of isolated B cells. or a pharma- ceutical acceptable salt thereof, The compound or salt is administered in an effective amount until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administered in a continuous daily dosing regimen, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0058] At least one prior anticancer therapy, including at least one BTK inhibitor-based therapy Proliferation and / or survival of activated B cells in patients with BTK-mediated cancers A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for use in inhibiting and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. Administered orally in a continuous daily dosing regimen until progression of cancer or unacceptable toxicity. Including, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0059] At least one prior anticancer therapy, including at least one BTK inhibitor-based therapy Proliferation and / or survival of activated B cells in patients with BTK-mediated cancers A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for use in inhibiting and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. Administered orally in a continuous daily dosing regimen until progression of cancer or unacceptable toxicity. Including, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0060] In patients with BTK-mediated cancers who have not received prior anticancer therapy including a BTK inhibitor BTK-1 for use in inhibiting proliferation and / or survival of activated B cells or a pharma- ceutical acceptable salt thereof, and administering to the subject a therapeutically effective amount of the compound or salt such that progression of BTK-mediated cancer or unacceptable toxicity does not occur. orally administering the compound in a continuous daily dosage regimen until The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0061] In patients with BTK-mediated cancers who have not received prior anticancer therapy including a BTK inhibitor BTK-1 for use in inhibiting proliferation and / or survival of activated B cells or a pharma- ceutical acceptable salt thereof, and administering to the subject a therapeutically effective amount of the compound or salt such that progression of BTK-mediated cancer or unacceptable toxicity does not occur. orally administering the compound in a continuous daily dosage regimen until The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0062] Activated B cells in patients with BTK-mediated cancers who received one prior anticancer therapy or a compound which is a BTK-I for use in inhibiting proliferation and / or survival of a and a pharma- ceutical acceptable salt thereof, wherein the compound is administered to a patient suffering from a BTK-mediated cancer in a therapeutically effective amount. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0063] Activated B cells in patients with BTK-mediated cancers who received one prior anticancer therapy or a compound which is a BTK-I for use in inhibiting proliferation and / or survival of a and a pharma- ceutical acceptable salt thereof, wherein the compound is administered to a patient suffering from a BTK-mediated cancer in a therapeutically effective amount. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0064] Activated B cells in patients with BTK-mediated cancer who had received two prior anticancer therapies or a compound which is a BTK-I for use in inhibiting proliferation and / or survival of a and a pharma- ceutical acceptable salt thereof, wherein the compound is administered to a patient suffering from a BTK-mediated cancer in a therapeutically effective amount. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0065] Activated B cells in patients with BTK-mediated cancer who had received two prior anticancer therapies or a compound which is a BTK-I for use in inhibiting proliferation and / or survival of a and a pharma- ceutical acceptable salt thereof, wherein the compound is administered to a patient suffering from a BTK-mediated cancer in a therapeutically effective amount. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0066] Activated B-cell proliferation in patients with BTK-mediated cancers who had received more than two prior anticancer therapies Compounds that are BTK-I or BTK-II for use in inhibiting cell proliferation and / or survival. or a pharma- ceutical acceptable salt thereof, wherein a therapeutically effective amount of the compound is administered to a patient suffering from a BTK-mediated cancer. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the compound in a dosage regimen comprising: The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0067] Activated B-cell proliferation in patients with BTK-mediated cancers who had received more than two prior anticancer therapies Compounds that are BTK-I or BTK-II for use in inhibiting cell proliferation and / or survival. or a pharma- ceutical acceptable salt thereof, wherein a therapeutically effective amount of the compound is administered to a patient suffering from a BTK-mediated cancer. The compound or salt is administered daily for consecutive days until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administering the compound in a dosage regimen comprising: The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0068] The present invention also provides compounds that are BTK-I or and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound, a pharma- ceutical acceptable salt thereof. or salt in successive daily doses until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administered in a regimen comprising: A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. The compound or a pharma- ceutically acceptable salt thereof may also be administered in an amount that results in greater than 90 percent inhibition. Preferably, the compound is BTK-I.

[0069] A compound that is a BTK-I or for use in treating BTK-mediated cancer. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound, a pharma- ceutical acceptable salt thereof. or salt in successive daily doses until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administered in a regimen comprising: A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. an amount that results in greater than 90 percent inhibition, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0070] BTK-I for use in treating a BTK-mediated cancer in a patient with relapsed or refractory cancer. or a pharma- ceutical acceptable salt thereof, comprising administering to a patient suffering from a BTK-mediated cancer: A therapeutically effective amount of the compound or salt is administered to a subject who is at risk of developing BTK-mediated cancer or who is at risk of developing unacceptable toxicity. orally administering in a continuous daily dosage regimen up to A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. The compound or a pharma- ceutically acceptable salt thereof may also be administered in an amount that results in greater than 90 percent inhibition. Provided herein. Preferably, the compound is BTK-I.

[0071] BTK-I for use in treating a BTK-mediated cancer in a patient with relapsed or refractory cancer. or a pharma- ceutical acceptable salt thereof, comprising administering to a patient suffering from a BTK-mediated cancer: A therapeutically effective amount of the compound or salt is administered to a subject who is at risk of developing BTK-mediated cancer or who is at risk of developing unacceptable toxicity. orally administering in a continuous daily dose regimen up to A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. an amount that results in greater than 90 percent inhibition, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0072] A compound that is a BTK-I for use in treating BTK-mediated cancers in which the patient is treatment naive. or a pharma- ceutical acceptable salt thereof, The compound or salt is administered in successive doses until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administered in a regular daily dosage regimen; A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. The compound or a pharma- ceutically acceptable salt thereof may also be administered in an amount that results in greater than 90 percent inhibition. Provided herein. Preferably, the compound is BTK-I.

[0073] A compound that is a BTK-I for use in treating BTK-mediated cancers in which the patient is treatment naive. or a pharma- ceutical acceptable salt thereof, The compound or salt is administered in successive doses until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administered in a regular daily dosage regimen; A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. an amount that results in greater than 90 percent inhibition, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0074] For use in the treatment of BTK-mediated cancers in which the patient has received at least one prior anticancer therapy A compound or a pharma- ceutical acceptable salt thereof that is a BTK-I for treating BTK-mediated cancer. The compound or salt is administered to a patient suffering from a BTK-mediated cancer progression or intolerance. orally in a continuous daily dosing regimen until insignificant toxicity occurs; A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. The compound or a pharma- ceutically acceptable salt thereof may also be administered in an amount that results in greater than 90 percent inhibition. Provided herein. Preferably, the compound is BTK-I.

[0075] For use in the treatment of BTK-mediated cancers in which the patient has received at least one prior anticancer therapy A compound or a pharma- ceutical acceptable salt thereof that is a BTK-I for treating BTK-mediated cancer. The compound or salt is administered to a patient suffering from a BTK-mediated cancer progression or intolerance. orally in a continuous daily dosing regimen until insignificant toxicity occurs; A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. an amount that results in greater than 90 percent inhibition, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0076] Patients must have had at least one prior anti-cancer therapy, including at least one BTK inhibitor-based therapy. and a compound which is a BTK-I or a compound thereof for use in the treatment of BTK-mediated cancers. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or or salts are administered at successive daily dose levels until progression of BTK-mediated cancer or unacceptable toxicity occurs. Oral administration with dimen, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. The compound or a pharma- ceutically acceptable salt thereof may also be administered in an amount that results in greater than 90 percent inhibition. Provided herein. Preferably, the compound is BTK-I.

[0077] Patients must have had at least one prior anti-cancer therapy, including at least one BTK inhibitor-based therapy. and a compound which is a BTK-I or a compound thereof for use in the treatment of BTK-mediated cancers. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or or salts are administered at successive daily dose levels until progression of BTK-mediated cancer or unacceptable toxicity occurs. Oral administration with dimen, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. an amount that results in greater than 90 percent inhibition, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0078] For use in the treatment of BTK-mediated cancers in which patients have not received prior anticancer therapy including a BTK inhibitor. A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of a chronic inflammatory condition, comprising: The present invention relates to a method for treating or preventing the progression or permissiveness of BTK-mediated cancer, comprising administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. orally administered in a continuous daily dosing regimen until unacceptable toxicity occurs; A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. The compound or a pharma- ceutically acceptable salt thereof may also be administered in an amount that results in greater than 90 percent inhibition. Provided herein. Preferably, the compound is BTK-I.

[0079] For use in the treatment of BTK-mediated cancers in which patients have not received prior anticancer therapy including a BTK inhibitor. A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of a chronic inflammatory condition, comprising: The present invention relates to a method for treating or preventing the progression or permissiveness of BTK-mediated cancer, comprising administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. orally administered in a continuous daily dosing regimen until unacceptable toxicity occurs; A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. an amount that results in greater than 90 percent inhibition, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0080] BTK for use in the treatment of BTK-mediated cancers, where the patient has received one prior anticancer therapy or a pharma- ceutical acceptable salt thereof, In one embodiment, a therapeutically effective amount of the compound or salt is administered to a subject in need of treatment with a BTK-mediated cancer that is not associated with progression of the cancer or is not associated with unacceptable toxicity. orally administering the compound in a continuous daily dosage regimen until the compound is administered orally; A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. The compound or a pharma- ceutically acceptable salt thereof may also be administered in an amount that results in greater than 90 percent inhibition. Provided herein. Preferably, the compound is BTK-I.

[0081] BTK for use in the treatment of BTK-mediated cancers, where the patient has received one prior anticancer therapy or a pharma- ceutical acceptable salt thereof, In one embodiment, a therapeutically effective amount of the compound or salt is administered to a subject in need of treatment with a BTK-mediated cancer that is not associated with progression of the cancer or is not associated with unacceptable toxicity. orally administering the compound in a continuous daily dosage regimen until the compound is administered orally; A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. an amount that results in greater than 90 percent inhibition, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and approximately 400 mg daily for any subsequent cycles. and a compound which is a BTK-I or a compound thereof for use in the treatment of BTK-mediated cancers. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or or salts are administered at successive daily dose levels until progression of BTK-mediated cancer or unacceptable toxicity occurs. Oral administration with dimen, A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. The compound or a pharma- ceutically acceptable salt thereof may also be administered in an amount that results in greater than 90 percent inhibition. Provided herein. Preferably, the compound is BTK-I.

[0082] BTK for use in the treatment of BTK-mediated cancers where the patient has received two prior anticancer therapies or a pharma- ceutical acceptable salt thereof, In one embodiment, a therapeutically effective amount of the compound or salt is administered to a subject in need of treatment with a BTK-mediated cancer that is not associated with progression of the cancer or is not associated with unacceptable toxicity. orally administering the compound in a continuous daily dosage regimen until the compound is administered orally; A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. an amount that results in greater than 90 percent inhibition, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0083] A BTK inhibitor for use in the treatment of BTK-mediated cancers in which the patient has received more than two prior anticancer therapies. A compound which is a KI or a pharma- ceutical acceptable salt thereof, and which is used to treat a patient suffering from a BTK-mediated cancer. and administering to a subject a therapeutically effective amount of the compound or salt, the subject being treated with a BTK-mediated cancer progression or unacceptable toxicity. orally administering in a continuous daily dose regimen until A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. The compound or a pharma- ceutically acceptable salt thereof may also be administered in an amount that results in greater than 90 percent inhibition. Provided herein. Preferably, the compound is BTK-I.

[0084] A BTK inhibitor for use in the treatment of BTK-mediated cancers in which the patient has received more than two prior anticancer therapies. A compound which is a KI or a pharma- ceutical acceptable salt thereof, and which is used to treat a patient suffering from a BTK-mediated cancer. and administering to a subject a therapeutically effective amount of the compound or salt, the subject being treated with a BTK-mediated cancer progression or unacceptable toxicity. orally administering in a continuous daily dose regimen until A therapeutically effective amount of the compound or salt is administered to a patient at steady state 24 hours after administration to increase the activity of BTK. an amount that results in greater than 90 percent inhibition, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0085] The present invention also provides compounds that are BTK-I or and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound, a pharma- ceutical acceptable salt thereof. or salt in successive daily doses until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administered in a regimen comprising: The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Preferably, the compound is a BTK inhibitor, -I.

[0086] A compound that is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of BTK-mediated cancer. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt, Orally in a continuous daily dosing regimen until progression of TK-mediated cancer or unacceptable toxicity occurs administering The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0087] BTK-I for use in treating a BTK-mediated cancer in a patient with relapsed or refractory cancer. or a pharma- ceutical acceptable salt thereof, comprising administering to a patient suffering from a BTK-mediated cancer: A therapeutically effective amount of the compound or salt is administered to a subject who is at risk of developing BTK-mediated cancer or who is at risk of developing unacceptable toxicity. orally administering in a continuous daily dose regimen up to The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0088] BTK-I for use in treating BTK-mediated cancer, wherein the patient is relapsed or refractory. A compound or a pharma- ceutical acceptable salt thereof is administered to a patient suffering from a BTK-mediated cancer. A therapeutically effective amount of the compound or salt is administered until progression of BTK-mediated cancer or unacceptable toxicity occurs. in a continuous daily dosage regimen, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The anti-CD20-based therapy may be administered in separate or sequential doses, preferably in the first two or more doses. Compound or compounds administered as split doses on days 1 or 1 and 2 of an 8-day cycle. or a pharma- ceutically acceptable salt thereof are also provided herein. The regimen is approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 On the first day and Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by Anti-CD20-based therapy may be administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered at least once every 4 to 8 weeks. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered on days 1 or as split doses on days 1 and 2, anti-CD20-based therapy is then administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Typically, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered daily starting on day 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, anti-CD2 0-based therapy may then be administered on day 1 or during each of any subsequent cycles. or not at all, and a BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The anti-CD20 based therapy is preferably rituximab. Preferably, the anti-CD20 based therapy is obinutuzumab. The D20-based regimen is R-CHOP. Preferably, rituximab is administered for the first 28 days. About 375 mg / m on day 1 of the cycle 2or as a split dose on days 1 and 2 Preferably, rituximab is administered at about 375 mg on days 1±3 of an initial 28-day cycle. / m 2 or as a split dose on days 1 and 2. Cimab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the first and second days Rituximab is administered as divided doses to the eyes, approximately 500 mg / m on day 1, followed by 2 in or not at all during each of any subsequent cycles. Preferably, venetoclax is administered at a dose of about 20 mg on days 1 to 7 of a fourth 28-day cycle. g, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg was administered on days 22-28 of the first cycle, followed by approximately Rituximab is administered daily at 400 mg on day 1 of the first 28-day cycle. Approximately 375 mg / m 2 Administered in single doses or as split doses on days 1 and 2 Cimab was then administered at approximately 500 mg / m on day 1. 2 or each of the following cycles venetoclax was administered either in the fourth or 28-day follow-up. During the cycle, approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 15 mg on days 15-20 of the cycle. It is administered at approximately 100 mg on days 21 to 28 of the cycle and at approximately 200 mg on days 22 to 28 of the cycle. and then about 400 mg daily for any subsequent cycles. -I is administered at approximately 200 mg daily, and rituximab is administered at approximately 3 mg daily on day 1 of the first 28-day cycle. 75 mg / m 2 or as split doses on days 1 and 2, and rituximab Then, on the first day, approximately 500 mg / m 2 or during each of any subsequent cycles. During the fourth 28-day cycle, venetoclax was administered either once or twice a day. 20 mg on days 1-7 of the cycle, 50 mg on days 8-14 of the cycle, and 15-21 of the cycle. It is administered at approximately 100 mg on days 22-28 of the cycle, and approximately 200 mg on days 22-28 of the cycle, followed by Any subsequent cycles will be dosed at approximately 400 mg daily.

[0089] A compound that is a BTK-I for use in treating BTK-mediated cancers in which the patient is treatment naive. or a pharma- ceutical acceptable salt thereof, The compound or salt is administered in successive doses until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administered in a regular daily dosage regimen; The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0090] A compound that is a BTK-I for use in treating BTK-mediated cancers in which the patient is treatment naive. or a pharma- ceutical acceptable salt thereof, The compound or salt is administered in successive doses until progression of BTK-mediated cancer or unacceptable toxicity occurs. orally administered in a regular daily dosage regimen; The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0091] For use in the treatment of BTK-mediated cancers in which the patient has received at least one prior anticancer therapy A compound or a pharma- ceutical acceptable salt thereof that is a BTK-I for treating BTK-mediated cancer. The compound or salt is administered to a patient suffering from a BTK-mediated cancer progression or intolerance. orally in a continuous daily dosing regimen until insignificant toxicity occurs; The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0092] For use in the treatment of BTK-mediated cancers in which the patient has received at least one prior anticancer therapy A compound or a pharma- ceutical acceptable salt thereof that is a BTK-I for treating BTK-mediated cancer. The compound or salt is administered to a patient suffering from a BTK-mediated cancer progression or intolerance. orally in a continuous daily dosing regimen until insignificant toxicity occurs; The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The anti-CD20-based therapy may be administered in separate or sequential doses, preferably in the first two or more doses. Compound or compounds administered as split doses on days 1 or 1 and 2 of an 8-day cycle. or a pharma- ceutically acceptable salt thereof are also provided herein. The regimen is approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 On the first day and Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by Anti-CD20-based therapy may be administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered at least once every 4 to 8 weeks. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered on days 1 or as split doses on days 1 and 2, anti-CD20-based therapy is then administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Typically, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered daily starting on day 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, anti-CD2 0-based therapy may then be administered on day 1 or during each of any subsequent cycles. or not at all, and a BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The anti-CD20 based therapy is preferably rituximab. Preferably, the anti-CD20 based therapy is obinutuzumab. The D20-based regimen is R-CHOP. Preferably, rituximab is administered for the first 28 days. About 375 mg / m on day 1 of the cycle 2 or as a split dose on days 1 and 2 Preferably, rituximab is administered at about 375 mg on days 1±3 of an initial 28-day cycle. / m 2 or as a split dose on days 1 and 2. Cimab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the first and second days Rituximab is administered as divided doses to the eyes, approximately 500 mg / m on day 1, followed by 2 in or not at all during each of any subsequent cycles. Preferably, venetoclax is administered at a dose of about 20 mg on days 1 to 7 of a fourth 28-day cycle. g, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg was administered on days 22-28 of the first cycle, followed by approximately Rituximab is administered daily at 400 mg on day 1 of the first 28-day cycle. Approximately 375 mg / m 2 Administered in single doses or as split doses on days 1 and 2 Cimab was then administered at approximately 500 mg / m on day 1. 2 or each of the following cycles venetoclax was administered either in the fourth or 28-day follow-up. During the cycle, approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 15 mg on days 15-20 of the cycle. It is administered at approximately 100 mg on days 21 to 28 of the cycle and at approximately 200 mg on days 22 to 28 of the cycle. and then about 400 mg daily for any subsequent cycles. -I is administered at approximately 200 mg daily, and rituximab is administered at approximately 3 mg daily on day 1 of the first 28-day cycle. 75 mg / m 2 or as split doses on days 1 and 2, and rituximab Then, on the first day, approximately 500 mg / m 2 or during each of any subsequent cycles. During the fourth 28-day cycle, venetoclax was administered either once or twice a day. 20 mg on days 1-7 of the cycle, 50 mg on days 8-14 of the cycle, and 15-21 of the cycle. It is administered at approximately 100 mg on days 22-28 of the cycle, and approximately 200 mg on days 22-28 of the cycle, followed by Any subsequent cycles will be dosed at approximately 400 mg daily. Patients who have received at least one prior anticancer therapy, including a TK inhibitor-based therapy, have a BTK-mediated A compound which is a BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer. Thus, a therapeutically effective amount of the compound or salt is administered to a patient suffering from a BTK-mediated cancer, thereby preventing or treating the BTK-mediated cancer. Administer orally in a continuous daily dosing regimen until progression or unacceptable toxicity. Including, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0093] Patients must have had at least one prior anti-cancer therapy, including at least one BTK inhibitor-based therapy. and a compound which is a BTK-I or a compound thereof for use in the treatment of BTK-mediated cancers. and administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or or salts are administered at successive daily dose levels until progression of BTK-mediated cancer or unacceptable toxicity occurs. Oral administration with dimen, The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day,2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0094] For use in the treatment of BTK-mediated cancers in which patients have not received prior anticancer therapy including a BTK inhibitor. A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of a chronic inflammatory condition, comprising: The present invention relates to a method for treating or preventing the progression or permissiveness of BTK-mediated cancer, comprising administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. orally administered in a continuous daily dosing regimen until unacceptable toxicity occurs; The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0095] For use in the treatment of BTK-mediated cancers in which patients have not received prior anticancer therapy including a BTK inhibitor. A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for use in the treatment of a chronic inflammatory condition, comprising: The present invention relates to a method for treating or preventing the progression or permissiveness of BTK-mediated cancer, comprising administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt. orally administered in a continuous daily dosing regimen until unacceptable toxicity occurs; The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0096] BTK for use in the treatment of BTK-mediated cancers, where the patient has received one prior anticancer therapy or a pharma- ceutical acceptable salt thereof, In one embodiment, a therapeutically effective amount of the compound or salt is administered to a subject in need of treatment with a BTK-mediated cancer that is not associated with progression of the cancer or is not associated with unacceptable toxicity. orally administering the compound in a continuous daily dosage regimen until the compound is administered orally; The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0097] BTK for use in the treatment of BTK-mediated cancers, where the patient has received one prior anticancer therapy or a pharma- ceutical acceptable salt thereof, In one embodiment, a therapeutically effective amount of the compound or salt is administered to a subject in need of treatment with a BTK-mediated cancer that is not associated with progression of the cancer or is not associated with unacceptable toxicity. orally administering the compound in a continuous daily dosage regimen until the compound is administered orally; The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0098] BTK for use in the treatment of BTK-mediated cancers where the patient has received two prior anticancer therapies or a pharma- ceutical acceptable salt thereof, In one embodiment, a therapeutically effective amount of the compound or salt is administered to a subject in need of treatment with a BTK-mediated cancer that is not associated with progression of the cancer or is not associated with unacceptable toxicity. orally administering the compound in a continuous daily dosage regimen until the compound is administered orally; The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0099] BTK for use in the treatment of BTK-mediated cancers where the patient has received two prior anticancer therapies or a pharma- ceutical acceptable salt thereof, In one embodiment, a therapeutically effective amount of the compound or salt is administered to a subject in need of treatment with a BTK-mediated cancer that is not associated with progression of the cancer or is not associated with unacceptable toxicity. orally administering the compound in a continuous daily dosage regimen until the compound is administered orally; The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day,2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0100] A BTK inhibitor for use in the treatment of BTK-mediated cancers in which the patient has received more than two prior anticancer therapies. A compound which is a KI or a pharma- ceutical acceptable salt thereof, and which is used to treat a patient suffering from a BTK-mediated cancer. and administering to a subject a therapeutically effective amount of the compound or salt, the subject being treated with a BTK-mediated cancer progression or unacceptable toxicity. orally administering in a continuous daily dose regimen until The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. Also provided herein is a compound, or a pharma- ceutically acceptable salt thereof, which is The compound is BTK-I.

[0101] A BTK inhibitor for use in the treatment of BTK-mediated cancers in which the patient has received more than two prior anticancer therapies. A compound which is a KI or a pharma- ceutical acceptable salt thereof, and which is used to treat a patient suffering from a BTK-mediated cancer. and administering to a subject a therapeutically effective amount of the compound or salt, the subject being treated with a BTK-mediated cancer progression or unacceptable toxicity. orally administering in a continuous daily dose regimen until The administration of a therapeutically effective amount of the drug results in an AUC (0~24) is approximately 52,400ng*h / mL or more And, A therapeutically effective amount of said administration results in an exposure of about 806 ng / mL or greater 24 hours after said administration. the law of nature, The compound or salt may be administered in combination with a BCL-2 inhibitor and / or an anti-CD20 based therapy. The compounds or pharma- ceutically acceptable salts thereof, administered separately or sequentially, are also contemplated herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is administered during the first 28 day cycle. Administered as a split dose on day 1 or days 1 and 2, anti-CD20-based therapy The method may then be administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Or, BTK-I is administered daily starting on day 1, and anti-CD20-based therapy is administered initially. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle to treat anti-CD The 20-based regimen is then administered on day 1 or during each of any subsequent cycles. Either not administered at all, and a BCL-2 inhibitor was administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. The BCL2-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. The BCL2-I inhibitor is preferably a BCL2-I inhibitor. Preferably, the anti-CD20 based therapy is obinutuzumab. The CD20-based therapy is R-CHOP. Preferably, rituximab is administered for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Preferably, rituximab is administered at about 375 mg / kg on days 1 ± 3 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 On or on the 1st and 2nd Rituximab is then administered at approximately 500 mg / m on day 1. 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered about 20 days on days 1 to 7 of the fourth 28-day cycle. mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of the cycle, and then on any subsequent cycles. Approximately 400 mg is dosed daily. Preferably, rituximab is administered daily for at least one day of the first 28-day cycle. About 375 mg / m2 in the eye 2 It is given in a single dose or as a split dose on days 1 and 2 and Ximab was then administered at approximately 500 mg / m on day 1. 2 or in any subsequent cycle Either not administered at all between each, and venetoclax was administered in the fourth 28 During the daily cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, and about 100 mg on days 1 to 3 of the cycle. It is administered at approximately 100 mg on days 5-21 and approximately 200 mg on days 22-28 of the cycle. Thereafter, it is dosed at about 400 mg daily for any subsequent cycles. KI was administered at approximately 200 mg daily, and rituximab was administered at approximately 1 mg daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as divided doses on days 1 and 2, Then, on the first day, 2 or each of any subsequent cycles. VENCLEXTA was administered in the fourth 28-day cycle or not at all in between. About 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, and about 15-20 mg on days 10-14 of the cycle. It is administered at approximately 100 mg on day 1 and approximately 200 mg on days 22-28 of the cycle, then and for any subsequent cycles, approximately 400 mg is dosed daily.

[0102] The present invention also relates to a compound which is BTK-I or a compound thereof for the manufacture of a medicament for the treatment of cancer. The use of a pharma- ceutically acceptable salt, wherein the compound or salt is administered to a patient in an amount of from about 120 mg to about 600 mg. The use is provided in a daily dose of about 125 mg to about 60 mg. 0 mg. Preferably, the compound is BTK-I.

[0103] A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. The use of a salt thereof, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg. and may be administered simultaneously, separately, or in combination with BCL-2 inhibitors and / or anti-CD20 based therapies. Alternatively, the dose is administered in continuous doses. 5 mg to about 600 mg. Preferably, the anti-CD20-based therapy is administered for the first 28 days. The antibody is administered on day 1 of the treatment phase or as a split dose on days 1 and 2 of the treatment phase. CD20-based therapy is administered at approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 So, or as split doses on days 1 and 2. Preferably, the anti-CD20 based Therapy is administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. and then anti-CD20-based therapy is administered on day 1 or on day 2 of any subsequent cycles. Either not administered at all between each other. is administered during the fourth 28-day cycle. Preferably, the anti-CD20 based therapy is administered during the first Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, anti-CD2 0-based therapy may then be administered on day 1 or during each of any subsequent cycles. or not at all, and a BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, BTK-I is administered daily starting on day 1, and anti-CD20-based Therapy is administered as a split dose on days 1 or 1 and 2 of the first 28-day cycle. and anti-CD20-based therapy is then administered on day 1 or on day 2 of any subsequent cycle. Either not administered at all between each, and the BCL-2 inhibitor was administered in the fourth 28 The BCL-2 inhibitor is preferably venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharma- ceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20 based therapy is Preferably, the anti-CD20 based therapy is obinutuzumab. Preferably, the anti-CD20 based therapy is R-CHOP. , approximately 375 mg / m on day 1 of the first 28-day cycle 2 or split into days 1 and 2 Preferably, rituximab is administered on day 1 ± 3 of the first 28-day cycle. Approximately 375 mg / m 2 The dose is administered in one dose, or as a split dose on days 1 and 2. Rituximab should be administered at a dose of approximately 375 mg / m on day 1 of the first 28-day cycle. 2 In or 1 Rituximab is then administered approximately 50 mg on day 1. 0 mg / m 2 or not at all during each of any subsequent cycles Preferably, venetoclax is administered during cycles 1 to 7 of a fourth 28-day cycle. Approximately 20 mg on the first day of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 100 mg on days 15-21 of the cycle. mg on days 22-28 of the cycle, and approximately 200 mg on days 22-28 of the cycle, followed by Rituximab is preferably administered at about 400 mg daily for the first 28 Approximately 375 mg / m on day 1 of the cycle 2 or as divided doses on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 Either or not administered at all during each of the subsequent cycles of During the fourth 28-day cycle, approximately 20 mg on days 1-7 of the cycle and approximately 50 mg on days 8-14 of the cycle. g, approximately 100 mg on days 15-21 of the cycle, and approximately 200 mg on days 22-28 of the cycle. At about 400 mg daily thereafter for any subsequent cycles. Alternatively, BTK-I is administered at approximately 200 mg daily, and rituximab is administered for the first 28-day cycle. Approximately 375 mg / m on day 1 2 or as split doses on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 Either administered at once or at any subsequent Either not administered during each of the four cycles or not administered at all. During the 28-day cycle, approximately 20 mg on days 1-7 of the cycle, approximately 50 mg on days 8-14 of the cycle, and approximately 10 mg on days 1-7 of the cycle. Approximately 100 mg is administered on days 15-21 of the cycle, and approximately 200 mg is administered on days 22-28 of the cycle. and then dosed at about 400 mg daily for any subsequent cycles.

[0104] A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. The use of a salt thereof, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg. and the patient is relapsed or refractory. The dosage is between about 125 mg and about 600 mg. Preferably, the compound inhibits BTK-I. be.

[0105] A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. The use of a salt thereof, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg. and the patient is relapsed or refractory, and the compound or salt is administered in combination with a BCL-2 inhibitor and and / or administered simultaneously, separately, or sequentially with anti-CD20-based therapy; Uses thereof are also provided herein. Preferably, the dose is from about 125 mg to about 600 mg. Preferably, the anti-CD20 based therapy is administered on day 1, or on days 1 and 2 of the first 28 day cycle. Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Approximately 375 mg / m on days 1 ± 3 of a 28-day cycle 2 or for splitting on days 1 and 2 Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28 day cycle. or as split doses on days 1 and 2, followed by anti-CD20-based The therapy is administered on day 1 or not at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 28 day cycle. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle or on day 1 of the first 28-day cycle. The anti-CD20-based therapy is administered as split doses on days 1 and 2, followed by 1 day either administered intraocularly or not administered at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. was administered daily starting on day 1, and anti-CD20-based therapy was administered on day 1 of the first 28-day cycle. Administered as split doses on days 1 and 2, anti-CD20-based therapy is , then administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. Preferably, the BCL-2 inhibitor is venetoclax. 2-I or a pharma- ceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL 2-I. Preferably, the anti-CD20 based therapy is rituximab. Preferably, the anti-CD20 based therapy is obinutuzumab. The preferred regimen is R-CHOP. Preferably, rituximab is administered approximately once daily on day 1 of the first 28-day cycle. 375 mg / m 2 or as a split dose on days 1 and 2. Rituximab was administered at approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 In, or It is administered as a split dose on days 1 and 2. Preferably, rituximab is administered on the first About 375 mg / m on day 1 of a 28-day cycle 2 or as divided doses on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 It is administered either Either not administered at all during each of the subsequent cycles. Venetoclax is administered at approximately 20 mg on days 1 to 7 of the fourth 28-day cycle and at approximately 20 mg on days 8 to 10 of the fourth 28-day cycle. Approximately 50 mg on day 4, approximately 100 mg on days 15-21 of the cycle, and approximately 22-28 of the cycle Approximately 200 mg per eye, then approximately 400 mg daily for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / kg on day 1 of the first 28-day cycle. m 2 or as split doses on days 1 and 2, and rituximab is then administered , approximately 500 mg / m on day 1 2 or during each of any subsequent cycles. VENCLEXTA was administered either once or twice daily during the fourth 28-day cycle. ~20 mg on day 7, ~50 mg on days 8-14 of the cycle, ~1 mg on days 15-21 of the cycle 00 mg on days 22-28 of the cycle, and approximately 200 mg on days 22-28 of the cycle, and then For subsequent cycles, the dose is about 400 mg daily. Preferably, the BTK-I is about 200 mg. g daily, with rituximab administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 in or as split doses on days 1 and 2, with rituximab administered daily thereafter. About 500 mg / m2 in the eye 2 or not administered at all during each of any subsequent cycles. VENCLEXTA is administered on days 1-7 of the fourth 28-day cycle. Approximately 20 mg in the eyes, approximately 50 mg on days 8-14 of the cycle, and approximately 100 mg on days 15-21 of the cycle. g, and approximately 200 mg on days 22-28 of the cycle, and then on any subsequent cycles It is also administered at approximately 400 mg daily.

[0106] A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. The use of a salt thereof, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg. Also provided herein is a use in which the patient is treatment naive. Between about 125 mg and about 600 mg. Preferably, the compound is BTK-I.

[0107] A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. The use of a salt thereof, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg. and the patient is treatment naïve and the compound or salt is administered in combination with a BCL-2 inhibitor and / or The use is also contemplated herein, and may be administered simultaneously, separately, or sequentially with an anti-CD20 based therapy. The dosage is preferably from about 125 mg to about 600 mg. , anti-CD20-based therapy on day 1 or days 1 and 2 of the first 28-day cycle. Preferably, the anti-CD20 based therapy is administered in divided doses over the first 28 days. Approximately 375 mg / m on days 1 ± 3 of the first period 2 or as divided doses on days 1 and 2 Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28 day cycle. or as split doses on days 1 and 2, after which anti-CD20-based therapy is Either administered on day 1 or not at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 28 day cycle. Preferably, the anti-CD20 based therapy is administered on day 1, or on days 1 and 2 of the first 28 day cycle. The anti-CD20-based therapy is then administered on day 1. or not at all during each of any subsequent cycles; The BCL-2 inhibitor is administered during the fourth 28 day cycle. Preferably, the BTK-I is administered on day 1. Anti-CD20-based therapy is administered daily starting on day 1 of the first 28-day cycle, and or as split doses on days 1 and 2, and anti-CD20-based therapy is then administered Either administered on day 1 or not at all during each of any subsequent cycles. and the BCL-2 inhibitor is administered during the fourth 28 day cycle. The BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or or a pharma- ceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20 based therapy is rituximab. The anti-CD20 based therapy is obinutuzumab. Preferably, the anti-CD20 based therapy is R- Preferably, rituximab is administered at about 375 mg / kg on day 1 of the first 28-day cycle. g / m 2 It is preferably administered in a single dose or as a split dose on days 1 and 2. Ximab is administered at approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Rituximab is administered as a split dose on days 1 and 2. Preferably, rituximab is administered twice daily for the first 28 days. Approximately 375 mg / m on day 1 of the period 2 given in a single dose or as a split dose on days 1 and 2 Rituximab was then administered at approximately 500 mg / m on day 1. 2 Either at or after Either venetoclave is administered during each of the subsequent cycles or not at all. During the fourth 28-day cycle, Lacus was administered at approximately 20 mg on days 1-7 of the cycle and 20 mg on days 8-14 of the cycle. Approximately 50 mg on days 15-21 of the cycle, approximately 100 mg on days 22-28 of the cycle, and approximately 2 00 mg daily, then approximately 400 mg daily for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle. 2 in, or as split doses on days 1 and 2, with rituximab then administered on day 1. Approximately 500 mg / m 2 or not administered at all during each of any subsequent cycles. VENCLEXTA is administered on days 1-7 of the fourth 28-day cycle. 20 mg on days 8-14 of the cycle, 50 mg on days 15-21 of the cycle, and 100 mg on days 16-22 of the cycle. and approximately 200 mg on days 22-28 of the cycle, and then in any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily. Rituximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle. 2 In, or It is given as split doses on days 1 and 2, with rituximab then administered approximately 5 times on day 1. 00mg / m 2 or not administered at all during each of any subsequent cycles. VENCLEXTA was administered approximately 2 times daily on days 1-7 of the fourth 28-day cycle. 0 mg, approximately 50 mg on days 8-14 of the cycle, approximately 100 mg on days 15-21 of the cycle, and Approximately 200 mg is administered on days 22-28 of each cycle, and then for any subsequent cycles. is also administered at approximately 400 mg daily.

[0108] A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. The use of a salt thereof, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg. Also provided herein are methods for administering a medicament for cancer resection, the method comprising administering to the patient ... Preferably, the dose is between about 125 mg and about 600 mg. is BTK-I.

[0109] A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. The use of a salt thereof, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg. and the patient has received at least one prior anticancer therapy and the compound or salt is administered Concurrent, separate, or sequential administration of BCL-2 inhibitors and / or anti-CD20-based therapies Also provided herein is a use in which the drug is administered at a dose of about 125 mg to about 6 Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle. or as a split dose on days 1 and 2. The regimen was approximately 375 mg / m on days 1 ± 3 of the first 28-day cycle. 2 Or on the first day Preferably, the anti-CD20 based therapy is administered as a split dose on days 1 and 2. Administered as a split dose on days 1 or 1 and 2 of a 28-day cycle, followed by The anti-CD20-based therapy is administered on day 1 or during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered in a fourth or second dose. Preferably, the anti-CD20 based therapy is adm...

Claims

1. 1. A medicament for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer, comprising: The pharmaceutical agent comprises a compound which is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide or a pharma- ceutically acceptable salt thereof; said use comprising orally administering to a patient suffering from a BTK-mediated cancer said compound, or a pharma- ceutical acceptable salt thereof, in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs; the compound or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 25 mg to 300 mg; By this administration, AUC （０～２４） becomes 52400ng*h / mL or more, said administration results in an exposure of 806 ng / mL or greater 24 hours after said administration.

2. The AUC （０～２４） The pharmaceutical product according to claim 1, wherein the concentration of 91,000 ng*h / mL or more is 91,000 ng*h / mL or more.

3. The pharmaceutical product of claim 1 or 2, wherein said administration results in a maximum drug concentration (C max ) of 3910 ng / mL or greater.

4. The pharmaceutical product of claim 3, wherein said administration results in a maximum drug concentration (C max ) of 5770 ng / mL or greater.

5. A pharmaceutical agent described in any one of claims 1 to 4, wherein said administration results in a mean trough plasma level of greater than 2200 ng / mL.

6. 1. A pharmaceutical product for use in the treatment of cancer, comprising: The pharmaceutical agent comprises a compound which is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide or a pharma- ceutically acceptable salt thereof; the compound or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 120 mg to 300 mg; By this administration, AUC （０～２４） A medicine that has a blood glucose level of 91,000 ng*h / mL or higher.

7. 1. A pharmaceutical product for use in the treatment of cancer, comprising: The pharmaceutical agent comprises a compound which is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide or a pharma- ceutically acceptable salt thereof; the compound or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 120 mg to 300 mg; The administration of said pharmaceutical agent results in a maximum drug concentration (C max ) of 5770 ng / mL or greater.

8. 1. A pharmaceutical product for use in the treatment of cancer, comprising: The pharmaceutical agent comprises a compound which is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide or a pharma- ceutically acceptable salt thereof; the compound or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 120 mg to 300 mg; The administration of said pharmaceutical product results in a mean trough plasma level of greater than 2200 ng / mL.

9. 1. A pharmaceutical product for use in the treatment of cancer, comprising: The pharmaceutical agent comprises a compound which is (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide or a pharma- ceutically acceptable salt thereof; the compound or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 25 mg to 300 mg; A pharmaceutical agent, wherein administration of said compound or a pharma- ceutically acceptable salt thereof results in a maximum drug concentration (Cmax) of 3910 ng / mL or greater.

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