Dosing of bruton's tyrosine kinase inhibitor

Abstract

To provide alternative treatment therapies for patients suffering from cancer and autoimmune diseases.SOLUTION: The present invention provides a method of administering doses of the BTK inhibitor, (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof, for use in treating conditions such as cancer and autoimmune diseases.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to the use of (S)-5-amino-3 for treating conditions such as cancer and autoimmune diseases -(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1 ,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.

Background Art

[0002] Bruton's tyrosine kinase (BTK) is a member of the src-related Tec family of cytoplasmic tyrosine kinases. BTK plays a major role in the B cell antigen receptor signaling pathway required for the development, activation, and survival of normal white blood cells known as B cells. BTK also plays an important role in the proliferation and survival of various B cell malignancies. Therefore, BTK is a useful molecular target for the treatment of a number of B cell leukemias and lymphomas, including, for example, indolent and aggressive mature B cell non-Hodgkin lymphomas, chronic lymphocytic leukemia / small lymphocytic lymphoma, Waldenström macroglobulinemia, mantle cell lymphoma, follicular lymphoma, diffuse large B cell lymphoma, B cell prolymphocytic leukemia, hairy cell leukemia, and marginal zone lymphoma. B cells have also been reported to play a prominent role in the development of chronic graft-versus-host disease (cGVHD), a life-threatening complication of allogeneic stem cell transplantation, and research on B cell-targeted therapies for the prevention and treatment of cGVHD has been promoted. Rituximab is a steroid

[0003] and treatment of cGVHD has been promoted. Rituximab is a steroid and treatment of cGVHD has been promoted. Rituximab is a steroid It has various effects in refractory cGVHD and may help prevent its onset. In addition, ibrutinib, a covalent BTK inhibitor, was approved by the US FDA in 20 17.

[0004] (S)-5-Amino-3-(4-((5-fluoro-2-methoxybenzamide)meth yl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo le-4-carboxamide compound (referred to as "BTK-I" herein) and its phar macologically acceptable salts are disclosed as selective inhibitors of BTK in WO17 / 103611 and WO 2020 / 028258.

[0005] Many patients being treated with BTK inhibitors for cancer, particularly BTK-mediated cancer, become refractory or resistant to further treatment or intolerant to treatment due to severe or life-threatening relapses or adverse events. For example, patients treated with ibrutinib, a BTK inhibitor, can become resistant and / or intolerant to further treatment. (M 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). For patients who develop resistance, increasing the dose of ibrutinib to overcome resistance is associated with neutropenia thrombocytopenia, diarrhea, anemia, musculoskeletal pain, rash, nausea, bruising, fatigue, bleeding, and hair loss. May not be a viable option due to the toxicity associated with ibrutinib containing heat .

[0006] As described by Mato (2018), in the case of ibrutinib, toxicity was the most common reason for discontinuation in all settings, accounting for 63.1% of discontinuations in real-world use and 50.2% of discontinuations in relapsed / refractory (R / R) use. Toxicity was the most common reason for discontinuation in several settings, including commercial use as well as clinical trial use (50% of discontinuations in commercial real-world use, 77.7% of discontinuations in clinical trial real-world use, 52.5% of discontinuations in R / R commercial use, and 39.7% of discontinuations in R / R clinical trial use). Toxicities associated with ibrutinib leading to dose interruption and treatment discontinuation included arthralgia, atrial fibrillation, rash, cytopenia, infections, pneumonia, bleeding, and diarrhea. In the literature, these toxicities were attributed to both on-target BTK inhibition and off-target inhibition of other kinases such as Tec. Notably, the proportion of discontinuations due to progressive disease (PD) was low, at 15.8% in the real-world setting and 20.9% in R / R use. Richter transformation to diffuse large B-cell lymphoma or Hodgkin lymphoma accounted for 5.3% of discontinuations in the real-world setting and 5.0% in the R / R setting. Interestingly, the starting dose of ibrutinib (420 mg per day vs less than 420 mg per day) was not correlated with the proportion of patients who discontinued ibrutinib due to toxicity (51% vs 50%) or disease progression (19.6% vs 21.4%). Retrospective analysis of the RESONATE trial showed that in R / R chronic lymphocytic leukemia patients with low ibrutinib dose intensity and dose interruptions lasting more than 7 days, the progression-free survival (PF ​​​​​​​​​​​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 combination, 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). From March 21, 2019 to September 27, 202 0, among 323 patients, over seven dose levels ranging from 25 mg once daily (QD) to 300 mg QD, the only treatment-emergent adverse events that occurred in ≥10% of patients (n = 323), regardless of attribute or grade, were fatigue (n = 65, 20%), diarrhea (n = 55, 17%), and bruising (n = 42, 13%). Among 121 patients with chronic lymphocytic leukemia (CLL) treated with cBTKi and evaluable for efficacy (median pre-line = 4), the overall response rate (ORR) was 62% (95% CI: 53 - 71), which increased to 84% in patients observed for 10 months. The ORR was similar in patients with previous cBTKi resistance (67%, 53 / 79), cBTKi intolerance (52%, 22 / 42) , BTK C481 variant (71%, 17 / 24), and BTK wild-type (66%, 43 / 65) disease (chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SL L)). Among 52 patients with mantle cell lymphoma (MCL) treated with cBTKi and evaluable for efficacy, the ORR was 52% (95% CI: 38 - 66). Of the 117 CLL or MCL patients who responded, all but 8 maintained progression-free status. Waldenström macroglobulinemia (WM) (n = 19, ORR 68%) and follicular lymphoma (FL) (n = 8, ORR 50%) also showed responses. Furthermore, drug-related adverse events (AEs) led to treatment interruption, dose reduction, and permanent discontinuation in 8.0% (26 patients), 2.2% (7 patients), and 1.5% (5 patients) of the patients, respectively. .

[0009] Atrial arrhythmia and bleeding are two major AEs associated with discontinuation of covalent BTK inhibitors. In the overall safety population of 323 patients, atrial fibrillation / flutter was seen in only 2 patients (0.6% ), both events were grade 2, and each was considered unrelated to BTK-I in light of the patient's prior history of atrial fibrillation. Only 1 patient experienced grade 3 bleeding, a subdural hemorrhage sustained during a bicycle accident. In total, 18 patients discontinued their previous BTK inhibitor due to vascular toxicity (15 patients) or bleeding (3 patients). None of the patients experienced recurrence of these events on BTK-I. The present invention provides a method of treating cancer or an autoimmune disease in a patient in need thereof. In one embodiment, the method comprises administering to the patient a daily dose of about 120 mg to about 600 mg of a compound that is a BTK-I or a pharmaceutically acceptable salt thereof. Preferably, the daily dose is between about 125 mg and about 600 mg. Preferably, the method treats cancer. Preferably, the compound is a BTK-I. Preferably, the patient is relapsed or refractory. Preferably, the patient is treatment-naive. Preferably, the patient has received at least one prior

[0010] antineoplastic therapy. Preferably, the patient has at least one B prior​​​​​​ Has received at least one prior anti-cancer therapy including a TK inhibitor-based therapy. Preferably the patient has not received a prior anti-cancer therapy including a BTK inhibitor. Preferably, the patient has received one prior anti-cancer therapy. Preferably, the patient has received two prior anti-cancer therapies. Preferably, the patient has received two or more prior anti-cancer therapies. In another embodiment, the method further comprises concurrent, separate, or sequential administration of a B-cell lymphoma 2 (BCL-2) inhibitor and / or an anti-CD20-based therapy. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably the anti-CD20-based therapy is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, ± 3 days, 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 divided doses on days 1 and 2 and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered 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 as divided doses on days 1 and 2, the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20 -based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2 administered, and the anti-CD20-based therapy is then administered on day 1 or not at all during any subsequent cycle, and the BCL-2 inhibitor is administered during the 28-day cycle of the fourth cycle. Preferably, the BCL-2 inhibitor is venetoclax . Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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 rituximab, cyclophosphamide, do xorubicin hydrochloride, vincristine sulfate, and prednisone (such therapy is referred to as "R-CHOP"). Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably 2 , rituximab is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is 2 administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or not at all during any subsequent cycle. Preferably 2 , venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 fourth 28-day cycle, and then about 400 mg for any subsequent cycle . Preferably , venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 fourth 28-day cycle, and then about 400 mg for any subsequent cycle It is administered daily. Preferably, rituximab is about 375 mg / m 2 on day 1 of the first 28-day cycle or administered as divided doses on days 1 and 2, and rituximab is subsequently administered at about 500 mg / m 2 on day 1 or not administered at all between each of any subsequent cycles. Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 00 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the fourth 28-day cycle, and thereafter, it is administered daily at about 400 mg for any subsequent cycle. Preferably, the BTK-I is administered daily at about 2 00 mg, and rituximab is about 375 mg / m on day 1 of the first 28-day cycle or administered as divided doses on days 1 and 2, and rituximab is subsequently administered at about 500 mg / m 2 on day 1 or not administered at all between each of any subsequent cycles. Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 2 00 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle, and thereafter, it is administered daily at about 400 mg for any subsequent cycle.

[0011] The present invention also provides a method of inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer, the method comprising orally administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of a BTK -I or a pharmaceutically acceptable salt thereof in a continuous daily dosage regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, the method comprising orally administering a therapeutically effective amount of a compound 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 on day 1, or as divided doses on days 1 and 2, the anti-CD20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD 20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m 2 on day 1 ± 3 days of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1 or not administered at all during each of any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is administered at about 500 mg / m on day 1 of any subsequent cycle, or not administered at all during each of any subsequent cycles. 2 Preferably, rituximab is administered at about 500 mg / m Yes. Preferably, venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then at about 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, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then at about 400 mg daily for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then at about 400 mg daily for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily, and rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then at about 400 mg daily for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily, and rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then at about 400 mg daily for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then at about 400 mg daily for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then at about 400 mg daily for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then at about 400 mg daily for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then at about 400 mg daily for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then at about 400 mg daily for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then at about 400 mg daily for any subsequent cycles.

[0012] The method also relates to a method of inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer, comprising orally administering to the patient a therapeutically effective amount of a BTK-I or a pharmaceutically acceptable salt thereof in a continuous daily dosing regimen until progression of the BTK-mediated (0~24) cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the administration results in an AUC of about 52400 ng*h / mL or more, and the therapeutically effective amount of the administration results in an exposure of about 806 ng / mL or more 24 hours after the administration. Preferably, the compound is BTK-I. Preferably, the patient is relapsed or refractory. Preferably, the patient is treatment-naive. Preferably, the patient has received at least one previous anti-cancer therapy. Preferably, the patient has received at least one previous anti-cancer therapy including at least one BTK inhibitor-based therapy. Preferably, the patient has not received a previous anti-cancer therapy including a BTK inhibitor. Preferably, the patient has received one previous anti-cancer therapy. Preferably, the patient has received two previous anti-cancer therapies. Preferably, the patient 2 has received more than two previous anti-cancer therapies. In another embodiment, the method further comprises concurrent, separate, The therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD2 0-based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28 day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle 2 or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle 2It is administered as a single dose or as divided doses on Days 1 and 2. Preferably, rituximab is administered at about 375 mg / m 2 on Day 1 of the first 28-day cycle, or as divided doses on Days 1 and 2, and rituximab is then administered at about 50 0 mg / m on Day 1, or not administered at all during each of any subsequent cycles 2 whichever is applicable. Preferably, venetoclax is administered at about 20 mg on Days 1 to 7, about 50 mg on Days 8 to 14, about 100 mg on Days 15 to 21, and about 200 mg on Days 22 to 28 during the 4th 28-day cycle, and then at about 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, or as divided doses on Days 1 and 2, and rituximab is then administered at about 500 mg / m on Day 1, or not administered at all during each of any subsequent cycles, and venetoclax is administered at about 20 mg on Days 1 to 7, about 50 mg on Days 8 to 14, about 100 mg on Days 15 to 21, and about 200 mg on Days 22 to 28 during the 4th 28-day cycle, and then at about 400 mg daily for any subsequent cycles. Preferably, 2 BTK-I is administered at about 200 mg daily, and rituximab is administered at about 375 mg / m on Day 1 of the first 28-day cycle, or as divided doses on Days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on Day 1, or not administered at all during each of any subsequent cycles, and venetoclax is administered at about 20 mg on Days 1 to 7, about 50 mg on Days 8 to 14, about 100 mg on Days 15 to 21, and about 200 mg on Days 22 to 28 during the 4th 28-day cycle, and then at about 400 mg daily for any subsequent cycles. Preferably, BTK-I is administered at about 200 mg daily, and rituximab is administered at about 375 mg / m on Day 1 of the first 28-day cycle, or as divided doses on Days 1 and 2, and rituximab is then administered at about 500 mg / m on Day 1, or not administered at all during each of any subsequent cycles, and rituximab is administered at about 375 mg / m 2 on Day 1 of the first 28-day cycle, or as divided doses on Days 1 and 2, and rituximab is then administered at about 500 mg / m on Day 1, or not administered at all during each of any subsequent cycles, and rituximab is 2 administered at about 500 mg / m either not administered at all during each of the cycles, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the 28-day cycle of the fourth and then, for any subsequent cycles, administered daily at about 400 mg. The present invention also provides a compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in the treatment of cancer or autoimmune diseases, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 6

[0013] 00 mg. Preferably, the dose is about 125 mg to about 600 mg. Preferably, the compound is a BTK-I

[0014] The present invention also provides a compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in the treatment of cancer, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg. Preferably, the dose is about 1 25 mg to about 600 mg. Preferably, the compound is a BTK-I.

[0015] The present invention also provides a compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in the treatment of cancer, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg and is administered simultaneously, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy. Preferably, the dose is 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 as a divided dose on days 1 and 2 Preferably, the anti-CD20-based therapy is about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, 2 the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and then the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and then the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and then the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD 20-based therapy is rituximab. Preferably, the anti-CD20-based therapy is obinutuzumab and then the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD 20-based therapy is rituximab. Preferably, the anti-CD20-based therapy is obinutuzumab oratumumab It is rituximab. Preferably, the anti-CD20-based therapy is R-CHOP. Preferably rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on day 1 and day 2. Preferably, rituximab is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day 2 cycle, or as a divided dose on day 1 and day 2 Preferably, rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on day 1 and day 2, and rituximab is subsequently administered at about 500 mg / m 2 on day 1, or not administered at all between each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 fourth 28-day cycle, and subsequently administered daily at about 400 mg for any subsequent cycle. Preferably, ritux imab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on day 1 2 and day 2, and rituximab is subsequently administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and 2 venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 fourth 28-day cycle, and subsequently administered daily at about 400 mg for any subsequent cycle and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on day 1 and day 2, and rituximab is It is administered daily. Preferably, the BTK-I is administered at about 200 mg daily, and rituximab is , at about 375 mg / m² on day 1 of the first 28-day cycle, or 2 administered as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1 or is not administered at all during each of any subsequent cycles, and bendamustine is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter is administered daily at about 400 mg for any subsequent cycle. 2 either, and bendamustine is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter is administered daily at about 400 mg for any subsequent cycle. administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter is administered daily at about 400 mg for any subsequent cycle. A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 recurrent or refractory, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, the compound is a BTK-I.

[0016] A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 recurrent or refractory, and the compound or salt is administered concomitantly, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 60 mg.

[0017] A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 recurrent or refractory, and the compound or salt is administered concomitantly, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 60 mg. mg. ​​​​​It is 0 mg. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is about 375 mg / m 2 on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered 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 as a divided dose on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD2 0-based therapy is either administered on day 1 or not administered 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. Preferably, the BCL- 2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL- 2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rituximab. 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 as a divided dose on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered 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 BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL- 2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rituximab. There is. Preferably, the anti-CD20-based therapy is obinutuzumab. Preferably, the anti-C D20-based therapy is R-CHOP. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day 2 cycle, or as a divided dose on days 1 and 2 is administered. Preferably, rituximab is administered at about 375 mg / m 2 on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, ritux imab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2 and rituximab is then administered at about 500 mg / m 2 on day 1 or is not administered at all between each of any subsequent cycles is one of. Preferably, venetoclax is administered at about 20 m g on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the 4th 28-day cycle, and then about 400 mg is administered daily for any subsequent cycle. Preferably, rituximab is administered at about 375 mg / m on day 1 2 of the first 28-day cycle, or as a divided dose on days 1 and 2, and ritux imab is then administered at about 500 mg / m 2 on day 1 or is not administered at all between each of any subsequent cycles and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the 4th 28-day cycle, and then Thereafter, it is administered daily at about 400 mg for any subsequent cycle. Preferably, BTK -I is administered daily at about 200 mg, and rituximab is about 3 on day 1 of the first 28-day cycle 75 mg / m 2 or administered as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1 2 or is not administered at all during each of any subsequent cycles and venetoclax is administered at about 20 mg on days 1 to 7 of the 4th 28-day cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle, and thereafter it is administered daily at about 400 mg for any subsequent cycle. A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in the treatment of cancer

[0018] is also provided herein, 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-naive. A compound or a pharmaceutically acceptable salt thereof is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, the compound is B TK-I.

[0019] A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in the treatment of cancer is also provided herein, 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-naive and the compound or salt is administered concurrently, separately, or sequentially with a therapy of a BCL-2 inhibitor and / or an anti-CD20 be vel. A compound or a pharmaceutically acceptable salt thereof is also provided herein. Preferably, the dose is about 125 mg to about 600 mg and Yes. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle 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 divided doses on days 1 and 2, and thereafter, the anti-CD2 0-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the B 2 TK-I is started on day 1 and administered daily, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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 administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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 administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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 administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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 administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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 administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rituximab. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rituximab. Preferably the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rituximab. Preferably the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rituximab. Preferably Alternatively, the anti-CD20-based therapy is obinutuzumab. Preferably, the anti-CD20 -based therapy is R-CHOP. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, 2 or as a divided dose on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m 2 on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or is not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the 4th 28-day cycle, and then is administered daily at about 400 m g for any subsequent cycle. Preferably, rituximab is administered at about 37 5 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or is not administered at all during each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the 4th 28-day cycle, and then for any subsequent cycle. For subsequent cycles of deviation, the daily dosage is also about 400 mg. Preferably, the BTK-I is about 200 mg is administered daily, and rituximab is about 375 mg on day 1 of the first 28-day cycle / m 2 or administered as a divided dose on days 1 and 2, and rituximab is about 500 mg / m on day 1 after that, or either not administered at all during each of any subsequent cycles, and venetoclax is about 2 20 mg on days 1-7 of the cycle, about 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 during the 4th 28-day cycle, and thereafter, for any subsequent cycles, the daily dosage is about 400 mg. A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer wherein the compound or salt is administered to a patient at a daily dosage of about 120 mg to about 600 mg, and the patient

[0020] has received at least one previous anti-cancer therapy, and the compound or its pharmaceutically acceptable salt is also provided herein. Preferably, the dosage is between about 125 mg and about 600 mg. Preferably the compound is a BTK-I.

[0021] A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer wherein the compound or salt is administered to a patient at a daily dosage of about 120 mg to about 600 mg, and the patient has received at least one previous anti-cancer therapy, and the compound or salt is administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, and the compound or its pharmaceutically acceptable salt is also provided herein. Preferably, the dosage is about ​It is from 125 mg to approximately 600 mg. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably , the anti-CD20-based therapy is approximately 375 mg / m² on day 1 ± 3 days of the first 28-day cycle , or as divided doses on days 1 and 2. Preferably, the anti-CD20-based 2 therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably , the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably , the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably , the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably , the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably , the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably , the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably , the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably , the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably , the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably , the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably , the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably , the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably , the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy The method is rituximab. Preferably, the anti-CD20-based therapy is obinutuzumab . Preferably, the anti-CD20-based therapy is R-CHOP. Preferably, rituxim ab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2 . Preferably, rituximab is administered at about 375 mg / m ± 2 3 days on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, and also as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or not administered at all between each of any subsequent cycles . Preferably, venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, about 1 00 mg on days 15-21 of the cycle, and about 200 mg on days 22-28 of the cycle during the fourth 28-day cycle, and then administered daily at about 400 mg for any subsequent cycle. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2 2 , and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and venetoclax 2 is administered at about 20 mg on days 1-7 of the cycle, about 5 0 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 during the fourth 28-day cycle and then administered daily at about 400 mg for any subsequent cycle It is administered at mg and then dosed daily at approximately 400 mg for any subsequent cycle. Preferably, the BTK-I is administered daily at approximately 200 mg and rituximab is administered on the first day of the first 28-day cycle at approximately 375 mg / m 2 or administered as a divided dose on the first and second days and rituximab is then administered at approximately 500 mg / m on the first day 2 or is not administered at all during any subsequent cycle, and venetoclax is administered at approximately 20 mg on days 1-7 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 22-28 of the fourth 28-day cycle, and then dosed daily at approximately 400 mg for any subsequent cycle.

[0022] A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in the treatment of cancer 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 previous anti-cancer therapy comprising at least one BTK inhibitor-based therapy is also provided herein. Preferably , the dose is between about 125 mg and about 600 mg. Preferably, the compound is a BTK-I .

[0023] A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in the treatment of cancer 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 previous anti-cancer therapy comprising at least one BTK inhibitor-based therapy and the compound or salt is a BCL-2 inhibitor and / or anti-CD20-based Compounds or pharmaceutically acceptable salts thereof, administered concomitantly, separately, or sequentially with a therapy, are also provided herein. Preferably, the dosage is from about 125 mg to about 600 mg. Preferably, the anti-CD20 based therapy is administered on day 1, or as divided doses on days 1 and 2, of the first 28-day cycle. Preferably, the anti-CD20 based therapy is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, the anti-CD20 based therapy is administered on day 1, or as divided doses on days 1 and 2, of the first 28-day cycle, and thereafter, the anti-CD20 based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the anti-CD20 based therapy is administered on day 1, or as divided doses on days 1 and 2, of the first 28-day cycle, and the anti-CD20 based 2 therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK- I is started on day 1 and administered daily, and the anti-CD20 based therapy is administered on day 1, or as divided doses on days 1 and 2, of the first 28-day cycle, and the anti-CD20 based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BC therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK- I is started on day 1 and administered daily, and the anti-CD20 based therapy is administered on day 1, or as divided doses on days 1 and 2, of the first 28-day cycle, and the anti-CD20 based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BC therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK- I is started on day 1 and administered daily, and the anti-CD20 based therapy is administered on day 1, or as divided doses on days 1 and 2, of the first 28-day cycle, and the anti-CD20 based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BC therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BC therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BC It is L2-I or a pharmaceutically 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. Preferably, the anti-CD20-based therapy is R-CHOP. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle 2 or as a divided dose on days 1 and 2. Preferably rituximab is administered at about 375 mg / m 2 on day 1 ± 3 days of the first 28-day cycle and as a divided 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 or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or 2 not administered at all during each of any subsequent cycles. Preferably venetoclax is administered at about 20 mg on days 1 to 7, about 50 mg on days 8 to 14, about 100 mg on days 15 to 21, and about 200 mg on days 22 to 28 during the fourth 28-day cycle, and then at about 400 mg daily for each of any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or not administered at all during each of any subsequent cycles, and venetoclax is administered during the fourth 28-day cycle, during the cycles 2 or not administered at all during each of any subsequent cycles, and venetoclax is administered during the fourth 28-day cycle, during the cycles On days 1 to 7, about 20 mg, on days 8 to 14 of the cycle, about 50 mg, on days 15 to 21 of the cycle, about 100 mg, and on days 22 to 28 of the cycle, about 200 mg are administered, and thereafter, for any subsequent cycle, it is dosed daily at about 400 mg. Preferably, the BTK-I is about 200 mg administered daily, and rituximab is about 375 mg / m on day 1 of the first 28-day cycle 2 or administered as divided doses on days 1 and 2, and rituximab is thereafter about 500 mg / m on day 1 2 is administered, or is not administered at all during each of any subsequent cycles, and venetoclax is on days 1 to 7 of the cycle, about 20 mg, on days 8 to 14 of the cycle, about 50 mg, on days 15 to 21 of the cycle, about 100 mg, and on days 22 to 28 of the cycle, about 200 mg are administered during the 4th 28-day cycle, and thereafter, for any subsequent cycle, it is dosed daily at about 400 mg. A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 not received a previous anti-cancer therapy comprising a BTK inhibitor, and the compound or its pharmaceutically acceptable

[0024] salt is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, the compound is a BTK-I.

[0025] A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg, the patient has not received a previous anti-cancer therapy comprising a BTK inhibitor, and the compound or salt is BCL-2 Also provided herein are compounds or pharmaceutically acceptable salts thereof administered in simultaneous, separate, or sequential administration with an inhibitor and / or an anti-CD20-based therapy. Preferably, the dosage 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 as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m² on day 1 ± 3 days of the first 28-day cycle 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 divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered 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 as divided doses on days 1 and 2, the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, the anti-CD20-based therapy is either administered on day 1 or not administered 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. are also provided herein. Preferably, the dosage 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 as divided doses on days 1 and 2. Preferably, the dosage 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 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 divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m² on day 1 ± 3 days of the first 28-day cycle or as divided doses on days 1 and 2. m 2 Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle 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 divided doses on days 1 and 2. Thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 28-day cycle. 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 as divided doses on days 1 and 2. Thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle 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 divided doses on days 1 and 2. Thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is administered during the fourth 28-day cycle. It is. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof It is. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rituximab. Preferably, the anti-CD20-based therapy is obinutuzumab It is. Preferably, the anti-CD20-based therapy is R-CHOP. Preferably, rituximab is administered at about 375 mg / m² on day 1 of the first 28-day cycle 2 or as a divided dose on days 1 and 2 It is preferably administered at about 375 mg / m² on day 1 ± 3 days of the first 28-day cycle or as a divided dose on days 1 and 2 2 It is preferably administered at about 375 mg / m² on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1 2 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and then administered daily at about 400 mg for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m² on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1 or not administered at all during each of any subsequent cycles, and venetoclax 2 is administered at about 500 mg / m² on day 1 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and then administered daily at about 400 mg for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m² on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and then administered daily at about 400 mg for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m² on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and then administered daily at about 400 mg for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m² on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1 2 or not administered at all during each of any subsequent cycles, and venetoclax is administered at about 500 mg / m² on day 1 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and then administered daily at about 400 mg for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m² on day 1 of the first 28-day cycle 2 or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1 or not administered at all during each of any subsequent cycles, and venetoclax Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the 4th 28-day cycle, and thereafter is dosed daily at about 400 mg for any subsequent cycle. Preferably, the BTK-I is administered daily at about 200 mg, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is thereafter administered at about 500 mg / m on day 1, or is not administered at all between each of any subsequent cycles, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the 4th 28-day cycle, and thereafter is dosed daily at about 400 mg for any subsequent cycle. or is not administered at all between each of any subsequent cycles, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the 4th 28-day cycle, and thereafter is dosed daily at about 400 mg for any subsequent cycle. or is not administered at all between each of any subsequent cycles, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the 4th 28-day cycle, and thereafter is dosed daily at about 400 mg for any subsequent cycle. A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, 2 A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, 2 A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably,

[0026] A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, the compound is a BTK-I.

[0027] A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, and the compound or salt is a BCL-2 inhibitor and / or a A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, and the compound or salt is a BCL-2 inhibitor and / or a A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 one previous anti-cancer therapy, and the compound or salt is a BCL-2 inhibitor and / or a or a compound or its pharmaceutically acceptable salts administered simultaneously, separately, or sequentially with an anti-CD20-based therapy are also provided herein. Preferably, the dosage is 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 as divided doses on days 1 and 2. Preferably, the anti-CD2 0-based therapy is about 375 mg / m on day 1 ± 3 days of the first 28-day cycle 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 divided doses on days 1 and 2, 2 and then, the anti-CD20-based therapy is either administered on day 1 or not administered 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 as divided doses on days 1 and 2, and then, the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and then, the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle and the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle and the anti-CD20-based therapy is either administered on day 1 or not administered 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. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and then, the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle and the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle and the anti-CD20-based therapy is either administered on day 1 or not administered 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. Preferably, The BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2 2 and. Preferably, rituximab is administered at about 3 75 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably 2 rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2 2 and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles 2 whichever is the case. Preferably, venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then administered daily at about 400 mg for any subsequent cycle. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles 2 whichever is the case, and venetoclax is administered at about 400 mg daily during the fourth cycle, rituximab is administered at about 375 mg / m 2 on day 1, or as a divided dose on days 1 and 2, rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles During the 28-day cycle, about 20 mg is administered on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle, and thereafter, for any subsequent cycle, it is administered daily at about 400 mg. Preferably, the BTK-I is administered daily at about 200 mg, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is thereafter administered at about 500 mg / m on day 1, or is not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 1 5 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28 2 -day cycle, and thereafter, for any subsequent cycle, it is administered daily at about 400 mg. A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 two previous anti-cancer therapies, the compound or its pharmaceutically acceptable salt is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, 2 the compound is a BTK-I. A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg, the patient has received two previous anti-cancer therapies, and the compound or salt is a BCL-2 inhibitor and / or During the 28-day cycle, about 20 mg is administered on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 1 5 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle, and thereafter, for any subsequent cycle, it is administered daily at about 400 mg. Thereafter, for any subsequent cycle, it is administered daily at about 400 mg.

[0028] A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 two previous anti-cancer therapies, the compound or its pharmaceutically acceptable salt is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, the compound is a BTK-I. A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg, the patient has received two previous anti-cancer therapies, and the compound or salt is a BCL-2 inhibitor and / or A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg, the patient has received two previous anti-cancer therapies, and the compound or salt is a BCL-2 inhibitor and / or the compound is a BTK-I.

[0029] A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 two previous anti-cancer therapies, the compound or its pharmaceutically acceptable salt is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably, the compound is a BTK-I. A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg, the patient has received two previous anti-cancer therapies, and the compound or salt is a BCL-2 inhibitor and / or or a compound or its pharmaceutically acceptable salts, which are administered concomitantly, separately, or sequentially with an anti-CD20-based therapy, are provided herein. Preferably, the dosage is 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 as divided doses on days 1 and 2. Preferably, the anti-CD2 0-based therapy is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle 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 divided doses on days 1 and 2, 2 and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered 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 as divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered 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 administered during the fourth 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered 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. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered 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 administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, The BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is ritux imab. Preferably, the anti-CD20-based therapy is obinutuzumab. Preferably the anti-CD20-based therapy is R-CHOP. Preferably, rituximab is, on the first day of the first 28-day cycle, about 375 mg / m 2 or as a divided dose on the first and second days and administered. Preferably, rituximab is, on the first day ± 3 days of the first 28-day cycle, about 3 75 mg / m 2 or as a divided dose on the first and second days. Preferably rituximab is, on the first day of the first 28-day cycle, about 375 mg / m 2 or as a divided dose on the first and second days, and rituximab is then, on the first day, about 500 mg / m 2 administered or not administered at all during each of any subsequent cycles, whichever is the case. Preferably, venetoclax is, during the 4th 28-day cycle, on days 1 to 7 of the cycle, about 20 mg, on days 8 to 14 of the cycle, about 50 mg, on days 15 to 21 of the cycle, and on days 22 to 28 of the cycle, about 200 mg, and then, for any subsequent cycle daily dosing is at about 400 mg. Preferably, rituximab is, on the first day of the first 28-day cycle about 375 mg / m 2 or as a divided dose on the first and second days and rituximab is then, on the first day, about 500 mg / m 2 administered or not administered at all during each of any subsequent cycles, and venetoclax is, on the 4th During the 28-day cycle, about 20 mg is administered on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle, and thereafter, for any subsequent cycle, it is administered daily at about 400 mg. Preferably, the BTK-I is administered daily at about 200 mg, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and rituximab is thereafter administered at about 500 mg / m on day 1 or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 1 5 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28 2 -day cycle, and thereafter, for any subsequent cycle, it is administered daily at about 400 mg. A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 2 has received more than two previous anti-cancer therapies, the compound or its pharmaceutically acceptable salt is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably the compound is a BTK-I. A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg, the patient has received more than two previous anti-cancer therapies, and the compound or salt is a BCL-2 inhibitor and / or A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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

[0030] A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 more than two previous anti-cancer therapies, the compound or its pharmaceutically acceptable salt is also provided herein. Preferably, the dose is between about 125 mg and about 600 mg. Preferably the compound is a BTK-I. A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the compound or salt is administered to a patient at a daily dose of about 120 mg to about 600 mg, the patient has received more than two previous anti-cancer therapies, and the compound or salt is a BCL-2 inhibitor and / or

[0031] A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, 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 more than two previous anti-cancer therapies, the compound or salt is administered to the patient at a daily dose of about 120 mg to about 600 mg, and the patient has received more than two previous anti-cancer therapies, and the compound or salt is a BCL-2 inhibitor and / or Also provided herein are compounds or pharmaceutically acceptable salts thereof, which are administered concurrently, separately, or sequentially with an anti-CD20-based therapy. Preferably, the dosage is from about 125 mg to about 600 mg. Preferably, the anti-CD20-based therapy is administered on day 1, or as divided doses on days 1 and 2, of the first 28-day cycle. Preferably, the anti-CD 20-based therapy is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered on day 1, or as divided doses on days 1 and 2, of the first 28-day cycle, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is 2 administered during the fourth 28-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1, or as divided doses on days 1 and 2, of the first 28 day cycle, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1, or as divided doses on days 1 and 2, of the first 28-day cycle, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered 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. Preferably ​​​​​​​​​​, the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably , the BCL-2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rit uximab. Preferably, the anti-CD20-based therapy is obinutuzumab. Preferably , the anti-CD20-based therapy is R-CHOP. Preferably, rituximab is the most about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2 and is administered. Preferably, rituximab is about 375 mg / m 2 on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably , rituximab is about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then about 500 m g / m 2 on day 1, or is not administered at all during each of any subsequent cycles, either way. Preferably, venetoclax is about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then is dosed daily at about 400 mg for any subsequent cycle. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then about 500 mg / m 2 on day 1, or is not administered at all during each of any subsequent cycles, either way, and venetoclax is 2 on day 1, or is not administered at all during each of any subsequent cycles, either way, and venetoclax is During the 28-day cycle of 4, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle, and then, for any subsequent cycle, it is administered daily at about 400 mg. Preferably the BTK-I is administered daily at about 200 mg, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, 2 or administered as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or is not administered at all between each of any subsequent cycles and venetoclax is 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 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the 28-day cycle of 4, and then, for any subsequent cycle, it is administered daily at about 400 mg.

[0032] The present invention also provides a compound or a pharmaceutically acceptable salt thereof, which is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer, comprising administering to the patient a therapeutically effective amount of the compound or salt in a continuous daily dosage regimen until the progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in more than 90 percent inhibition of BTK in the patient at steady state 24 hours after administration, and the proliferation and survival of activated B cells are inhibited, and provides a compound or a pharmaceutically acceptable salt thereof. Preferably, the compound is a BTK-I.

[0033] A compound or a pharmaceutically acceptable salt thereof, which is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK-mediated cancer, wherein a therapeutically effective amount of the compound or salt is orally administered to the patient suffering from BTK-mediated cancer in a continuous daily dose regimen until the progression of BTK-mediated cancer or unacceptable toxicity occurs, comprising, wherein the therapeutically effective amount of the compound or salt results in inhibition of more than 90% of BTK at steady state in the patient 24 hours after administration, and the proliferation and survival of activated B cells are inhibited, and wherein the compound or salt is administered simultaneously, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, and the compound or a pharmaceutically acceptable salt thereof is also provided in this specification. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle, 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 divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all between 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 as divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m 2 on day 1 ± 3 of the first 28-day cycle, 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 divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all between 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 as divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all between 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 as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles. Either cannot be, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably or, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is, initially on day 1 of the first 28-day cycle, or on days 1 and 2 as divided doses, and the anti-CD 20-based therapy is then either administered on day 1 or not administered at all between each of any subsequent cycles and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle or as divided doses on days 1 and 2 2 and administered. Preferably, rituximab is about 375 mg / m on day 1 ± 3 days of the first 28-day cycle or as divided doses on days 1 and 2 and administered. Preferably, ritux 2 imab is about 375 mg / m on day 1 of the first 28-day cycle 2 or as divided doses on days 1 and 2 and rituximab is then either administered at about 500 mg / m 2 on day 1 or not administered at all between each of any subsequent cycles . Preferably, venetoclax is about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and during the 4th 28-day cycle Administered at about 200 mg on days 22 to 28 of the cycle, and thereafter, for any subsequent cycle Administered daily at about 400 mg. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle 2 or administered as a divided dose on days 1 and 2, and ritux imab is thereafter administered at about 500 mg / m 2 on day 1 or not administered at all between any subsequent cycles and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 00 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28 -day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. Preferably, BT K-I is administered daily at about 200 mg, and rituximab is about 375 mg / m on day 1 of the first 28-day cycle or administered as a divided dose on days 1 and 2, and rituxim 2 ab is thereafter administered at about 500 mg / m on day 1 or not administered at all between any subsequent cycles 2 and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 2 1 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter for any subsequent cycle, administered daily at about 400 mg. A compound or a salt thereof which is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer that is refractory or relapsed and thereafter, for any subsequent cycle, administered daily at about 400 mg.

[0034] or refractory and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer that is refractory or relapsed 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 It is administered as a divided dose on the 2nd day of the call. Preferably, the anti-CD20-based therapy is initially administered on the first day of the first 28-day cycle, or as a divided dose on the first and second days, and then the anti-CD20-based therapy is either administered on the first day or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the anti-CD20-based therapy is administered on the first day of the first 28-day cycle, or as a divided dose on the first and second days, and the anti-CD20-based therapy is then either administered on the first day or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on the first day and administered daily, and the anti-CD20-based therapy is administered on the first day of the first 28-day cycle, or as a divided dose on the first and second days, and the anti-CD20-based therapy is then either administered on the first day or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on the first day of the first 28-day cycle, or as a divided dose on the first and second days and administered, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on the first day of the first 28-day cycle, or as a divided dose on the first and second days and administered, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on the first day of the first 28-day cycle, or as a divided dose on the first and second days and administered, and then 2 administered, or as a divided dose on the first and second days and is administered. Preferably, rituximab is about 375 m g / m 2 on day 1 ± 3 of the first 28-day cycle or administered as a divided dose on days 1 and 2. Preferably, ritux imab is about 375 mg / m 2 on day 1 of the first 28-day cycle or administered as a divided dose on days 1 and 2 and rituximab is then either about 500 mg / m 2 administered on day 1 or not administered at all between each of any subsequent cycles There is. Preferably, venetoclax is about 20 mg on days 1 - 7 of the cycle, about 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 during the fourth 28-day cycle and is then dosed daily at about 400 mg for any subsequent cycle. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle or administered as a divided dose on days 1 and 2 2 and ritux imab is then either about 500 mg / m 2 administered on day 1 or not administered at all between each of any subsequent cycles and venetoclax is about 20 mg on days 1 - 7 of the cycle, about 50 mg on days 8 - 14 of the cycle, about 1 5 - 21 of the cycle, and about 200 mg on days 22 - 28 of the cycle during the fourth 28 day cycle and is then dosed daily at about 400 mg for any subsequent cycle. Preferably, BT K-I is administered daily at about 200 mg and rituximab is about 375 mg / m on day 1 of the first 28-day cycle or administered as a divided dose on days 1 and 2 2 and rituxima b is then either about 500 mg / m2 administered in, or not administered at all during any of the subsequent cycles, and Venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 fourth 28-day cycle, and thereafter, for each subsequent cycle, is dosed daily at about 400 mg. A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in patients suffering from treatment-naive BTK-mediated cancer, comprising orally administering to a patient suffering from BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK at steady state in the patient 24 hours after administration and inhibits the proliferation and survival of activated B cells, is also provided herein. Preferably,

[0036] the compound is a BTK-I. / or survival of activated B cells in patients suffering from treatment-naive BTK-mediated cancer, a compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in patients suffering from treatment-naive BTK-mediated cancer, comprising orally administering to a patient suffering from BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK at steady state in the patient 24 hours after administration and inhibits the proliferation and survival of activated B cells, is also provided herein. Preferably, the compound is a BTK-I. A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in patients suffering from treatment-naive BTK-mediated cancer, comprising orally administering to a patient suffering from BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK at steady state in the patient 24 hours after administration and inhibits the proliferation and survival of activated B cells, is also provided herein. Preferably, the compound is a BTK-I.

[0037] A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in patients suffering from treatment-naive BTK-mediated cancer, comprising orally administering to a patient suffering from BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK at steady state in the patient 24 hours after administration and inhibits the proliferation and survival of activated B cells, is also provided herein. Preferably, the compound is a BTK-I. A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in patients suffering from treatment-naive BTK-mediated cancer, comprising orally administering to a patient suffering from BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, an amount that results in more than 90% inhibition and inhibits the proliferation and survival of activated B cells and a compound or salt thereof is also provided herein, which is administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy . Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle 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 2 or as divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between 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 as divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle . Preferably the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle and is provided. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, BCL -2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, 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. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28 2 day cycle, or as a divided dose on days 1 and 2 . Preferably, rituximab is administered at about 375 m g / m 2 on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, ritux imab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2 . Rituximab is then administered at about 500 mg / m 2 on day 1, or not administered at all between each of any subsequent cycles . Preferably, venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and then administered daily at about 400 mg for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2 2 . Ritux imab is then administered at about 500 mg / m 2 on day 1, or for any subsequent cycle either not administered at all between each, and Venetoclax is 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, 1 On days 5 to 21, about 100 mg, and on days 22 to 28 of the cycle, about 200 mg are administered, After that, for any subsequent cycle, it is dosed daily at about 400 mg. Preferably, BT K-I is administered daily at about 200 mg, and rituximab is about 375 mg / m 2 on day 1 of the first 28-day cycle, or administered as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or either not administered at all between each of any subsequent cycles and Venetoclax is the fourth 28-day cycle During the cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, 15 to 2 On day 1 of the cycle, about 100 mg, and on days 22 to 28 of the cycle, about 200 mg are administered, and then For any subsequent cycle, it is dosed daily at about 400 mg.

[0038] A BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer who has received at least one previous anti-cancer therapy is a compound or a pharmaceutically acceptable salt thereof, which comprises orally administering to a patient suffering from a BTK-mediated cancer a therapeutically effective dose of the compound or salt in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective dose of the compound or salt is an amount that results in more than 90 percent inhibition of BTK at steady state in the patient 24 hours after administration, and inhibits the proliferation and survival of activated B cells ​​​​Compounds or pharmaceutically acceptable salts thereof that are damaged are also provided herein. Preferably , the compound is a BTK-I.

[0039] A BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer who has received at least one previous anti-cancer therapy is a compound or a pharmaceutically acceptable salt thereof, which comprises orally administering to a patient suffering from a BTK-mediated cancer a therapeutically effective dose of the compound or salt in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective dose of the compound or salt is an amount that results in more than 90 percent inhibition of BTK in the patient at steady state 24 hours after administration, inhibits the proliferation and survival of activated B cells, and the compound or salt is provided herein for co-, separate, or sequential administration with a BCL-2 inhibitor and / or an anti-CD20-based therapy. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle, 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 divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is on the 4th 2 and Compounds or pharmaceutically acceptable salts thereof that are administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy are also provided herein. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle, 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 divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is on the 4th 2 2 and 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 divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is on the 4th 2 and the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is on the 4th 2 and the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is on the 4th 2 It is administered in an 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1, or as a divided dose on days 1 and 2, of the first 28-day cycle, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, the anti-CD20-based therapy is administered on day 1, or as a divided dose on days 1 and 2, of the first 28-day cycle, and the anti-CD 20-based therapy is then either administered on day 1 or not administered at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and preferably, rituximab is about 375 mg / m ± 3 days on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then about 500 mg / m 2 on day 1, and preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then about 500 mg / m 2 on day 1, and rituximab is then about 500 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then about 500 mg / m 2 on day 1, or as a divided dose on days 1 and 2, and rituximab is then about 500 mg / m 2 Either administered or not administered at all during each of any subsequent cycles There is. Preferably, venetoclax is about 20 mg on days 1-7 of the cycle, about 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 during the 4th 28-day cycle, and thereafter, for any subsequent cycle administered daily at about 400 mg. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle 2 or administered as a divided dose on days 1 and 2, and ritux imab is thereafter administered at about 500 mg / m 2 on day 1, or either not administered at all during each of any subsequent cycles Venetoclax is about 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, about 1 5-21 mg on days 15-21 of the cycle, and about 200 mg on days 22-28 of the cycle during the 4th 28 day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. Preferably, BT K-I is administered daily at about 200 mg, and rituximab is about 375 mg / m 2 on day 1 of the first 28-day cycle, or administered as a divided dose on days 1 and 2, and rituxima b is thereafter administered at about 500 mg / m 2 on day 1, or either not administered at all during each of any subsequent cycles Venetoclax is about 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, about 15-2 1 mg on days 15-21 of the cycle, and about 200 mg on days 22-28 of the cycle during the 4th 28-day cycle, and thereafter for any subsequent cycle, administered daily at about 400 mg. Thereafter, for any subsequent cycle, administered daily at about 400 mg.

[0040] At least one previous anti-cancer therapy comprising at least one BTK inhibitor-based therapy For use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer who has received A compound or a pharmaceutically acceptable Salt thereof which is a BTK-I, wherein a therapeutically effective amount of the compound or salt is orally administered to a patient suffering from a BTK-mediated cancer in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs Including Wherein the therapeutically effective amount of the compound or salt results in more than 90% inhibition of BTK at steady state in the patient 24 hours after administration, and the proliferation and survival of activated B cells are inhibited A compound or a pharmaceutically acceptable salt thereof is also provided herein. Preferably The compound is a BTK-I

[0041] At least one previous anti-cancer therapy comprising at least one BTK inhibitor-based therapy For use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer who has received A compound or a pharmaceutically acceptable Salt thereof which is a BTK-I, wherein a therapeutically effective amount of the compound or salt is orally administered to a patient suffering from a BTK-mediated cancer in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs Including Wherein the therapeutically effective amount of the compound or salt results in more than 90% inhibition of BTK at steady state in the patient 24 hours after administration, and the proliferation and survival of activated B cells are inhibited And The compound or salt is administered concomitantly with a BCL-2 inhibitor and / or an anti-CD20-based therapy ​​​​, compounds or pharmaceutically acceptable salts thereof administered separately or continuously are also provided in this specification. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m 2 on day 1 ± 3 days of the first 28-day cycle 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 divided doses on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD 20-based therapy is thereafter either administered on day 1 or not administered at all between 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. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL -2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL -2 The inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rituximab is. Preferably, the anti-CD20-based therapy is obinutuzumab. Preferably, 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 administered as divided doses on days 1 and 2. Preferably, rituximab is about 375 m g / m 2 on day 1 ± 3 days of the first 28-day cycle, or administered as divided doses on days 1 and 2. Preferably, ritux imab is about 375 mg / m 2 on day 1 of the first 28-day cycle, or administered as divided doses on days 1 and 2, and rituximab is then either about 500 mg / m 2 administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, venetoclax is about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and then about 400 mg daily for any subsequent cycle. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or administered as divided doses on days 1 and 2, and ritux 2 imab is then either about 500 mg / m administered on day 1 or not administered at all between each of any subsequent cycles, and venetoclax is about 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, about 1 2 mg on days 15-21 of the cycle during the fourth 28-day cycle, and then about 400 mg daily for any subsequent cycle. During the 28-day cycle, about 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, about 1 administered at about 100 mg on days 5 to 21 and about 200 mg on days 22 to 28 of the cycle, and thereafter, for each subsequent cycle, administered daily at about 400 mg. Preferably, BT K-I is administered daily at about 200 mg, and rituximab is about 375 mg / m 2 on day 1 of the first 28-day cycle or administered as a divided dose on days 1 and 2, and rituximab is thereafter administered at about 500 mg / m 2 on day 1 or not administered at all during each subsequent cycle, and venetoclax is about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 00 mg on days 15 to 21 of the 4th 28-day cycle, and about 200 mg on days 22 to 28 of the cycle, and thereafter administered daily at about 400 mg for each subsequent cycle.

[0042] For use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer who has not received prior anti-cancer therapy comprising a BTK inhibitor A compound or a pharmaceutically acceptable salt thereof which is BTK- I, comprising orally administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosage regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in inhibition of more than 90 percent of BTK at steady state in the patient 24 hours after administration, and the proliferation and survival of activated B cells are inhibited, is also provided herein. Preferably the compound is BTK-I.

[0043] For use in a patient suffering from a BTK-mediated cancer who has not received a prior anti-cancer therapy comprising a BTK inhibitor A BTK- I compound or a pharmaceutically acceptable salt thereof, which, in a patient suffering from a BTK-mediated cancer administering a therapeutically effective amount of the compound or salt orally in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs wherein the therapeutically effective amount of the compound or salt results in inhibition of more than 90% of BTK at steady state in the patient 24 hours after administration, and the proliferation and survival of activated B cells are inhibited and the compound or salt is administered concomitantly, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, and the compound or a pharmaceutically acceptable salt thereof is also provided in this specification Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2 Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle 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 divided doses on days 1 and 2, and thereafter 2 the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles Preferably, the BCL-2 inhibitor is administered during the 4th 2 8-day cycle Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle The method is then either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD 20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 m g / m on day 1 ± 3 days of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then either administered at about 500 mg / m on day 1 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg / m 2 on days 1 to 7 of the cycle during the 4th 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m g / m 2 on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then either administered at about 500 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then either administered at about 500 mg / m 2 on day 1 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg / m 2 on days 1 to 7 of the cycle during the 4th 28-day cycle, or as divided doses on days 1 and 2. Preferably, venetoclax is administered at about 20 mg / m mg, about 50 mg on days 8 - 14 of the cycle, about 100 mg on days 15 - 21 of the cycle, and administered at about 200 mg on days 22 - 28 of the cycle, and thereafter, for any subsequent cycle administered daily at about 400 mg. Preferably, rituximab is about 375 mg / m on day 1 of the first 28 - day cycle, 2 or administered as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or not administered at all between any subsequent cycles. Venetoclax is about 20 mg on days 1 - 7 of the cycle, about 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 fourth 28 - day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. Preferably, BTK - I is administered daily at about 200 mg, and rituximab is about 375 mg / m on day 1 of the first 28 - day cycle, or administered as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between any subsequent cycles. Venetoclax is about 20 mg on days 1 - 7 of the cycle, about 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 fourth 28 - day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. 2 or administered as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or not administered at all between any subsequent cycles. Venetoclax is about 20 mg on days 1 - 7 of the cycle, about 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 fourth 28 - day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. In patients with BTK - mediated cancer who have received one prior anti - cancer therapy, activated B cells are about 100 mg on days 15 - 21 of the cycle, and about 200 mg on days 22 - 28 of the cycle, and thereafter for any subsequent cycle, administered daily at about 400 mg.

[0044] In patients with BTK - mediated cancer who have received one prior anti - cancer therapy, activated B cells A compound that is a BTK-I for use in inhibiting the proliferation and / or survival of or a pharmaceutically acceptable salt thereof, comprising 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 the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90% inhibition of BTK at steady state in the patient 24 hours after administration, and the proliferation and survival of activated B cells are inhibited, also provided herein is a compound or a pharmaceutically acceptable salt thereof. Preferably, the compound is a BTK-I.

[0045] A compound that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer who has received one prior anti-cancer therapy or a pharmaceutically acceptable salt thereof, comprising 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 the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90% inhibition of BTK at steady state in the patient 24 hours after administration, and the proliferation and survival of activated B cells are inhibited, also provided herein is a compound or a pharmaceutically acceptable salt thereof, wherein the compound or salt is administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based ​​​​​​​​The therapy with [[[drug name]]] is administered at about 375 mg / m 2 on day 1 ± 3 of the first 28-day cycle, or as divided doses on day 1 and day 2. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on day 1 and day 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between 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 as divided doses on day 1 and day 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on day 1 and day 2, and the anti-CD 20-based therapy is thereafter either administered on day 1 or not administered at all between 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. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle 2or administered as divided doses on Day 1 and Day 2 is administered. Preferably, rituximab is about 375 m g / m 2 or administered as divided doses on Day 1 and Day 2. Preferably, ritux imab is about 375 mg / m 2 on Day 1 of the first 28-day cycle, or administered as divided doses on Day 1 and Day 2, and rituximab is then about 500 mg / m 2 administered on Day 1 or not administered at all between each of any subsequent cycles Preferably, venetoclax is about 20 mg on Days 1 to 7 of the cycle, about 50 mg on Days 8 to 14 of the cycle, about 100 mg on Days 15 to 21 of the cycle, and about 200 mg on Days 22 to 28 of the cycle during the 4th 28-day cycle, and thereafter, for any subsequent cycle administered daily at about 400 mg. Preferably, rituximab is about 375 mg / m on Day 1 of the first 28-day cycle, or 2 administered as divided doses on Day 1 and Day 2, and ritux imab is then about 500 mg / m 2 administered on Day 1 or not administered at all between each of any subsequent cycles and venetoclax is about 20 mg on Days 1 to 7 of the cycle, about 50 mg on Days 8 to 14 of the cycle, about 1 5 to 21 of the cycle, and about 200 mg on Days 22 to 28 of the cycle during the 4th 28 day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. Preferably, BT K-I is administered daily at about 200 mg, and rituximab is about 375 mg / m on Day 1 of the first 28-day cycle, or 2 administered as divided doses on Day 1 and Day 2, and rituxima Drug B is then either administered at about 500 mg / m 2 on day 1 or not administered at all during any of the subsequent cycles, and Venetoclax is administered at about 20 mg on days 1 - 7, about 50 mg on days 8 - 14, about 100 mg on days 15 - 2 1, and about 200 mg on days 22 - 28 of the 4th 28 - day cycle, and thereafter is dosed daily at about 400 mg for any subsequent cycles. A compound which is a BTK - I or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK - mediated cancer who has received two prior anti - cancer therapies, comprising orally administering to the patient suffering from BTK - mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK - mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK in the patient at steady state 24 hours after administration and inhibits the proliferation and survival of activated B cells, is also provided herein. Preferably

[0046] A compound which is a BTK - I or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK - mediated cancer who has received two prior anti - cancer therapies, comprising orally administering to the patient suffering from BTK - mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK - mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK in the patient at steady state 24 hours after administration and inhibits the proliferation and survival of activated B cells, is also provided herein. A compound which is a BTK - I or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK - mediated cancer who has received two prior anti - cancer therapies, comprising orally administering to the patient suffering from BTK - mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK - mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK in the patient at steady state 24 hours after administration and inhibits the proliferation and survival of activated B cells, is also provided herein. A compound which is a BTK - I or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK - mediated cancer who has received two prior anti - cancer therapies, comprising orally administering to the patient suffering from BTK - mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK - mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK in the patient at steady state 24 hours after administration and inhibits the proliferation and survival of activated B cells, is also provided herein. A compound which is a BTK - I or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK - mediated cancer who has received two prior anti - cancer therapies, comprising orally administering to the patient suffering from BTK - mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK - mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK in the patient at steady state 24 hours after administration and inhibits the proliferation and survival of activated B cells, is also provided herein. Preferably, the compound is a BTK - I.

[0047] A compound which is a BTK - I or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK - mediated cancer who has received two prior anti - cancer therapies, comprising orally administering to the patient suffering from BTK - mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK - mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK in the patient at steady state 24 hours after administration and inhibits the proliferation and survival of activated B cells, is also provided herein. A compound which is a BTK - I or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK - mediated cancer who has received two prior anti - cancer therapies, comprising orally administering to the patient suffering from BTK - mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK - mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK in the patient at steady state 24 hours after administration and inhibits the proliferation and survival of activated B cells, is also provided herein. A compound which is a BTK - I or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK - mediated cancer who has received two prior anti - cancer therapies, comprising orally administering to the patient suffering from BTK - mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK - mediated cancer or unacceptable toxicity occurs, A therapeutically effective amount of a compound or salt thereof results in greater than 90% inhibition of BTK at steady state in a patient 24 hours after administration, inhibits the proliferation and survival of activated B cells, and a compound or salt thereof is provided herein for administration concomitantly with, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle, 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 divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD 2 20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered at all between 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 as divided doses on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD 20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Either not administered at all, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. 2 Preferably, rituximab is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, ritux imab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or either not administered at all between each of any subsequent cycles. 2 Preferably, venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and then administered daily at about 400 mg for any subsequent cycle. Preferably, rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and ritux imab is then administered at about 500 mg / m on day 1, or either not administered at all between each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and then administered daily at about 400 mg for any subsequent cycle. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and ritux 2 imab is then administered at about 500 mg / m on day 1, or either not administered at all between each of any subsequent cycles. 2administered or not administered at all between any of the subsequent cycles, Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and thereafter, for any subsequent cycle, is dosed daily at about 400 mg. Preferably, BTK-I is administered daily at about 200 mg, and Rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1, or not administered at all between any of the subsequent cycles, Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and thereafter, for any subsequent cycle, is dosed daily at about 400 mg. either not administered at all between each of them, and Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and thereafter, for any subsequent cycle, is dosed daily at about 400 mg. Preferably, BTK-I is administered daily at about 200 mg, and Rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1, or not administered at all between any of the subsequent cycles, Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and thereafter, for any subsequent cycle, is dosed daily at about 400 mg. thereafter, for any subsequent cycle, is dosed daily at about 400 mg. Preferably, BTK-I is administered daily at about 200 mg, and Rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1, or not administered at all between any of the subsequent cycles, Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and thereafter, for any subsequent cycle, is dosed daily at about 400 mg. Preferably, BTK-I is administered daily at about 200 mg, and Rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1, or not administered at all between any of the subsequent cycles, Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1, or not administered at all between any of the subsequent cycles, Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and 2 thereafter, for any subsequent cycle, is dosed daily at about 400 mg. Preferably, BTK-I is administered daily at about 200 mg, and Rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1, or not administered at all between any of the subsequent cycles, Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and on day 1, or not administered at all between any of the subsequent cycles, Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and 2 either not administered at all between each of them, and Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and thereafter, for any subsequent cycle, is dosed daily at about 400 mg. Preferably, BTK-I is administered daily at about 200 mg, and Rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1, or not administered at all between any of the subsequent cycles, Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and thereafter, for any subsequent cycle, is dosed daily at about 400 mg. Preferably, BTK-I is administered daily at about 200 mg, and Rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1, or not administered at all between any of the subsequent cycles, Venetoclax is administered at about 20 mg on days 1-7 of the 4th 28-day cycle, about 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, and thereafter, for any subsequent cycle, is dosed daily at about 400 mg. thereafter, for any subsequent cycle, is dosed daily at about 400 mg.

[0048] A compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in patients suffering from BTK-mediated cancer who have received more than two previous anti-cancer therapies, comprising orally administering to a patient suffering from BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in inhibition of more than 90% of BTK in the patient at steady state 24 hours after administration, and inhibits the proliferation and survival of activated B cells. wherein the therapeutically effective amount of the compound or salt results in inhibition of more than 90% of BTK in the patient at steady state 24 hours after administration, and inhibits the proliferation and survival of activated B cells. wherein the therapeutically effective amount of the compound or salt results in inhibition of more than 90% of BTK in the patient at steady state 24 hours after administration, and inhibits the proliferation and survival of activated B cells. wherein the therapeutically effective amount of the compound or salt results in inhibition of more than 90% of BTK in the patient at steady state 24 hours after administration, and inhibits the proliferation and survival of activated B cells. wherein the therapeutically effective amount of the compound or salt results in inhibition of more than 90% of BTK in the patient at steady state 24 hours after administration, and inhibits the proliferation and survival of activated B cells. wherein the therapeutically effective amount of the compound or salt results in inhibition of more than 90% of BTK in the patient at steady state 24 hours after administration, and inhibits the proliferation and survival of activated B cells. Compounds or pharmaceutically acceptable salts thereof that are damaged are also provided herein. Preferably , the compound is a BTK-I.

[0049] A BTK-I compound or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in patients suffering from BTK-mediated cancer who have received more than two previous anti-cancer therapies, wherein the compound or pharmaceutically acceptable salt thereof is administered orally to a patient suffering from BTK-mediated cancer in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt is an amount that results in more than 90% inhibition of BTK at steady state in the patient 24 hours after administration, and the proliferation and survival of activated B cells are inhibited, and compounds or salts thereof that are administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or anti-CD20-based therapy are also provided herein. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered 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 during the first 28-day cycle of and compounds or salts thereof that are administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or anti-CD20-based therapy are also provided herein. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered 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 during the first 28-day cycle at, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and thereafter 2 at, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is either administered on day 1 or not administered 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 during the first 28-day cycle at, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is either administered on day 1 or not administered 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 during the first 28-day cycle at, or as a divided dose on days 1 and 2, and then the anti-CD20-based therapy is either administered on day 1 or not administered 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 during the first 28-day cycle either on day 1 or not administered 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 during the first 28-day cycle during the fourth 28-day cycle. Preferably, the anti-CD20-based therapy is administered during the first 28-day cycle On the first day, or as a divided dose on the first and second days, the anti-CD20-based therapy is then either administered on the first day or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is started on the first day and administered daily, and the anti-CD20-based therapy is administered on the first day of the first 28-day cycle, or as a divided dose on the first and second days, and the anti-CD 20-based therapy is then either administered on the first day or not administered 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. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on the first day of the first 28-day cycle, or as a divided dose on the first and second days, and preferably rituximab is about 375 mg / m ± 3 days on the first day of the first 28-day cycle, or as a divided dose on the first and second days. Preferably, rituximab is about 375 mg / m on the first day of the first 28-day cycle, or as a divided dose on the first and second days, and rituximab is then either administered at about 500 mg / m 2 on the first day or not administered at all during each of any subsequent cycles. and preferably rituximab is about 375 mg / m on the first day of the first 28-day cycle, or as a divided dose on the first and second days, and rituximab is then either administered at about 500 mg / m 2 on the first day or not administered at all during each of any subsequent cycles. Preferably, rituximab is about 375 mg / m on the first day of the first 28-day cycle, or as a divided dose on the first and second days, and rituximab is then either administered at about 500 mg / m 2 on the first day or not administered at all during each of any subsequent cycles, and rituximab is then either administered at about 500 mg / m on the first day or not administered at all during each of any subsequent cycles. 2 or not administered at all during each of any subsequent cycles. Yes. Preferably, Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. Preferably, Rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 2 5 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. Preferably, BT 2 K-I is administered daily at about 200 mg, and Rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 5 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. Preferably, BT K-I is administered daily at about 200 mg, and Rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and Rituxima b is thereafter administered at about 500 mg / m 2 on day 1, or not administered at all between each of any subsequent cycles, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 5 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle and thereafter, for any subsequent cycle, administered daily at about 400 mg. Preferably, Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 2 1 of the cycle, and about 200 mg on days 22 to 28 of the cycle, and thereafter

[0050] The present invention also relates to a compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer, comprising administering to the patient a therapeutically effective amount of the compound or salt in a continuous daily dose regimen until progression of the BTK-mediated (0~24) cancer or unacceptable toxicity occurs, wherein the therapeutically effective administration results in an AUC of about 52400 ng*h / mL or more and an exposure of about 806 ng / mL or more 24 hours after the administration, and providing a compound or a pharmaceutically

[0051] acceptable salt thereof. Preferably, the compound is a BTK-I. Also provided herein is a compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer, comprising administering to the patient a therapeutically effective amount of the compound or (0~24) salt in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective administration results in an AUC of about 52400 ng*h / mL or more and an exposure of about 806 ng / mL or more 24 hours after the administration, and wherein the compound or salt is administered concomitantly, or administered as a divided dose on Day 1 and Day 2. Preferably, the anti-CD20-based therapy is about 375 mg / m on Day 1 ± 3 days of the first 28-day cycle 2 or on Day 1 and administered as a divided dose on Day 2. Preferably, the anti-CD20-based therapy is initially administered on Day 1 of the 28-day cycle, or as a divided dose on Day 1 and Day 2, and then the anti-CD20-based therapy is either administered on Day 1 or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the 4th 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on Day 1 of the first 28-day cycle or as a divided dose on Day 1 and Day 2, and the anti-CD20-based therapy is then either administered on Day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably the BTK-I is started on Day 1 and administered daily, and the anti-CD20-based therapy is administered on Day 1 of the first 28-day cycle or as a divided dose on Day 1 and Day 2, and the anti-CD 20-based therapy is then either administered on Day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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 ofatumumab. Preferably, the anti-CD20-based therapy is trastuzumab. Preferably, the anti-CD20-based therapy is tositumomab. Preferably, the anti-CD20-based therapy is ofatumumab. Preferably, the anti-CD20-based therapy is trastuzumab. Preferably, the anti-CD20-based therapy is The CD20-based therapy is R-CHOP. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, 2 and is preferably administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 either on day 1 or not at all between each of any subsequent cycles, and is preferably administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m either on day 1 or not at all between each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1 - 7 of the cycle, about 50 mg on days 8 - 14 of the cycle, about 100 mg on days 15 - 21 of the cycle, and 2 about 200 mg on days 22 - 28 of the cycle during the fourth 28-day cycle, and then is dosed daily at about 400 mg for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m either on day 1 or not at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 - 7 of the cycle, about 50 mg on days 8 - 14 of the cycle, about 100 mg on days 1 5 - 21 of the cycle, and about 200 mg on days 22 - 28 of the cycle during the fourth 28-day cycle, and then is dosed daily at about 400 mg for any subsequent cycles. Preferably, BT is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m either on day 1 or not at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 - 7 of the cycle, about 50 mg on days 8 - 14 of the cycle, about 100 mg on days 1 2 5 - 21 of the cycle, and about 200 mg on days 22 - 28 of the cycle during the fourth 28-day cycle, and then is dosed daily at about 400 mg for any subsequent cycles. Preferably, BT is administered at about 20 mg on days 1 - 7 of the cycle, about 50 mg on days 8 - 14 of the cycle, about 1 5 - 21 of the cycle, and about 200 mg on days 22 - 28 of the cycle during the fourth 28-day cycle, and then is dosed daily at about 400 mg for any subsequent cycles. Preferably, BT K-I is administered daily at about 200 mg, and rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or not administered at all during any of the subsequent cycles, and venetoclax is administered at about 20 mg on days 1-7, about 50 mg on days 8-14, about 100 mg on days 15-2 1, and about 200 mg on days 22-28, during the 4th 28-day cycle, and thereafter for any subsequent cycle, is dosed daily at about 400 mg.

[0052] A compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer which is relapsed or refractory, comprising orally administering to a patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt for successive daily dose regimens until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein said therapeutically effective administration results in an AUC of about 52400 ng*h / mL or more, and said therapeutically effective administration results in an exposure of about 806 ng / mL or more 24 hours after said administration, is also provided herein. Preferably, the compound is a BTK-I. (0~24)

[0053] A compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer which is relapsed or refractory

[0053] ​​A pharmaceutically acceptable salt, wherein a patient suffering from BTK-mediated cancer is orally administered a therapeutically effective amount of the compound or salt in a continuous daily dosage regimen until the progression of BTK-mediated cancer or unacceptable toxicity occurs, comprising: wherein said therapeutically effective administration results in an AUC (0~24) of about 52400 ng*h / mL or more, and wherein said therapeutically effective administration results in an exposure of about 806 ng / mL or more 24 hours after said administration, and the compound or salt is administered in combination with, separately from, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, and the compound or its pharmaceutically acceptable salt is also provided in this specification. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle, 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, 2 or as divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the 4th 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, Alternatively, the BTK-I is initiated on Day 1 and administered daily, and the anti-CD20-based therapy is administered on the first day of the first 28-day cycle, or as a divided dose on Days 1 and 2, and the anti-CD 20-based therapy is then administered either on Day 1 or not at all between 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. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is administered at about 375 mg / m on the first day of the first 28-day cycle, or as a divided dose on Days 1 and 2 . Preferably, rituximab is administered at about 375 mg / m 2 on Day 1 ± 3 days of the first 28-day cycle, or as a divided dose on Days 1 and 2 . Preferably, rituximab is administered at about 375 mg / m on the first day of the first 28-day cycle, or as a divided dose on Days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on Day 1 or not at all between each of any subsequent cycles . Preferably, venetoclax is administered at about 20 mg on Days 1 to 7, about 50 mg on Days 8 to 14, about 100 mg on Days 15 to 21, and 2 about 200 mg on Days 22 to 28 during the fourth 28-day cycle, and thereafter, for any subsequent cycle . Preferably, rituximab is administered at about 500 mg / m 2 on Day 1 or not at all between each of any subsequent cycles . Preferably, venetoclax is administered at about 20 mg on Days 1 to 7, about 50 mg on Days 8 to 14, about 100 mg on Days 15 to 21, and about 200 mg on Days 22 to 28 during the fourth 28-day cycle, and thereafter, for any subsequent cycle . It is administered daily at about 400 mg. Preferably, rituximab is administered on day 1 of the first 28-day cycle at about 375 mg / m 2 or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or is not administered at all between each of the subsequent cycles. Venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, about 1 2 00 mg on days 15-21 of the cycle, and about 200 mg on days 22-28 of the cycle during the fourth 28 -day cycle, and then is administered daily at about 400 mg for any subsequent cycle. Preferably, BT K-I is administered daily at about 200 mg, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or is not administered at all between each of the subsequent cycles. Venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, about 1 00 mg on days 15-21 of the cycle, and about 200 mg on days 22-28 of the cycle during the fourth 28-day cycle, and then is administered daily at about 400 mg for any subsequent cycle. 375 mg / m 2 or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or is not administered at all between each of the subsequent cycles. Venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, about 1 2 00 mg on days 15-21 of the cycle, and about 200 mg on days 22-28 of the cycle during the fourth 28-day cycle, and then is administered daily at about 400 mg for any subsequent cycle. A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in patients with treatment-naive BTK-mediated cancer, and administering a therapeutically effective amount of the compound or salt to a patient with BTK-mediated cancer. on days 15-21 of the cycle, and about 200 mg on days 22-28 of the cycle during the fourth 28-day cycle, and then is administered daily at about 400 mg for any subsequent cycle. Thereafter, it is administered daily at about 400 mg for any subsequent cycle.

[0054] A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in patients with treatment-naive BTK-mediated cancer, and administering a therapeutically effective amount of the compound or salt to a patient with BTK-mediated cancer. acceptable salt thereof that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in patients with treatment-naive BTK-mediated cancer, and administering a therapeutically effective amount of the compound or salt to a patient with BTK-mediated cancer. administering orally in a continuous daily dose regimen until progression of BTK-mediated cancer or unacceptable toxicity occurs comprising wherein said administration in a therapeutically effective amount results in an AUC (0~24) of about 52400 ng*h / mL or more and wherein said administration in a therapeutically effective amount results in an exposure of about 806 ng / mL or more 24 hours after said administration Also provided herein is a compound or a pharmaceutically acceptable salt thereof. Preferably, the compound is a BTK-I A compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from treatment-naive BTK-mediated cancer

[0055] administering orally in a continuous daily dose regimen to a patient suffering from BTK-mediated cancer until progression of BTK-mediated cancer or unacceptable toxicity occurs / or survival, comprising wherein said administration in a therapeutically effective amount results in an AUC administering orally in a continuous daily dose regimen until progression of BTK-mediated cancer or unacceptable toxicity occurs comprising wherein said administration in a therapeutically effective amount results in an AUC (0~24) of about 52400 ng*h / mL or more and wherein said administration in a therapeutically effective amount results in an exposure of about 806 ng / mL or more 24 hours after said administration and wherein the compound or salt is administered concomitantly, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy Also provided herein is a compound or a pharmaceutically acceptable salt thereof. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2 Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle 2 or on days 1 and It is administered as a divided dose on the second day of the call. Preferably, the anti-CD20-based therapy is initially administered on day 1, or as a divided dose on days 1 and 2, of the first 28-day cycle, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of the 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 as a divided dose on days 1 and 2, of the first 28-day cycle, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, the anti-CD20-based therapy is administered on day 1, or as a divided dose on days 1 and 2, of the first 28-day cycle, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and is administered orally at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and is administered. Preferably, rituximab is about 375 m g / m 2 on day 1 ± 3 of the first 28-day cycle, or administered as divided doses on days 1 and 2. Preferably, ritux imab is about 375 mg / m 2 on day 1 of the first 28-day cycle, or administered as divided doses on days 1 and 2 and rituximab is then about 500 mg / m 2 administered on day 1 or not administered at all between each of any subsequent cycles whichever is the case. Preferably, venetoclax is about 20 mg on days 1 - 7 of the cycle, about 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 during the 4th 28-day cycle and is then dosed daily at about 400 mg for any subsequent cycle. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or administered as divided doses on days 1 and 2 2 and rituximab is then about 500 mg / m administered on day 1 or not administered at all between each of any subsequent cycles 2 and venetoclax is about 20 mg on days 1 - 7 of the cycle, about 50 mg on days 8 - 14 of the cycle, about 1 5 - 21 of the cycle, and about 200 mg on days 22 - 28 of the cycle during the 4th 28 day cycle and is then dosed daily at about 400 mg for any subsequent cycle. Preferably, BT K-I is dosed daily at about 200 mg and rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or administered as divided doses on days 1 and 2 and rituximab is then about 500 mg / m 2 administered on day 1 or rituxima b is not administered at all between each of any subsequent cycles2 either administered during or not administered at all during any subsequent cycle, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the fourth 28-day cycle, and thereafter, for any subsequent cycle, is dosed daily at about 400 mg. A BTK-I compound or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer who has received at least one prior anti-cancer therapy, comprising orally administering to the patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein said administration at a therapeutically effective amount results in an AUC

[0056] of about 52400 ng*h / mL or more, and said administration at a therapeutically effective amount results in an exposure of about 806 ng / mL or more 24 hours after said administration, is also provided herein. Preferably, the compound is a BTK-I. A BTK-I compound or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer who has received at least one prior anti-cancer therapy, comprising orally administering to the patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein said administration at a therapeutically effective amount results in an AUC (0~24) of about 52400 ng*h / mL or more, and said administration at a therapeutically effective amount results in an exposure of about 806 ng / mL or more 24 hours after said administration, is also provided herein. Preferably, the compound is a BTK-I.

[0057] A BTK-I compound or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer who has received at least one prior anti-cancer therapy, comprising orally administering to the patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein said administration at a therapeutically effective amount results in an AUC of about 52400 ng*h / mL or more, and ​Administration of a therapeutically effective amount results in an AUC (0~24) of about 52400 ng*h / mL or more and administration of a therapeutically effective amount results in an exposure of about 806 ng / mL or more 24 hours after the administration and also provided herein is a compound or a salt thereof, which is administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy . Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle 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 2 or as divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered 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 as divided doses on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably , the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably , the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably , the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably the anti-CD20-based therapy is either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably Either not administered at all, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or 2 administered as a divided dose on days 1 and 2. Preferably, rituximab is about 375 m g / m 2 on day 1 ± 3 days of the first 28-day cycle, or administered as a divided dose on days 1 and 2. Preferably, ritux imab is about 375 mg / m 2 on day 1 of the first 28-day cycle, or administered as a divided dose on days 1 and 2, and rituximab is then about 500 mg / m 2 on day 1, or either not administered at all between each of any subsequent cycles. Preferably, venetoclax is about 20 mg on days 1-7 of the cycle, about 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 during the 4th 28-day cycle, and then administered daily at about 400 mg for any subsequent cycle. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or 2 administered as a divided dose on days 1 and 2, and ritux imab is then about 500 mg / m 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, Administration of a therapeutically effective amount results in an exposure of about 806 ng / mL or more 24 hours after the administration Also provided herein are compounds or pharmaceutically acceptable salts thereof that, upon administration of a therapeutically effective amount, result in an exposure of about 806 ng / mL or more 24 hours after the administration. Preferably, the compound is a BTK-I

[0059] A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from a BTK-mediated cancer who has received at least one previous anti-cancer therapy comprising at least one BTK inhibitor-based therapy comprising orally administering to the patient suffering from a BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs Administration of a therapeutically effective amount results in an AUC (0~24) of about 52400 ng*h / mL or more Administration of a therapeutically effective amount results in an exposure of about 806 ng / mL or more 24 hours after the administration Also provided herein are compounds or pharmaceutically acceptable salts thereof that are administered concomitantly, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2 Preferably, the anti-CD20-based therapy is administered at about 375 mg / m 2 on day 1 ± 3 of the first 28-day cycle, 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 divided doses on days 1 and 2, and thereafter ​​​​​​​​​​, The 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 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then 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. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then 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. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2 . Preferably, rituximab is about 375 m g / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, ritux imab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, ritux 2 imab is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, ritux imab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, ritux Ksimab is administered at about 375 mg / m² on day 1 of the first 28-day cycle, 2 or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1, 2 either that or not administered at all between each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1 to 7, about 50 mg on days 8 to 14, about 100 mg on days 15 to 21, and about 200 mg on days 22 to 28 during the 4th 28-day cycle, and then administered daily at about 400 mg for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m² on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, 2 and rituximab is then administered at about 500 mg / m² on day 1, either that or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7, about 50 mg on days 8 to 14, about 1 2 5 to 21, and about 200 mg on days 22 to 28 during the 4th 28-day cycle, and then administered daily at about 400 mg for any subsequent cycles. Preferably, BTK-I is administered daily at about 200 mg, and rituximab is administered at about 375 mg / m² on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1, either that or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7, about 50 mg on days 8 to 14, about 1 5 to 21, and about 200 mg on days 22 to 28 during the 4th 28-day cycle, 2 or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1, either that or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7, about 50 mg on days 8 to 14, about 1 2 5 to 21, and about 200 mg on days 22 to 28 during the 4th 28-day cycle, either that or not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7, about 50 mg on days 8 to 14, about 1 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, Administration of a therapeutically effective amount results in an exposure of about 806 ng / mL or more 24 hours after the administration and also provided herein is a compound or salt thereof, which is administered concomitantly, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle 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 2 or as divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the 4th 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles and the BCL-2 inhibitor is administered during the 4th 28-day cycle Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and the anti-CD20-based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles and the BCL-2 inhibitor is administered during the 4th 28-day cycle is provided. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, BCL -2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, 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. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2 2 and. Preferably, rituximab is administered at about 375 m g / m on day 1 ± 3 days of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, ritux 2 imab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2 2 and rituximab is then administered at about 500 mg / m on day 1, or not administered at all between each of any subsequent cycles 2 either. Preferably, venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter, for any subsequent cycle is dosed daily at about 400 mg. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2 and rituximab is then administered at about 500 mg / m 2 on day 1, or ritux imab is then administered at about 500 mg / m 2 on day 1, or for any subsequent cycle Either not administered at all between each, and Venetoclax is 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, 1 About 100 mg on days 5 to 21, and about 200 mg on days 22 to 28 of the cycle, After that, for any subsequent cycle, it is dosed daily at about 400 mg. Preferably, BT K-I is administered daily at about 200 mg, and Rituximab is about 375 mg / m 2 On day 1, or administered as a divided dose on days 1 and 2, and Rituximab Is then administered at about 500 mg / m 2 On day 1, or either not administered at all between each of any subsequent cycles And Venetoclax is the fourth 28-day cycle During, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, 15 to 2 About 100 mg on day 1, and about 200 mg on days 22 to 28 of the cycle, and then For any subsequent cycle, it is dosed daily at about 400 mg.

[0062] A BTK-I compound or its pharmaceutically acceptable salt for use in inhibiting the proliferation and / or survival of activated B cells in patients with BTK-mediated cancer who have received one previous anti-cancer therapy, Administering a therapeutically effective amount of the compound or salt to a patient with BTK-mediated cancer in a continuous daily dose regimen until the progression of BTK-mediated cancer or unacceptable toxicity occurs, Including, By said administration of a therapeutically effective amount, the AUC Becomes about 52400 ng*h / mL or more, By said administration of a therapeutically effective amount, the exposure becomes about 806 ng / mL or more 24 hours after said administration (0~24) And Become, And Compounds or pharmaceutically acceptable salts thereof are also provided herein. Preferably, the compound is a BTK-I.

[0063] A compound that is a BTK-I or a pharmaceutically acceptable salt thereof for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK-mediated cancer who has received one previous anti-cancer therapy, comprising orally administering to the patient a therapeutically effective amount of the compound or salt in a continuous daily dosing regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective administration results in an AUC (0~24) of about 52400 ng*h / mL or more and wherein the therapeutically effective administration results in an exposure of about 806 ng / mL or more 24 hours after the administration, Compounds or salts thereof are also provided herein, wherein the compound or salt is administered concomitantly, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20 based therapy. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, the anti-CD20 based therapy is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, ± 3 days, 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 divided doses on days 1 and 2, and thereafter the anti-CD20 based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is on day 4 of the It is administered in an 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1, or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20- based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is 2 preferably about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is preferably about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then about 500 mg / m 2 on day 1, or as a divided dose on days 1 and 2, and rituximab is then about 500 mg / m 2 Either administered or not administered at all during each of any subsequent cycles There is. Preferably, venetoclax is about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and administered at about 200 mg on days 22 to 28 of the cycle, and thereafter, for any subsequent cycle administered daily at about 400 mg. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle 2 or administered as a divided dose on days 1 and 2, and ritux imab is thereafter administered at about 500 mg / m 2 on day 1, or either not administered at all during each of any subsequent cycles Venetoclax is about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 5 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the 4th 28 day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. Preferably, BT K-I is administered daily at about 200 mg, and rituximab is about 375 mg / m 2 on day 1 of the first 28-day cycle, or administered as a divided dose on days 1 and 2, and rituxima b is thereafter administered at about 500 mg / m 2 on day 1, or either not administered at all during each of any subsequent cycles Venetoclax is about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 15 to 2 1 of the cycle, and about 100 mg on days 22 to 28 of the cycle during the 4th 28-day cycle, and thereafter administered daily at about 400 mg for any subsequent cycle. Thereafter, for any subsequent cycle, administered daily at about 400 mg.

[0064] Activated B cells in patients with BTK-mediated cancer who have received two prior anti-cancer therapies A compound that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in patients with BTK-mediated cancer who have received two prior anti-cancer therapies or a pharmaceutically acceptable salt thereof, comprising administering to a patient with BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective administration results in an AUC of about 52400 ng*h / mL or more and the therapeutically effective administration results in an exposure of about 806 ng / mL or more 24 hours after the administration. Also provided herein is a compound or a pharmaceutically acceptable salt thereof. Preferably, the compound is a BTK-I. wherein the therapeutically effective administration results in an AUC (0~24) of about 52400 ng*h / mL or more and the therapeutically effective administration results in an exposure of about 806 ng / mL or more 24 hours after the administration. Also provided herein is a compound or a pharmaceutically acceptable salt thereof. Preferably, the compound is a BTK-I. A compound or a pharmaceutically acceptable salt thereof, wherein the compound or salt is administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, is also provided herein. Preferably, the compound is a BTK-I.

[0065] Activated B cells in patients with BTK-mediated cancer who have received two prior anti-cancer therapies A compound that is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in patients with BTK-mediated cancer who have received two prior anti-cancer therapies or a pharmaceutically acceptable salt thereof, comprising administering to a patient with BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective administration results in an AUC of about 52400 ng*h / mL or more and the therapeutically effective administration results in an exposure of about 806 ng / mL or more 24 hours after the administration. Also provided herein is a compound or a pharmaceutically acceptable salt thereof. Preferably, the compound is a BTK-I. wherein the therapeutically effective administration results in an AUC (0~24) of about 52400 ng*h / mL or more and the therapeutically effective administration results in an exposure of about 806 ng / mL or more 24 hours after the administration. Also provided herein is a compound or a pharmaceutically acceptable salt thereof. Preferably, the compound is a BTK-I. and a compound or salt, wherein the compound or salt is administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, is also provided herein. A compound or a pharmaceutically acceptable salt thereof, wherein the compound or salt is administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, is also provided herein. It is provided in writing. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m 2 on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and the anti-CD 20-based therapy is then either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle and is administered. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL -2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rituximab . Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL -2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rituximab It is. Preferably, the anti-CD20-based therapy is obinutuzumab. Preferably, the anti- CD20-based therapy is R-CHOP. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or administered as a divided dose on days 1 and 2. 2 Preferably, rituximab is about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or administered as a divided dose on days 1 and 2. Preferably, rituximab is about 375 mg / m g / m 2 on day 1 of the first 28-day cycle, or administered as a divided dose on days 1 and 2. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or administered as a divided dose on days 1 and 2, and rituximab is then either about 500 mg / m 2 on day 1 or not administered at all between each of any subsequent cycles. Preferably, venetoclax is about 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, about 100 mg on days 15-21 of the cycle, and 2 about 200 mg on days 22-28 of the cycle during the fourth 28-day cycle, and then about 400 mg daily for any subsequent cycles. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or administered as a divided dose on days 1 and 2, and rituximab is then either about 500 mg / m on day 1 or not administered at all between each of any subsequent cycles, and venetoclax is about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and then about 400 mg daily for any subsequent cycles. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or administered as a divided dose on days 1 and 2, and rituximab is then either about 500 mg / m 2 on day 1 or not administered at all between each of any subsequent cycles, and venetoclax is about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and 2 then either about 500 mg / m on day 1 or not administered at all between each of any subsequent cycles, and venetoclax is about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and then about 400 mg daily for any subsequent cycles. Thereafter, it is dosed daily at about 400 mg for any subsequent cycle. Preferably, BT K-I is administered daily at about 200 mg, and rituximab is about 375 mg / m 2 on day 1 of the first 28-day cycle or administered as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1 or not administered at all during each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 00 mg on days 15 to 2 1 of the cycle, and about 200 mg on days 22 to 28 of the cycle, and thereafter is dosed daily at about 400 mg for any subsequent cycle.

[0066] A compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK-mediated cancer who has received more than two prior anti-cancer therapies, comprising orally administering to the patient suffering from BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein said administration of a therapeutically effective amount results in an AUC of about 52400 ng*h / mL or more, and said administration of a therapeutically effective amount results in an exposure of about 806 ng / mL or more 24 hours after said administration, is also provided herein. Preferably, the compound is a BTK-I. (0~24) becomes about 52400 ng*h / mL or more, and an exposure of about 806 ng / mL or more 24 hours after said administration, is also provided herein. Preferably, the compound is a BTK-I. is a BTK-I.

[0067] A compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in inhibiting the proliferation and / or survival of activated B cells in a patient suffering from BTK-mediated cancer who has received more than two prior anti-cancer therapies, A compound, which is a BTK-I for use in inhibiting the proliferation and / or survival of cells, or a pharmaceutically acceptable salt thereof, for a patient suffering from a BTK-mediated cancer, continuously administering a therapeutically effective amount of the compound or salt orally in a daily dosage regimen until the progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective administration results in an AUC of about 52400 ng*h / mL or more, and the therapeutically effective administration results in an exposure of about 806 ng / mL or more 24 hours after the administration, and the compound or salt is administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, and the compound or its pharmaceutically acceptable salt is also provided in this specification. Preferably, the anti-CD20-based therapy is administered on day 1, or as a divided dose on days 1 and 2, of the first 28-day cycle. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m (0~24) on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered on day 1, or as a divided dose on days 1 and 2, of the first 28-day cycle, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered 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 as a divided dose on days 1 and 2, of the first 28-day cycle, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles. becomes, and the therapeutically effective administration results in an exposure of about 806 ng / mL or more 24 hours after the administration, becomes, and the compound or salt is administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, and the compound or its pharmaceutically acceptable salt is also provided in this specification. Preferably, the anti-CD20-based therapy is administered on day 1, or as a divided dose on days 1 and 2, of the first 28-day cycle. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered on day 1, or as a divided dose on days 1 and 2, of the first 28-day cycle, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered 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 as a divided dose on days 1 and 2, of the first 28-day cycle, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered 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 as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles. 2 or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered 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 as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles. the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and thereafter, the anti-CD20-based therapy is either administered on day 1 or not administered 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 as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the anti-CD20-based therapy is either administered on day 1 or not administered 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 as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then either administered on day 1 or not administered 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 as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles. Preferably, the anti-CD20-based therapy is either administered on day 1 or not administered 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 as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles. It is either one of them, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on the first day of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD 20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on the first day of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is about 375 mg / m 2 on day 1 ± 3 days of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is about 375 mg / m on the first day of the first 28-day cycle, 2 or as divided doses on days 1 and 2, and rituximab is then either about 500 mg / m on day 1 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and 2 during the 4th 28-day cycle, about 100 mg on days 22 to 28 of the cycle. Preferably, rituximab is about 375 mg / m 2 on the first day of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then either about 500 mg / m on day 1 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is about 20 mg, about 50 mg, about 100 mg, and about 100 mg during the 4th 28-day cycle, on days 1 - 7, 8 - 14, 15 - 21, and Administered at about 200 mg on days 22 to 28 of the cycle, and thereafter, for any subsequent cycle administered daily at about 400 mg. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle 2 or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or is not administered at all between any subsequent cycles. Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 00 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28 -day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. Preferably, BT K-I is administered daily at about 200 mg, and rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1, or is not administered at all between any subsequent cycles. Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 2 1 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter 2 for any subsequent cycle, administered daily at about 400 mg. The present invention also relates to a compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in the treatment of BTK-mediated cancer, and which comprises a therapeutically effective amount of the compound in a patient suffering from BTK-mediated cancer. Thereafter, for any subsequent cycle, administered daily at about 400 mg.

[0068] The present invention also relates to a compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in the treatment of BTK-mediated cancer, and which comprises a therapeutically effective amount of the compound 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. It is administered in an 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is thereafter administered either on day 1 or not at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is thereafter administered either on day 1 or not at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is thereafter administered at about 500 mg / m on day 1. It is administered on day 1, or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is thereafter administered either on day 1 or not at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. It is administered either on day 1 or not at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. It is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is thereafter administered either on day 1 or not at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is thereafter administered either on day 1 or not at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. It is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is thereafter administered either on day 1 or not at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. It is administered either on day 1 or not at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. It is administered either on day 1 or not at all between each of the subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. It is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. 2 It is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. It is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. 2 It is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. 2 It is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2. It is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is thereafter administered at about 500 mg / m on day 1. 2 administered during or not administered at all during any subsequent cycle Preferably, Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter about 400 mg daily for any subsequent cycle. Preferably, Rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1 or not administered at all during any subsequent cycle, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 2 5 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter about 400 mg daily for any subsequent cycle. Preferably, BTK-I is administered at about 200 mg daily, and Rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1 or not administered at all during any subsequent cycle, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 5 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter about 400 mg daily for any subsequent cycle. Preferably, BTK-I is administered at about 200 mg daily, and Rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and Rituximab is thereafter administered at about 500 mg / m on day 1 or not administered at all during any subsequent cycle, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 5 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and 2 thereafter about 400 mg daily for any subsequent cycle. on day 1 or not administered at all during any subsequent cycle, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 2 5 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter about 400 mg daily for any subsequent cycle. Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 5 to 21 of the cycle, and about 100 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter about 400 mg daily for any subsequent cycle. administered at about 400 mg daily for any subsequent cycle.

[0070] A BTK-I for use in the treatment of BTK-mediated cancer in patients who are refractory or relapsed which is a compound or a pharmaceutically acceptable salt thereof, and which comprises administering to a patient suffering from BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs which comprises oral administration, and wherein the therapeutically effective amount of the compound or salt results in >90% inhibition of BTK at steady state in the patient 24 hours after administration is also provided herein. Preferably, the compound is a BTK-I A BTK-I for use in the treatment of BTK-mediated cancer in patients who are refractory or relapsed which is a compound or a pharmaceutically acceptable salt thereof, and which comprises administering to a patient suffering from BTK-mediated cancer

[0071] a therapeutically effective amount of the compound or salt in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs which comprises oral administration, and wherein the therapeutically effective amount of the compound or salt results in >90% inhibition of BTK at steady state in the patient 24 hours after administration and wherein the compound or salt is administered concomitantly, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy is also provided herein. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle or as a divided dose on days 1 and 2 Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle or as a divided dose on days 1 and 2 of the first 28-day cycle or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle or as a divided dose on days 1 and 2 2 or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at the beginning On the first day of a 28-day cycle, or as a divided dose on the first and second days, and then the anti-CD20-based therapy is either administered on the first day or not at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on the first day of the first 28-day cycle, or as a divided dose on the first and second days, and the anti-CD20-based therapy is then either administered on the first day 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 BTK-I is started on the first day and administered daily, the anti-CD20-based therapy is administered on the first day of the first 28-day cycle, or as a divided dose on the first and second days, and the anti-CD 20-based therapy is then either administered on the first day 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. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on the first day of the first 28-day cycle, or as a divided dose on the first and second days. Preferably, rituximab is about 375 m g / m on the first day ± 3 days of the first 28-day cycle and, or as a divided dose on the first and second days. Preferably, rituximab is about 375 m g / m on the first day of the first 28-day cycle, or as a divided dose on the first and second days, and rituximab is preferably administered at about 375 mg / m 2 on the first day of the first 28-day cycle, or as a divided dose on the first and second days. Preferably, rituximab is about 375 mg / m on the first day ± 3 days of the first 28-day cycle g / m 2or administered as divided doses on Day 1 and Day 2. Preferably, Rituximab is administered at about 375 mg / m on Day 1 of the first 28-day cycle 2 or as divided doses on Day 1 and Day 2, and Rituximab is then administered at about 500 mg / m on Day 1 2 either administered or not administered at all during each of any subsequent cycles Preferably, Venetoclax is administered at about 20 mg on Days 1-7 of the cycle, about 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 during the 4th 28-day cycle, and then administered daily at about 400 mg for any subsequent cycles. Preferably, Rituximab is administered at about 375 mg / m on Day 1 of the first 28-day cycle or as divided doses on Day 1 and Day 2, and Rituximab 2 is then administered at about 500 mg / m on Day 1 either administered or not administered at all during each of any subsequent cycles 2 and Venetoclax is administered at about 20 mg on Days 1-7 of the cycle, about 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 during the 4th 28-day cycle and then administered daily at about 400 mg for any subsequent cycles. Preferably, BT K-I is administered daily at about 200 mg, and Rituximab is administered at about 375 mg / m on Day 1 of the first 28-day cycle or as divided doses on Day 1 and Day 2, and Rituximab is then administered at about 500 mg / m on Day 1 either administered or not administered at all during each of any subsequent cycles 2 or as divided doses on Day 1 and Day 2, and Rituximab is then administered at about 500 mg / m on Day 1 2 either administered or not administered at all during each of any subsequent cycles Either not administered at all in between, and Venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the fourth 28-day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. In the cycle, about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg.

[0072] A compound or a pharmaceutically acceptable salt thereof, which is a BTK-I for use in the treatment of BTK-mediated cancer in a treatment-naive patient, comprising orally administering to a patient suffering from BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in inhibition of more than 90 percent of BTK in the patient at steady state 24 hours after administration, is provided herein. Preferably, the compound is a BTK-I.

[0073] A compound or a pharmaceutically acceptable salt thereof, which is a BTK-I for use in the treatment of BTK-mediated cancer in a treatment-naive patient, comprising orally administering to a patient suffering from BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dose regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in inhibition of more than 90 percent of BTK in the patient at steady state 24 hours after administration, and wherein the compound or salt is administered concurrently, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy, is also provided herein. It is provided in writing. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m 2 on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and the anti-CD20-based therapy is then either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably the BTK-I is started on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle or as a divided dose on days 1 and 2, and the anti-CD 20-based therapy is then either administered on day 1 or not administered at all between 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. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically acceptable salt thereof. Preferably, the BCL -2 inhibitor is BCL2-I. Preferably, the anti-CD20-based therapy is rituximab ​​​That is. Preferably, the anti-CD20-based therapy is obinutuzumab. Preferably, the anti- CD20-based therapy is R-CHOP. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, 2 and is administered. Preferably, rituximab is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, ritux- imab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1, or is not administered at all between each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 50 mg on days 8-14 of the cycle, about 100 mg on days 15-21 of the cycle, and 2 about 200 mg on days 22-28 of the cycle during the fourth 28-day cycle, and thereafter is administered daily at about 400 mg for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and ritux- imab is then administered at about 500 mg / m on day 1, or is not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and thereafter is administered daily at about 400 mg for any subsequent cycles. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and ritux- 2 imab is then administered at about 500 mg / m on day 1, or is not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, 2 and is administered at about 500 mg / m on day 1, or is not administered at all between each of any subsequent cycles, and venetoclax is administered at about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and is administered at about 20 mg on days 1-7 of the cycle, about 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 during the fourth 28-day cycle, and is administered at about 100 mg on days 15-21 of the cycle, and about 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. including oral administration in a continuous daily dose regimen until toxicity occurs, wherein a therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK at steady state in a patient 24 hours after administration, and the compound or salt is administered concomitantly, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20 based therapy, which is also provided herein. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, the anti-CD20 based therapy is administered at about 375 mg / m on day 1 ± 3 of the first 28-day cycle, 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 divided doses on days 1 and 2, and thereafter, the anti-CD20 based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 2 2 8-day cycle. Preferably, the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20 based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD 20 based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20 based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles, and the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20 based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD 20 based therapy is thereafter either administered on day 1 or not administered at all between each of any subsequent cycles. Either not administered at all, or the BCL-2 inhibitor is administered during the fourth 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, 2 or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, 2 or as divided doses on days 1 and 2. Preferably, ritux imab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m 2 on day 1 or not administered at all between each of any subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle, and thereafter, administered daily at about 400 mg for any subsequent cycle. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and ritux 2 imab is then administered at about 500 mg / m on day 1, 2administered or not administered at all during any subsequent cycle and Venetoclax is administered either not at all or at approximately 20 mg on days 1 - 7, approximately 50 mg on days 8 - 14, approximately 100 mg on days 15 - 21, and approximately 200 mg on days 22 - 28 of the 4th 28-day cycle and thereafter at approximately 400 mg daily for any subsequent cycle. Preferably, BTK-I is administered at approximately 200 mg daily and Rituximab is administered at approximately 375 mg / m on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and Rituximab is thereafter administered at approximately 500 mg / m on day 1 or either not at all or not administered at all during any subsequent cycle, and Venetoclax is administered either not at all or at approximately 20 mg on days 1 - 7, approximately 50 mg on days 8 - 14, approximately 100 mg on days 15 - 21, and approximately 200 mg on days 22 - 28 of the 4th 28-day cycle and thereafter at approximately 400 mg daily for any subsequent cycle. 2 2 on day 1 of the first 28-day cycle or as divided doses on days 1 and 2, and Rituximab is thereafter administered at approximately 500 mg / m on day 1 or either not at all or not administered at all during any subsequent cycle, and Venetoclax is administered either not at all or at approximately 20 mg on days 1 - 7, approximately 50 mg on days 8 - 14, approximately 100 mg on days 15 - 21, and approximately 200 mg on days 22 - 28 of the 4th 28-day cycle 2 and thereafter at approximately 400 mg daily for any subsequent cycle. and Venetoclax is administered either not at all or at approximately 20 mg on days 1 - 7, approximately 50 mg on days 8 - 14, approximately 100 mg on days 15 - 21, and approximately 200 mg on days 22 - 28 of the 4th 28-day cycle and thereafter at approximately 400 mg daily for any subsequent cycle. and Venetoclax is administered at approximately 20 mg on days 1 - 7, approximately 50 mg on days 8 - 14, approximately 100 mg on days 15 - 21, and approximately 200 mg on days 22 - 28 of the 4th 28-day cycle, and thereafter at approximately 400 mg daily for any subsequent cycle.

[0076] A compound or a pharmaceutically acceptable salt thereof which is a BTK-I for use in the treatment of BTK-mediated cancer in a patient who has received at least one previous anti-cancer therapy comprising at least one BTK inhibitor-based therapy comprising orally administering to a patient suffering from BTK-mediated cancer a therapeutically effective amount of the compound or salt in a continuous daily dosage regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK at steady state in the patient 24 hours after administration wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK at steady state in the patient 24 hours after administration ​​​Provided herein. Preferably, the compound is a BTK-I.

[0077] A compound or a pharmaceutically acceptable salt thereof that is a BTK-I for use in the treatment of BTK-mediated cancer in a patient who has received at least one previous anti-cancer therapy comprising at least one BTK inhibitor-based therapy, wherein a therapeutically effective amount of the compound or salt is orally administered to the patient in a continuous daily dosage regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs, wherein the therapeutically effective amount of the compound or salt results in greater than 90 percent inhibition of BTK in the patient at steady state 24 hours after administration, and wherein the compound or salt is administered concomitantly, separately, or sequentially with a BCL-2 inhibitor and / or an anti-CD20-based therapy is also provided herein. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, the anti-CD20-based therapy is administered at about 375 mg / m on day 1 ± 3 days of the first 28-day cycle, 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 divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy, 2 2 or as divided doses on days 1 and 2, and preferably the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and thereafter the anti-CD20-based therapy is either administered on day 1 or not administered at all between each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the fourth 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD20-based therapy, The method is then either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is initiated on day 1 and administered daily, and the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and the anti-CD 20-based therapy is then either administered on day 1 or not administered at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, rituximab is administered at about 375 m g / m on day 1 ± 3 days of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, ritux imab is administered at about 375 mg / m on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered at about 20 2 during days 1 to 7 of the cycle during the 4th 28-day cycle Preferably, rituximab is administered at about 375 mg / m g / m 2 on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2. Preferably, ritux imab is administered at about 375 mg / m 2 on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m on day 1 or not administered at all during each of any subsequent cycles. Preferably, venetoclax is administered at about 20 2 mg / m during days 1 to 7 of the cycle during the 4th 28-day cycle mg, about 50 mg on days 8 to 14 of the cycle, about 100 mg on days 15 to 21 of the cycle, and administered at about 200 mg on days 22 to 28 of the cycle, and thereafter, for any subsequent cycle administered daily at about 400 mg. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle 2 or administered as a divided dose on days 1 and 2, and ritux imab is thereafter administered at about 500 mg / m 2 on day 1 or not administered at all between each of any subsequent cycles. Venetoclax is about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 0 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28 day cycle, and thereafter, for any subsequent cycle, administered daily at about 400 mg. Preferably, BT K-I is administered daily at about 200 mg, and rituximab is about 375 mg / m on day 1 of the first 28-day cycle 2 or administered as a divided dose on days 1 and 2, and rituxima b is thereafter administered at about 500 mg / m 2 on day 1 or not administered at all between each of any subsequent cycles. Venetoclax is about 20 mg on days 1 to 7 of the cycle, about 50 mg on days 8 to 14 of the cycle, about 1 0 mg on days 15 to 21 of the cycle, and about 200 mg on days 22 to 28 of the cycle during the fourth 28-day cycle and thereafter, for any subsequent cycle, administered daily at about 400 mg. For the treatment of BTK-mediated cancer in patients who have not received a previous anti-cancer therapy containing a BTK inhibitor

[0078] used 2. A compound which is BTK-I or a pharma- ceutical acceptable salt thereof for use in an anti-BTK therapy. 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 either on day 1 or not at all during each of any subsequent cycles. Preferably, the BCL-2 inhibitor is administered during the 4th 2 8-day cycle. Preferably, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD20-based ther apy is then administered either on day 1 or not at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BTK-I is started on day 1 and administered daily, the anti-CD20-based therapy is administered on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2, and the anti-CD 20-based therapy is then administered either on day 1 or not at all during each of any subsequent cycles, and the BCL-2 inhibitor is administered during the 4th 28-day cycle. Preferably, the BCL-2 inhibitor is venetoclax. Preferably, the BCL -2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2 . Preferably, the BCL-2 inhibitor is BCL2-I or a pharmaceutically 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. Preferably, rituximab is about 375 mg / m on day 1 of the first 28-day cycle, or as a divided dose on days 1 and 2 2 . Preferably, rituximab is about 375 m g / m on day 1 ± 3 days of the first 28-day cycle, or as a divided dose on days 1 and 2. Preferably, ritux 2 imab is about 375 mg / m Ksimab is administered at about 375 mg / m² on day 1 of the first 28-day cycle, 2 or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1, 2 either for each subsequent cycle or not administered at all during any of the subsequent cycles. Preferably, venetoclax is administered at about 20 mg on days 1 to 7, about 50 mg on days 8 to 14, about 100 mg on days 15 to 21, and about 200 mg on days 22 to 28 during the 4th 28-day cycle, and then administered daily at about 400 mg for any subsequent cycle. Preferably, rituximab is administered at about 375 mg / m² on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab 2 is then administered at about 500 mg / m² on day 1, either for each subsequent cycle or not administered at all during any of the subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7, about 50 mg on days 8 to 14, about 1 2 5 to 21, and about 200 mg on days 22 to 28 during the 4th 28-day cycle, and then administered daily at about 400 mg for any subsequent cycle. Preferably, BTK-I is administered daily at about 200 mg, and rituximab is administered at about 375 mg / m² on day 1 of the first 28-day cycle, or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1, either for each subsequent cycle or not administered at all during any of the subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7, about 50 mg on days 8 to 14, about 1 5 to 21, and about 200 mg on days 22 to 28 during the 4th 28-day cycle, 2 or as divided doses on days 1 and 2, and rituximab is then administered at about 500 mg / m² on day 1, 2 either for each subsequent cycle or not administered at all during any of the subsequent cycles, and venetoclax is administered at about 20 mg on days 1 to 7, about 50 mg on days 8 to 14, about 1 5 to 21, and about 200 mg on days 22 to 28 during the 4th 28-day cycle, On days 1 to 7 of the cycle, about 20 mg, on days 8 to 14 of the cycle, about 50 mg, on days 15 to 2 On day 1, about 100 mg, and on days 22 to 28 of the cycle, about 200 mg, and thereafter For any subsequent cycle, it is administered daily at about 400 mg.

[0080] A BTK-I compound or a pharmaceutically acceptable salt thereof for use in the treatment of BTK-mediated cancer in a patient who has received one previous anti-cancer therapy Wherein a therapeutically effective amount of the compound or salt is orally administered to a patient suffering from BTK-mediated cancer in a continuous daily dosage regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs Wherein a therapeutically effective amount of the compound or salt is orally administered to a patient suffering from BTK-mediated cancer in a continuous daily dosage regimen until progression of the BTK-mediated cancer or unacceptable toxicity occurs Including, until progression of the BTK-mediated cancer or unacceptable toxicity occurs, orally administering a therapeutically effective amount of the compound or salt to the patient in a continuous daily dosage regimen Wherein the therapeutically effective amount of the compound or salt results in greater than 90% inhibition of BTK at steady state in the patient 24 hours after administration Also provided herein is a compound or a pharmaceutically acceptable salt thereof, which is an amount that results in greater than 90% inhibition of BTK at steady state in the patient 24 hours after administration Preferably, the compound is BTK-I.

[0081] A BTK-I ...

Claims

1. 1. A method of treating cancer or an autoimmune disease in a patient in need thereof, comprising: Patients were administered (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide ) methyl) phenyl) -1- (1,1,1-trifluoropropan-2-yl) -1H- About 12 of a compound which is a pyrazole-4-carboxamide or a pharma- ceutically acceptable salt thereof Administering a daily dose of from 0 mg to about 600 mg.

2. 10. The method of claim 1, wherein the method is treating cancer.

3. The compound is (S)-5-amino-3-(4-((5-fluoro-2-methoxyphenyl)benzene 1-(1,1,1-trifluoropropan-2-yl) The method according to claim 1 or 2, wherein the compound is -1H-pyrazole-4-carboxamide.

4. 4. The method according to claim 1, wherein the dose is between about 125 mg and about 300 mg. Method of posting.

5. 5. The method according to claim 1, wherein the dose is between about 175 mg and about 300 mg. Method of posting.

6. The method of any one of claims 1 to 5, wherein the dose is about 200 mg.

7. The method of any one of claims 1 to 6, wherein the cancer is B-cell non-Hodgkin's lymphoma. 。

8. The method of any one of claims 1 to 6, wherein the cancer is mantle cell lymphoma.

9. Any of claims 1 to 6, wherein the cancer is chronic lymphocytic leukemia / small lymphocytic lymphoma.

3. The method according to claim 1 .

10. The method of any one of claims 1 to 9, wherein the patient is relapsed or refractory.

11. The method of any one of claims 1 to 9, wherein the patient is treatment naive.

12. 11. The method according to claim 1, wherein the patient has undergone at least one prior anti-cancer therapy. The method according to claim 5.

13. 10. The method of claim 1, wherein the patient has not received a previous anti-cancer therapy comprising a BTK inhibitor.

13. The method according to any one of claims 12 to 13.

14. It is used to treat cancer or autoimmune diseases, administered at a daily dose of about 120 mg to about 600 mg. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzaldehyde) for use (1,1,1-trifluoropropan-2-yl)-1-(1,1,1-trifluoropropan-2-yl)- A compound which is H-pyrazole-4-carboxamide or a pharma- ceutically acceptable salt thereof.

15. 15. The compound or compound for use according to claim 14, wherein said use is in the treatment of cancer. salt.

16. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo 16. The compound for use according to claim 14 or 15, which is a aryl-4-carboxamide. Or salt.

17. 17. Any one of claims 14 to 16, wherein the dose is between about 125 mg and about 300 mg.

2. A compound or salt for use as defined in claim 1.

18. 18. Any one of claims 14 to 17, wherein the dose is between about 175 mg and about 300 mg.

2. A compound or salt for use as defined in claim 1.

19. The use according to any one of claims 14 to 18, wherein the dose is between about 200 mg. A compound or salt for use in treating a chronic condition.

20. The method according to any one of claims 14 to 19, wherein the cancer is B-cell non-Hodgkin's lymphoma. The compound or salt for use.

21. The use according to any one of claims 14 to 19, wherein the cancer is mantle cell lymphoma. A compound or salt for use in treating a chronic condition.

22. Any of claims 14 to 19, wherein the cancer is chronic lymphocytic leukemia / small lymphocytic lymphoma.

2. A compound or salt for use according to any one of claims 1 to 11.

23. The compound or salt is administered to a patient with relapsed or refractory disease.

3. A compound or salt for use according to any one of claims 2.

24. 23. The method of claim 14, wherein the compound or salt is administered to a treatment-naive patient.

2. A compound or salt for use according to any one of claims 1 to 11.

25. The compound or salt is administered to a patient who has received at least one prior anti-cancer therapy. A compound or salt for use according to any one of claims 14 to 23.

26. The compound or salt is administered to a patient who has not received prior anti-cancer therapy that includes a BTK inhibitor. A compound for use according to any one of claims 14 to 23 or 25, is salt.

Images