TW201628620A - Compositions and methods for treatment of chronic lymphocytic leukemia and small lymphocytic leukemia using a BTK inhibitor - Google Patents

Abstract

Therapeutic methods and pharmaceutical compositions for treating chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) are described. In certain embodiments, the invention includes therapeutic methods of treating CLL and SLL using a BTK inhibitor. In certain embodiments, the invention includes therapeutic methods of treating subtypes of CLL and SLL using a BTK inhibitor, including subtypes of CLL in patients sensitive to thrombosis and subtypes of CLL that increase monocytes and NK cells in peripheral blood after treatment with a BTK inhibitor. In certain embodiments, the invention includes pharmaceutical compositions for treating hematological malignancies comprising a combination of a BTK inhibitor and an anti-CD20 antibody.

Description

Composition and method for treating chronic lymphocytic leukemia and small lymphocytic leukemia using Bruton's tyrosine kinase (BTK) inhibitor

The present invention discloses pharmaceutical compositions and methods of treatment for the treatment of chronic lymphocytic leukemia and other leukemias and lymphomas using Bruton's tyrosine kinase (BTK) inhibitors.

Bruton's tyrosine kinase (BTK or Btk) is a TEC family non-receptor protein kinase expressed in B cells and bone marrow cells. The function of BTK in the signaling pathway activated by the binding of B cell receptor (BCR) to FCER1 on obese cells has been fully established. A functional mutation in human BTK results in a primary immunodeficiency disease characterized by a defective B cell development defect between the original B cell and the pre-B cell stage. The result is almost no B lymphocytes, resulting in a significant reduction in all types of serum immunoglobulins. These findings support the pivotal role of BTK in regulating the production of autoantibodies in autoimmune diseases.

Other diseases that play an important role in dysfunctional B cells The disease is a B cell malignant disease. The reported role of BTK in the regulation of B cell proliferation and apoptosis indicates the possibility of treating B cell lymphoma with a BTK inhibitor. Therefore, the development of BTK inhibitors has become a possible treatment, as described in O.J. D'Cruz and F.M. Uckun, OncoTargets and Therapy 2013, 6, 161-176.

B-cell chronic lymphocytic leukemia (CLL) is one of the most prevalent B-cell malignancies in adults. CLL is characterized by the expansion of mature B cells per plant. CLL patients who relapse after standard treatment often experience adverse consequences. Although survival has been improved by the addition of immunotherapy (such as rituximab) to standard chemotherapy (such as fludarabine and cyclophosphamide), such as M. Hallek et al., Lancet, 2010, 76, 1164-74, but many standard therapies are associated with toxicity and immunosuppression. Therefore, there is a great need for the identification of CLL with lower toxicity and high efficiency. Small lymphocytic leukemia (SLL) is closely related to CLL, with the only difference being that the single lymphocyte value observed in the blood is lower than in the CLL with increased spleen or lymph nodes. There is also a great need for the identification of SLL with lower toxicity and high efficiency.

CLL (and SLL) cells rapidly accumulate and resist apoptosis in vivo, but are known to die rapidly in vitro. M. Buchner et al., Blood 2010, 115, 4497-506. One cause of this effect is the survival of non-malignant helper cells in the tumor microenvironment, such as cells that are exposed to the stromal cells. It is known that stromal cells in bone marrow and lymph nodes have anti-apoptotic and protective effects on CLL cells, protecting these cells from chemotherapy and spontaneous Both are apoptotic. R.E. Mudry et al., Blood 2000, 96, 1926-32. The chemokine SDF1α (CXCL12) directs CLL cells back to a protective niche. M. Burger et al., Blood 2005, 106, 1824-30. Existing drugs targeting the BCR pathway in B cell malignancies can cause some lymphocytosis, that is, lymphocytes cause cell migration from the lymph nodes by disturbing CXCR4-SDF1α signaling and other adhesion factors in the bone marrow. However, existing therapies are unlikely to eliminate malignant B cell populations that remain in the microenvironment of bone marrow and lymph nodes that prevent apoptosis by protective stromal cells. Therefore, there is an urgent need for treatments that reduce or overcome the protective effects of the microenvironment on CLL cells and have excellent clinical response in patients.

The CD20 antigen (also known as the human B-lymphocyte-restricted differentiation antigen Bp35 or B1) is found on the surface of normal anterior tibial B and mature B lymphocytes, including malignant B lymphocytes. L. M. Nadler et al. J. Clin. Invest. 1981, 67, 134-40; P. Stashenko et al. J. Immunol. 1980, 139, 3260-85. The CD20 antigen is a glycosylated integral membrane protein having a molecular weight of about 35 kD. T. F. Tedder et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 208-12. CD20 is also expressed on most B-cell non-Hodgkin lymphoma cells, but not on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. Anti-CD20 antibodies are currently used in the treatment of many B cell hematological malignancies, including for painless NHL, invasive NHL, and CLL/SLL. S.H. Lim et al., Haematologica 2010, 95, 135-43; S. A. Beers et al., Sem. Hematol. 2010, 47, 107-14; C. Klein et al. mAbs 2013, 5, 22-33. However, there is an urgent need for a treatment that provides more effective energy in many B cell hematological malignancies.

In a preferred embodiment, the invention provides a pharmaceutical composition comprising an anti-CD20 antibody and a Bruton's tyrosine kinase (BTK) inhibitor, wherein the anti-CD20 anti-system is selected from the group consisting of: Toximab, opinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, And fragments, derivatives, conjugates, variants thereof, radioisotope-labeled complexes and biomolecules; and wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, wherein: X is CH, N, O or S; Y is C(R ₆ ), N, O or S; Z is CH, N or a bond; A is CH or N; B ₁ is N or C(R ₇ ); B ₂ is N or C(R ₈ ); B ₃ is N or C(R ₉ ); B ₄ is N or C(R ₁₀ ); R ₁ is R ₁₁ C(=O), R ₁₂ S(=O), R ₁₃ S(=O) ₂ or (C _1-6 )alkyl optionally substituted by R ₁₄ ; R ₂ is H, (C _1-3 )alkyl or (C _3-7 )cycloalkyl; R ₃ is H, (C _1-6 )alkyl or (C _3-7 )cycloalkyl); R ₂ and R ₃ together with the N and C atoms to which they are attached form a (C _3-7 )heterocycloalkyl group optionally substituted with one or more fluorine, hydroxy, (C _1-3 )alkyl, (C _1-3 ) alkoxy or pendant oxy group; R ₄ is H or (C _1-3 )alkyl; R ₅ is H, halogen, cyano, (C _1-4 )alkyl, (C _{1- 3} ) alkoxy, (C _3-6 )cycloalkyl, any of which is optionally substituted by one or more halogens; or R ₅ is (C _6-10 )aryl or (C _2-6 a heterocycloalkyl group; R ₆ is H or (C _1-3 )alkyl; or R ₅ together with R ₆ may form (C _3-7 )cycloalkenyl or (C _2-6 )heterocyclenyl, each of these are optionally substituted by (C _1-3) alkyl or substituted with one or more halo; R ₇ H, halogen, CF _3, (C _1-3) alkyl or (C _1-3) alkoxy; R ₈ is H, halogen, CF _3, (C _1-3) alkyl or (C _1-3 Alkoxy; or R ₇ and R ₈ together with the carbon atom to which they are attached form a (C _6-10 ) aryl or (C _1-9 )heteroaryl; R ₉ is H, halo, (C _{1- 3} ) alkyl or (C _1-3 ) alkoxy; R ₁₀ is H, halogen, (C _1-3 ) alkyl or (C _1-3 ) alkoxy; R _{11 is} independently selected from the group consisting of Group of: (C _1-6 )alkyl, (C _2-6 )alkenyl and (C _2-6 )alkynyl, wherein each alkyl, alkenyl or alkynyl group is optionally selected from one or more Substituted by the following group: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 ) Alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl, and (C _3-7 )heterocycloalkyl; or R ₁₁ Is (C _1-3 )alkyl-C(O)-S-(C _1-3 )alkyl; or R ₁₁ is (C _1-5 )heteroaryl optionally substituted by one or more selected from Substituted as a group consisting of: halogen and cyano; R ₁₂ and R _{13 are} independently selected from the group consisting of (C _2-6 )alkenyl or (C _2-6 )alkynyl, alkenyl And alkynyl optionally passed one or One selected from the group consisting of substituents: hydroxy, (C _1-4) alkyl, (C _3-7) cycloalkyl, [(C _1-4) alkyl] amino, di [(C _{1 -4} )alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl and (C _3-7 )heterocycloalkyl; Or (C _1-5 )heteroaryl, optionally substituted by one or more groups selected from the group consisting of halogen and cyano; and R _{14 are} independently selected from the group consisting of halogen a cyano group, a (C _2-6 )alkenyl group and a (C _2-6 )alkynyl group optionally substituted by one or more groups selected from the group consisting of hydroxyl groups, (C _{1 -4} ) alkyl, (C _3-7 )cycloalkyl, (C _1-4 )alkylamino, bis[(C _1-4 )alkyl]amino, (C _1-3 ) alkoxy (C _3-7 )cycloalkoxy, (C _6-10 )aryl, (C _1-5 )heteroaryl and (C _3-7 )heterocycloalkyl.

In a preferred embodiment, the invention provides a pharmaceutical composition comprising an anti-CD20 antibody and a Bruton's tyrosine kinase (BTK) inhibitor, wherein the anti-CD20 anti-system is selected from the group consisting of: Topximab, octopuzumab, ovalimumab, vitolizumab, tocilizumab, isobemozumab, and fragments, derivatives, conjugates, variants thereof , radioisotope-labeled complexes and biomolecules, of which BTK inhibitors: Or a pharmaceutically acceptable salt, co-crystal, solvate or hydrate thereof.

In a preferred embodiment, the invention provides a pharmaceutical composition comprising an amount of anti-CD20 antibody between 25 mg and 2000 mg and an amount of BTK inhibitor between 5 mg and 500 mg.

In a preferred embodiment, the invention provides a pharmaceutical composition comprising an amount of BTK inhibitor between 25 mg and 125 mg.

In a preferred embodiment, the present invention provides a composition comprising A pharmaceutical composition of the group consisting of BTK inhibitors of the following composition: 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 Mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg and 500 mg.

6. The composition according to any one of claims 1 to 5, which comprises an anti-CD20 antibody amount selected from the group consisting of 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg And 2000 mg.

The composition according to any one of claims 1 to 6, further comprising an anticoagulant or an antiplatelet agent, wherein the anticoagulant or antiplatelet agent is selected from the group consisting of: Clopidogrel, prasugrel, ticagrelor, ticlopidine, warfarin, acenocoumarol, dicoumarol ( Dicumarol), phenprocoumon, heparin, low molecular weight heparin, fondaparinux and idapainux.

The composition according to any one of claims 1 to 7, which further comprises at least one pharmaceutically acceptable excipient.

In one embodiment, the invention includes a method of treating CLL and/or SLL comprising the step of orally administering a Bruton's tyrosine kinase (BTK) inhibitor to a human in need thereof, wherein the BTK inhibitor (S)-4-(8-Amino-3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridin 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof.

In one embodiment, the invention includes a method of treating CLL and/or SLL comprising the step of orally administering a Luton's tyrosine kinase (BTK) inhibitor to a human in need thereof, wherein the BTK inhibitor (S)-4-(8-Amino-3-(1-(but-2-yl)pyrrolidin-2-yl)imidazo[1,5-a]pyridin 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, wherein the BTK inhibitor is selected from the group consisting of The doses of the group formed were administered once a day: 100 mg, 175 mg, 250 mg, and 400 mg.

In one embodiment, the invention includes a method of treating CLL and/or SLL comprising the step of orally administering a Bruton's tyrosine kinase (BTK) inhibitor to a human in need thereof, wherein the BTK inhibitor (S)-4-(8-Amino-3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridin 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, wherein the BTK inhibitor is 100 mg The dose is administered twice daily.

In one embodiment, the invention includes a method of treating CLL and/or SLL comprising the step of orally administering a Bruton's tyrosine kinase (BTK) inhibitor to a human in need thereof, wherein the BTK inhibitor (S)-4-(8-Amino-3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridin a -1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, wherein a section of the formula (II) is treated After the period, CLL increases mononuclear and NK cells in the peripheral blood, which is selected from the group consisting of: about 14 days, about 28 days, and about 56 days.

In one embodiment, the invention includes a method of treating CLL and/or SLL comprising the step of orally administering a Bruton's tyrosine kinase (BTK) inhibitor to a human in need thereof, wherein the BTK inhibitor (S)-4-(8-Amino-3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridin a -1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, eutectic or prodrug thereof, wherein the CLL is selected from the group consisting of Group: IgV _H mutation-negative CLL, ZAP-70-positive CLL, CLL via ZAP-70 methylation in CpG3, CD38-positive CLL, CLL with 17p13.1 (17p) deletion, with 11q22.3 (11q) deletion CLL, CLL in people who are susceptible to platelet-mediated thrombosis, CLL in people who are suffering from thrombocytosis, CLL in people who have thrombocytosis of platelet vectors, and combinations thereof.

In one embodiment, the invention includes a method of treating CLL and/or SLL comprising the step of orally administering a Bruton's tyrosine kinase (BTK) inhibitor to a human in need thereof, wherein the BTK inhibitor (S)-4-(8-Amino-3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridin a -1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, the method further comprising administering a therapeutically effective dose Steps of an anti-CD20 antibody selected from the group consisting of rituximab, octetuzumab, ovalimumab, vitolizumab, tocilizumab, isobemo Anti-, and their fragments, derivatives, conjugates, variants, radioisotope-labeled complexes and biomolecules.

In one embodiment, the invention includes a method of treating CLL and/or SLL comprising the step of orally administering a Bruton's tyrosine kinase (BTK) inhibitor to a human in need thereof, wherein the BTK inhibitor (S)-4-(8-Amino-3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridin a -1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, the method further comprising administering a therapeutically effective dose The step of anti-coagulant activity or anti-platelet activity of the pharmaceutical ingredient.

In one embodiment, the invention includes a method of treating CLL and/or SLL comprising the step of orally administering a Bruton's tyrosine kinase (BTK) inhibitor to a human in need thereof, wherein the BTK inhibitor (S)-4-(8-Amino-3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridin a -1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, the method further comprising administering a therapeutically effective dose a step of anti-coagulant activity or anti-platelet activity of a pharmaceutical ingredient, wherein the anti-coagulant activity or the anti-platelet activity of the pharmaceutical ingredient is selected from the group consisting of acenocoumarol, anagrelide, Anagrelide hydrochloride, abciximab, alooxiprin, antithrombin, apixaban, argatroban, aspirin, aspirin With extended release dipyridamole, beraprost, betrixaban, bivalirudin, carbasalate calcium, cilostazol ), clopidogrel, clopidogrel hydrogen sulphate, cloricromen, dabigatran etexilate, darexaban, dalteparin, dalteparin, go Defiboride, dicoumarin, diphenadione, dipyridamole , ditazole, desirudin, edoxaban, enoxaparin, enoxaparin sodium, eptifibatide, fondaparinux, fondaparin Heparin sodium, heparin, heparin sodium, heparin calcium, idaparin, idaparin sodium, iloprost, indobufen, lepirudin, low molecular weight heparin, melagatran (melagatran), nadroparin, otamixaban, parnaparin, phenindione, phenylpropanoid, prasugrel, picotamide , prostacyclin, ramatroban, reviparin, rivaroxaban, sulodexide, terutroban, Truro Banan, ticagrelor, ticlopidine, ticlopidine hydrochloride, tinzaparin, tinzaparin sodium, tirofiban, tirofiban hydrochloride, trod Treprostinil, trifluralin, triflusal, vorapaxar, warfarin, warfarin, North American group (ximelagatran), of their salts, solvates, hydrates and various combinations of the above.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl a 1-methyl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is selected from the group consisting of Group consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodge Gold's lymphoma, B-cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenström's macroglobulinemia (WM), Burkitt Lymphoma, multiple myeloma, and spinal fibrosis.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl a 1-methyl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is selected from the group consisting of Groups consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymph Tumor, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma and Spinal fibrosis, wherein the BTK inhibitor is administered once daily at a dose selected from the group consisting of 100 mg, 175 mg, 250 mg, and 400 mg.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl a 1-methyl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is selected from the group consisting of Groups consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymph Tumor, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma and Spinal fibrosis, in which BTK inhibitors are administered twice daily at a dose of 100 mg.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl a 1-methyl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is selected from the group consisting of Groups consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymph Tumor, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma and Spinal fibrosis, wherein after a period of treatment with formula (II), hematological malignant disease increases mononuclear and NK cells in the peripheral blood, the period selected from the group consisting of: about 14 days, about 28 days, and About 56 days.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is non-Hodge Gold's lymphoma (NHL), wherein the NHL is selected from the group consisting of painless NHL and invasive NHL.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is diffuse large B-cell lymphoma (DLBCL), wherein the DLBCL line is selected from the group consisting of activated B-cell diffuse large B-cell lymphoma (DLBCL-ABC) and germline center B-cell diffuse large B-cell lymphoid Tumor (DLBCL-GCB).

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is a set of cell lymphocytes Tumor (MCL), wherein the MCL line is selected from the group consisting of the outer layer MCL, the nodular MCL, the diffuse MCL, and the maternal MCL.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is B cell acute Lymphocytic leukemia (B-ALL), wherein the B-ALL is selected from the group consisting of early pre-B-cell B-ALL, pre-B-cell B-ALL, and mature B-cell B-ALL.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is Burkitt Lymphoma, wherein the Burkitt's lymphoma is selected from the group consisting of sporadic Burkitt's lymphoma, regional Burkitt's lymphoma, and human immunodeficiency virus-associated Burkitt's lymph tumor.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is multiple bone marrow Tumor, wherein the multiple myeloma is selected from the group consisting of hyperdiploid multiple myeloma and non-hyperploid multiple myeloma.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is spinal fibrosis , wherein the spinal fibrosis is selected from the group consisting of primary spinal fibrosis, spinal fibrosis secondary to erythrocytosis, and spinal fibrosis secondary to cost-effective thrombocytosis.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl a 1-methyl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is selected from the group consisting of Groups consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymph Tumor, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma and For spinal fibrosis, the method further comprises the step of administering a therapeutically effective amount of an anti-CD20 antibody selected from the group consisting of rituximab, octopuzumab, oxazumab, vitopa Monoclonal antibodies, tocilizumab, isobezumab, and fragments, derivatives, conjugates, variants thereof, radioisotope-labeled complexes, and biomolecules.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl a 1-methyl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is selected from the group consisting of Groups consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymph Tumor, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma and Spinal fibrosis, the method further comprising the step of administering a therapeutically effective amount of an anticoagulant or anti-platelet active pharmaceutical ingredient.

In one embodiment, the invention includes a method of treating a hematological malignancy in a human comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-amino- 3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridyl a 1-methyl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, and wherein the blood malignant disease is selected from the group consisting of Groups consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymph Tumor, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma and For spinal fibrosis, the method further comprises the step of administering a therapeutically effective amount of a pharmaceutical component of anticoagulant activity or antiplatelet activity, wherein the pharmaceutical component of anticoagulant activity or antiplatelet activity is selected from the group consisting of: Vinegar acetophenone, anagrelide, anagrelide hydrochloride, abciximab, aloprostat, antithrombin, apixaban, argatroban, aspirin, aspirin and extended release Pyridamo, beraprost, betrixaban, bivalirudin, kababulin calcium, cilostazol, chlorine Pyridoxine, clopidogrel hydrogen sulphate, clopidogrel, dabigatran etexilate, darsone, dalteparin, dalteparin, defibrin, dicoumarin, dibenzophenone, dipyridamole Mo, diltiazem, diazepam, etoxaban, enoxaparin, enoxaparin sodium, eptifibatide, fondaparinux, fondaparinux, heparin, heparin sodium, heparin calcium, idaparin, Itaparin sodium, iloprost, indobufen, lepirudine, low molecular weight heparin, melagatran, nadroparin, omeproxaban, paparin, benzodiazepine, phenylpropanol , prasugrel, pyridoxamine, prostacyclin, rema plaque, remiparin, rivaroxaban, sulodex, truroban, trubalban, tigrelar, ticlopidine Diazepam, ticlopidine hydrochloride, tinzaparin, tinzaparin sodium, tirofiban, tirofiban hydrochloride, trironil, trifluralin sodium, trifluoro-willow, flara Pasha, warfarin, warfarin sodium, ximeltide, their salts, their solvates and their hydrates, and various combinations thereof.

The foregoing summary of the invention, as well as the following detailed description

Figure 1 illustrates the in vivo efficacy of formula (II) (labeled with the 〝BTK inhibitor 〞) and ibuprotinib. Mice were sacrificed by increasing the drug concentration in tube feeding and at one time point (3 hours after dosing). The BCR to stimulate IgM, and the activation markers CD69 and CD86 expression in flow cytometry-based monitoring, to determine the value of ₅₀ EC. The results show that formula (II) is more effective at inhibiting the activation of the marker than ibunotetin.

Figure 2 illustrates the in vivo efficacy of Formula (II), Ibbutinib, and CC-292 in suppressing signals passing through B cell receptors in whole blood.

Figure 3 illustrates EGF receptor phosphorylation in vitro in formula (II) and Ibubinib.

Figure 4 illustrates the results of a clinical study of Formula (II) (labeled with the 〝BTK inhibitor 〞) in CLL and SLL patients, which is shown in JC Byrd et al., N. Engl. J. Med. 2013, 369, A comparison of the results of Ibubinib reported in Figure 1A of 32-42. The result shows BTK of formula (II) The inhibitor caused a decrease in the absolute number of lymphocytes (ALC) relative to the BTK inhibitor ibupotinib and a decrease in the absolute number of lymphocytes (ALC) relative to the BTK inhibitor ibufenib. The sum of products (SPD) of the largest diameter during treatment with BTK inhibitors also decreased more rapidly than with the BTK inhibitor, ibufibrate.

Figure 5 shows the total response data as a function of the BTK inhibitor dose of formula (II) for SPD of enlarged lymph nodes in CLL and SLL patients.

Figure 6 shows a comparison of progression-free survival (PFS) in CLL and SLL patients treated with the BTK inhibitor, ibutinib or a BTK inhibitor of formula (II). Ibbutinib data is taken from J. C. Byrd et al., N. Engl. J. Med. 2013, 369, 32-42. Includes CLL and SLL patients treated with formula (II) for at least 8 days.

Figure 7 shows a comparison of the number of patients at risk for CLL and SLL patients treated with the BTK inhibitor, ibutinib or a BTK inhibitor of formula (II). Includes CLL and SLL patients treated with formula (II) for at least 8 days.

Figure 8 shows a comparison of progression-free survival (PFS) in CLL and SLL patients exhibiting 17p deletion and treatment with the BTK inhibitor, ibupotinib or a BTK inhibitor of formula (II). Ibbutinib data is taken from J. C. Byrd et al., N. Engl. J. Med. 2013, 369, 32-42.

Figure 9 shows a comparison of the number of patients at risk for patients with CLL and SLL who exhibit a 17p deletion and are treated with the BTK inhibitor, ibupotinib or a BTK inhibitor of formula (II). Ibbutinib data was taken from J.C. Byrd et al., N. Engl. J. Med. 2013, 369, 32-42. Includes CLL patients treated with formula (II) for at least 8 days.

Figure 10 shows the improved BTK target occupancy in patients with relapsed/refractory CLL and SLL with lower doses of formula (II) relative to ibbutinib.

Figure 11 is a graph showing the % change in ALC of the bone marrow-derived suppressor cells (MDSC) (monuclear sphere) values over 28 days versus cycle 1, day 28 (C1D28).

Figure 12 shows the ALC change % of the MDSC (mononuclear sphere) value over the 28-day change versus the cycle 2, day 28 (C2D28) as a trend line.

Figure 13 is a graph showing the % change in ALC of natural killer (NK) cell values over 28 days versus cycle 1, day 28 (C1D28).

Figure 14 shows the % change in ALC of the NK cell value over 28 days versus the cycle 2, day 28 (C2D28) as a trend line.

Figure 15 shows the % change in MDSC (monuclear sphere) value over 28 days and the % change in NK cell value over 28 days versus cycle 1, on day 28 (C1D28), ALC change % versus CD4 ⁺ T cell value, CD8 ⁺ T cell value, CD4 ⁺ /CD8 ⁺ T cell ratio, NK-T cell value, PD-1 ⁺ CD4 ⁺ T cell value, and % change of PD-1 ⁺ CD8 ⁺ T cell value were also relative to cycle 1, day 28 ( Comparison of % ALC change of C1D28). The trend line is shown by % change in MDSC (mononuclear sphere) value and % change in NK cell value.

Figure 16 shows the % change in MDSC (monuclear sphere) value over 28 days and the % change in NK cell value over 28 days versus period 2, on day 28 (C2D28), ALC change % and CD4 ⁺ T cell value, CD8 ⁺ T cell value, CD4 ⁺ /CD8 ⁺ T cell ratio, NK-T cell value, PD-1 ⁺ CD4 ⁺ T cell value, and % change of PD-1 ⁺ CD8 ⁺ T cell value were also relative to cycle 2, day 28 ( Comparison of % ALC change of C2D28). The trend line is shown by % change in MDSC (mononuclear sphere) value and % change in NK cell value.

Figure 17 shows an update of the data presented in Figure 4.

Figure 18 shows an update of the data presented in Figure 10 and includes BID dosing results.

Figure 19 illustrates PFS in patients with 11p deletion.

Figure 20 illustrates PFS throughout a relapsed/refractory patient with a 11p deletion and a 17q deletion without an 11p deletion.

Figure 21 illustrates PFS in patients with 17q deletion without 11p deletion.

Figure 22 illustrates updated SPD results for a clinical study of formula (II) in relapsed/refractory CLL and SLL patients (N=58).

Figure 23 illustrates that CLL and SLL patients treated with formula (II) cause an increase in apoptosis.

Figure 24 illustrates the observed decrease in CXCL12 values in patients treated with formula (II).

Figure 25 illustrates the observed decrease in CCL2 values in patients treated with formula (II).

Figure 26 illustrates laser-injured wounds of VWF HA1 mutant mice perfused with human platelets in the absence or presence of various BTK inhibitors. Representative photomicrographs and comparisons of the largest thrombus size in the small arteries. Representative micrographs are given as a comparison of the maximum thrombus size in the small arteries that were injured by laser (shown as a 1 [mu]M concentration).

Figure 27 illustrates quantitative comparisons obtained by in vivo analysis of early thrombus kinetics using a 1 [mu]M concentration of three BTK inhibitors in a humanized mouse laser injury mode.

Figure 28 illustrates the effect of the tested BTK inhibitor on thrombosis. The conditions used were N=4, 3 mice per drug; anticoagulant <2000 μM ² . In the study with ibufibrate, 48% of MCL bleeding events were observed with 560 mg QD and 63% of CLL bleeding events were observed with 420 mg QD, which were defined as subdural hematoma, ecchymosis, GI bleeding or hematuria.

Figure 29 illustrates the effect of the concentration of the tested BTK inhibitor on thrombosis.

Figure 30 illustrates the results of platelet aggregation of platelet collagen receptor glycoprotein VI (GPVI) platelets of formula (II) (IC ₅₀ = 1.15 μM) and Ibubinib (IC ₅₀ = 0.13 μM).

Figure 31 illustrates the results of a GPVI platelet aggregation study of Formula (II) and Ibubinib.

Figure 32 shows in vitro analysis of antibody-dependent NK cell-mediated INF-γ release with BTK inhibitors. To assess NK cell function, purified NK cells were isolated from healthy peripheral blood mononuclear cells and treated with rituximab-coated (10 μg/ml) lymphoma cells, DHL4 or trastuzumab (trastuzumab)-coating (10 μg/ ML) of HER2+ breast cancer cells, HER18 were incubated with 0.1 or 1 μM of ibufenib or 1 μM of formula (II) for 4 hours, and the supernatant was collected and analyzed by enzyme-linked immunosorbent assay for interferon-gamma (IFN- γ). All in vitro experiments were repeated three times. The labels are defined as follows: *p=0.018, **p=0.002, ***p=0.001.

Figure 33 shows in vitro analysis of antibody-dependent NK cell media degranulation with BTK inhibitors. To assess NK cell function, purified NK cells were isolated from healthy peripheral blood mononuclear cells and treated with rituximab-coated (10 μg/ml) lymphoma cells, DHL4 or trastuzumab - Coating (10 μg/ml) of HER2+ breast cancer cells, HER18 was incubated with 0.1 or 1 μM of ibutinib or 1 μM of formula (II) for 4 hours, and NK cells were isolated and analyzed by flow cytometry for movement with CD107a Degranulate. All in vitro experiments were repeated three times. The labels are defined as follows: *p=0.01, **p=0.002, ***p=0.003, ****p=0.0005.

Figure 34 shows that ibbutinib antagonizes antibody-dependent NK cell cytotoxicity using Raji cell lines. NK cytotoxicity as a percentage of tumor cell lysis was analyzed in a chromium release assay to purify NK cells at different concentrations of rituximab with a fixed 25:1 effector: target ratio and Ibupro Nie (1 μM), formula (II) (1 μM) or other ITK-protected BTK inhibitors CGI-1746, inhibA (1 μM) and BGB-3111 (〝inhib B〞, 1 μM) were incubated with chromium-labeled Raji for 4 hours. All in vitro experiments were repeated three times. The label is defined as follows: *p=0.001.

Figure 35 shows a summary of the results given in Figure 34 at the highest concentration of rituximab (〝Ab〞) (10 μg/ml).

Figure 36 shows that Ibbutinib antagonizes antibody-dependent NK cell-mediated cytotoxicity in primary CLL cells, as in Figure 34 of Raji cells.

Figure 37 shows after 4 hours of stimulation of whole blood with BTK inhibitor for 1 hour and with 1 μg/ml of oxifizumab and cetuximab opsonized MEC-1 cells, The results of NK cell degranulation/ADCC assays from normal donor whole blood were used (n=3).

Figure 38 shows the BTK inhibitory effect on cytotoxicity by systemic NK cell media.

Figure 39 shows that Formula (II) has no adverse effects on T helper 17 (Th17) cells, which are a subset of T helper cells that produce interleukin 17 (IL17), while Ibubinib strongly inhibits Th17 cells.

Figure 40 shows that Formula (II) has no effect on the development of regulatory T cells (Treg), while Ibubinib strongly increases Treg development.

Figure 41 shows that formula (II) has no effect on CD8 ⁺ T cell viability development, while ibbutinib strongly affects CD8 ⁺ T cell viability at higher doses.

a brief description of the sequence listing

SEQ ID NO: 1 is the heavy chain amino acid sequence of the anti-CD20 monoclonal antibody rituximab.

SEQ ID NO: 2 is the light chain amino acid sequence of the anti-CD20 monoclonal antibody rituximab.

SEQ ID NO: 3 is the heavy chain amino acid sequence of the anti-CD20 monoclonal antibody oxifizumab.

SEQ ID NO: 4 is the light chain amino acid sequence of the anti-CD20 monoclonal antibody oxifizumab.

SEQ ID NO: 5 is the variable heavy chain amino acid sequence of the anti-CD20 monoclonal antibody ovalimumab.

SEQ ID NO: 6 is the variable light chain amino acid sequence of the anti-CD20 monoclonal antibody ovalimumab.

SEQ ID NO: 7 is the Fab fragment heavy chain amino acid sequence of the anti-CD20 monoclonal antibody ovalimumab.

SEQ ID NO: 8 is the Fab fragment light chain amino acid sequence of the anti-CD20 monoclonal antibody ovalimumab.

SEQ ID NO: 9 is the heavy chain amino acid sequence of the anti-CD20 monoclonal antibody vitolizumab.

SEQ ID NO: 10 is the light chain amino acid sequence of the anti-CD20 monoclonal antibody vitolizumab.

SEQ ID NO: 11 is the heavy chain amino acid sequence of the anti-CD20 monoclonal antibody tocilizumab.

SEQ ID NO: 12 is the light chain amino acid sequence of the anti-CD20 monoclonal antibody tocilizumab.

SEQ ID NO: 13 is the heavy chain amino acid sequence of the anti-CD20 monoclonal antibody isobezumab.

SEQ ID NO: 14 is the light chain amino acid sequence of the anti-CD20 monoclonal antibody isobezumab.

Detailed description of the invention

While the preferred embodiment of the present invention has been shown and described, the embodiments of the present invention are not intended to limit the scope of the invention. The invention may be practiced in various alternative ways of carrying out the embodiments described herein.

All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art of the invention, unless otherwise defined.

The term "co-administered" and "in combination with", as used herein, includes administration of two or more active pharmaceutical ingredients to an individual such that the two agents and/or their metabolites are identical. Time exists in the individual. Co-administration includes administration of separate compositions at the same time, administration at separate compositions at different times, or compositions in which two agents are present.

The term "in vivo" refers to an event that occurs in an individual's body.

The term "intra-tube" refers to an event that occurs outside the body of an individual. In-vitro assays include cell-based assays in which live or dead cells are used and may also include cell-free assays in which incomplete cells are used. set.

The term 〝IC ₅₀ 〞 refers to the maximum inhibitory concentration of half, that is, the inhibition of 50% of the desired activity. The term 〝EC ₅₀ 〞 refers to the concentration of a drug that achieves half of the maximum response.

The term "effective amount" or "therapeutically effective amount" refers to an amount of the active pharmaceutical ingredient as described herein or a combination of active pharmaceutical ingredients sufficient to achieve the desired application, including but not limited to disease treatment. The therapeutically effective amount depends on the intended application (in vitro or in vivo) or the individual being treated and the condition of the disease (eg, the individual's weight, age, and sex), the severity of the condition, the mode of administration, and may be familiar to those skilled in the art. Change by other factors that are easily determined. The term also applies to doses that elicit a particular response in a target cell (eg, to reduce platelet adhesion and/or cell migration). The dosage will vary depending on the particular compound selected, the administration regimen followed, whether the compound is administered in combination with other compounds, the time course of administration, the tissue to be administered, and the physical delivery system in which the compound is administered.

The term "therapeutic effect" as used herein encompasses therapeutic and/or prophylactic benefits as described above. Prophylactic effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of a disease or condition, slowing, halting or reversing the progression of the disease or condition, or any combination of these.

The term 〝QD〞, 〝qd〞 or 〝q.d.〞 means once a day, once a day or once a day. The term 〝BID〞, 〝bid〞 or 〝b.i.d.〞 means twice daily, twice a day or twice a day. The term 〝TID〞, 〝tid〞 or 〝t.i.d.〞 means three times a day, three times a day or Three times a day. The term 〝QID〞, 〝qid〞 or 〝q.i.d.〞 means four times a day, four times a day or four times a day.

The term "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. The organic acid includes, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid. Methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases. Inorganic bases include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In selected embodiments, the pharmaceutically acceptable base addition salt is selected from the group consisting of ammonium, potassium, sodium, calcium and magnesium salts. The term "eutectic lanthanide" refers to a molecular complex derived from a number of co-crystal formers known in the art. Unlike salts, eutectics generally do not involve proton transfer between the eutectic and the drug, but rather involve intermolecular interactions between the eutectic and the drug in the crystal structure, such as hydrogen bonding, aromatic ring stacking or Dispersive power.

The pharmaceutically acceptable carrier, or pharmaceutically acceptable excipient, is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. Active medicine Such media and agents of the ingredients are well known in the art. The use of such media and agents in the therapeutic compositions of the present invention is encompassed by any of the conventional media and agents that are incompatible with the active pharmaceutical ingredients. Supplementary active pharmaceutical ingredients can also be incorporated into the compositions described.

Prodrugs are intended to account for substances which convert to the biologically active pharmaceutical ingredients described herein under physiological conditions or by solvolysis. Thus, the term pro-drug prodrug refers to a precursor of a pharmaceutically acceptable biologically active compound. Prodrugs may be inactive when administered to an individual, but are converted to active pharmaceutical ingredients in vivo, for example by hydrolysis. Prodrug compounds often provide the advantage of solubility, histocompatibility or delayed release in mammals (see, for example, H. Bundgaard, Design of Prodrugs, Elsevier, Amsterdam (1985)). The term "prodrug" is also intended to include any covalently bonded carrier which releases the active pharmaceutical ingredient in vivo when administered to an individual. Prodrugs of the active pharmaceutical ingredients as described herein can be prepared by modifying the functional groups present in the active pharmaceutical ingredient in such a manner that the modifications are cleaved by conventional procedures or in vivo to yield the active pharmaceutical ingredient. Prodrugs include, for example, compounds in which a hydroxy, amine or sulfhydryl group is bonded to any group. When a prodrug of an active pharmaceutical ingredient is administered to a mammalian subject, the bond cleaves to form a free hydroxyl group, a free amine group or a free sulfhydryl group, respectively. . Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols in active pharmaceutical ingredients, various ester derivatives of carboxylic acids, or amine amines of amidine functional groups, formazan. Amine and benzamide derivatives.

When used herein to describe, for example, physical or chemical properties, such as molecular weight or chemical formula, it is intended to be encompassed within the scope and All combinations and sub-combinations within the application. When a numerical or numerical range is recited, the use of the term "about" means that the numerical or numerical range recited is an approximation of the range of experimental variability (or within the range of statistical experimental error), and thus may vary the number or The range of numbers is, for example, between 1% and 15% of the range of numbers or numbers. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including" includes those embodiments, such as Consistt of "consist of" or "consist essentially" of any composition of matter, method, or process of said characteristic.

The fluorenylalkyl group means a linear or branched hydrocarbon group (for example, a C ₁ -C ₁₀ alkyl group) having only from carbon and hydrogen atoms and having no unsaturated and having from 1 to 10 carbon atoms. Whenever it appears herein, a numerical range (such as 〝1 to 10〞) means every integer within a given range, for example 〝1 to 10 carbon atoms 〞 means that the alkyl group can be 1 carbon atom, 2 The carbon atom, the three carbon atoms, and the like up to and including 10 carbon atoms, although the definition is also intended to cover the term "indenyl" which does not explicitly dictate the numerical range. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, isobutyl, tert-butyl, pentyl, Isoamyl, neopentyl, hexyl, heptyl, octyl, decyl and decyl. The alkyl moiety can be attached to the remainder of the molecule by a single bond, such as methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl , n-pentyl, 1,1-dimethylethyl (t-butyl) and 3-methylhexyl. Unless otherwise specifically stated in the specification, an alkyl group is optionally substituted with one or more of the following substituents independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N (R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, Alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

〝alkylaryl 〞 refers to -(alkyl)aryl, wherein aryl and alkyl are as disclosed herein, and are optionally subjected to one of the substituents respectively suitable for the aryl group and the alkyl group or Replaced by many.

A nonylheteroaryl hydrazone refers to an -(alkyl)heteroaryl group, wherein the heteroaryl and alkyl are as disclosed herein, and which are optionally employed in the substituents appropriate for the aryl and alkyl groups, respectively. Replaced by one or more.

A nonylheterocycloalkylalkyl group is an -(alkyl)heterocyclyl group wherein alkyl and heterocycloalkyl are as disclosed herein, and which are optionally employed as described above for heterocycloalkyl and alkyl groups, respectively. One or more of the substituents are substituted.

The oxime olefin moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and the decyne oxime moiety is composed of at least two carbon atoms and at least one carbon-carbon bond. Group. alkyl Part (whether saturated or unsaturated) may be branched, straight or cyclic.

The decyl oxime refers to a linear or branched hydrocarbon group (i.e., C ₂ -C ₁₀ alkenyl) which consists of only carbon and hydrogen atoms, contains at least one double bond, and has from 2 to 10 carbon atoms. Whenever it appears herein, the numerical range (such as 〝2 to 10〞) refers to each integer within a given range, for example 〝2 to 10 carbon atoms 〞 means that the alkenyl group can be 2 carbon atoms, 3 The carbon atoms are up to and including up to 10 carbon atoms. The alkenyl moiety can be attached to the remainder of the molecule by a single bond, such as a vinyl group (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pentane 1-enyl and pentane-1,4-dienyl. Unless otherwise specifically stated in the specification, alkenyl is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl. , aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N( R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkane A fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl group.

Terpene-cycloalkylfluorenyl refers to -(alkenyl)cycloalkyl, wherein alkenyl and cycloalkyl are as disclosed herein, and are optionally adapted as described above Substituting one or more of the substituents of the alkenyl group and the cycloalkyl group.

The decynyl fluorene means a linear or branched hydrocarbon group (i.e., a C ₂ -C ₁₀ alkynyl group) having only at least one reference bond and having from 2 to 10 carbon atoms consisting of only carbon and hydrogen atoms. Whenever it appears herein, the numerical range (such as 〝2 to 10〞) refers to each integer within a given range, for example 〝2 to 10 carbon atoms 〞 means that the alkynyl group can be 2 carbon atoms, 3 The carbon atoms are up to and including up to 10 carbon atoms. An alkynyl group can be attached to the remainder of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless otherwise specifically stated in the specification, an alkynyl group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl. , aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N( R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkane A fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl group.

〝 alkynyl-cycloalkyl hydrazine refers to -(alkynyl)cycloalkyl, wherein alkynyl and cycloalkyl are as disclosed herein, and are optionally substituted by the substituents described above for alkynyl and cycloalkyl, respectively. One or more of the bases are replaced.

〝Formaldehyde oxime refers to the -(C=O)H group.

〝Carboxylium refers to the -(C=O)OH group.

Indole cyano is a -CN group.

Anthracenylcycloindole refers to a monocyclic or polycyclic group containing only carbon and hydrogen and which may be saturated or partially unsaturated. The cycloalkyl group includes a group having from 3 to 10 ring atoms (that is, a C ₂ -C ₁₀ cycloalkyl group). Whenever it appears herein, a numerical range (such as 〝3 to 10〞) means every integer within a given range, for example 〝3 to 10 carbon atoms 〞 means that the cycloalkyl group can be from 3 carbon atoms up to It consists of 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl, Cyclodecyl, thiol and the like. Unless otherwise specifically stated in the specification, a cycloalkyl group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkane , aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N _{^{(R a) 2, N (}} R a) C (NR a) N (R a) 2, -N (R a) S (O) t R a ( where t is 1 or 2), - S (O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, Alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

An anthracenecycloalkyl-alkenyl group is a -(cycloalkyl)alkenyl group, wherein a cycloalkyl group and an alkenyl group are as disclosed herein, and optionally substituted by the substituents described above for cycloalkyl and alkenyl groups, respectively. One or more of the bases are replaced.

〝Cycloalkyl-heterocycloalkyl hydrazine refers to -(cycloalkyl)heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are as disclosed herein, and are optionally adapted to naphthenic One or more of the substituents of the group and the heterocycloalkyl group are substituted.

An anthracenecycloalkyl-heteroaryl hydrazone refers to a -(cycloalkyl)heteroaryl group, wherein cycloalkyl and heteroaryl are as disclosed herein, and are optionally adapted to cycloalkyl and heterocyclic, respectively, as described herein. One or more of the substituents of the aryl group are substituted.

The term "decyloxy" refers to the group -O-alkyl, which is attached to the parent structure via oxygen, including straight, branched or cyclic configurations of from 1 to 8 carbon atoms and combinations thereof. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, and cyclohexyloxy. The fluorene alkoxy alkoxy group means an alkoxy group having 1 to 6 carbon atoms.

The term "substituted alkoxy" refers to an alkoxy group in which an alkyl group is substituted (i.e., -O-(substituted alkyl)). Unless otherwise specifically stated in the specification, the alkyl portion of the alkoxy group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl. ,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane Base, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N( R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C (O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), - S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^a Independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term "decyloxycarbonyl" refers to a radical of the formula (alkoxy)(C=O)- linked via a carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus, a C ₁ -C ₆ alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms which is bonded to a carbonyl linking group via its oxygen. The fluorene alkoxycarbonyl hydrazine refers to an alkoxycarbonyl group in which the alkoxy group is a lower alkoxy group.

The term "substituted alkoxycarbonyl" refers to a group (substituted alkyl)-OC(O)- wherein the group is attached to the parent structure via a carbonyl function. Unless otherwise specifically stated in the specification, the alkyl portion of the alkoxycarbonyl group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkane , heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl矽alkyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N (R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a ) C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S (O) _t oR ^a (wherein t is 1 or 2), - S (O) t N (R a) 2 ( where t is 1 or 2), or PO ₃ (R ^a) _2, wherein each R ^a independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl .

Mercapto group refers to the group (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C ( O)- and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure via a carbonyl function. If the R group is heteroaryl or heterocycloalkyl, the heterocyclic or chain atom contributes to the total number of chains or ring atoms. Unless otherwise specifically stated in the specification, the alkyl, aryl or heteroaryl portion of the indenyl group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitrate , trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a ,- OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a ,- N(R ^a )C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or Heteroarylalkyl.

An oxime oxime refers to an aR(C=O)O- group, wherein 〝R〞 is an alkyl, aryl, heteroaryl, heteroalkyl or heterocycloalkyl group as described herein. If the R group is heteroaryl or heterocycloalkyl, the heterocyclic or chain atom contributes to the total number of chains or ring atoms. Unless otherwise specifically stated in the specification, 醯R〞 of the methoxy group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl ,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane Base, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N( R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C (O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), - S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^a Independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Amidoxime or amidoxime refers to a -N(R ^a ) ₂ group, wherein each R ^{a is} independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aryl Alkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless otherwise specifically stated in the specification. When the -N(R ^a ) ₂ group has two R ^a substituents other than hydrogen, the substituents may be combined with a nitrogen atom to form a 4, 5, 6 or 7 membered ring. For example, -N(R ^a ) _{2 is} intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless otherwise specifically stated in the specification, the amine group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl , aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N( R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkane A fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl group.

The term "substituted amino group" also refers to the N-oxides of the groups -NHR ^d and NR ^d R ^d as described above, respectively. The N-oxide can be prepared by treating the corresponding amine group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

Amidoxime or guanamine oxime refers to a chemical moiety having the formula -C(O)N(R) ₂ or -NHC(O)R, wherein R is selected from the group consisting of hydrogen, alkane The group, the cycloalkyl group, the aryl group, the heteroaryl group (bonded via a ring carbon) and the heteroalicyclic group (bonded via a ring carbon), the parts of which are themselves optionally substituted. The R ₂ of -N(R) ₂ of the indoleamine may optionally form a 4, 5, 6 or 7 membered ring together with the nitrogen to which it is attached. Unless otherwise specified in the specification, the guanamine group is optionally used independently for one or more substituents as described herein for an alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group. Replace. The guanamine can be an amino acid or peptide molecule attached to a compound of formula (I) to form a prodrug. The procedures and specific groups for the manufacture of such guanamines are well known to those skilled in the art and can be readily found in groundbreaking sources such as TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons, New York (1999).

〝Aromatic 〝 or 〝 aryl 〞 or 〝Ar〞 means an aromatic group having 6 to 10 ring atoms (for example, C ₆ -C ₁₀ aromatic or C ₆ -C ₁₀ aryl) having at least one A ring having a conjugated pi electron system which is a carbocyclic ring (e.g., phenyl, anthracenyl, and naphthyl). A divalent group formed from a substituted benzene derivative and having a free valence on a ring atom is designated as a substituted phenyl group. A divalent group derived from a monovalent polycyclic hydrocarbon group terminated by a fluorenyl-yl (-yl) fluorene group by removing a hydrogen atom from a carbon atom having a free valence is a fluorene group (-idene). It is named by adding the name of the corresponding monovalent group, for example, a naphthyl group having two points of attachment is referred to as a naphthylene group. Whenever it appears herein, the numerical range (such as 〝6 to 10〞) refers to each integer within a given range, for example 〝6 to 10 ring atoms 〞 means that the aryl group can be 6 ring atoms, 7 A ring atom is composed up to and including 10 ring atoms. The term includes monocyclic or fused ring polycyclic (ie, a ring that shares an adjacent ring atom pair). Unless otherwise specifically stated in the specification, the aryl moiety is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkane , aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N (R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, Alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

An alkynylalkyl or arylarylalkyl group refers to an (aryl)alkyl- group, wherein the aryl and alkyl groups are as disclosed herein, and are optionally substituted with substituents for the aryl group and the alkyl group, respectively. One or more of the substituents are substituted.

An oxime ester is a chemical group of the formula -COOR wherein the R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (via ring carbon bonding) and heteroalicyclic (via ring carbon bonding). The procedures for making esters and the specific groups are well known to those skilled in the art and can be readily found in groundbreaking sources such as TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons, New. York (1999). Unless otherwise specifically stated in the specification, the ester group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkane , aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N (R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, Alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

A fluoroalkylalkyl group means an alkyl group as defined above substituted with one or more fluoro groups as defined above, for example trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl. Base, 1-fluoromethyl-2-fluoroethyl and the like. The alkyl portion of the fluoroalkyl group can be optionally substituted as defined above for the alkyl group.

The hydrazine hydrazine, the hydrazine halide or the other selected hydrazine halogen is intended to be referred to as fluorine, chlorine, bromine or iodine. The term "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and substituted by one or more halo groups or a combination thereof. Alkoxy structure. For example, the terms fluorinated alkyl fluorene and fluorinated alkoxy fluorene each include a haloalkyl group and a haloalkoxy group in which the halogen group is fluorine.

The deuterated alkyl anthracene, the deuterated alkenyl anthracene, and the alkynyl alkynyl group include an optionally substituted alkyl group, an alkenyl group, and an alkynyl group, and have one or more skeleton chain atoms selected from atoms other than carbon, For example, oxygen, nitrogen, sulfur, phosphorus or a combination thereof. Numerical range may be given, for example, C ₁ -C ₄ heteroalkyl which refers to the total length of the chain, which in this example is 4 atoms in length. Heteroalkyl groups may be substituted by one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl , heteroarylalkyl, hydroxy, halo, cyano, nitro, pendant oxy, thioxoxy, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N (R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S( O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylene Alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Doped alkylaryl hydrazine refers to a -(heteroalkyl)aryl group, wherein heteroalkyl and aryl are as disclosed herein, and are optionally employed as described above for the substituents of heteroalkyl and aryl, respectively. One or more of the substituents are substituted.

Deuterated alkylheteroaryl is a -(heteroalkyl)heteroaryl group, wherein heteroalkyl and heteroaryl are as disclosed herein, and are optionally adapted to heteroalkyl and heteroaryl, respectively. Substituting one or more of the substituents described for the substituent.

Doped alkylheterocycloalkyl hydrazine is a -(heteroalkyl)heterocycloalkyl group, wherein heteroalkyl and heterocycloalkyl are as disclosed herein, and are optionally adapted to heteroalkyl and hetero, respectively. One or more of the substituents described for the substituent of the cycloalkyl group are substituted.

Doped alkylcycloalkyl hydrazine refers to -(heteroalkyl)cycloalkyl, wherein heteroalkyl and cycloalkyl are as disclosed herein, and are optionally adapted to heteroalkyl and cycloalkyl, respectively. Substituting one or more of the substituents described for the substituent.

Heteroaryl hydrazine or doped aromatic hydrazine or hydrazine HetAr 〞 refers to a 5 to 18 membered aromatic group (eg, C ₅ -C ₁₃ heteroaryl), which includes one or more selected from the group consisting of nitrogen, oxygen, and sulfur. Ring heteroatoms and which may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems. Whenever it appears herein, a numerical range (such as 〝5 to 18 〞) refers to each integer within a given range, for example 〝5 to 18 ring atoms 〞 means that the heteroaryl group can be 5 ring atoms, The 6 ring atoms are composed up to and including 18 ring atoms. A divalent group derived from a monovalent heteroaryl group terminated by a fluorenyl-yl (-yl) fluorene by removing a hydrogen atom from an atom having a free valence is added by a fluorene group (-idene) Named in the name of the corresponding monovalent group, for example, a pyridyl group having two points of attachment is referred to as a pyridylene group. The N-containing doped aromatic fluorene or deuterated aryl fluorene moiety refers to an aromatic group in which at least one of the skeleton atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group can be fused or unfused. The heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms, if any, are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule via any atom of the ring. Examples of heteroaryl groups include, but are not limited to, aziridine, acridinyl, benzimidazolyl, benzindenyl, 1,3-benzodioxan, benzofuranyl, benzoxazolyl, benzene And [d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxoheptyl, benzo[b][1,4] Base, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxanyl, benzodioxanyl, benzoxazolyl, benzene And pyranyl, benzopyranone, benzofuranyl, benzofuranone, benzofurazyl, benzothiazolyl, benzothienyl (benzothiophenyl) Benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-α]pyridinyl, oxazolyl, porphyrinyl, cyclopentyl Dienyl[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h Quinazolinyl, 5,6-dihydrobenzo[h]porphyrinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptadieno[1,2-c]indole , dibenzofuranyl, dibenzothiophenyl, furyl, furazyl, furanone, furo[3,2-c]pyridyl, 5,6,7,8,9,10-hexa Hydrocyclooctadieno[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctadieno[d]fluorene ,5,6,7,8,9,10-hexahydrocyclooctadieno[d]pyridyl, isothiazolyl, imidazolyl, oxazolyl, indolyl, carbazolyl, isodecyl , indanyl, isoindoline, isoquinolyl, anthracene Base, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinyl, oxadiazole, 2 - Ketoazinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H -pyrrolyl, brown Thiophene Base Base , pteridinyl, fluorenyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl, pyridine [3,4-d]pyrimidinyl, pyridyl Base, pyrimidinyl, oxime , pyrrolyl, quinazolinyl, quinoxalinyl, quinolyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7 , 8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptadieno[4,5]thieno[ 2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]indole Base, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, tri , thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl and thiophenyl (ie, thienyl) )). Unless otherwise specifically stated in the specification, the heteroaryl moiety is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle. Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, pendant oxy, thioxoxy, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N( R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkane A fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl group.

Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridyl N-oxide.

Doped arylalkyl hydrazine refers to a moiety having an aryl moiety as described herein attached to an alkylene moiety as described herein, wherein the remainder of the molecule is attached via an alkylene group.

〝Heterocycloalkyl hydrazine refers to a stable 3 to 18 membered non-aromatic ring group containing from 2 to 12 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, the numerical range (such as 〝3 to 18〞) refers to each integer within a given range, for example 〝3 to 18 ring atoms 〞 means that the heterocycloalkyl group can be composed of 3 ring atoms. 4 ring atoms, etc. up to and including 18 ring atoms. Unless otherwise specifically stated in the specification, heterocycloalkyl monocyclic, bicyclic, tricyclic or tetracyclic ring systems may include fused or bridged ring systems. The hetero atom in the heterocycloalkyl group can be optionally oxidized. One or more nitrogen atoms, if any, are optionally quaternized. Heterocycloalkyl groups are partially saturated or fully saturated. A heterocycloalkyl group can be attached to the remainder of the molecule via any atom of the ring. Examples of such heterocycloalkyl groups include, but are not limited to, dioxolane, thienyl [1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, Isoxazolidinyl, morpholinyl, octahydroindenyl, octahydroisodecyl, 2-ketopipe Base, 2-ketopiperidinyl, 2-ketopyrrolidinyl, oxazolidinyl, piperidinyl, piperidine Base, 4-piperidinone, pyrrolidinyl, pyrazolyl, Pyridyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-keto-thiomorpholinyl and 1,1-dione Thiomorpholinyl. Unless otherwise specifically stated in the specification, a heterocycloalkyl moiety is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, pendant oxy, thioxoxy, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N (R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, Alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

〝Heterocycloalkyl fluorene also includes a bicyclic ring system in which one non-aromatic ring (generally having 3 to 7 ring atoms) contains, in addition to 1 to 3 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen. a combination of at least 2 carbon atoms and at least one of the foregoing heteroatoms; and other rings (generally having 3 to 7 ring atoms) optionally containing 1 to 3 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen And not for the aromatics.

The oxime isomers are compounds having the same molecular formula. The oxime stereoisomers are isomers that differ only in the arrangement of atoms in space - that is, have different stereochemical configurations. The 〝 mirror isomer is a pair of stereoisomers that are non-superimposable mirror images of each other. A pair of mirror image isomers in a 1:1 mixture is a racemic ruthenium mixture. The term 〝(±)〞 is used to calibrate the racemic mixture where appropriate. The non-image isomer is a stereoisomer having at least two asymmetric atoms but not mirror images of each other. Absolute stereochemistry is specified according to the Rahn S-system of Cahn-Ingold-Prelog. When the compound is a pure mirror image isomer, the stereochemistry of each palm carbon can be specified by R or S. An isolated compound of unknown absolute configuration may be scaled (+) or (-) depending on its direction (right-handed or left-handed) that rotates the plane-polarized light at the sodium D-line wavelength. Certain compounds described herein contain one or more asymmetric centers and may therefore result in a mirror image isomer, a non-image isomer, and other stereoisomers that may be defined as (R) or (S) by absolute stereochemistry. Object type. The chemical entities, pharmaceutical compositions and methods of the present invention are meant to include all possible such isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using palm synthetic components or palmitic reagents or isolated using conventional techniques. When a compound described herein contains an olefinic double bond or other geometrically asymmetric center and unless otherwise specified, it is intended that the compound include both E and Z geometric isomers.

As used herein, 〝image isomer purity 〞 refers to the relative amount of a particular mirror image isomer relative to other smectomers, expressed as a percentage. For example, if it is possible to have a (R)- or (S)-isomer configuration The compound is present as a racemic mixture, and the mirror image isomer purity is about 50% with respect to the (R)- or (S)-isomer. If the compound has an isomeric form that exceeds other forms, such as 80% (S)- and 20% (R)-, the mirror image isomer purity of the compound is 80% relative to the (S)-isomer form. . The mirror image isomer purity of a compound can be determined in a number of ways known in the art including, but not limited to, chromatography using a palmitic carrier, optical rotation measurements of polarized light rotation, nuclear magnetic resonance spectroscopy using a palm displacement reagent (this Reagents include, but are not limited to, lanthanides containing a palm compound or Pirkle's alcohol, or compounds derived using a palm compound such as Mosher acid, followed by chromatography or Nuclear magnetic resonance spectroscopy.

Part of the oxime refers to a specific segment or functional group of the molecule. The chemical moiety is often an identified chemical entity that is embedded or attached to the molecule.

Nitrosoguanidine refers to the -NO ₂ group.

Anthraquinone refers to an -O- group.

The oxime oxime refers to the =0 group.

The oxime tautomers are structurally different isomers which are converted into each other by tautomerization. The oxime isomerization oxime is an isomerized form and includes proton transfer or proton shift tautomerization, which is considered to be a subset of acid-base chemistry. Proton transfer tautomerization 〞 or 〝 proton displacement tautomerization 〞 involves a proton transfer accompanied by a bond-level change in the exchange of a single bond with an adjacent double bond. The chemical equilibrium of the tautomers can be achieved when tautomerization is feasible (eg, in solution). An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the mutual conversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomer Chemical. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol with a pyridine-4(1H)-one tautomer.

As used herein, the terms 〝 enriched mirror-isomerized 〞, 〝 mirror-isomerized pure 〞 and 〝 non-race 〞 are those in which the weight percentage of one mirror image is greater than the control mixture of the racemic composition. A composition of an amount of mirror image isomers (e.g., greater than 1:1 by weight). For example, an enriched mirror-isomerized formulation of (S)-mirrranomer is meant to have greater than 50% by weight (such as at least 75% by weight, such as at least 80% by weight) relative to the (R)-mirroromer. A compound preparation of (S)-mirroromer. In some embodiments, the enrichment can be substantially greater than 80% by weight to provide for the substantial enrichment of the mirror image isomers, the substantially mirror image isomerism, or the substantially non-racemic properties. Formulation, which refers to a formulation of a composition having at least 85% by weight (such as at least 90% by weight and such as at least 95% by weight) of one mirror image isomer relative to other mirror image isomers. As used herein, the term "enriched non-image-isomerized" and "non-image-isomerized" means that one of the non-image isomers has a weight percentage greater than that of the non-mirromeric control mixture. A composition of the amount of isomers. In some embodiments, the enrichment can be substantially greater than 80% by weight to provide a formulation in which the ruthenium is substantially enriched with non-image-isomerized ruthenium or ruthenium substantially non-image-isomerically pure ruthenium, which is relative to Other non-image isomers having a formulation of at least 85% by weight (such as at least 90% by weight and such as at least 95% by weight) of a composition of a non-image isomer.

In a preferred embodiment, the group of enriched mirror isomerism The adult has an effect on the therapeutic utility per unit mass greater than the racemic mixture of the composition. The mirror image isomers may be separated from the mixture by methods known to those skilled in the art, including palm oil high pressure liquid chromatography (HPLC) and the formation and crystallization of palm salts; or preferred mirror images. Isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York (1994).

The ruthenium radical or atomic oxime is any group or atom that cleaves from the starting material under selected reaction conditions, thus promoting the reaction at a particular location. Examples of such groups include a halogen atom and a methylsulfonyloxy group, a p-nitrophenylsulfonyloxy group, and a toluenesulfonyloxy group unless otherwise specified.

The hydrazine protecting group is intended to mean a group that selectively blocks one or more reactive sites in the polyfunctional compound such that the chemical reaction can be selectively carried out at another unprotected reactive site, and then The protecting group can be easily removed after the selective reaction is completed. Various protecting groups are disclosed, for example, in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons, New York (1999).

By hydrazine hydrate is meant a compound that is physically associated with one or more molecules in a pharmaceutically acceptable solvent.

The group to which the hydrazine is substituted may be attached to one or more additional moieties which are individually and independently selected, for example, from the group consisting of decyl, alkyl, alkane Alkyl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio , cyano, halo, carbonyl, ester, thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, pendant oxy, perhaloalkyl and perfluoroalkane a group, a phosphoric acid group, a sulfhydryl group, a sulfinyl group, a sulfonyl group, a sulfonylamino group, a sulfoxyl group, a sulfonic acid group, a urea group, and an amine group, including mono- and disubstituted amine groups; They are protected derivatives. Substituents may be substituted, for example, a cycloalkyl substituent may have a halide substituent on one or more of its ring carbons.

Sulfonyl sulfonium refers to -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S a group of (optionally substituted heterocycloalkyl).

〝 sulfinyl hydrazine refers to -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino group), - S(O)-(optionally substituted aryl), -S(O)-(optionally substituted heteroaryl) and -S(O)-(optionally substituted heterocycloalkyl) Group.

Sulfosyl hydrazine is meant to include -S(O ₂ )-H, -S(O ₂ )-(optionally substituted alkyl), -S(O ₂ )-(optionally substituted amino group) , -S(O ₂ )-(optionally substituted aryl), -S(O ₂ )-(optionally substituted heteroaryl) and -S(O ₂ )- (optionally substituted) a group of a cycloalkyl group.

Sulfonamidyl hydrazine or sulfonylamino (sulfonylamino) hydrazine refers to a -S(=O) ₂ -NRR group, wherein each R system is independently selected from the group consisting of Group: hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded via a ring carbon) and heteroalicyclic (bonded via a ring carbon). The R groups in the -NRR of -S(=O) ₂ -NRR may form a 4, 5, 6 or 7 membered ring together with the nitrogen to which they are attached. The sulfonamide group is optionally substituted with one or more of the substituents described for the alkyl group, the cycloalkyl group, the aryl group, and the heteroaryl group, respectively.

〝 碸 碸 〞 refers to the -S(=O) ₂ OH group.

An anthracene sulfonate group refers to a -S(=O) ₂ -OR group, wherein the R group is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (via a ring) Carbon bonds) and heteroalicyclic groups (bonded via a ring carbon). The sulfonic acid group is optionally substituted on R by one or more of the substituents described for the alkyl group, the cycloalkyl group, the aryl group, and the heteroaryl group, respectively.

The compounds of the invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs of compounds, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates). , configuration polymorphs and amorphous forms, and mixtures thereof. The crystalline form 〞 and 〝 polymorphs are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polycrystals. Forms (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless particular crystalline and amorphous forms are mentioned.

The compounds of the invention also include antibodies. The term "antibody" and its plural form "antibodies" refers to a total immunoglobulin and any antigen-binding fragment (〝 antigen-binding portion 〞) or a single strand thereof. The 〝 antibody 〞 further refers to a glycoprotein or an antigen binding site thereof comprising at least two heavy (H) chains and two light (L) chains inter-connected via a disulfide bond. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as _VH ) and a heavy chain constant region. The heavy chain constant region is composed of three domains CH1, CH2 and CH3. Each light chain line (abbreviated herein as V _L) by a light chain variable region and light chain constant region is composed. The light chain constant region is composed of one domain C _L . V _H and V _L regions of an antibody can be further subdivided into regions of hypervariability, which are known as complementarity determining region (CDR) or hypervariable region (the HVR), and may be more conserved regions referred to as framework regions (FR) of Interspersed. Each V _H and V _L is composed of three CDR-based four FR and consisting, in the following order from amino - terminus to the carboxy - terminus arrangement: FR1, CDR1, FR2, CDR2 , FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with epitopes or determining regions and the like. The constant region of the antibody mediates binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and a first component of the typical complement system (Clq).

The term "monomimetic antibody 〞, 〝mAb 〞, 〝 monoclonal antibody composition 〞 or a plurality thereof refers to an antibody molecule preparation of a single molecular composition. The monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope. The specificity of the monoclonal antibody to CD20 can be achieved by injecting the test subject with the CD20 antigen and then isolating the fusion tumor expressing the antibody having the desired sequence or functional characteristics using the knowledge and skill of the present technology. The DNA-encoded monoclonal antibody system is readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of specifically binding to genes encoding the heavy and light chains of monoclonal antibodies). Fusion tumor cells are suitable as a preferred source of such DNA. Once isolated, the DNA can be placed into an expression vector, which is then transfected into a host cell that does not otherwise produce an immunoglobulin. Among them, such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells or myeloma cells, to obtain synthesis of monoclonal antibodies in recombinant host cells. The production of recombinant antibodies will be described in more detail below.

As used herein, the term "antigen-binding portion of an antibody" or "antigen-binding fragment" (or simply a portion of a purine antibody) refers to one or more fragments of an antibody that retain the ability to specifically bind an antigen, such as CD20. It has been shown that the antigen binding function of an antibody can be carried out by a fragment of a full length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include: (i) a Fab fragment, a monovalent fragment consisting of _VL , _VH , _CL and CH1 domains; (ii) F(ab ' a fragment comprising two bivalent fragments of a Fab fragment linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of a _VH and CH1 domain; (iv) an Fv fragment, which is antibodyized composed of a single arm of V _H and V _L domains; (V) domain antibody (dAb) fragment (Ward et al's Nature, 1989,341,544-546), which may be V _H or V _L domains composed; and (vi) Isolated complement determining regions (CDRs). Furthermore, although the two domains V _L and V _H based Fv fragment encoded by the individual genes, but their recombination methods may be used to synthesize the sub-engaging coupling, make their as a single protein chain in which the V _L and V _H regions Pairing forms a monovalent molecule known as single-chain Fv (scFv); see, for example, Bird et al., Science 1988, 242, 423-426; and Huston et al., Proc. Natl. Acad. Sci. USA 1988, 85, 5879-5883. Such scFv chain antibodies are also intended to be encompassed within the term 〝 antigen binding portion 〞 or 〝 antigen binding fragment 抗体 of the antibody. Such antibody fragments are obtained using conventional techniques known to those skilled in the art, and the availability of such fragments is screened in the same manner as intact antibodies.

The term "human antibody" as used herein is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immune protein sequences. Furthermore, if the antibody contains a constant region, the constant region is also derived from a human germline immunoglobulin sequence. Human antibodies of the invention may include amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or position-specific mutations in vitro or by somatic mutations in vivo). The term "human antibody" as used herein is not intended to include antibodies in which the CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

The term "human monoclonal antibody" refers to an antibody having a variable region that exhibits a single binding specificity, wherein both the framework and CDR regions are derived from human germline immune protein sequences. In one embodiment, the human monoclonal antibody system is produced by a fusion cell comprising a B cell obtained from a gene-transgenic non-human animal (eg, a genetically-transferred mouse), the gene-transgenic non-human animal having a fusion comprising Human heavy chain gene transgenic and light chain gene transgenic genomes of immortalized cells.

The term "recombinant human antibody" as used herein includes all human antibodies prepared, expressed, produced or isolated by recombinant means, such as (a) from a gene having a human immunoglobulin gene or a chromosomal transfer animal ( For example, a mouse isolated antibody or a fusion tumor obtained therefrom (described further below), (b) an antibody isolated from a host cell transformed with a human antibody (for example, a transfectoma), (c) An antibody isolated in a recombinant combinatorial human antibody library, and (d) an antibody produced, expressed, produced or isolated by any other means involving splicing of a human immunoglobulin gene sequence to other DNA sequences. Such recombinant human antibodies have variable regions in which the framework regions and CDR regions are derived from human germline immunoglobulin sequences. However, in certain embodiments, in vitro mutations can be administered to such recombinant human antibodies (or in vivo somatic mutations when transgenic animals using human Ig sequences), and thus recombinant antibodies amino acid sequences V _H and V _L, the region is not possible naturally present in a living human sequences spectrum line expressing antibody species, although these sequences are derived from human germline V _H and V _L, and the sequence It is related to the sequence.

As used herein, a scorpion isoform refers to a class of antibodies (eg, IgM or IgGl) encoded by a heavy chain constant region gene.

The phrase 〝 〝 〝 〝 〝 〝 〝 〝 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。

The term "human antibody derivative" refers to any modified form of a human antibody, such as a conjugate of an antibody with another agent or antibody. The term 〝 conjugate 〞 or 〝 immunoconjugate 〞 refers to an antibody or fragment thereof conjugated to a therapeutic moiety, such as a bacterial toxin, a cytotoxic drug, or a radionuclide containing toxin. Toxic moieties can be conjugated to the antibodies of the invention using methods available in the art.

The terms humanized antibody 〞, humanized antibodies 〝 and humanized 〞 are intended to mean that the CDR sequences of the germline derived from another mammalian species, such as a mouse, have been An antibody grafted onto a human framework sequence. Additional frame area repair The decoration can be performed within the human frame sequence. A humanized version of a non-human (e.g., murine) antibody is a chimeric antibody comprising a minimal sequence derived from a non-human immunoglobulin. To a large extent, humanized antibodies are human immunoglobulins (recipient antibodies) in which residues from the hypervariable regions of the recipient are derived from non-human species with the desired specificity, affinity and ability ( Residues of 15 hypervariable regions (supplier antibodies) such as mouse, rat, rabbit or non-human primate are replaced. In some instances, the Fv framework region (FR) residues of human immunoglobulin are replaced with corresponding non-human residues. Furthermore, a humanized antibody can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications can be made to further refine the antibody properties. A humanized antibody typically comprises substantially all of at least one and usually two variable domains, wherein all or substantially all of the hypervariable loops correspond to the loops of the non-human immunoglobulin, and all or substantially all The FR region is the region of the human immunoglobulin sequence. The humanized antibody also optionally comprises at least a portion of an immunoglobulin constant region (Fc), typically a human immunoglobulin constant region. For further details, see Jones et al., Nature 1986, 321, 522-525; Riechmann et al., Nature 1988, 332, 323-329; and Presta, Curr. Op. Struct. Biol. 1992, 2, 593-596.

The term "chimeric antibody" is intended to mean an antibody in which the variable region sequence is derived from one species and the constant region sequence is derived from another species, such as wherein the variable region sequence is derived from a mouse antibody and the constant region sequence is derived from Antibody to human antibodies.

The 〝 bifunctional antibody 〞 is a small antibody fragment having two antigen binding positions. Fragments comprise a heavy-chain variable domain _{(V H) (V H -V} L or V _L -V _H) is connected in the same polypeptide chain a light chain variable domain (V _L) of. By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complement domain of the other chain and create two antigen binding sites. Bifunctional antibodies are more fully described, for example, in European Patent No. EP 404,097; International Patent Publication No. WO 93/11161; and Bolliger et al., Proc. Natl. Acad. Sci. USA 1993, 90, 6444-6448.

The term "glycosylated oxime" refers to a modified antibody derivative. Non-glycosylated antibodies lack glycosylation. Glycosylation can be altered to, for example, increase the affinity of the antibody for the antigen. Modification of such carbohydrates can be accomplished, for example, by altering one or more glycosylation sites within the antibody sequence. For example, one or more amino acid substitutions can be made resulting in the elimination of one or more variable region framework glycosylation sites, thereby eliminating glycosylation at that position. Non-glycosylation increases the affinity of the antibody for the antigen as described in U.S. Patent Nos. 5,714,350 and 6,350,861. Additionally or alternatively, the antibody may be rendered with an altered type of glycosylation, such as a low fucosylated antibody having a reduced amount of fucosyl residues or an antibody having an increased halved GlcNac structure. The ability of these altered glycosylation patterns to increase antibodies has been demonstrated. Modification of such carbohydrates can be accomplished, for example, by expressing the antibody in a host cell having altered glycosylation. Cells with altered glycosylation are described in the art and can be used as host cells in which the recombinant antibodies of the invention are expressed, thereby producing antibodies with altered glycosylation. For example, the cell lines Ms704, Ms705 and Ms709 lack the fucosyltransferase gene FUT8 (α(1,6) fucosyltransferase), resulting in Ms704, Ms705 and Antibodies expressed in the Ms709 cell line lack fucose on their carbohydrates. The Ms704, Ms705 and Ms709 FUT8-/- cell lines were generated by targeting the FUT8 gene in CHO/DG44 cells using two replacement vectors (see, e.g., U.S. Patent Publication No. 2004/0110704 or Yamane-Ohnuki et al. Biotechnol. Bioeng., 2004, 87, 614-622). European Patent No. EP 1,176,195, which is another example, describes a cell line having a functionally disrupted FUT8 gene encoding a fucosyltransferase such that antibodies expressed in such cell lines are reduced or eliminated due to α1,6 The key-related enzyme exhibits low fucosylation, and also indicates a low-enzyme activity having N-acetyl glucosamine which adds fucose to the Fc region of the antibody, or a cell having no enzyme activity For example, the murine myeloma cell line YB2/0 (ATCC CRL 1662). International Patent Publication WO 03/035835 describes a variant CHO cell line Lec13 cell having the ability to reduce attachment of fucose to Asn(297) linked carbohydrates, as well as to antibodies expressed in the host cell. Low fucosylation (see also Shields et al., J. Biol. Chem. 2002, 277, 26733-26740. International Patent Publication WO 99/54342 describes engineered cell lines to represent glycoprotein modified glycosylation Transferase (eg, β(1,4)-N-ethyl glucosyltransferase III (GnTIII)) such that antibodies expressed in engineered cell lines exhibit increased bisecting GlcNac structure, This results in increased antibody ADCC activity (see also Umana et al., Nat. Biotech. 1999, 17, 176-180). Alternatively, the fucose residue of the antibody can be cleaved using a fucosidase enzyme. For example, fucoside The enzyme (α-L-fucosidase) removes fucose residues from the antibody, such as Tarentino et al. Biochem. 1975, 14, 5516-5523.

Pegylation refers to a modified antibody or fragment thereof, typically in combination with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, in one or more PEG groups. The reaction is carried out under conditions attached to the antibody or antibody fragment. PEGylation can, for example, increase the biological (e.g., serum) half-life of an antibody. PEGylation is preferably carried out via a deuteration or alkylation reaction with a reactive PEG molecule (or a similar reactive water soluble polymer). The term 〝polyethylene glycol hydrazine as used herein is intended to include any form of PEG used to derivatize other proteins, such as mono(C ₁ -C ₁₀ )alkoxy- or aryloxy-polyethylene glycol or poly. Ethylene glycol-maleimide. The antibody to be PEGylated may be an aglycosylated antibody. Methods of PEGylation are antibodies known in the art and applicable to the present invention. See, for example, European Patent No. EP 0154316 and EP 0401384.

An antibody which specifically binds to human CD20〞 as used herein is intended to mean 1 × 10 ^-7 M or less, more preferably 5 × 10 ^-8 M or less, still more preferably 1 × 10 ^-8 M or smaller, more preferably 5 x 10 ^-9 M or less K _D binds to human CD20 antibody.

The term "radioisotope-labeled complex" refers to a radioisotope (such as ⁹⁰ Y, ¹¹¹ In or ¹³¹ I) that is also non-covalently and covalently attached to an antibody.

The term "biosynthesis" means a biological product that is highly similar to a reference biological product approved by the United States, although the difference in clinically inactive components is small, and the safety and purity of the product between the biological product and the reference product. There are no clinically meaningful differences in efficacy. In addition, A similar biopharmaceutical or neoplastic mimic is a biologic similar to another biologic that has been authorized for use by the European Medicines Agency. The term biosynthesis is also used synonymously by the authorities of other countries and regions. A biological product or a biological drug is a drug produced or derived from a biological source such as bacteria or yeast. The drugs may consist of relatively small molecules such as human insulin or erythropoietin or complex molecules such as monoclonal antibodies. For example, if the reference anti-CD20 monoclonal antibody is rituximab, the anti-CD20 biomimetic monoclonal antibody recognized by the drug regulatory authority with reference to rituximab is the rituximab biosynthesis. 〞 or rituximab for its biosynthesis.

BTK inhibitor

In one embodiment, the BTK inhibitor is a compound of formula (I): Or a pharmaceutically acceptable salt thereof, wherein: X is CH, N, O or S; Y is C(R ₆ ), N, O or S; Z is CH, N or a bond; A is CH or N; ₁ is N or C(R ₇ ); B ₂ is N or C(R ₈ ); B ₃ is N or C(R ₉ ); B ₄ is N or C(R ₁₀ ); and R ₁ is R ₁₁ C( =O), R ₁₂ S(=O), R ₁₃ S(=O) ₂ or (C _1-6 )alkyl optionally substituted by R ₁₄ ; R ₂ is H, (C _1-3 )alkyl Or (C _3-7 )cycloalkyl; R ₃ is H, (C _1-6 )alkyl or (C _3-7 )cycloalkyl); or N and C to which R ₂ and R _{3 are} attached The atoms together form a (C _3-7 )heterocycloalkyl group optionally substituted with one or more of a fluorine, a hydroxyl group, a (C _1-3 )alkyl group, a (C _1-3 ) alkoxy group or a pendant oxy group; R ₄ is H or (C _1-3 )alkyl; R ₅ is H, halogen, cyano, (C _1-4 )alkyl, (C _1-3 ) alkoxy, (C _3-6 ) ring An alkyl group, any of which is optionally substituted by one or more halogens; or R ₅ is (C _6-10 ) aryl or (C _2-6 )heterocycloalkyl; R ₆ is H or (C _1-3 ) an alkyl group; or R ₅ and R ₆ together may form a (C _3-7 )cycloalkenyl group or a (C _2-6 )heterocyclenyl group, each of which optionally passes (C _1-3 ) or alkyl substituted with one or more halo; R ₇ is H, halogen, CF _3, (C _1-3) alkyl or (C _1-3) Group; R ₈ is H, halogen, CF _3, (C _1-3) alkyl or (C _1-3) alkoxy; or R ₇ and R and their attached carbon atoms together form a ₈ (C _{6 -10} ) aryl or (C _1-9 )heteroaryl; R ₉ is H, halogen, (C _1-3 )alkyl or (C _1-3 )alkoxy; R ₁₀ is H, halogen, ( C _1-3 )alkyl or (C _1-3 )alkoxy; R _{11 is} independently selected from the group consisting of: (C _1-6 )alkyl, (C _2-6 )alkenyl and A C _2-6 ) alkynyl group, wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, (C _1-4 )alkyl, ( C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl]amino, (C _1-3 )alkoxy, (C _{3- 7} ) a cycloalkoxy group, (C _6-10 ) aryl group and (C _3-7 ) heterocycloalkyl group; or R ₁₁ is (C _1-3 )alkyl-C(O)-S-(C _{1 -3} )alkyl; or R ₁₁ is (C _1-5 )heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen and cyanide; R ₁₂ and R ₁₃ is independently selected from the group consisting of consisting of the following: (C _2-6) alkenyl and (C _2-6) alkynyl group, the alkenyl and alkynyl groups optionally substituted by one or more groups selected from the group consisting of the following Group of substituents: hydroxy, (C _1-4) alkyl, (C _3-7) cycloalkyl, [(C _1-4) alkyl] amino, di [(C _1-4) Alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl, and (C _3-7 )heterocycloalkyl; or (C _1-5 ) a heteroaryl group optionally substituted by one or more substituents selected from the group consisting of halogen and cyano; and R _{14 are} independently selected from the group consisting of halogen a cyano group, a (C _2-6 )alkenyl group and a (C _2-6 )alkynyl group optionally substituted by one or more substituents selected from the group consisting of hydroxyl groups, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, (C _1-4 )alkylamino, bis[(C _1-4 )alkyl]amino, (C _1-3 ) Alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl, (C _1-5 )heteroaryl and (C _3-7 )heterocycloalkyl; prerequisite: X 0, 2 atoms of Y, Z may be heteroatoms at the same time; when one atom selected from X, Y is O or S, then Z is a bond and other atoms selected from X, Y may not be O or S; When C or N, Y is C(R ₆ ) or N and X are C or N; 0 to 2 atoms of B ₁ , B ₂ , B ₃ and B ₄ are N The term used has the following meanings: (C _1-2 )alkyl means an alkyl group having 1 to 2 carbon atoms which is a methyl group or an ethyl group, and (C _1-3 )alkyl means having 1 a branched or unbranched alkyl group of 3 carbon atoms which is methyl, ethyl, propyl or isopropyl; (C _1-4 )alkyl means a branch having 1 to 4 carbon atoms Or an unbranched alkyl group which is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a second butyl group and a t-butyl group, preferably a (C _1-3 ) alkyl group. (C _1-5 )alkyl means a branched or unbranched alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Dibutyl, tert-butyl, pentyl and isopentyl are preferred to (C _1-4 )alkyl. (C _1-6 )alkyl means a branched or unbranched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ortho Amyl and n-hexyl. Preferred is (C _1-5 )alkyl, preferably (C _1-4 )alkyl; (C _1-2 )alkoxy means alkoxy having 1-2 carbon atoms, alkyl moiety Has the same meaning as previously defined; (C _1-3 ) alkoxy means an alkoxy group having 1 to 3 carbon atoms, and the alkyl moiety has the same meaning as previously defined. The (C _1-2 ) alkoxy group is preferred; the (C _1-4 ) alkoxy group means an alkoxy group having 1 to 4 carbon atoms, and the alkyl moiety has the same meaning as previously defined. Preferably, the (C _1-3 ) alkoxy group is the (C _1-2 ) alkoxy group; the (C _2-4 ) alkenyl group means a branched or unbranched chain having 2 to 4 carbon atoms. An alkenyl group such as a vinyl group, a 2-propenyl group, an isobutenyl group or a 2-butenyl group; (C _2-6 )alkenyl means a branched or unbranched alkenyl group having 2 to 6 carbon atoms, such as ethylene a 2-butenyl group and a n-pentenyl group, preferably (C _2-4 )alkenyl; (C _2-4 ) alkynyl means a branched or unbranched alkynyl group having 2 to 4 carbon atoms , such as ethynyl, 2-propynyl or 2-butynyl; (C _2-6 )alkynyl means a branched or unbranched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propyne A group, n-butynyl, n-pentynyl, isopenynyl, isohexynyl or n-hexynyl. Preferred is (C _2-4 )alkynyl; (C _3-6 )cycloalkyl means cycloalkyl having 3 to 6 carbon atoms which is cyclopropyl, cyclobutyl, cyclopentyl or cyclic (C _3-7 )cycloalkyl means a cycloalkyl group having 3 to 7 carbon atoms which is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group; (C _{2- 6} ) Heterocycloalkyl means a heterocycloalkyl group having 2 to 6 carbon atoms (preferably 3-5 carbon atoms) and one or two hetero atoms selected from N, O and/or S, It may be attached via a hetero atom or a carbon atom which may be employed; preferred heteroatoms are N or O; it is also preferably piperidine, morpholine, pyrrolidine and piperazine. The most preferred (C _2-6 )heterocycloalkyl group is pyrrolidine; the heterocycloalkyl group can be attached via a hetero atom as possible; (C _3-7 )heterocycloalkyl means having 3 to 7 carbon atoms (preferably 3-5 carbon atoms) and one or two heterocycloalkyl groups selected from heteroatoms of N, O and/or S. Preferred heteroatoms are N or O; preferred (C _3-7 )heterocycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl; more preferably (C _3-7 )heterocycloalkyl is piperidine, morpholine and pyrrolidine; and heterocycloalkyl can be linked via a possible hetero atom; (C _3-7 )cycloalkoxy means via ring carbon An atom is bonded to a cycloalkyl group having 3 to 7 carbon atoms of the outer epoxy atom, the cycloalkyl group having the same meaning as previously defined; (C _6-10 ) aryl means having 6 to 10 carbon atoms An aromatic hydrocarbon group such as a phenyl group, a naphthyl group, a tetrahydronaphthyl group or a fluorenyl group; preferably a (C _6-10 ) aryl group is a phenyl group; (C _1-5 ) a heteroaryl group means having 1 to 5 a substituted or unsubstituted aromatic group of a carbon atom and 1 to 4 hetero atoms selected from N, O and/or S; (C _1-5 )heteroaryl optionally substituted; preferred (C _1-5 )heteroaryl is tetrazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, tri More preferably, the (C _1-5 )heteroaryl group is a pyrimidinyl group; the (C _1-9 )heteroaryl group means having 1 to 9 carbon atoms and 1 to 4 are selected from N a substituted or unsubstituted aromatic group of a hetero atom of O and/or S; a (C _1-9 )heteroaryl group optionally substituted; preferably a (C _1-9 )heteroaryl group is Quinoline, isoquinoline and anthracene; [(C _1-4 )alkyl]amino group means an amino group monosubstituted by an alkyl group having from 1 to 4 carbon atoms and having the same meaning as previously defined Preferred [(C _1-4 )alkyl]amino group is methylamino group; bis[(C _1-4 )alkyl]amino group means alkyl group substituted by alkyl group, each alkyl group Containing from 1 to 4 carbon atoms and having the same meaning as previously defined; preferred bis[(C _1-4 )alkyl]amino group is dimethylamino; halogen means fluorine, chlorine, bromine or iodine; C _1-3 )alkyl-C(O)-S-(C _1-3 )alkyl means alkyl-carbonyl-thio-alkyl, each alkyl group having 1 to 3 carbon atoms and having the same meaning as previously defined The same meaning; (C _3-7 )cycloalkenyl means a cycloalkenyl group having from 3 to 7 carbon atoms (preferably from 5 to 7 carbon atoms); preferably a (C _3-7 ) ring; Alkenyl is cyclopentenyl or cyclohexenyl; Best hexenyl; _(2-6 C) means a heterocycloalkenyl group having 2-6 carbon atoms (preferably 3-5 carbon atoms) and one from N, O and / or S heteroatoms of A heterocyclic alkenyl group of the atom; preferred (C _2-6 ) heterocycloalkenyl is oxycyclohexenyl and azacyclohexenyl.

In the above definition having a polyfunctional group, the point of attachment is on the last group.

In the definition of a substituent, when all of the alkyl hydrazines of the substituent are indicated as being optionally substituted, this also includes the alkyl portion of the alkoxy group.

A circle in the ring of formula (I) indicates that the ring is aromatic.

Depending on the ring formed, if nitrogen is present in X or Y, the nitrogen can carry hydrogen.

The term "substituted" means that one or more hydrogens on a calibrated atom/atom are replaced by a selected designated group, provided that the normal valence of the atom calibrated in the prior environment is not exceeded and the substitution is stabilized. compound of. Combinations of substituents and/or variants may be permitted, provided that such combinations result in stable compounds. The oxime-stabilizing compound 〞 or 〝-stabilized structure 定义 is defined as a sufficiently strong compound or structure that survives from the reaction mixture and is separated into useful purity and formulated into a drug containing a potent active pharmaceutical ingredient.

The term "arbitrarily substituted" means optionally substituted at the specified group, radical or moiety.

In the embodiment of formula (I), B ₁ is C(R ₇ ); B ₂ is C(R ₈ ); B ₃ is C(R ₉ ); B ₄ is C(R ₁₀ ); R ₇ , R ₉ and R ₁₀ are each H; and R ₈ is hydrogen or methyl.

In an embodiment of formula (I), the ring system containing X, Y and Z is selected from the group consisting of pyridyl, pyrimidinyl, indole Base, three Base, thiazolyl, oxazolyl and isoxazolyl.

In an embodiment of formula (I), the ring system containing X, Y and Z is selected from the group consisting of pyridyl, pyrimidinyl and indole .

In an embodiment of formula (I), the ring system containing X, Y and Z is selected from the group consisting of pyridyl and pyrimidinyl.

In the embodiment of formula (I), the ring containing X, Y and Z is pyridine.

In an embodiment of formula (I), R ₅ is selected from the group consisting of hydrogen, fluorine, methyl, methoxy, and trifluoromethyl.

In the embodiment of formula (I), R ₅ is hydrogen.

In an embodiment of formula (I), R ₂ and R ₃ together form a heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and high piperazine. The pyridine group and the morpholinyl group are optionally substituted by one or more of a fluorine, a hydroxyl group, a (C _1-3 ) alkyl group and a (C _1-3 ) alkoxy group.

In an embodiment of formula (I), R ₂ and R ₃ together form a heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl.

In an embodiment of formula (I), R ₂ and R ₃ together form a pyrrolidinyl ring.

In an embodiment of formula (I), R _{1 is} independently selected from the group consisting of: (C _1-6 )alkyl, (C _2-6 )alkenyl, and (C _2-6 )alkynyl Each of these is optionally substituted with one or more substituents selected from the group consisting of hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _{1 -4} )alkyl]amino, bis[(C _1-4 )alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 ) Aryl and (C _3-7 )heterocycloalkyl.

In the embodiment of formula (I), B ₁ , B ₂ , B ₃ and B ₄ are CH; X is N; Y and Z are CH; R ₅ is CH ₃ ; A is N; R ₂ , R ₃ And R ₄ is H; and R ₁ is CO-CH ₃ .

In the embodiment of formula (I), B ₁ , B ₂ , B ₃ and B ₄ are CH; X and Y are N; Z is CH; R ₅ is CH ₃ ; A is N; R ₂ , R ₃ And R ₄ is H; and R ₁ is CO-CH ₃ .

In the embodiment of formula (I), B ₁ , B ₂ , B ₃ and B ₄ are CH; X and Y are N; Z is CH; R ₅ is CH ₃ ; A is CH; R ₂ and R ₃ The piperidinyl ring is formed together; R ₄ is H; and R ₁ is CO-vinyl.

In an aspect of formula (I) _{in, B 1, B 2, B} 3 and B ₄ is CH; X, Y, and Z is CH; R ₅ is H; A is CH; R ₂ and R ₃ together form a pyrrolidin piperidinyl ring; R ₄ is H; and R ₁ is CO- propynyl.

In the embodiment of formula (I), B ₁ , B ₂ , B ₃ and B ₄ are CH; X, Y and Z are CH; R ₅ is CH ₃ ; A is CH; and R ₂ is formed together with R ₃ Piperidinyl ring; R ₄ is H; and R ₁ is CO-propynyl.

Embodiment aspect in formula (I) _{in, B 1, B 2, B} 3 and B ₄ is CH; X and Y is N; Z is CH; R ₅ is H; A is CH; R ₂ and R ₃ together A morpholinyl ring is formed; R ₄ is H; and R ₁ is a CO-vinyl group.

In the embodiment of formula (I), B ₁ , B ₂ , B ₃ and B ₄ are CH; X and Y are N; Z is CH; R ₅ is CH ₃ ; A is CH; R ₂ and R ₃ The morpholinyl ring is formed together; R ₄ is H; and R ₁ is CO-propynyl.

In a preferred embodiment, the BTK inhibitor is a compound of formula (II): Or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof. The compound of formula (II) is also known as (S)-4-(8-amino-3-(1-(butyl-2-indolyl)pyrrolidin-2-yl)imidazo[1,5-a]pyridin -1-yl)-N-(pyridin-2-yl)benzamide. In one embodiment, the BTK inhibitor is (S)-4-(8-amino-3-(1-(but-2-yl)pyrrolidin-2-yl)imidazo[1,5- a]pyridyl 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof. The preparation of this compound is described in Example 6 of U.S. Patent Application Publication No. US 2014/0155385 A1, the disclosure of which is incorporated herein by reference. In short, the preparation of formula (II) can be accomplished by the following procedure. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (also known as HATU, N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethylammonium N-fluorophosphate Oxide and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (18.75 mg, 0.049 mmol) added to dichloro (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrene in methane (2 mL) 1-yl)-N-(pyridin-2-yl)benzamide (19.7 mg, 0.049 mmol), triethylamine (20 mg, 0.197 mmol, 0.027 mL) and 2-butynoic acid In the solution. The mixture was stirred at room temperature for 30 minutes. The mixture was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by preparative liquid chromatography. The fractions containing the product were collected and reduced to dryness to provide 10.5 mg of the formula (II) (18.0% yield).

Pharmaceutical composition

In selected embodiments, the invention provides pharmaceutical compositions for the treatment of lymphoma and leukemia, including CLL and SLL.

The pharmaceutical composition is typically formulated to provide a therapeutically effective amount of a BTK inhibitor, including a BTK inhibitor of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate thereof Or a derivative. Where necessary, the pharmaceutical composition contains a pharmaceutically acceptable salt and/or a complex thereof and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants. When necessary, the active ingredient other than the BTK inhibitor of the formula (I) or the formula (II) may be mixed into the preparation or the preparation may be prepared by using the two components in combination or in combination.

In selected embodiments, the concentration of the BTK inhibitor of formula (I) or formula (II) provided in the pharmaceutical composition of the invention is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8% 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05 %, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v.

In selected embodiments, the concentration of the BTK inhibitor of formula (I) or formula (II) provided in the pharmaceutical composition of the invention is independently greater than 90%, 80%, 70%, 60%, 50. %, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25%18%, 17.75%, 17.50%, 17.25%17%, 16.75%, 16.50%, 16.25%16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75 %, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%9%, 8.75%, 8.50%, 8.25%8%, 7.75%, 7.50%, 7.25%7%, 6.75%, 6.50%, 6.25 %6%, 5.75%, 5.50%, 5.25%5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2% 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02 %, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v.

In selected embodiments, the concentration of the BTK inhibitor of Formula (I) or Formula (II) is independently in the range of from about 0.0001% to about 50%, from about 0.001% to about 40%, about 0.01%. Up to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to From about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12% or from about 1% to about 10 %w/w, w/v or v/v.

In selected embodiments, the concentration of the BTK inhibitor of Formula (I) or Formula (II) is independently within the range of from about 0.001% to about 10%, from about 0.01% to about 5%, and about 0.02%. Up to about 4.5%, from about 0.03% to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, from about 0.1% to about 0.9% w/w, w/v or v/v.

In selected embodiments, the amount of the BTK inhibitor of formula (I) or formula (II) is independently equal to or less than 10 grams, 9.5 grams, 9.0 grams, 8.5 grams, 8.0 grams, 7.5 grams, 7.0 grams, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g , 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 Grams, 0.05 grams, 0.04 grams, 0.03 grams, 0.02 grams, 0.01 grams, 0.009 grams, 0.008 grams, 0.007 grams, 0.006 grams, 0.005 grams, 0.004 grams, 0.003 grams, 0.002 grams, 0.001 grams, 0.0009 grams, 0.0008 grams, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g.

In selected embodiments, the amount of the BTK inhibitor of formula (I) or formula (II) is independently greater than 0.0001 grams, 0.0002 grams, 0.0003 Grams, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g , 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 Grams, 0.5 grams, 0.55 grams, 0.6 grams, 0.65 grams, 0.7 grams, 0.75 grams, 0.8 grams, 0.85 grams, 0.9 grams, 0.95 grams, 1 gram, 1.5 grams, 2 grams, 2.5 grams, 3 grams, 3.5 grams, 4 grams, 4.5 grams, 5 grams, 5.5 grams, 6 grams, 6.5 grams, 7 grams, 7.5 grams, 8 grams, 8.5 grams, 9 grams, 9.5 grams or 10 grams.

The BTK inhibitor of formula (I) or formula (II) is effective over a wide dosage range. For example, in the treatment of adults, it is independently from 0.01 to 1000 mg per day, from 0.5 to 100 mg, from 1 to 50 mg, and in the range of doses from 5 to 40 mg per day. The exact dose will depend on the route of administration, the form in which the compound is administered, the sex and age of the individual to be treated, the weight of the individual to be treated, and the preferences and experience of the attending physician.

Non-limiting exemplary pharmaceutical compositions and methods for their preparation are described below.

Oral administration of pharmaceutical composition

In selected embodiments, the present invention provides a pharmaceutical composition for oral administration comprising a BTK inhibitor of formula (I) or formula (II) and a pharmaceutical excipient suitable for oral administration. .

In selected embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising (i) an effective amount of a BTK inhibitor of formula (I) or formula (II), and (ii) suitable A pharmaceutical excipient that is administered orally. In selected embodiments, the composition additionally contains (iii) an effective amount of at least one additional active ingredient.

In selected embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption. The pharmaceutical compositions of the present invention suitable for oral administration may be in discrete dosage forms such as capsules, cachets or lozenges, or in liquid or aerosol sprays, each containing a predetermined amount in powder or in granules, An active ingredient in a solution or suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion or a water-in-oil type liquid emulsion. These dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with carriers which comprise one or more essential ingredients. The compositions are typically prepared by uniformly and intimately admixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and, if necessary, the product. For example, tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. The compressed tablet may be in the form of a free-flowing active ingredient (such as a powder or a mixture of excipients such as, but not limited to, a binder, a lubricant, an inert diluent and/or a surfactant or a dispersing agent) Granules are prepared by compression in a suitable machine. Molded tablets can be used A powdered compound moistened with an inert diluent is molded in a suitable machine.

The invention additionally comprises anhydrous pharmaceutical compositions and dosage forms, as water can contribute to the degradation of some of the compounds. For example, water (e.g., 5%) may be added to the medical technology as a means of simulating long-term storage to facilitate the determination of characteristics such as shelf life or stability of the formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition and dosage form of the invention containing lactose can be prepared if it is expected to have substantial contact with moisture and/or humidity during manufacture, packaging, and/or storage. Anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is maintained. Accordingly, the anhydrous composition can be packaged using materials known to prevent exposure to water such that the composition can be contained within a suitable blending kit. Examples of suitable packaging include, but are not limited to, sealed foil, plastic or the like, unit dose containers, blister packs, and strip packs.

The BTK inhibitor of formula (I) or formula (II) can be combined in a tight blend with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation to be administered. In preparing the composition of the oral dosage form, any of the usual pharmaceutical media can be used as a carrier, such as water in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols, Alcohol, oil, alcohol, flavoring agent, preservative, coloring agent and the like; or in the case of oral solid preparations such as starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, adhesive And the carrier of the disintegrant, in some embodiments, no milk is used sugar. For example, suitable carriers for solid oral formulations include powders, capsules and lozenges. If necessary, the tablets can be coated with standard aqueous or non-aqueous techniques.

Adhesives suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums (such as acacia), sodium alginate, alginic acid, other alginates, powders. Astragalus gum, guar gum, cellulose and its derivatives (such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidine, methyl cellulose , pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powders), microcrystalline cellulose, powdered cellulose, polydextrose (dextrate). , kaolin, mannitol, citric acid, sorbitol, starch, pregelatinized starch and mixtures thereof.

Disintegrants can be used in the compositions of the present invention to provide disintegration of the tablet when exposed to an aqueous environment. Too much disintegrant can cause the tablet to disintegrate in the bottle. Too little disintegrant may not be sufficient to cause disintegration, thus altering the rate and extent of release of the active ingredient from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient can be used to form the dosage form of the compounds disclosed herein. The disintegration dosage used can vary depending on the type of formulation and the mode of administration, and can be readily identified by those of ordinary skill in the art. From about 0.5 to about 15% by weight of the disintegrant or from about 1 to about 5% by weight of the disintegrant can be used in the pharmaceutical composition. Available Disintegrating agents for forming the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, and pollackin ( Polacrilin) potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algains, other celluloses, gums or mixtures thereof.

Lubricants useful in forming the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, others Glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (eg peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, laurel Ethyl acetate, agar or a mixture of the others. Additional lubricants include, for example, solid silicone, synthetic cerium oxide condensed aerosols or mixtures thereof. The lubricant may be optionally added in an amount of less than about 1% by weight of the pharmaceutical composition.

When it is desired to be orally administered as an aqueous suspension and/or elixirs, the active ingredients and the various sweetening or flavoring agents, colouring substances or dyes, and if desired emulsifiers and/or suspending agents It is combined with a diluent such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

Tablets may be uncoated or encapsulated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Oral formulations can also be presented as hard gelatin A capsule wherein the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsule, wherein the active ingredient is mixed with a water or oil medium (for example, peanut oil, liquid paraffin or olive oil).

Surfactants useful in forming the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. It is also possible to use a mixture of hydrophilic surfactants, a mixture of lipophilic surfactants, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant.

Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may typically have an HLB value of about 10 or less. The experimental parameter used to characterize the relative hydrophilicity and hydrophobicity of the nonionic amphoteric compound is the hydrophilic-lipophilic balance (〝HLB〞 value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oil, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions. Sex. Hydrophilic surfactants are generally considered to be those having an HLB value greater than about 10, as well as anionic, cationic or zwitterionic compounds which are generally not suitable for the HLB scale. Likewise, a lipophilic (i.e., hydrophobic) surfactant is a compound having an HLB value of equal to or less than about 10. However, the HLB value of the surfactant is only a brief guide that is commonly used to formulate industrial, pharmaceutical, and cosmetic emulsions.

The hydrophilic surfactant can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; Acid salts; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides, lecithin and hydrogenated lecithin, lysolecithin and hydrogenated lysolecithin, phospholipids and their derivatives , lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, sodium docusate, acylactylate, monoacids and diglycerides Ester mono- and diacetylated tartrates, amber mono- and di-glycerides, citric acid esters of mono- and diglycerides, and mixtures thereof.

Within the foregoing group, ionic surfactants include (by way of example): lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfates Salts, fatty acid salts, sodium sulphate, decyl lactate, mono and diglycerides, mono and diethoxylated tartrates, amber monobasic and diglycerides, monoacids and diglycerides The citric acid esters of the esters and mixtures thereof.

The ionic surfactant may be in the form of ionization of lecithin, lysolecithin, phospholipid choline, phospholipid oxime ethanolamine, phospholipid glycerol, phosphatidic acid, phospholipid lysine, lysophosphatidylcholine, hemolysis Phospholipids, ethanolamine, lysophosphatidylcholine glycerol, lysophosphatidic acid, lysophospholipid, lysine, PEG-phospholipid, ethanolamine, PVP-phospholipid, ethanolamine, fatty acid decyl ester, 2-lactyl lactate, sodium stearyl lactate, Amber deuterated monoglyceride, mono/diglyceride mono/diethylated tartrate, monoacid/diglyceride citrate, cholinsarcosine, hexanoate, Octanoate, phthalate, laurate, myristate, palmitate, oleate, ricinoleate, flax Oleic acid ester, linoleic acid oleate, stearate, lauryl sulfate, tetradecyl sulfate, polylactate, lauryl carnitine, palmitoyl carnitine, myristyl carnitine and Salt and mixture.

Hydrophilic nonionic surfactants can include, but are not limited to, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl polyethylene glycol glycerides, polyalkylene oxide alkyl ethers (such as polyethyl b) Glycol alkyl ether), polyalkylene oxide alkyl phenol (such as polyethylene glycol alkyl phenol), polyalkylene oxide alkyl phenol fatty acid ester (such as polyethylene glycol fatty acid monoester and polyethylene glycol fatty acid) Diester); polyethylene glycol glycerol fatty acid ester, polyglycerin fatty acid ester, polyalkylene oxide sorbitan fatty acid ester (such as polyethylene glycol sorbitan fatty acid ester); polyol and at least one Hydrophilic transesterification products of members of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyethylene oxide sterols, derivatives and analogs thereof; polyoxyethylation a vitamin and a derivative thereof; a polyethylene oxide-polypropylene oxide block copolymer and a mixture thereof; a polyethylene glycol sorbitan fatty acid ester; and a polyol and at least one group consisting of the following Hydrophilic transesterification products of members: triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerin, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol and sugar.

Other hydrophilic nonionic surfactants include (non-limiting) PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate , PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleic acid Ester, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 triolein Ester, PEG-32 dioleate, PEG-20 lauric acid glyceride, PEG-30 lauric acid glyceride, PEG-20 glyceryl stearate, PEG-20 oleic acid glyceride, PEG-30 oleic acid glyceride , PEG-30 lauric acid glyceride, PEG-40 lauric acid glyceride, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG -40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 tannic acid / caprylic acid glyceride, PEG-8 capric acid / caprylic acid glyceride, polyglycerol-10 laurate, PEG-30 Cholesterol, PEG-25 phytosterol, PEG-30 soy sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopherol PEG-100 succinate, PEG- 24 cholesterol, polyglycerol-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose Monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers (poloxamer).

Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters. , polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, monoacids and a lactic acid derivative of a glyceride; a polyol and at least one A hydrophobic transesterification product of a member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil soluble vitamins/vitamin derivatives; and mixtures thereof. Preferred lipophilic surfactants within this group include glycerin fatty acid esters, polypropylene glycol fatty acid esters, and mixtures thereof, or hydrophobicity of a polyol and at least one member of the group consisting of Transesterification products: vegetable oils, hydrogenated vegetable oils and triglycerides.

In one embodiment, the composition can include a solubilizing agent to ensure good dissolution and/or dissolution of the compounds of the invention and to minimize precipitation of the compounds of the invention. This can be especially important for compositions that are not used by the mouth, such as for the composition of the injection. Solubilizers may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

Examples of suitable solubilizing agents include, but are not limited to, the following: alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and isomers thereof, glycerin, pentaerythritol, sorbitol, mannitol Alcohol, diethylene glycol monoethyl ether (transcutol), dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol; hydroxypropyl methylcellulose and other cellulose derivatives, Cyclodextrin and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of from about 200 to about 6000 (such as tetrahydrofurfuryl PEG ether (glycofurol) or methoxy PEG); Amines and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone Pyridone, N-alkyl caprolactone Amine, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, triethyl citrate, tributyl citrate, citric acid Triethyl ester, ethyl oleate, ethyl octanoate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ - Valenturate and its isomers, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethylacetamide, isosorbide, N-A Pyrrolidone, monooctanoin, diethylene glycol monoethyl ether and water.

Mixtures of solubilizers can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl octanoate, dimethyl acetamide, N-methylpyrrolidone, N-hydroxyethyl pyrrolidone, poly Vinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, tetrahydrofuran polyglycol ether, diethylene glycol monoethyl ether, propylene glycol and isosorbide Dimethyl ether. Particularly preferred solubilizing agents include sorbitol, glycerin, triacetin, ethanol, PEG-400, tetrahydrofuran polyglycol ether, and propylene glycol.

The amount of solubilizing agent that can be included is not particularly limited. The amount of solubilizing agent given can be limited to biologically acceptable amounts, which can be readily determined by those skilled in the art. In some cases, it may be advantageous to include an amount of solubilizing agent that is well above the biologically acceptable amount, such as maximizing the concentration of the drug, and removing excess by conventional techniques (such as distillation or evaporation) prior to providing the patient composition. Solvent. Thus, if a solubilizer is present, the weight ratio may be 10% by weight, 25% by weight, 50% by weight, 100% by weight or up to about 200% by weight based on the combined weight of the drug and other excipients. To A very small amount of solubilizing agent, such as 5% by weight, 2% by weight, 1% by weight or even less, can also be used. The solubilizer can generally be present in an amount from about 1% to about 100% by weight, more typically from about 5% to about 25% by weight.

The composition may additionally comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include (non-limited) anti-adhesive agents, antifoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, colorants, odorants , opacifiers, suspending agents, binders, fillers, plasticizers, lubricants and mixtures thereof.

Additionally, an acid or base can be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, Synthetic aluminum citrate, synthetic water calcite, magnesium aluminum hydride, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, hydroxymethylamine Methane (TRIS) and the like. Also suitable bases are the salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, lemon Acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, -toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, citric acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. Can also be used Salts of polyprotonic acids such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate. When the base is a salt, the cation can be any suitable and pharmaceutically acceptable cation such as ammonium, alkali metal and alkaline earth metal. Examples can include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid , gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid Acid, succinic acid, citric acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid.

Pharmaceutical composition for injection

In selected embodiments, the invention provides a pharmaceutical composition for injection comprising a BTK inhibitor of formula (I) or formula (II) and a pharmaceutical excipient suitable for injection. The components and amounts of the agent in the composition are as described herein.

Forms which may be incorporated into the compositions of the invention for injection administration include aqueous or oily suspensions or emulsions (with sesame oil, corn oil, cottonseed oil or peanut oil), as well as elixirs, mannitol, dextrose or sterile aqueous solutions. , and similar pharmaceutical agents.

Aqueous solutions in saline are also known for injection. Can also Ethanol, glycerin, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils are used. Proper fluidity can be maintained, for example, by using a coating agent (such as lecithin) that maintains the desired particle size in the case of dispersions and by using a surfactant. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and thimerosal.

Sterile injectable solutions are prepared by incorporating the requisite amount of a BTK inhibitor of formula (I) or formula (II) with a suitable solvent such as those listed above, followed by filter sterilization, if desired. . Dispersions are generally prepared by incorporating the various sterilized active ingredients into a dispersion vehicle containing base dispersion medium and other ingredients from those enumerated above. In the examples of sterile powders for the preparation of sterile injectable solutions, some of the desired methods of preparation are vacuum drying and freeze drying techniques which yield the active ingredient plus any additional desired ingredients from previously sterile filtered solutions. powder.

Pharmaceutical composition for partial delivery

In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery comprising a BTK inhibitor of formula (I) or formula (II) and a pharmaceutical excipient suitable for transdermal delivery.

Formulations of the present invention are formulated in solid, semi-solid or liquid form suitable for topical or topical administration, such as gels, water-soluble jelly, creams, lotions, suspensions, foams, Powder, serum, ointment, solution, oil, paste, suppository, spray, lotion, salt An aqueous solution, a solution based on dimethyl hydrazine (DMSO). Carriers of higher density generally provide long-term exposure of the active ingredient to the area. Conversely, solution formulations provide for immediate exposure of the active ingredient to the selected area.

The pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients which are compounds which allow the therapeutic molecule to increase penetration through the stratum corneum barrier barrier of the skin or aid in the delivery of therapeutic molecules. Many of these penetration enhancing molecules are known to those trained in topical formulation techniques. Examples of such carriers and excipients include, but are not limited to, humectants (eg, urea), glycols (eg, propylene glycol), alcohols (eg, ethanol), fatty acids (eg, oleic acid), surfactants (eg, myristate) Propyl ester and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, hydrazine, hydrazine (such as menthol), amines, guanamines, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, Starch, cellulose derivatives, gelatin and polymers such as polyethylene glycol.

Another exemplary formulation for use in the methods of the invention employs a transdermal delivery device (〝Plate). A BTK inhibitor of formula (I) or formula (II) which is controlled in such amounts as to provide continuous or discontinuous perfusion with or without another active pharmaceutical ingredient can be used.

The construction and use of transdermal patches for the delivery of pharmaceutical agents are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. These patches are constructed for continuous, pulsed or as needed delivery of a pharmaceutical agent.

Other pharmaceutical compositions

The pharmaceutical composition may also be administered from the compositions described herein and one or more pharmaceutically acceptable agents suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural or spinal administration. Prepared by the agent. The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson et al., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, Principles of Drug Action, Third Edition, Churchill Livingston, N.Y., 1990.

The administration of a BTK inhibitor of formula (I) or formula (II) or a pharmaceutical composition of such compounds can be accomplished by any method which enables the delivery of the compound to the site of action. Such methods include the oral route, the intraduodenal route, the parenteral route (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or perfusion), topical (for example transdermal administration), and rectal administration. , by a catheter or stent via partial delivery, or by inhalation. Combinations of compounds can also be administered intra-fat or intrathecally.

Exemplary parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions, such as propylene glycol or aqueous dextrose. These dosage forms can be suitably buffered if desired.

The invention also provides kits. The kit includes BTK inhibitors of formula (I) or formula (II), alone or in combination, in suitable packages, and written materials that may include instructions for use, clinical research, and side effects. Such kits may also include information such as scientific literature bibliographies, package inserts, clinical trial results and/or summaries of such information and the like. To indicate or establish the activity and/or advantages of the composition, and/or to indicate other information for administration, administration, side effects, drug interaction, or useful to a health care provider. This information can be based on the results of various studies, such as the use of experimental animals involving in vivo models and studies based on human clinical trials. The kit may additionally contain another active pharmaceutical ingredient. Suitable packaging and additional articles of use (e.g., measuring cups for liquid formulations, foil wrappers that minimize exposure to air, and the like) are known in the art and can be incorporated into kits. The kits described herein may be provided, sold, and/or marketed to health care providers, including physicians, nurses, pharmacists, dispensing personnel, and the like. In selected implementations, the kit can also be sold directly to the consumer. In one embodiment, the invention provides a kit comprising a BTK inhibitor of Formula (I) or Formula (II) for use in the treatment of CLL or SLL, a hematological malignancy, or any of the other cancers described herein .

Dosage and drug delivery system

The amount of BTK inhibitor administered will depend on the mammal being treated, the severity of the condition or condition, the rate of administration, the handling of the compound, and the discretion of the prescribing physician. However, an effective dose is a single or divided dose in the range of from about 0.001 to about 100 mg/kg body weight per day, such as from about 1 to about 35 mg/kg/day. For a 70 kg person, the amount can be equivalent to about 0.05 to 7 grams per day, such as from about 0.05 to about 2.5 grams per day. In some instances, a dose value below the lower limit of the foregoing range may be more appropriate, although in other examples larger doses may be used without causing any deleterious side effects - for example by dividing the larger dose into a few small The dose is administered throughout the day.

In some embodiments, the BTK inhibitor of Formula (I) or Formula (II) is administered in a single dose. This administration is usually by injection for rapid introduction of the agent - for example by intravenous injection. However, other approaches may be used where appropriate. A single dose of a BTK inhibitor of formula (I) or formula (II) can also be used to treat an acute condition.

In some embodiments, the BTK inhibitor of Formula (I) or Formula (II) is administered in multiple doses. Administration may be once, twice, three times, four times, five times, six times or more than six times a day. Administration may be once a month, once every two weeks, once a week, or once every other day. In other embodiments, the administration of the BTK inhibitor of Formula (I) or Formula (II) is about once a day to about 6 times per day. In some embodiments, the administration of the BTK inhibitor of Formula (I) or Formula (II) is once daily, while in other embodiments, the BTK inhibitor of Formula (I) or Formula (II) The administration is administered twice daily, and in other embodiments, the administration of the BTK inhibitor of formula (I) or formula (II) is administered three times a day.

The BTK inhibitor of formula (I) or formula (II) can be administered continuously as long as necessary. In some embodiments, the BTK inhibitor of Formula (I) or Formula (II) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the BTK inhibitor of Formula (I) or Formula (II) is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the BTK inhibitor of Formula (I) or Formula (II) is administered chronically on a continuous basis - for example, for the treatment of chronic effects. In another embodiment, the BTK inhibitor of Formula (I) or Formula (II) is administered continuously for less than about 7 days. In yet another In the embodiment, continuous administration is for more than about 6, 10, 14, 28 days, two months, six months or one year. In some embodiments, continuous administration is achieved and maintained as necessary.

In some embodiments, an effective amount of a BTK inhibitor of Formula (I) or Formula (II) is in the range of from about 1 mg to about 500 mg, from about 10 mg to about 300 mg, and about 20 mg to About 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 Millimeters, from about 30 mg to about 70 mg, from about 40 mg to about 60 mg, from about 45 mg to about 55 mg, from about 48 mg to about 52 mg, from about 50 mg to about 150 mg, from about 60 mg to about 140 mg, From about 70 mg to about 130 mg, from about 80 mg to about 120 mg, from about 90 mg to about 110 mg, from about 95 mg to about 105 mg, from about 150 mg to about 250 mg, from about 160 mg to about 240 mg, about 170 Millions to about 230 mg, from about 180 mg to about 220 mg, from about 190 mg to about 210 mg, from about 195 mg to about 205 mg, or from about 198 mg to about 202 mg. In some embodiments, the effective amount of the BTK inhibitor of Formula (I) or Formula (II) is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175. Milligram, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, Or about 500 mg. In some embodiments, the effective dose of the BTK inhibitor of Formula (I) or Formula (II) is 25 Mill, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450 mg, 475 mg, or 500 mg.

In some embodiments, an effective dose of a BTK inhibitor of Formula (I) or Formula (II) is in the range of from about 0.01 mg/kg to about 4.3 mg/kg, from about 0.15 mg/kg to about 3.6. Mg/kg, from about 0.3 mg/kg to about 3.2 mg/kg, from about 0.35 mg/kg to about 2.85 mg/kg, from about 0.15 mg/kg to about 2.85 mg/kg, from about 0.3 mg to about 2.15 mg/kg, From about 0.45 mg/kg to about 1.7 mg/kg, from about 0.15 mg/kg to about 1.3 mg/kg, from about 0.3 mg/kg to about 1.15 mg/kg, from about 0.45 mg/kg to about 1 mg/kg, about 0.55 From mg/kg to about 0.85 mg/kg, from about 0.65 mg/kg to about 0.8 mg/kg, from about 0.7 mg/kg to about 0.75 mg/kg, from about 0.7 mg/kg to about 2.15 mg/kg, about 0.85 mg/kg From kilograms to about 2 mg/kg, from about 1 mg/kg to about 1.85 mg/kg, from about 1.15 mg/kg to about 1.7 mg/kg, from about 1.3 mg/kg to about 1.6 mg/kg, from about 1.35 mg/kg to About 1.5 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg /kg to about 3.4 mg / kg, about 2.4 mg / kg to about 3.3 mg / kg, about 2.6 mg / kg to about 3.15 mg / kg, about 2.7 mg / kg to about 3 mg / kg, about 2.8 mg / kg To about 3 mg/kg, or about 2.85 mg/kg to about 2.95 mg/kg. In some embodiments, the BTK inhibitor of formula (I) or formula (II) An effective dose is about 0.35 mg/kg, about 0.7 mg/kg, about 1 mg/kg, about 1.4 mg/kg, about 1.8 mg/kg, about 2.1 mg/kg, about 2.5 mg/kg, about 2.85 mg/kg. , about 3.2 mg / kg, about 3.6 mg / kg.

In some embodiments, the BTK inhibitor of Formula (I) or Formula (II) is administered at a dose of 10 to 400 mg BID, including 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg. Dosages of 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, and 400 mg BID.

An effective amount of a combination of a BTK inhibitor of formula (I) or formula (II) can be administered in a single or multiple doses, including the rectum, by any of the modes of administration of the accepted agent having similar utility. , buccal, sublingual, intranasal, and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

Methods for treating hematological malignancies, cancer and other diseases

In one embodiment, the invention relates to a method of treating human CLL comprising a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal, a solvent The step of administering the compound or hydrate to the person. In one embodiment, the invention relates to a method of treating a human SLL comprising administering a therapeutically effective amount of a BTK inhibitor of formula (II), or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal, a solvent The step of administering the compound or hydrate to the person. In one embodiment, the invention relates to a method of treating human CLL comprising a therapeutically effective amount of Formula (I) The step of administering the BTK inhibitor, or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof, to the human. In one embodiment, the invention relates to a method of treating a human SLL comprising a therapeutically effective amount of a BTK inhibitor of formula (I), or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal, a solvent The step of administering the compound or hydrate to the person.

In one embodiment, the invention relates to a method of treating human CLL comprising administering a BTK inhibitor of formula (II), or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof The procedure is administered to the individual in an administration system selected from the group consisting of 100 mg QD, 175 mg QD, 250 mg QD, 400 mg QD, and 100 mg BID. In one embodiment, the invention relates to a method of treating human CLL comprising administering a BTK inhibitor of formula (I), or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof The procedure is administered to the individual in an administration system selected from the group consisting of 100 mg QD, 175 mg QD, 250 mg QD, 400 mg QD, and 100 mg BID.

In one embodiment, the invention relates to the use of a composition of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof for the manufacture of a medicament for the treatment of CLL Where the treatment comprises the step of administering one or more doses of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof. In one embodiment, the invention relates to the use of a composition of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof for the manufacture of a medicament for the treatment of SLL Where the treatment comprises administering one or more agents A step of the formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof. In one embodiment, the invention relates to the use of a composition of formula (I) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof for the manufacture of a medicament for the treatment of CLL Where the treatment comprises the step of administering one or more doses of formula (I) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof. In one embodiment, the invention relates to the use of a composition of formula (I) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof for the manufacture of a medicament for the treatment of SLL Where the treatment comprises the step of administering one or more doses of formula (I) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof.

In one embodiment, the invention relates to a method of treating CLL in a mammal comprising administering a therapeutically effective amount of a BTK inhibitor of formula (II), or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal, The step of administering the solvate or hydrate to the mammal. In one embodiment, the invention relates to a method of treating SLL in a mammal comprising administering a therapeutically effective amount of a BTK inhibitor of formula (II), or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal, The step of administering the solvate or hydrate to the mammal. In one embodiment, the invention relates to a method of treating CLL in a mammal comprising administering a therapeutically effective amount of a BTK inhibitor of formula (I), or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal, The step of administering the solvate or hydrate to the mammal. In one embodiment, the invention relates to a method of treating SLL in a mammal comprising administering a therapeutically effective amount of a BTK inhibitor of formula (I), or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal, The step of administering the solvate or hydrate to the mammal. In one embodiment, the mammalian in any of the foregoing embodiments is selected from the group consisting of humans, canines, felines, and equines. In one embodiment, the mammal in any of the foregoing embodiments is a companion animal.

In one embodiment, the invention relates to a method of treating a human CLL subtype comprising administering a therapeutically effective amount of a BTK inhibitor of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or ester thereof, The step of administering the prodrug, co-crystal, solvate or hydrate to the mammal. Many CLL subtypes have been characterized. CLL is often classified by immunoglobulin heavy chain variable region (IgV _H ) mutation status in leukemia cells. RNDamle et al., Blood 1999, 94, 1840-47; TJ Hamblin et al., Blood 1999, 94, 1848-54. Patients with IgV _H mutations usually live longer than patients who do not have IgV _H mutations. ZAP70 expression (positive or negative) was also used to characterize CLL. LZ Rassenti et al., N. Engl. J. Med. 2004, 351, 893-901. Methylation by CAPG3 via ZAP-70 is also used to characterize CLL, for example by pyrosequencing. R. Claus et al., J. Clin. Oncol. 2012, 30, 2483-91; JAWoyach et al., Blood 2014, 123, 1810-17. CLL is also classified by disease stage under the Binet or Rai criteria. JLBinet et al., Cancer 1977, 40, 855-64; KRRai, T. Han, Hematol. Oncol. Clin. North Am. 1990, 4, 447-56. Other common mutations, such as 11p deletions, 13q deletions, and 17p deletions, can be assessed using well-known techniques, such as fluorescence in situ hybridization (FISH). In one embodiment, the invention relates to a method of treating human CLL comprising a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal, a solvent The step of administering the compound or hydrate to the mammal, wherein the CLL line is selected from the group consisting of IgV _H mutation-negative CLL, ZAP-70-positive CLL, CLL of ZAP-70 methylated at CpG3 CD38-positive CLL, chronic lymphocytic leukemia characterized by 17p13.1 (17p) deletion and CLL characterized by 11q22.3 (11q) deletion.

In one embodiment, the invention relates to a method of treating human CLL comprising a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal, a solvent The step of administering the compound or hydrate to the mammal, wherein the CLL undergoes a Richter transformation. Methods for assessing the Rickert's transformation (also known as Richter's syndrome) are described in P. Jain and S. O'Brien, Oncology, 2012, 26, 1146-52. The Ricker's transformation is a CLL subtype observed in 5-10% of patients. It involves the development of invasive lymphoma from CLL and usually has a poor prognosis.

In one embodiment, the invention relates to a method of treating a human CLL subtype comprising a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal And a step of administering a solvate or hydrate to the mammal, wherein the CLL subtype is for increasing mononuclear cells in the peripheral blood when measured by a period of treatment of a group selected from the group consisting of: (II) CLL subtype of NK cells: about 14 days, about 28 days, about 56 days, about 1 month, about 2 months, about 3 months, about 6 months, and about 1 year, and wherein the term 〝 about 〞 Means +/- 2 days Measurement interval.

In one embodiment, the invention relates to a method of treating chronic lymphocytic leukemia in a patient, wherein the chronic lymphocytic leukemia is chronic lymphocytic leukemia in a patient susceptible to lymphocytosis. In one embodiment, the invention relates to a method of treating chronic lymphocytic leukemia in a patient, wherein the chronic lymphocytic leukemia is a disease exhibiting lymphocytosis caused by a condition selected from the group consisting of Chronic lymphocytic leukemia: viral infection, bacterial infection, protozoal infection, and splenectomy status. In one embodiment, the viral infection in any of the foregoing embodiments is selected from the group consisting of infectious mononucleosis, hepatitis, and cytomegalovirus. In one embodiment, the bacterial infection in any of the foregoing embodiments is selected from the group consisting of pertussis, tuberculosis, and brucellosis.

The above methods can be used as first-line cancer therapies or after treatment with chemotherapeutic active pharmaceutical ingredients including the following: cyclophosphamide, fludarabine, cyclophosphamide and fludarabine (FC chemotherapy) and benzene Chlorambucil. The above method can also be adjuvanted with immunotherapy by monoclonal antibodies, such as anti-CD52 monoclonal antibody (alemtuzumab). In one embodiment, the invention relates to a method of treating human CLL comprising a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt, ester, prodrug, co-crystal, solvent thereof a step of administering the compound or hydrate to the human, and additionally comprising the step of administering to the human an active pharmaceutical ingredient selected from the group consisting of cyclophosphamide, fludarabine, cyclophosphamide, Chlorambucil, their salts, esters, prodrugs, co-crystals, solvates or water Combinations, and combinations thereof, and alemtuzumab, antigen-binding fragments, derivatives, conjugates, variants thereof, and radioisotope-labeled complexes.

In one embodiment, the invention relates to a method of treating a human hematological malignancy comprising comprising a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal The step of administering the solvate or hydrate to the human. Hematological malignancies include CLL and SLL, as well as other blood cancers, including B-cell malignancies. In one embodiment, the invention relates to a method of treating a human hematological malignancy selected from the group consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B-cell acute lymphoblastic leukemia (B-ALL), Waldenstrom's macroglobulinemia WM), Burkitt's lymphoma, multiple myeloma, and spinal fibrosis, the method comprising administering a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester thereof, a prodrug, A step of co-crystals, solvates or hydrates.

In one embodiment, the invention relates to a method of treating an NHL selected from the group consisting of: painless NHL and invasive NHL, the method comprising administering a therapeutically effective amount of a BTK inhibitor of formula (II) or A step of a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof.

In one embodiment, the invention relates to a method of treating a DLBCL selected from the group consisting of activated B cell-like diffuse large B-cell lymphoma (DLBCL-ABC) and germline center B-cell-like Diffuse large B-cell lymphoma (DLBCL-GCB), the method comprising administering a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate thereof Or the step of hydrate.

In one embodiment, the invention is directed to a method of treating MCL selected from the group consisting of a coat of MCL, a nodular MCL, a diffuse MCL, and a maternal MCL (also known as a parental cell variant MCL). This method comprises the step of administering a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof.

In one embodiment, the invention relates to a method of treating a B-ALL selected from the group consisting of: early pre-B-cell B-ALL, pre-B-cell B-ALL, and mature B-cell B-ALL (also known as B-ALL) In the case of Burkitt's leukemia, the method comprises the step of administering a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof. .

In one embodiment, the invention is directed to a method of treating Burkitt's lymphoma selected from the group consisting of sporadic Burkitt's lymphoma, regional Burkitt's lymphoma, and human immunodeficiency Viral-associated Burkitt's lymphoma, the method comprising administering a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof A step of.

In one embodiment, the invention is directed to a method of treating multiple myeloma selected from the group consisting of hyperdiploid multiple myeloma and non-hyperploid multiple myeloma, the method comprising administering Treatment An effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof.

In one embodiment, the invention is directed to a method of treating spinal fibrosis selected from the group consisting of primary spinal fibrosis (also known as chronic idiopathic spinal fibrosis) and secondary erythropoiesis Cardiac fibrosis of a multidrug or orthostatic thrombocytosis comprising administering a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal, or a solvate thereof Or the step of hydrate.

In one embodiment, the invention relates to a method of treating a human hematological malignancy subtype comprising administering a therapeutically effective amount of a BTK inhibitor of formula (II), or a pharmaceutically acceptable salt or ester thereof, a prodrug, A eutectic, solvate or hydrate is administered to the human, wherein the blood malignant disease subtype is a mononuclear ball in the peripheral blood that is measured after a period of treatment of a segment selected from the group consisting of: (II) And NK cell blood malignant disease subtype: about 14 days, about 28 days, about 56 days, about 1 month, about 2 months, about 3 months, about 6 months, and about 1 year, and wherein the term 〝 Approximately +/- 2 days of measurement interval, and wherein the hematological malignancy is selected from the group consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), filtration Follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B-cell acute lymphoblastic leukemia (B-ALL), Waldenstrom's macroglobulinemia (WM) ), Burkitt's lymphoma, multiple myeloma, and spinal fibrosis.

Treating cancer in patients susceptible to thrombosis

In selected embodiments, the invention provides a method of treating cancer in a human susceptible to platelet-mediated thrombosis, comprising administering a therapeutically effective amount of a BTK inhibitor, or a pharmaceutically acceptable salt thereof, co-crystal, hydration a step of a substance, solvate or prodrug. In one embodiment, the invention provides a method of treating cancer in a human susceptible to platelet-mediated thrombosis, comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is of formula (II) or A pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug. In one embodiment, the invention provides a method of treating cancer in a human susceptible to platelet-mediated thrombosis, comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is of formula (II) or A pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug, additionally comprising the step of administering a therapeutically effective amount of a pharmaceutical component of anticoagulant activity or anti-platelet activity.

In selected embodiments, the BTK inhibitor of formula (I) or formula (II) and the pharmaceutical component of anticoagulant activity or antiplatelet activity are administered sequentially. In selected embodiments, the BTK inhibitor of formula (I) or formula (II) is administered in combination with an anticoagulant or anti-platelet active pharmaceutical ingredient. In selected embodiments, the BTK inhibitor of formula (I) or formula (II) is administered prior to the pharmaceutical component of anticoagulant activity or antiplatelet activity. In selected embodiments, the BTK inhibitor of formula (I) or formula (II) is administered after the anti-coagulant or anti-platelet activity pharmaceutical ingredient.

In selected embodiments, the invention provides a method of treating cancer in a person susceptible to thrombocytosis of platelets, comprising administering A step of treating an effective amount of a BTK inhibitor, wherein the BTK inhibitor is of formula (II), and wherein the cancer is selected from the group consisting of CLL, SLL, NHL, DLBCL, FL, MCL, Hodgkin's lymph Tumor, B-ALL, WM, Burkitt's lymphoma, multiple myeloma, and spinal fibrosis, the method comprising administering a therapeutically effective amount of a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt thereof or The step of an ester, prodrug, co-crystal, solvate or hydrate.

In selected embodiments, the invention provides a method of treating cancer in a human susceptible to platelet-mediated thrombosis, comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is of formula (II), And wherein the cancer is selected from the group consisting of acute myeloid leukemia, squamous cell tumor (including chronic myelogenous leukemia), bladder cancer, head and neck tumors, pancreatic duct adenoma (PDA), pancreas Cancer, colon tumor, breast tumor, breast cancer, fibrosarcoma, mesothelioma, renal cell tumor, tumor, thymoma, prostate cancer, colorectal cancer, ovarian cancer, thymic carcinoma, brain cancer, squamous cell carcinoma, skin Cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral and oropharyngeal cancer, gastric adenocarcinoma, stomach cancer, cervical cancer, kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer , esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immunodeficiency syndrome (AIDS)-related cancer (such as lymphoma and Kaposi's sarcoma), virus-induced cancer, glia Cell tumor, esophageal tumor, hematological tumor, non-small cell lung cancer, esophageal cancer, hepatitis C virus infection, hepatoma, metastatic colon cancer, multiple myeloma, ovarian tumor, pancreatic tumor, renal cell tumor, Small Cell Lung Cancer And stage IV melanoma.

In one embodiment, the invention provides a method of treating cancer in a human susceptible to platelet-mediated thrombosis, comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is of formula (I) or (II) or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, wherein the cancer is a blood malignant disease, and wherein the blood malignant disease is selected from the group consisting of chronic lymphocytes Leukemia, B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma.

In one embodiment, the invention provides a method of treating cancer in a human susceptible to platelet-mediated thrombosis, comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is of formula (II) or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug, the method additionally comprising the step of administering a therapeutically effective amount of a pharmaceutical component of anticoagulant activity or anti-platelet activity, wherein the cancer is a hematological malignancy And wherein the hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia, B cell acute lymphoblastic leukemia, and non-Hodgkin's lymphoma.

Preferred anti-platelet agents and anticoagulants for use in the methods of the invention include, but are not limited to, cyclooxygenase inhibitors (e.g., aspirin), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel) And ticlopidine), phosphodiesterase inhibitors (eg cilostazol), glycoprotein IIb/IIIa inhibitors (eg abciximab, eptifibatide and tirofiban), adenosine reabsorption Inhibitors (such as dipyridamole) and acetylsalicylic acid (aspirin). Examples of anti-platelet active pharmaceutical ingredients for use in the methods of the invention include vinegar nitrate Coumarin, anagrelide, anagrelide hydrochloride, abciximab, aloprostat, antithrombin, apixaban, argatroban, aspirin, aspirin and extended release dipyridamole Mo, beraprost, betrixaban, bivalirudin, carbachol calcium, cilostazol, clopidogrel, clopidogrel hydrogen sulphate, cloncloma, dabigatran etexilate, daring Shaban, dalteparin, dalteparin sodium, defibrin, dicoumarin, dibenzophenone, dipyridamole, diltazole, diazepam, etoxaban, enoxaparin, enoxaparin Sodium, eptifibatide, fondaparinux, fondaparinux, heparin, heparin sodium, heparin calcium, idaparin, idaparin sodium, iloprost, indobufen, lepirudine, low molecular weight heparin, Melagatran, nadroparin, omeproxaban, paparin, benzodiazepine, phenylpropanol, prasugrel, pyrotoxamine, prostacyclin, rema spot, reiver heparin, Rivaroxaban, sulodexide, truroban, trubalban, tigrelad, ticlopidine, ticlopidine hydrochloride, tinzaparin, tinza Sodium, tirofiban, tirofiban hydrochloride, trirobilil, trifluralin sodium, triflumuron, flappasa, warfarin, warfarin sodium, ximegat group, Salts, solvates, hydrates, co-crystals, prodrugs, and various combinations thereof.

In one embodiment, the invention provides a method of treating cancer in a human susceptible to platelet-mediated thrombosis, comprising the step of administering a therapeutically effective amount of a BTK inhibitor, wherein the BTK inhibitor is of formula (II) or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug, the method additionally comprising the step of administering a therapeutically effective amount of a pharmaceutical component of anticoagulant activity or anti-platelet activity, wherein the anticoagulant activity or The pharmaceutical ingredient for anti-platelet activity is selected from the group consisting of: vinegar nitrate Coumarin, anagrelide, anagrelide hydrochloride, abciximab, aloprostat, antithrombin, apixaban, argatroban, aspirin, aspirin and extended release dipyridamole Mo, beraprost, betrixaban, bivalirudin, carbachol calcium, cilostazol, clopidogrel, clopidogrel hydrogen sulphate, cloncloma, dabigatran etexilate, daring Shaban, dalteparin, dalteparin sodium, defibrin, dicoumarin, dibenzophenone, dipyridamole, diltazole, diazepam, etoxaban, enoxaparin, enoxaparin Sodium, eptifibatide, fondaparinux, fondaparinux, heparin, heparin sodium, heparin calcium, idaparin, idaparin sodium, iloprost, indobufen, lepirudine, low molecular weight heparin, Melagatran, nadroparin, omeproxaban, paparin, benzodiazepine, phenylpropanol, prasugrel, pyrotoxamine, prostacyclin, rema spot, reiver heparin, Rivaroxaban, sulodexide, truroban, trubalban, tigrelad, ticlopidine, ticlopidine hydrochloride, tinzaparin, tinza Sodium, tirofiban, tirofiban hydrochloride, trirobilil, trifluralin sodium, triflumuron, flappasa, warfarin, warfarin sodium, ximegat group, Salts, solvates, hydrates, co-crystals, prodrugs, and various combinations thereof.

Combination of BTK inhibitor and anti-CD20 antibody

The BTK inhibitors of formula (I) and formula (II) can also be safely co-administered with antibodies to immunotherapies, such as anti-CD20 antibodies: rituximab, octetuzumab, atorvazumab, vitamins Tocilizumab, tocilizumab and isobezumab, and/or antigen-binding fragments, derivatives, conjugates, variants thereof and radioisotope-labeled complexes, such BTK The inhibitors can be given alone or in combination with conventional active pharmaceutical ingredients of therapeutic therapies, such as those described herein. The CD20 antigen (also known as human B-lymphocyte-restricted differentiation antigen, Bp35 or B1) is found on the surface of the general sputum B 〞 and mature B lymphocytes (including malignant B lymphocytes). L. M. Nadler et al. J. Clin. Invest. 1981, 67, 134-40; P. Stashenko et al. J. Immunol. 1980, 139, 3260-85. The CD20 antigen is a glycosylated integral membrane protein having a molecular weight of about 35 kD. T. F. Tedder et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 208-12. CD20 is also expressed on most B-cell non-Hodgkin's lymphoma cells, but not on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. Anti-CD20 antibodies are currently used in the treatment of many hematological malignancies, including for painless NHL, invasive NHL, and CLL/SLL. Ha. Mat., et al., Haemmatologica 2010, 95, 135-43; S. A. Beers et al., Sem. Hematol. 2010, 47, 107-14; C. Klein et al., mAbs 2013, 5, 22-33.

In one embodiment, the invention relates to a method of treating a human hematological malignancy comprising BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate thereof Or a step of administering the hydrate to the human, and additionally comprising the step of administering an anti-CD20 antibody, wherein the anti-CD20 antibody is a monoclonal antibody or antigen-binding fragment, derivative, conjugate, variant thereof and radioisotope-labeled Complex. In one embodiment, the invention relates to a method of treating a human hematological malignancy comprising BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate thereof Or a step of administering the hydrate to the human, and additionally comprising the step of administering an anti-CD20 antibody, wherein the anti-CD20 monoclonal antibody or antigen-binding fragment, derivative, conjugate, variant thereof, and radioisotope thereof the labeled complex, and wherein the anti-CD20 antibody is selected from the group to consisting of K _D of specifically binding to a human CD20: 1 × 10 ^-7 M or less, 5 × 10 ^-8 M or less, 1 × 10 ^-8 M or less, and 5 × 10 ^-9 M or less.

In one embodiment, the invention relates to a method of treating human CLL or SLL comprising a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate thereof Or a step of administering the hydrate to the human, and additionally comprising the step of administering an anti-CD20 antibody, wherein the anti-CD20 antibody is a monoclonal antibody or antigen-binding fragment, derivative, conjugate, variant thereof and radioisotope-labeled Complex. In one embodiment, the invention relates to a method of treating human CLL or SLL comprising a BTK inhibitor of formula (II) or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate thereof Or a step of administering the hydrate to the human, and additionally comprising the step of administering an anti-CD20 antibody, wherein the anti-CD20 monoclonal antibody or antigen-binding fragment, derivative, conjugate, variant thereof, and radioisotope thereof the labeled complex, and wherein the anti-CD20 antibody is selected from the group to consisting of K _D of specifically binding to a human CD20: 1 × 10 ^-7 M or less, 5 × 10 ^-8 M or less, 1 × 10 ^-8 M or less, and 5 × 10 ^-9 M or less.

In selected embodiments, the BTK inhibitor of formula (I) or formula (II) and the anti-CD20 monoclonal antibody system are administered sequentially. In selected embodiments, the BTK inhibitor of formula (I) or formula (II) and the anti-CD20 monoclonal antibody resistance system Combined investment. In selected embodiments, the BTK inhibitor of Formula (I) or Formula (II) is administered prior to the anti-CD20 monoclonal antibody. In selected embodiments, the BTK inhibitor of formula (I) or formula (II) is administered after the anti-coagulant or anti-platelet activity pharmaceutical ingredient. In selected embodiments, the BTK inhibitor of formula (I) or formula (II) and the anti-CD20 monoclonal antibody system are administered in the same period, and the BTK inhibitor is administered in anti-CD20 monoclonal antibody. Continue to vote later.

In one embodiment, the anti-CD20 monoclonal antibody is rituximab or an antigen binding fragment, derivative, conjugate, variant thereof, and a radioisotope-labeled complex. Human monoclonal antibody, and which structure comprises an immunoglobulin IgG1 κ, containing murine light and heavy chain variable region sequences and human constant region sequences - rituximab oriented against the chimeric murine CD20. Rituximab consists of two 451 amino acid heavy chains and two 213 amino acid light chains. The amino acid sequence of the heavy chain of rituximab is set forth in SEQ ID NO: 1. The amino acid sequence of the light chain of rituximab is set forth in SEQ ID NO:2. Rituximab is commercially available and its properties and use in cancer and other diseases are described in more detail in W. Rastetter et al. Ann. Rev. Med. 2004, 55, 477-503 and GLP1osker and DPFiggett, Drugs , 2003, 63, 803-43. In one embodiment, the anti-CD20 monoclonal antibody is an anti-CD20 biomimetic monoclonal antibody that is approved by the drug regulatory authorities with reference to rituximab. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% heavy chain sequence identity relative to SEQ ID NO:1. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% light chain sequence identity to SEQ ID NO:2. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% heavy chain sequence identity relative to SEQ ID NO:1. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% light chain sequence identity to SEQ ID NO:2. In one embodiment, the anti-CD20 monoclonal antibody has greater than 98% heavy chain sequence identity relative to SEQ ID NO:1. In one embodiment, the anti-CD20 monoclonal antibody has greater than 98% light chain sequence identity to SEQ ID NO:2. In one embodiment, the anti-CD20 monoclonal antibody has greater than 99% heavy chain sequence identity relative to SEQ ID NO:1. In one embodiment, the anti-CD20 monoclonal antibody has greater than 99% light chain sequence identity to SEQ ID NO:2.

In one embodiment, the anti-CD20 monoclonal antibody is omebituzumab or an antigen-binding fragment, derivative, conjugate, variant thereof, and a radioisotope-labeled complex. Orbitolizumab is also known as Afutuzumab or GA-101. Obitocilizumab is a humanized monoclonal antibody directed against CD20. The amino acid sequence of the heavy chain of octopuzumab is set forth in SEQ ID NO:3. The amino acid sequence of the light chain of octopuzumab is set forth in SEQ ID NO:4. The use of octopuzumab on the market and its properties and use in cancer and other diseases are described in more detail in T. Robak, Curr. Opin. Investig. Drugs 2009, 10, 588-96. In one embodiment, the anti-CD20 monoclonal antibody is an anti-CD20 biomimetic monoclonal antibody that is approved by the drug regulatory authority with reference to oxifizumab. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% heavy chain sequence identity relative to SEQ ID NO:3. In one implementation In an aspect, the anti-CD20 monoclonal antibody has greater than 90% light chain sequence identity relative to SEQ ID NO:4. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% heavy chain sequence identity relative to SEQ ID NO:3. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% light chain sequence identity relative to SEQ ID NO:4. In one embodiment, the anti-CD20 monoclonal antibody has greater than 98% heavy chain sequence identity relative to SEQ ID NO:3. In one embodiment, the anti-CD20 monoclonal antibody has greater than 98% light chain sequence identity relative to SEQ ID NO:4. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% heavy chain sequence identity relative to SEQ ID NO:3. In one embodiment, the anti-CD20 monoclonal antibody has greater than 99% light chain sequence identity relative to SEQ ID NO:4. In one embodiment, the anti-CD20 monoclonal antibody oxifizumab is immunoglobulin G1, anti-(human B lymphocyte antigen CD20 (transmembrane 4-domain subfamily A member 1, B lymphocyte surface) Antigen B1, Leu-16 or Bp35)), humanized mouse monoclonal epitapuzumab des-CH3107-K-γ1 heavy chain (222-219')-disulfide and humanized mouse single Obitocilizumab κ light chain dimer (228-228": 231-231") - double disulfide antibody.

In one embodiment, the anti-CD20 monoclonal antibody is ovalimumab or an antigen-binding fragment, derivative, conjugate, variant or radioisotope-labeled complex thereof. Atramuzumab is described in B. D. Cheson, J. Clin. Oncol. 2010, 28, 3525-30. The crystal structure of the Fab fragment of ovamuzumab has been reported in Protein Data Bank reference 3GIZ and Du et al. Mol. Immunol. 2009, 46, 2419-2423 in. Autumuzumab is commercially available and its preparation, properties, and use in cancer and other diseases are described in more detail in U.S. Patent No. 8,529,202 B2, the disclosure of which is incorporated herein by reference. In one embodiment, the anti-CD20 monoclonal antibody is an anti-CD20 biomimetic monoclonal antibody that is approved by the drug regulatory authority with reference to oxalimumab. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% variable heavy chain sequence identity relative to SEQ ID NO:5. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% variable light chain sequence identity relative to SEQ ID NO: 6. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% variable heavy chain sequence identity relative to SEQ ID NO:5. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% variable light chain sequence identity relative to SEQ ID NO: 6. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% variable heavy chain sequence identity relative to SEQ ID NO:5. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% variable light chain sequence identity relative to SEQ ID NO: 6. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% variable heavy chain sequence identity relative to SEQ ID NO:5. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% variable light chain sequence identity relative to SEQ ID NO: 6. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% Fab fragment heavy chain sequence identity relative to SEQ ID NO:7. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% Fab fragment light chain sequence identity relative to SEQ ID NO:8. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% relative to SEQ ID NO: 7. Fab fragment heavy chain sequence identity. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% Fab fragment light chain sequence identity relative to SEQ ID NO:8. In one embodiment, the anti-CD20 monoclonal antibody has greater than 98% Fab fragment heavy chain sequence identity relative to SEQ ID NO: 7. In one embodiment, the anti-CD20 monoclonal antibody has greater than 98% Fab fragment light chain sequence identity relative to SEQ ID NO:8. In one embodiment, the anti-CD20 monoclonal antibody has greater than 99% Fab fragment heavy chain sequence identity relative to SEQ ID NO:7. In one embodiment, the anti-CD20 monoclonal antibody has greater than 99% Fab fragment light chain sequence identity relative to SEQ ID NO:8. In one embodiment, the anti-CD20 monoclonal antibody ovalimumab is immunoglobulin G1, anti-(human B lymphocyte antigen CD20 (transmembrane 4-domain subfamily A member 1, B lymphocyte surface antigen B1) , Leu-16 or Bp35)), human single ovalimumab CD20 γ1 heavy chain (225-214')-disulfide and human single aumuizumab CD20 κ light chain dimer (231-231" :234-234")-Disulfide antibody.

In one embodiment, the anti-CD20 monoclonal antibody is vititolizumab or an antigen-binding fragment, derivative, conjugate, variant or radioisotope-labeled complex thereof. Vittozumab is also known as hA20. Vittozumab is described in Leuk. Lymphoma 2010, 51, 747-55 by D. M. Goldenberg et al. In one embodiment, the anti-CD20 monoclonal antibody is an anti-CD20 biomimetic monoclonal antibody referenced by a drug regulatory authority with reference to vitolizumab. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% heavy chain sequence identity relative to SEQ ID NO:9. In a In an embodiment, the anti-CD20 monoclonal antibody has greater than 90% light chain sequence identity relative to SEQ ID NO: 10. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% heavy chain sequence identity relative to SEQ ID NO:9. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% light chain sequence identity relative to SEQ ID NO: 10. In one embodiment, the anti-CD20 monoclonal antibody has greater than 98% heavy chain sequence identity relative to SEQ ID NO:9. In one embodiment, the anti-CD20 monoclonal antibody has greater than 98% light chain sequence identity relative to SEQ ID NO: 10. In one embodiment, the anti-CD20 monoclonal antibody has greater than 99% heavy chain sequence identity relative to SEQ ID NO:9. In one embodiment, the anti-CD20 monoclonal antibody has greater than 99% light chain sequence identity relative to SEQ ID NO: 10. In one embodiment, the anti-CD20 monoclonal antibody ovalimumab is immunoglobulin G1, anti-(human B lymphocyte antigen CD20 (transmembrane 4-domain subfamily A member 1, Leu-16, Bp35) ), [218-arginine, 360-glutamic acid, 362-methionine] humanized mouse single hA20 γ1 heavy chain (224-213')-disulfide and humanized mouse single Strain hA20 κ light chain (230-230": 233-233") - double disulfide dimer.

In one embodiment, the anti-CD20 monoclonal antibody is tocilizumab or an antigen-binding fragment, derivative, conjugate, variant or radioisotope-labeled complex thereof. In one embodiment, the anti-CD20 monoclonal antibody is a ¹³¹ I-labeled tocilizumab. In one embodiment, the anti-CD20 monoclonal antibody is an anti-CD20 biomimetic monoclonal antibody that is approved by the drug regulatory authority with reference to tositumomab. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% heavy chain sequence identity relative to SEQ ID NO:11. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% light chain sequence identity relative to SEQ ID NO: 12. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% heavy chain sequence identity relative to SEQ ID NO:11. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% light chain sequence identity relative to SEQ ID NO: 12. In one embodiment, the anti-CD20 monoclonal antibody has greater than 98% heavy chain sequence identity relative to SEQ ID NO:11. In one embodiment, the anti-CD20 monoclonal antibody has greater than 98% light chain sequence identity relative to SEQ ID NO: 12. In one embodiment, the anti-CD20 monoclonal antibody has greater than 99% heavy chain sequence identity relative to SEQ ID NO:11. In one embodiment, the anti-CD20 monoclonal antibody has greater than 99% light chain sequence identity relative to SEQ ID NO: 12.

In one embodiment, the anti-CD20 monoclonal antibody is isobezumab or an antigen-binding fragment, derivative, conjugate, variant or radioisotope-labeled complex thereof. The activation form of isobemozumab used in the treatment is thitumumb tiuxetan. When used with isobezumab, the chelate tiuxetan (diexe) Ethylenetriamine pentaacetic acid) is complexed with a radioactive isotope such as ⁹⁰ Y or ¹¹¹ In. In one embodiment, the anti-CD20 monoclonal antibody is tiltanisemuzumab or a radioisotope-labeled complex thereof. In one embodiment, the anti-CD20 monoclonal antibody is an anti-CD20 biomimetic monoclonal antibody that is approved by the drug regulatory authority with reference to tositumomab. In one embodiment, the anti-CD20 monoclonal antibody has relative to the SEQ ID NO: 13 and greater than 90% heavy chain sequence identity. In one embodiment, the anti-CD20 monoclonal antibody has greater than 90% light chain sequence identity relative to SEQ ID NO: 14. In an embodiment In the anti-CD20 monoclonal antibody, greater than 95% of the heavy chain sequence identity is relative to SEQ ID NO: 13. In one embodiment, the anti-CD20 monoclonal antibody has greater than 95% relative to SEQ ID NO: 14. Light chain sequence identity. In one embodiment, the anti-CD20 monoclonal antibody has an antibody relative to S EQ ID NO: 13 and greater than 98% heavy chain sequence identity. In one embodiment, the anti-CD20 monoclonal antibody has greater than 98% light chain sequence identity relative to SEQ ID NO: 14. In an aspect, the anti-CD20 monoclonal antibody has greater than 99% heavy chain sequence identity relative to SEQ ID NO: 13. In one embodiment, the anti-CD20 monoclonal antibody has greater than SEQ ID NO: 14 99% light chain sequence identity.

In one embodiment, the antigen-binding fragment selected from the group consisting of octopuzumab, ovalimumab, vitolizumab, tocilizumab, and isobezumab, and/or the same, is derived from The anti-CD20 anti-system of the group consisting of a conjugate, a variant, and a radioisotope-labeled complex is administered to the individual by infusing a dose selected from the group consisting of: about 100 mg, about 200 Millimeters, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, About 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, and about 2000 Mg. In one embodiment, the anti-CD20 anti-system is administered weekly. In one embodiment, the anti-CD20 anti-system is administered monthly. In one embodiment, the anti-CD20 anti-system is administered at a lower initial dose, which is increased upon subsequent administration at intervals of monthly administration. For example, a first infusion can deliver 300 mg of anti-CD20 antibody, and then a weekly dose of 2,000 mg of anti-CD20 antibody can be delivered over 8 weeks, followed by a monthly dose of 2,000 mg of anti-CD20 antibody. During any of the foregoing embodiments, the BTK inhibitor of Formula (I) or Formula (II) can be administered in the above dosages once daily, twice daily, or at different intervals as described above.

In one embodiment, the invention provides a kit for treating any of CLL or SLL, a hematological malignancy, a B cell malignancy, or other disease described herein, comprising: comprising formula (I) or A composition of a BTK inhibitor of formula (II) and a composition comprising an anti-CD20 antibody selected from the group consisting of rituximab, octetuzumab, ovalimumab, vitopa Monoclonal antibody, tocilizumab, and isobezumab, and their antigen-binding fragments, derivatives, conjugates, variants, and radioisotope-labeled complexes. The composition is usually two pharmaceutical compositions. The kit is used to co-administer anti-CD20 antibodies and BTK inhibitors simultaneously or separately to treat any of CLL or SLL, hematological malignancies, B cell malignancies, or other diseases described herein.

Example

The embodiments contained herein are now described with reference to the following examples. The embodiments are provided for illustrative purposes only and are included herein The disclosure should not be construed as being limited to the embodiments, but should be construed to include any and all variations that are apparent from the teachings provided herein.

Example 1 - Preclinical Studies of Second Generation BTK Inhibitors for CLL/SLL

BTK inhibitor ibupotinib ((1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine- 1-yl]piperidin-1-yl]prop-2-en-1-one) is a first-generation BTK inhibitor. In clinical trials as a single drug therapy in individuals with hematologic malignancies, Ibubutin Nitrogen is generally well tolerated at dose values up to 840 mg (the highest test dose). RHAdvani et al., J. Clin. Oncol. 2013, 31, 88-94; JC Byrd et al., N. Engl. .Med. 2013, 369, 32-42; ML Wang et al., N. Engl. J. Med. 2013, 369, 507-16. There is no significant maximum tolerated dose (MTD) within the dose range tested. The overall tolerable duration of the drug was found to be extended to >2 years. No individual had tumor lysis syndrome. No significant myelosuppressive pattern was associated with ibupotinib treatment. No cyclically related CD4 ⁺ T was indicated for drug-related reduction. Cell or serum immunoglobulin. Adverse events that are clearly associated with the study drug include diarrhea and rash.

In individuals with multiple pre-treatments of non-Hodgkin's lymphoma (NHL), ibbutinib showed substantial anti-tumor activity, inducing prolonged regression of lymphadenopathy and splenomegaly in most individuals. Improvements in disease-related anemia and thrombocytopenia were observed. Type of individual with CLL There have been significant changes. A single dose of ibbutinib causes a rapid and substantial reduction in lymph node size, with redistribution of malignant sites to the peripheral blood. An increase in asymptomatic absolute lymphocyte count (ALC) was observed, which reached maximum and usually decreased during the first few months of treatment, but may persist in some individuals, or in individuals who discontinued and resumed drug therapy. Repeat to see.

In summary, these data for ibbutinib support the potential benefit of selective BTK inhibition in treating individuals with recurrent lymphoma. However, although it is highly potent in inhibiting BTK, Ibubinib also shows in vitro activity against other kinases having cysteine at the same position as Cys481 in BTK, and the drug is covalently bonded to other kinases. For example, Ibbutinib inhibits the epidermal growth factor receptor (EGFR), which may be the cause of diarrhea and rash associated with ibufitinib. In addition, Ibubinib is a matrix of both cytochrome P450 (CYP) enzymes 3A4/5 and 2D6, which increases the likelihood of drug-drug interaction. These unfavorable conditions support the development of alternative BTK inhibitors for lymphoma therapy.

The preclinical selectivity and efficacy profile of the second generation (B) BTK inhibitor was compared to the first generation BTK inhibitor, Ibupotinib. In Table 1, a panel of kinases comparing the compounds (performed by Life Technologies or based on literature data) is shown.

The results shown in Table 1 were obtained from a 10-point biochemical assay generated from a 10-point concentration curve. The BTK inhibitor of formula (II) showed a much greater selectivity for BTK than ibunotetin compared to other kinases.

A comparison of the in vivo potency results of the BTK inhibitor of formula (II) with Ibubinib is shown in Figure 1. CD86 and CD69 are cell surface proteins of the BCR activation marker. To obtain in vivo efficacy results, mice were gavaged at increasing drug concentrations and sacrificed at one time point (3 hours after dosing). The BCR stimulation to IgM and flow cytometry to monitor the intensification marker CD69 and CD86 expression and the measured values ₅₀ EC.

Formula (II) has been evaluated in studies of canine spontaneous B-cell lymphoma. Twenty-one dogs were treated with a BTK inhibitor of formula (II) at a dose of 2.5 mg/kg twice daily to 20 mg/kg twice daily with an average study time of 24 days. The intra-subject dose is allowed to increase. Six of the 11 dogs were started at 2.5 or 5 mg/kg once a day and at a dose of 10 mg/kg twice daily. Of all dose groups, 8 dogs had >20% target lesion reduction; the best tumor response was between 45-49% reduction in the total target lesions in both dogs. Complete response (〝CR〞) is defined as every evaluator judges that all signs of the disease disappear; and no new lesions appear. Vali et al., Vet. Comp. Oncol. 2010, 8, 28-37. No CR was observed in the study.

The in vitro and in vivo safety pharmacology studies of formula (II) demonstrate favorable non-clinical safety profiles. Formula (II) shows resistance only to A3 adenosine when screened at 10 μM in assays for binding to 80 known pharmacological targets such as G-protein coupled receptors, nuclear receptors, proteases and ion channels. significant activity of the receptor; subsequent dose - response experiments indicated 2.7μM of IC _50, a schematic off-target effects of low clinical risk. 10 μM of the formula (II) showed no in vitro EGFR phosphorylation inhibition in the A431 human epidermoid carcinoma cell line, while ibupotinib had an IC _{50 of} 66 nM. The in vitro effect of formula (II) on human ether-à-go-go related gene (hERG) channel activity was studied in human embryonic kidney cells stably transfected with hERG in vitro. Inhibition of 25% of hERG channel activity by 10 μM of formula (II), schematic (II) can induce a low clinical risk of clinical QT prolongation, as predicted by this assay. Formula (II) is well tolerated in standard in vivo Good Laboratory Practices (GLP) studies for pharmacological safety. A functional observation battery in rats at doses up to 300 mg/kg (highest dose value) showed no adverse effects on neurobehavioral effects or body temperature at any dose values. Respiratory function studies in rats also indicated that there were no treatment-related adverse effects at doses up to 300 mg/kg (highest dose values). In a cardiovascular functional study in a conscious, telemetered Migru male dog, a single dose of formula (II) up to a dose of 300 mg/kg (the highest dose value) did not induce meaningful body temperature, heart Changes in blood vessel or electrocardiogram (ECG) (including QT interval) parameters. The results indicate that formula (II) is unlikely to cause severe off-target effects or adverse effects on important organ systems.

The drug-drug interaction potential of formula (II) was also evaluated. In-vitro experiments to assess the loss of a parent drug catalyzed by CYP indicate that formula (II) is metabolized with CYP3A4. In vitro metabolism studies using mouse, rat, dog, rabbit, monkey, and human hepatocytes cultured with ¹⁴ C-labeled formula (II) indicated two oxidized metabolites and glutathione conjugates Things. No unique human metabolites were identified. Preliminary assessment of metabolites in plasma, bile, and urine of rats, dogs, and monkeys indicates metabolic processes of oxidation, glutathione binding, and hydrolysis. It shows that formula (II) binds to glutathione in vitro but does not deplete glutathione. The non-clinical CYP interaction study data indicates that formula (II) is highly unlikely to cause clinical drug-drug interactions by altering the metabolism of the drug, which is the matrix of CYP enzymes.

The in vitro potency of inhibition of signals through the B cell receptor in whole blood was also assessed for formula (II), ibutinib and CC-292. Blood from 4 healthy donors was incubated with the indicated concentration range of compounds for 2 hours and then stimulated with anti-human IgD [10 μg/ml] for 18 hours. CD69 (and CD86, data not shown) The mean fluorescence intensity (MFI) of selected CD19+ B cells was measured by flow cytometry. The MFI values were normalized such that 100% represents CD69 in stimulated cells without inhibitor and 0% represents unstimulated/no drug status. The results are shown in Figure 2. The EC ₅₀ values obtained by formula (II), Ibubinib and CC-292 were 8.2 nM (95% confidence interval: 6.5-10.3), 6.1 nM (95% confidence interval: 5.2-7.2) and 121nM (95% confidence interval: 94-155).

EGF receptor phosphorylation in tubes of formula (II) and ibupotinib was also determined. Epidermal-like carcinoma A431 cells were incubated with dose-adjusted formula (II) or Ibubinib for 2 hours and then stimulated with EGF (100 ng/ml) for 5 minutes to induce EGFR phosphorylation (p-EGFR). The cells were fixed with 1.6% paraformaldehyde and infiltrated with 90% MeOH. Phospho-flow cytometry was performed with p-EGFR (Y1069). The MFI values were normalized such that 100% represents the p-EGFR value in stimulated cells without inhibitor and 0% represents unstimulated/no drug status. The results are shown in Figure 3. In 10μM of formula (II) have an inhibitory effect as measured over 7% of EGF- induced on the p-EGFR, erlotinib IBB having 66nM the EC _50. The more potent inhibition of EGF-induced p-EGFR by ibbutinib may be associated with increased side effects including diarrhea and rash.

Example 2 - Preclinical Studies of Second Generation BTK Inhibitors for CLL/SLL

Clinical studies have shown that targeting BCR signaling pathways by inhibiting BTK produces significant clinical benefits in patients with non-Hodgkin's lymphoma (NHL). The second generation BTK inhibitor formula (II) achieves significant oral bioavailability and efficacy, and has advantageous preclinical characteristics as described above. The aim of this study was to evaluate the safety and efficacy of a second generation (II) BTK inhibitor in the treatment of individuals with chronic lymphocytic leukemia (CLL) and small lymphoblastic lymphoma (SLL).

The design and implementation of this study was performed on a person with lymphoma Body history and understanding of current therapies, knowledge of the activity and safety of the first generation BTK inhibitor, Ibubinib, in individuals with hematological cancer; and non-clinical information on effective (II) Get support. The data collected supports the following conclusions. BTK expression plays an important role in the biology of lymphoma, which represents a serious and life-threatening condition with persistent unmet medical needs. The clinical evaluation of formula (II) as a potential treatment for these conditions is based on the following observations with sound scientific principles: the compounds selectively abolish BTK activity and show activity in non-clinical models of lymphoma. These data are supported by clinical documents with clinically active Ibbutinib (first generation BTK inhibitors) in these diseases. The clinical data of ibbutinib and the non-clinical safety pharmacology and toxicology studies of formula (II) support the safety of formula (II) tested in individuals with B cell malignancies.

The main objectives of clinical research are as follows: (1) establishing the safety and MTD of oral administration of formula (II) in individuals with CLL/SLL; (2) determining the formula (II) of oral administration Pharmacokinetics (PK) and identification of its major metabolites; and (3) measurement of pharmacodynamic (PD) parameters, including BTK drug occupancy, target enzymes, and effects on biomarkers of B cell function.

A secondary goal of clinical research is to assess tumor response in patients treated with formula (II).

This study was a multicenter, open-label, non-randomized, sequential group, dose escalation study. Evaluate the following dose groups:

Group 1: 100 mg / day 28 days (=1 cycle)

Group 2: 175 mg / day 28 days (=1 cycle)

Group 3: 250 mg / day 28 days (=1 cycle)

Group 4: 350 mg / day 28 days (=1 cycle)

Group 5: 450 mg / day 28 days (=1 cycle)

Group 6: measured in milligrams per day for 28 days (=1 cycle)

Each group was registered with 6 individuals in each group. If observed in the group during cycle 1 The dose-limiting toxicity (DLT) at position 1 is increased until the next group continues. If 4 of the 6 individuals registered in the group complete cycle 1 without experiencing DLT, and the remaining 2 individuals are completing the assessment, the next group of individuals may be registered. If observed during cycle 1 With a 2-digit DLT, this dose and higher doses were discontinued and the MTD was established as in the previous group. MTD is defined as the daily maximum dose of less than 33% of individuals undergoing DLT during cycle 1. When the MTD is reached or greater than the full BTK occupancy at the 3 dose values, whichever comes first, the dose escalation is ended. The overall BTK occupancy rate was defined as >80% of the formula (II) active site occupancy (average of all individuals in the group) at 24 hours post dose. If it is necessary to increase to group 6, the dose is determined based on the overall data from groups 1 to 5, which includes safety, efficacy, and PK/PD results. The dose of Group 6 does not exceed 900 mg/day.

Treatment with formula (II) can last for > 28 days until disease progression or unacceptable drug-related toxicity occurs. Individuals with disease progression were removed from the study. All individuals who discontinued the study drug had a 30 (±7) day safety follow-up visit after the last study drug dose, unless the individuals started another cancer therapy within that time period. Radiological tumor assessment will be screening Time and at the end of Cycle 2, Cycle 4, and Cycle 12, and at the discretion of the investigator. Complete response (CR) needs to be confirmed by bone marrow analysis and radiological tumor assessment. Individuals who remained in the study for >11 months were required to undergo mandatory bone marrow extraction and biopsy and radiological tumor assessment simultaneously in cycle 12.

All individuals have a standard hematology, chemical and urinalysis safety review conducted at screening. This study also included pancreatic functional assessment (serum amylase and serum lipase) due to pancreatic findings in the GLP rat toxicity study on day 28. Once dosing is initiated, all individuals are assessed weekly, once a week, once every other week, and then monthly for safety. Blood samples were collected during the first week of treatment for PK/PD assessment. The ECG is performed at the time of screening and on days 15 and 28 of cycle 1, 1-2, 8, 15, 22, 28, cycle 2, and then until cycle 6 on a monthly basis. Only the screened ECG was repeated three times. A single ECG test is then performed unless a repeated ECG test is required.

Dose-limiting toxicity is defined as any of the following events (assuming it is not related to disease progression): (1) any grade 3 continued non-hematologic toxicity (except for hair loss), despite the single course of standard outpatient symptomatic treatment (eg, diarrhea at level 3 of the reaction to a single therapeutic dose of Imodium® is not considered to be DLT); (2) grade 3 extended corrected QT interval (QTc) as determined by central ECG laboratory overread; (3) continuation of treatment for >7 days after discontinuation of treatment without growth factor or after discontinuation of treatment and dependence on growth factors Neutral neutropenia with grade 4 of >5 days (absolute neutrophil count [ANC] <500/μl) (ie neutrophils of grade 4 that did not last as long as specified) Reduction is not considered to be DLT), (4) Thrombocytopenia (platelet count <20,000/μl) that continues for >7 days after discontinuation of treatment or grade 4 requiring infusion (ie, does not continue as long as specified) Grade 4 thrombocytopenia is not considered to be DLT), and (5) Delay in administration due to toxicity > 7 consecutive days.

The efficacy parameters of the study included total response rate, response period, and progression-free survival (PFS). The safety parameters of the study included the attributes of DLT and MTD, frequency, severity, and adverse events (AE) based on Common Terminology Criteria for Adverse Events (CTCAE v4.03). M. Hallek et al., Blood 2008, 111, 5446-5456.

The assessment procedure is as follows: All days of the statement have the following meaning: the given day or +/- 2 days from the given day. Physical examination (including vital signs and weight) is at the time of screening, days 1, 8, 15, 22 and 28 of period 1, periods 15 and 28 of period 2, and days 28 of period 3 to 24, And at the time of tracking (after the last dose). Screening physical examinations include, at a minimum, the general appearance of the individual, height (screening only) and body weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system. A symptom-oriented physical examination is then performed. Vital characteristics (blood pressure, pulse, respiratory rate, and body temperature) are assessed after the individual has rested in the seat. The Eastern Cooperative Oncology Group (ECOG) status is at the time of screening, on days 1, 8, 15, 22, and 28 of cycle 1, and on days 15 and 28 of cycle 2, Published ECOG performance status indicators as described in Oken et al., Am. J. Clin. Oncol. 1982, 5, 649-655, on day 28 of the period 3 to 24, and at the time of tracking. The ECG test is at the time of screening, on days 1, 8, 15, 22 and 28 of cycle 1, on days 15 and 28 of cycle 2, on days 28 of cycle 3 to 24, and during tracking get on. At the time of screening, the 12-lead ECG test was repeated three times ( 1 minute interval). The calculated QTc average of 3 ECGs must be < 480 microseconds to be a qualified value. A single ECG system on day 1 of cycle 1 and day 8 of cycle 1 was performed before administration and at 1, 2, 4, and 6 hours after administration. A single ECG on day 2 of cycle 1 was performed prior to dosing. A single ECG line on days 15, 22, and 28 of cycle 1 was performed 2 hours after dosing. A single ECG beginning with cycle 2 is performed at each visit. Before studying the relevant ECG, the individual should be in a supine position and rested for at least 10 minutes. Two consecutive machine readings of QTc > 500 microseconds or >60 microseconds above baseline require a central ECG review. Hematology (including the number of whole blood cells with cell classification and the number of platelets and the number of reticulocytes) is at the time of screening, on days 1, 8, 15, 22, and 28 of period 1, and during period 2 15 and 28 days, on day 28 of the period 3 to 24, and at the time of tracking. Serum chemistry at screening, on days 1, 8, 15, 22, and 28 during cycle 1, on days 15 and 28 during cycle 2, on days 28 from cycle 3 to 24, and during tracking assessment. Serum chemistry includes albumin, alkaline phosphatase, ALT, AST, bicarbonate, urea nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate, potassium, Sodium, total bilirubin, total protein and uric acid. Cell number and serum immunoglobulin line were performed at screening, on day 28 of cycle 2, and every 6 months thereafter until the final dose, and included T/B/NK/monocyte number (CD3, CD4, CD8, CD14, CD19, CD19, CD16/56 and other cell numbers as needed) and serum immunoglobulins (IgG, IgM, IgA and total immunoglobulin). Bone marrow withdrawal is performed in cycle 12. Pharmacodynamic samples were taken on days 1, 2 and 8 of Cycle 1 and at follow-up. On days 1 and 8, pharmacodynamic samples were drawn before administration and 4 hours after administration (±10 minutes), and on day 2, pharmacodynamic samples were drawn prior to administration. The pharmacokinetic samples were drawn on days 1, 2, 8, 15, 22 and 28 of cycle 1. The pharmacokinetic samples on day 1 of cycle 1 were drawn before dosing and at 0.5, 1, 2, 4, 6 and 24 hours after dosing (before dosing on day 2). Samples on day 8 of cycle 1 were drawn before dosing and at 0.5, 1, 2, 4 and 6 hours after dosing. On days 15, 22 and 28 of cycle 1, the PK sample was drawn prior to dosing and the second PK sample was taken prior to ECG acquisition (which was 2 hours after dosing) (up to 10 minutes prior). The pre-treatment radiological tumor assessment was performed within 30 days prior to the first dose. Computerized tomography (CT) scans of the chest, abdomen, and pelvis are required (with contrast unless contraindicated). In addition, individuals with SLL must undergo positron emission tomography (PET) or PET/CT. The radiological tumor assessment was mandatory at the end of cycle 2 (-7 days), cycle 4 (-7 days), and cycle 12 (-7 days). Otherwise, radiological tumor assessment is performed at the discretion of the investigator. Individuals with CLL are required to have CT of the chest, abdomen, and pelvis (with contrast unless contraindicated). In addition, individuals with SLL are required to undergo PET/CT. It is required to determine the complete response (CR) by both bone marrow and radioactivity. The clinical assessment of tumor response should be performed at the end of cycle 6 and every 3 months thereafter. Molecular markers were measured at screening and included interphase cytogenetics, stimulated karyotypes, IgHV mutation status, ZAP-70 methylation and β-2 microglobulin values. Urinalysis is performed at screening and includes pH, ketone, specific gravity, bilirubin, protein, blood, and glucose. Other assessments including informed consent, qualifications, medical history, and pregnancy testing were performed at screening.

The researchers are based on the latest guidelines for CLL (as given in M. Hallek et al., Blood 2008, 111, 5446-56) and the latest guidelines for SLL (eg BD Cheson et al., J. Clin. Oncol. 2007). , given in 25, 579-586, to verify the individual's response to treatment. The criteria for assessing the response to CLL are summarized in Table 2.

a. This assessment requires a computed tomography (CT) scan of the abdomen, pelvis, and chest. b. No exogenous growth factors are required. c. The sum of the lymph nodes of 6 or the largest diameter of the enlarged lymph nodes, and no increase in any lymph nodes or newly enlarged lymph nodes

The criteria for assessing the response to SLL are summarized in Table 3.

The PK parameters were studied as follows. Plasma PK lines of formula (II) and metabolites were characterized using non-compartmental analysis. The following PK parameters were calculated from plasma concentrations of formula (II) whenever possible: AUC _(0-t) : Calculate the area under the plasma concentration-time curve from time 0 to time t using linear trapezoidal summation, where t For the last measurable concentration (Ct) time, AUC _(0-24) : Calculate the area under the plasma concentration-time curve from 0 to 24 hours using linear trapezoidal summation, AUC _(0-∞) : using the formula :AUC _(0-∞) =AUC _(0-t) +Ct/λz Calculate the area under the plasma concentration-time curve from 0 to infinity, where λz is the apparent end elimination rate constant, C _max :maximum Observed plasma concentration, T _max : time of maximum plasma concentration (not obtained by extrapolation), t _1⁄2 : terminal exclusion half-life (whenever possible), λ _z : terminal exclusion rate constant (whenever possible), Cl/ F: oral clearance rate.

The PD parameters were studied as follows. The BTK occupancy of formula (II) is measured in peripheral blood mononuclear spheres (PBMC) by means of biotinylated analog (II) analog probes. The effect of formula (II) on biomarkers of B cell function was also assessed.

The statistical analysis used in this study is as follows. Conduct a hypothetical informal statistical experiment. Descriptive statistics (including mean, standard deviation, and ratio of median and discrete variables of continuous variables) are summarized as appropriate.

Use the following definitions for security and performance analysis sets: Security Analysis Set: Accepted by all registered individuals 1 study drug dose; pre-protocol (PP) analysis set: all registered individuals accepted 1 study drug dose and accepted after treatment 1 tumor response assessment. The safety parameters in this study were evaluated using a safety analysis set. The performance parameters in this study were analyzed in a PP analysis set.

The calculation of the value of the missing data is not carried out, except for the omission of the adverse event or the partial start or end date, and the combined medication is set according to the pre-designated conservative calculation rules. The systems of loss (or exit) are included in the statistical analysis with their final assessment points.

The safety endpoint analysis was performed as follows. The safety summary includes a summary in the form of a table and a list. The frequency (number and percentage) of treatment for adverse events is described in each treatment group according to the Medical Dictionary for Regulatory Activities (MedDRA) systemic organ categories and preferred terms. The summary is also based on the severity of the adverse events and the relationship with the study drug. Laboratory mobile watches with counts and percentages are prepared according to treatment assignments, laboratory parameters, and time. Prepare a summary table for each laboratory parameter. Generate a laboratory parameter map that changes over time. Lifetime features, ECG and physical examinations are tabulated and summarized.

Additional analyses included individual structural statistics, baseline characteristics, compliance, and a summary of synchronized treatments. The combined medications are coded and tabulated according to the World Health Organization (WHO) drug dictionary.

The performance parameter analysis was performed as follows. A point estimate for the total response rate of the PP analysis set is calculated. A corresponding 95% confidence interval is also derived. The total response period is measured from the time of the CR or PR (what is recorded first) measurement criteria until the first day of the disease recurrence or progression is objectively recorded (the smallest measured value recorded since the start of treatment as a reference for disease progression) test). The no-event curve and corresponding amount (including the median) were evaluated using the Kaplan-Meier method. Progression-free survival was measured from the time of the first study drug until the first day of objective recurrence or progression (the smallest measured value since the start of treatment was used as a reference for disease progression). The no-event curve and corresponding amount (including the median) were evaluated using the Kaplan-Meier method.

The research process is incremental for sequential groups. Each group consists of 6 individuals. The size of the sample studied was from 24 to 36 individuals depending on the dose increasing to subsequent groups. Group 1 (N=6) consisted of Formula (II) with 100 mg QD over 28 days. Group 2 (N=6) consisted of Formula (II) with 175 mg QD over 28 days. Group 3 (N=6) consisted of Formula (II) with 250 mg QD over 28 days. Group 4 (N=6) consisted of Formula (II) with 350 mg QD over 28 days. Group 5 (N=6) was obtained from formula (II) with 450 mg QD for 28 days. Group 6 (N=6) consisted of Formula (II) at a dose QD to be determined over 28 days. The dose values for Group 6 are based on safety and efficacy of Groups 1 through 5 and do not exceed 900 mg/day. The increment is terminated by the MTD group or 3 values greater than the full BTK occupancy rate (which is observed first). An additional study team team explored 100 mg BID administration. Treatment with oral formula (II) can last for more than 28 consecutive days until disease progression or unacceptable drug-related toxicity occurs.

The criteria for inclusion in the study are as follows: (1) Have a confirmed CLL/SLL 18-year-old male and female, tied 2 times of CLL/SLL relapsed or became recalcitrant after prior treatment; however, if the individual relapsed or became recalcitrant after one previous CLL/SLL treatment, the individual with the 17p deletion was eligible; (2) body weight 60 kg; (3) ECOG performance status 2; (4) if sexually active and able to have a child, agree to contraception during the study period and 30 days after the last dose of study drug; (5) willing and able to participate in all the assessments and procedures required in this research project, Includes no difficulty in swallowing capsules; or (6) understanding the purpose and risks of the study and providing signed and dated informed consent and the ability to authorize the use of protected health information (according to national and local individual privacy regulations).

The dosage forms and strengths of formula (II) used in clinical studies were prepared using standard pharmaceutical grade excipients (microcrystalline cellulose) and each contained 25 mg of hard gelatin capsules of formula (II). The capsule color is Swedish orange. The path is administered as an oral (per os or PO). The dosage regimen is once daily or twice daily, on a fasting basis (defined as 2 hours prior to dosing and 30 minutes after dosing), as specified by the group.

Baseline characteristics of patients enrolled in clinical studies are listed in Table 4.

The results of clinical studies in patients with relapsed/refractory CLL are summarized in Table 5.

Figure 4 shows the % change in median ALC and SPD from baseline in a clinical study of formula (II), which is in accordance with JC Byrd et al., N. Engl. J. Med. 2013, 369, 32-42. Reported by Ibubinib in Figure 1A The results are compared compared to the results. The results show that formula (II) causes a faster patient response in CLL/SLL than the corresponding treatment with ibufibrate. This effect is exemplified by, for example, the SPD median change %, which was treated in the study of the present invention for 7 months with formula (II) to achieve the same status as compared to 18 months of treatment with ibufenib. The % change in SPD observed in the different groups (i.e., different in dosage and administration regime) is shown in Figure 5 and shows a significant response in all examples.

The Kaplan-Meier curve showing the PFS of the clinical CLL/SLL study of formula (II) is shown in Figure 6. Survival curves were compared using the Log-Rank (Mantle-Cox) test, with a p-value of 0.0206 indicating a different survival curve. The number of patients at risk is shown in Figure 7. Both Figures 6 and 7 show the results of Formula (II) compared to the results reported by Ibbutinib in J. C. Byrd et al., N. Engl. J. Med. 2013, 369, 32-42. Improved survival and reduced risk were observed in CLL patients treated with formula (II) compared to patients treated with ibufibrotide.

Based on the data and comparisons shown in Figures 4 through 7, the CLL study of Formula (II) shows that the efficacy of Formula (II) is surprisingly superior to the efficacy of Ibbutinib.

In the literature study of Ibbutinib, increased disease progression was associated with patients with high-risk cytogenetic lesions (17p13.1 deletion or 11q22.3 deletion), such as N. Engl by JCByrd et al. As shown in Figure 3A of J. Med. 2013, 369, 32-42, it shows the PFS of Ibubinib, including the PFS that is abnormally aborted by the gene. The 17p and 11q deletions were confirmed to be high risk characteristics of CLL and the 17p deletion was the highest risk. in In Fig. 8, compared with the results obtained by Ibbutinib in JC Byrd et al., N. Engl. J. Med. 2013, 369, 32-42, the expression is shown in patients with 17p deletion ( II) PFS. A p-value of 0.0696 was obtained. In Figure 9, the number of patients at risk of 17p deletion was compared. To date, formula (II) does not cause 17p disease progression.

Adverse events observed in clinical studies of relapsed/refractory CLL/SLL are listed in Table 6. No DLT was observed. The MTD was not reached. No serious adverse events (SAE) associated with treatment were observed.

Clinical studies of formula (II) therefore show other surprisingly superior results compared to ibufenib therapy. No lymphocytosis was observed in the study. Furthermore, only grade 1 AEs were observed, and these AEs can be attributed to the high BTK selectivity of formula (II).

The BTK target occupancy of relapsed/refractory CLL patients was measured and the results are shown in FIG. The BTK inhibitor of formula (II) administered with 200 mg QD observed a BTK occupancy of about 94%-99% with excellent 24-hour coverage and less inter-patient variability was also observed. Observation of BTK inhibitor ibbutinib with 420 mg and 840 mg QD To 80%-90% of BTK occupancy, with more inter-patient variability and capping occupancy. These results indicate that the BTK inhibitor of formula (II) achieves superior BTK occupancy over ibufibrate in CLL/SLL patients.

The effect of formula (II) relative to the percentage of cell subpopulations was also assessed by flow cytometry using peripheral blood. The results are shown in Figures 11, 12, 13, 14, 15, and 16. The potential changes in PBMC samples from CLL/SLL patient samples taken before (predose) and 28 days after dosing were compared in cell subsets. PBMCs were stained with monoclonal antibodies conjugated to fluorescent labels (fluorescent dyes) and cell subpopulations were identified by flow cytometry. The non-viable cell line was excluded from the analysis using the dye 7-aminoactinomycin D (7-AAD). Use the following steps to get a measure of the percentage change. First, each cell subpopulation is defined by a hierarchical flow cytometry selection. The frequency change of each subpopulation of cells was then calculated (between day 1 and day 28). The MDSC subpopulation was measured as % of all bone marrow cells. T cell subsets were measured as % of all CD3 ⁺ cells, and NK cell lines were measured as % of all viable CD45 ⁺ cells. In FIGS. 11 and 12, the results show the % change in the % of the MDSC (mononuclear sphere) value over 28 days relative to the 28th day of cycle 1 (C1D28) and the 28th day of cycle 2 (C2D28). The period is 28 days. Patients with a reduced ALC% were observed to have a tendency to increase MDSC (mononuclear sphere)%. This can include patients with rapidly resolved lymphocytosis and those without initial lymphocytosis. This provides evidence that treatment with Formula (II) moves MDSC and thus affects the CLL tumor microenvironment in bone marrow and lymph nodes, which is an unexpected potency for superior efficacy. In Fig. 13 and Fig. 14, the results show that the % change in NK cell value over 28 days is relative to the % change in ALC measured in C1D28 or C2D28, and it is observed that the patient having a decreased ALC% has an increase in NK cell%. A similar trend. This can include patients with rapidly resolved lymphocytosis and those without initial lymphocytosis. The effect of the dose including 100 mg BID, 200 mg QD, and 400 mg QD in multiple groups was observed in Figures 11-14. In Figures 15 and 16, the effect of % change in NK cells and MDSC cells with many other markers relative to ALC at C1D28 and C2D28 was compared. Such other markers include CD4+ T cells, CD8+ T cells, CD4+/CD8+ T cell ratios, NK-T cells, PD-1+CD4+ T cells, and PD-1+ CD8+ T cells. The effect on NK cells and MDSC cells was observed to be more pronounced than any of these other markers.

These results indicate that the CLL microenvironment undergoes a change after administration of formula (II), wherein the NK cell and mononuclear MDSC subpopulation increase the frequency of ALC number decline in the peripheral blood of the patient, which is important in CLL. Clinical parameters. An increase in NK cells may reflect an overall increase in cytolytic activity against B-CLL, resulting in a decrease in ALC%. An increase in MDSC% in the blood may be due to the removal of such cells from the lymph nodes, spleen and bone marrow (possible locations of CLL proliferation). Less MDSC at the CLL hyperplasia center may result in a decrease in the immunosuppressive microenvironment, resulting in increased cellular immunity against tumors, reduced tumor proliferation, and ultimately lower ALC% in circulation.

The clinical results updated from the CLL/SLL study are shown in Figures 17-22. Figure 17 shows an update of the data presented in Figure 4. Figure 18 shows an update of the data presented in Figure 10 and includes a BID dosing knot. fruit. Formula (II) administered at 200 mg QD gave 94%-99% BTK occupancy, 24 hours coverage and less inter-patient variability. Ibbutinib administered with 420 mg and 840 mg QD gave 80%-90% BTK occupancy, more inter-patient variability and capping occupancy. Formula (II) administered at 100 mg BID gave 97%-99% BTK occupancy, complete BTK coverage and less inter-patient variability. The PFS of patients with 11p deletion and 17q deletion is exemplified in Figures 19, 20 and 21. The updated SPD results are illustrated in Figure 22.

Treatment of CLL/SLL patients with formula (II) also resulted in increased apoptosis, as exemplified in FIG. The apoptotic B-CLL line is defined by flow cytometry as having a split PARP ⁺ , Caspase 3 ⁺ , CD19 ⁺ and CD5 ⁺ phenotype. 82% of the test samples have a baseline change greater than 25%. Treatment of patients with CLL/SLL with formula (II) has also been shown to reduce plasma chemokines associated with MDSC homing and retention. Significantly reduced CXCL12 and CCL2 values were observed in patients treated with formula (II) as shown in Figures 24 and 25, respectively.

In summary, Formula (II) shows superior efficacy over monotherapy of first generation BTK inhibitors (such as Ibubinib) or PI3K-delta inhibitors (such as, for example, Idelalisib). Formula (II) has better target occupancy and better pharmacokinetic and metabolic parameters than ibufibrate, resulting in improved B cell apoptosis. Furthermore, unlike treatment with ibutinib and PI3K-delta inhibitors, treatment with formula (II) did not affect NK cell function. Finally, treatment with formula (II) results in a CLL/SLL tumor microenvironment effect by excluding MDSC cells from bone marrow and lymph nodes and reducing the number of such cells.

Example 3 - Effect of BTK inhibitors on thrombosis

Clinical studies have shown that targeting BCR signaling pathways by inhibiting BTK yields significant clinical benefits (JC Byrd et al., N. Engl. J. Med. 2013, 369, 32-42; ML Wang et al., N. Engl. J.Med. 2013, 369, 507-16). However, up to 50% of patients treated with ibufenib were reported to have bleeding in these studies. Most bleeding events have grade 1-2 (spontaneous cyanosis or ecchymoses), but 5% of patients have grade 3 or higher bleeding after trauma. These results are reflected in the prescribing information published with ibufenib, in which about half of the patients reported to have received ibufenib have any grade of bleeding (including cyanosis or ecchymoses) (US Food and Drug Administration) The US Food and Drug Administration revised the IMBRUVICA package insert and prescription information in July 2014).

The composition or abnormal activation of the BCR communication cascade involves the propagation and maintenance of various B cell malignancies. Small molecule inhibitors of BTK (a protein that is early in this cascade and particularly expressed in B cells) have emerged as a new class of targeted agents. There are many BTK inhibitors in clinical development, including CC-292 and Ibubinib (PCI-32765). CC-292 means (N-(3-((5-fluoroethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl) Acrylamide or a pharmaceutically acceptable salt thereof, including its hydrochloride or besylate. Initial clinical trials have found that ibufibrate in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma Special activity in (MCL) indicates that inhibitors of this class can play a major role in various types of cancer (Aalipour and Advani, Br. J. Haematol. 2013, 163, 436-43). However, these effects are not limited to leukemia or lymphoma, as platelets also rely on Tec kinase family members BTK and Tec for signal transduction of various thrombotic stimuli (Oda et al., Blood 2000, 95(5), 1663- 70; Atkinson et al., Blood 2003, 102(10), 3592-99). In fact, both Tec and BTK play an important role in regulating the downstream of phospholipase Cγ2 (PLCγ2) of GPVI in human platelets. In addition, BTK is activated upon challenge of the platelet thrombin receptor and undergoes tyrosine phosphorylation, which requires the binding of αIIbβ3 integrin to PI3K activity (FESF Lett. 1999, 443(1), 66-70 of Laffargue et al.). It also involves GPIbα-dependent thrombus stability at the site of vascular injury (Liu et al., Blood 2006, 108(8), 2596-603). Therefore, BTK and Tec are involved in a number of important processes that support the formation of stable tampon, which has the key to preventing significant blood loss from reactive vascular injury. Thus, the effector of the BTK inhibitor of formula (II) and ibufibrate evaluated the thrombus formation by human platelet media using in vivo human thrombosis in the VWF HA1 mouse model, as described by Chen et al. In Nat. Biotechnol. 2008, 26(1), 114-19.

Anesthesia was administered in mice, inserted into veins and arterial catheters, fluorescently labeled and administered to human platelets (5 × 10 ⁸ /ml), and surgical preparation for levator muscle (Chen et al. Nat Biotechnol) .2008, 26(1), 114-19). Pulsed nitrogen dye laser (440 nm, Photonic Instruments) applied to a small artery (-40-65 mm diameter) using a 20x immersion Olympus objective (LUMPlanFl, 0.5 numerical aperture (NA)) by a Zeiss Axiotech vario microscope ) Damage to the blood vessel wall. The interaction between human platelets and the wall is achieved by using a 488 nm and 561 nmere with a Yokogawa CSU-22 rotating disk confocal scanner, an iXON EM camera, and a BCECF-labeled and rose-red-labeled platelet, respectively. A fluorescence microscope (Revolution XD, Andor Technology) of the ray system was seen. The degree of thrombosis was assessed 2 minutes after injury and the coverage area (square micrometers) was determined (Image IQ, Andor Technology). Regarding formula (II), CC-292, and ibufibrate inhibition studies, BTK inhibitors were added to purified human platelets for 30 minutes prior to administration.

The in vivo coagulation effect of BTK inhibitors (II), CC-292 and Ibubutinib is an assessment of thrombus formation by human platelet media using in vivo human thrombosis in the VWF HA1 mouse model. Previously described (Chen et al., Nat Biotechnol. 2008, 26(1), 114-19). Purified human platelets were pre-incubated with various concentrations of BTK inhibitor (0.1 μM, 0.5 μM or 1 μM) or DMSO and then administered to VWFHA1 mice, which were then subjected to laser-induced thrombosis. Human platelets treated with BTK inhibitors were fluorescently labeled and continuously perfused via a catheter inserted into the femoral artery. The performance of laser-induced vascular injury in their responses was monitored using a two-channel confocal in vivo microscope (Furie and Furie, J. Clin. Invest. 2005, 115(12), 2255-62). Upon induction of arteriolar injury, untreated platelets rapidly formed a thrombus having an average thrombus size of 6,450 ± 292 square millimeters (mean ± sem), as shown in Figures 26, 27 and 28. Similarly, platelets treated with formula (II) (1 μM) formed a slightly smaller average thrombus size of 5733 ± 393 square millimeters (mean ± sem) but no significantly different thrombus. Conversely, a dramatic reduction in thrombus size in platelets pretreated with 1 μM of ibufenib: 2600 ± 246 mm 2 (mean ± sem) resulted in a reduction of thrombus size of up to approximately 61% compared to the control group ( P>0.001) (Figures 26 and 28). Platelets pretreated with 500 nM of formula (II) or Ibufenib gave similar results: thrombus sizes of 5946 ± 283 mm 2 and 2710 ± 325 mm 2 , respectively. These preliminary results may provide some explanation of the physical background and compare Ibrahimovic for ^TM Phase III study RESONATE Nepal and Austria logging mAbs reported in the bleeding-related adverse event rate of 44%. The results obtained with CC-292 are similar to those of Ibbutinib, as shown in Figures 26, 27 and 28. The effect of BTK inhibitor concentration is shown in Figure 29. These results demonstrate the surprising advantage of the BTK inhibitor of formula (II), which does not interfere with thrombus formation, while the BTK inhibitor CC-292 and ibbutinib interfere with thrombosis.

The purpose of this study was to evaluate in vivo thrombosis in the presence of BTK inhibitors. In vivo testing of novel antiplatelet agents requires the formation of biomarkers. We evaluated Formula (II), CC-292, and the von Willebrand factor (VWFR1326H) model using a genetically modified mouse von Willebrand factor (VWFR1326H) model that supports human but does not support platelet-mediated thrombosis in mice. The effect of ibbutinib on thrombosis. These results show that formula (II) has no significant effect on thrombus formation in human platelet media, and that ibufibrate can limit this process, resulting in a maximum 61% thrombus size reduction compared to the control group. CC-292 shows results similar to ibutinib. The results of ibbutinib showing reduced thrombosis at physiologically relevant concentrations can be graded 3 bleeding events (such as subdural hematoma, gastrointestinal bleeding, hematuria, and postoperative bleeding) provide some physical background, The bleeding event was reported in 6% of patients treated with ibufenib.

GPVI platelet aggregation of formula (II) and Ibubinib was measured. Blood is obtained from untreated individuals and platelets from protein-rich plasma are purified by centrifugation. The cells were at pH 7.4 containing 145 mM NaCl/liter, 10 mM HEPES/liter, 0.5 mM Na ₂ HPO ₄ / liter, 5 mM KCl/L, 2 mM MgCl ₂ / The suspension was resuspended in a buffer of 1 mM CaCl ₂ /liter and 0.1% glucose to a final concentration of 350,000 / microliter. A stock solution of Convulxin (CVX) GPVI was prepared on the day of the experiment and added to the platelet suspension 5 minutes before induction of agglutination (37 ° C, 1200 rpm). The agglutination line was assessed on a Chronolog Lumi-aggregator (Model 540 VS; Chronolog, Havertown, PA) and allowed to continue for 6 minutes after the addition of the agonist. The results were reported as the percentage change in maximum light transmission from baseline, using platelet buffer as a reference. The results are shown in Fig. 30.

The results of platelet aggregation by CVX-induced (250 ng/ml) 15 minutes before and after administration of BTK inhibitors to 6 healthy individuals are shown in FIG.

The results described in Figures 30 and 31 indicate that the BTK inhibitor, Ibupotinib, significantly inhibits GPVI platelet aggregation, whereas the BTK inhibitor of formula (II) does not, further illustrating the surprising benefit of the latter compound.

Example 4 - Use of Rituximab for Antibody-Dependent NK Cell Media Cytotoxic BTK inhibitory effect

Rituximab combination therapy is currently the standard of care in CD20 ⁺ B-cell malignancies. Previous studies have investigated and determined that ibufibrate antagonizes NK cell-mediated rituximab antibody-dependent cellular mediator cytotoxicity (ADCC). This may be due to the secondary irreversible binding of Ibubinib to the tyrosine kinase (ITK) induced by interleukin-2, which is essential for FcR-stimulated NK cell function, including calcium movement, particle release and overall ADCC. Kohrt et al., Blood 2014, 123, 1957-60.

In this example, the effect of Formula (II) and Ibbutinib on NK cell function was assessed in healthy primary volunteers and primary NK cells from CLL patients. Activation of NK cells co-cultured with antibody-coated target cells is strongly inhibited by Ibubinib. The secretion of IFN-γ was reduced by 48% (p=0.018) and 72% (p=0.002) and significantly decreased in cultures treated with 0.1 and 1.0 μM of ibufenib, respectively, compared to the control cultures. NK cells are degranulated. Treatment with formula (II) at a clinically relevant concentration of 1 [mu]M did not inhibit IFN-[gamma] or NK cell degranulation. The ADCC line of the rituximab vector was evaluated in NK cells from healthy volunteers and from NK cells from CLL patients targeting autologous CLL cells. In both examples, ADCC was not subjected to inhibition by treatment of formula (II) at 1 μM. Conversely, ibufibrate added to the ADCC assay strongly inhibited the cytotoxicity of target cells via the rituximab vehicle and observed no increase in natural cytotoxicity at any rituximab concentration . This result indicates that the combination of rituximab and formula (II) provides an accident in the treatment of CLL. Benefits.

BTK is a non-receptor enzyme in the Tec kinase family expressed in hematopoietic-derived cells, including B cells, bone marrow cells, obese cells, and platelets, which regulate many cellular processes, including proliferation, differentiation, and apoptosis. Cell migration. W. N. Khan, Immunol Res. 2001, 23, 147-56; A. J. Mohamed et al., Immunol Rev. 2009, 228, 58-73; J. M. Bradshaw, Cell Signal. 2010, 22, 1175-84. The non-functional mutation of BTK in humans causes the hereditary disease X-linked agammaglobulinemia, which is characterized by the lack of mature peripheral B cells. M. Vihinen et al., Front Biosci. 2000, 5, D917-28. Conversely, BTK activation involves the pathogenicity of many B-cell malignancies. SEHerman et al., Blood, 2011, 117, 6287-96; LPKil et al., Am. J. Blood Res. 2013, 3, 71-83; YTTai et al., Blood 2012, 120, 1877-87; JJ Buggy , L. Elias, Int. Rev. Immunol. 2012, 31, 119-32 (Corrigendum: Int. Rev. Immunol. 2012, 31, 428). In addition, BTK-dependent activation of obese cells and other immune cells in the surrounding inflammatory matrix has been shown to be a complex microenvironment necessary for maintenance of lymphatic and solid tumors. L. Soucek et al., Neoplasia 2011, 13, 1093-100; S. Ponader et al., Blood 2012, 119, 1182-89; M. F. de Rooij et al., Blood 2012, 119, 2590-94. Taken together, these findings suggest that inhibition of BTK may provide a strategy for treating B-cell tumors, other hematological malignancies, and solid tumors.

Ibbutinib (PCI-32765, IMBRUVICA) is the first therapeutic BTK inhibitor. This orally delivered small molecule drug was developed by Pharmacyclics, Inc. for the treatment of B-cell malignant diseases. As described above, ibbutinib exhibits substantial antitumor activity in patients with painless non-Hodgkin's lymphoma (iNHL), mantle cell lymphoma (MCL), and CLL who have undergone multiple pretreatments, inducing large The majority of individuals have long-lasting regression of lymphadenopathy and splenomegaly. J. Clin. Oncol. 31, 88-94 (2013) by RHAdvani et al.; N. Engl. J. Med. 2013, 369, 32-42 by JC Byrd et al; N. Engl. by ML Wang et al. J. Med. 2013, 369, 507-16; S. O'Brien et al., Blood 2012, 119, 1182-89. There are significant changes in the CLL. Ibbutinib inhibits BTK-induced malignant CLL cells from rapid and substantial movement from the tissue site to the peripheral blood, as described in JAWoyach et al., Blood 2014, 123, 1810-17; this effect reduces CLL protection The adhesion of stromal cells is consistent. S. Ponader et al., Blood 2012, 119, 1182-89; M. F. de Rooij et al., Blood 2012, 119, 2590-94. Ibbutinib is usually well tolerated. At dose values associated with total BTK occupancy, no dose limiting toxicity was identified and the individual was found to have an overall tolerable period of >2.5 years.

In view of the homology between BTK and interleukin-2 evoked tyrosine kinase (ITK), it has recently been confirmed that ibupotinib irreversibly binds to ITK. JADubovsky et al., Blood 2013, 122, 2539-2549. ITK performance in Fc receptor (FcR)-stimulated NK cells results in increased calcium movement, particle release, and cytotoxicity. D. Khurana et al. J. Immunol. 2007, 178, 3575-3582. Because rituximab is the backbone of lymphoma therapy with a mechanism of action including ADCC and direct induction of apoptosis and complement-dependent cytotoxicity, and FcR stimulation is necessary for ADCC, we studied Ibbutinib or Does Formula (II) (lack of ITK inhibition) affect the anti-lymphoma activity of rituximab in vitro by assessing NK cell IFN-by using CD20 ⁺ cell lines and autologous patient samples with CLL Gamma secretion, degranulation with CD107a movement and cytotoxicity with chromium release.

Formula (II) is a more selective inhibitor than ibufenib, as previously shown. Formula (II) is not a potent Itk kinase inhibitor, as opposed to Ibupotinib (see Table 1). Itk kinase is essential for FcR-stimulated NK cell function, including calcium movement, particle release, and overall ADCC. Because anti-CD20 antibodies (such as rituximab) are standard care drugs, often part of a combination regimen for the treatment of CD20+ B-cell malignancies, evaluation of ibupotinib or (II) antagonizes ADCC in vitro Effectiveness. We hypothesized that a Btk inhibitor (formula (II) that does not have activity against Itk) retains NK cell function and thus synergistically, but not antagonizes, the ADCC via the rituximab medium. Cytotoxicity via rituximab-dependent NK cell media was assessed using lymphoma cell lines as well as autologous CLL tumor cells.

The cell culture conditions are as follows. The cell lines Raji and DHL-4 were maintained in RPMI 1630 supplemented with fetal bovine serum, L-glutamic acid, 2-mercaptoethanol and penicillin-streptomycin in a humidified incubation chamber at 37 °C. HER18 cells were maintained in DEM supplemented with fetal bovine serum and penicillin-streptomycin. HER18 cells were collected using trypsin-EDTA (ethylenediaminetetraacetic acid) prior to assay, washed with phosphate buffered saline (PBS) containing 5% serum and subjected to viable cell counting. In order to culture the primary target cells, peripheral blood from CLL patients was subjected to density centrifugation to obtain peripheral blood mononuclear spheres (PBMC). The cell preparation was washed and then positive selection of CD5 ⁺ CD19 ⁺ CLL cells was performed using magnetic beads (MACS, Miltenyi Biotech). Fresh cell preparations are used after selection. The peripheral blood collected from the sodium citrate anticoagulation tube was enriched with NK cells from CLL patients and healthy volunteers and then the cells were subjected to density centrifugation. Non-NK cell removal was performed using a negative selection with MACS separation. Freshly isolated NK cells were washed three times, counted and immediately used for ADCC assays.

The measurement of cytokine secretion was as follows. Degranulation and cytokine release by rituximab and trastuzumab-dependent NK cell media were assessed using lymphoma and HER2+ breast cancer cell lines (DHL-4 and HER18, respectively). Target cells in rituximab (DHL-4) or trastuzumab (HER18) containing 10 μg/ml and test articles (0.1 or 1 μM Ibbutinib, 1 μM (II) or DMSO vehicle The control group was cultured in a flat bottom plate. NK cells from healthy donors were enriched as described above, then cells were added to target cells and incubated for 4 hours at 37 °C. The culture was repeated three times with NK cells from the donor. After incubation, the supernatant was collected, briefly centrifuged and then analyzed for interferon-gamma using an enzyme-linked immunosorbent assay (ELISA) (R&D Systems, Minneapolis, MN, USA).

The dissolution of dissolved particles was determined as follows. NK cells from healthy donors are enriched and cultured in the presence of target cells, monoclonal antibodies, and test articles, as described above. After 4 hours, the cultures were harvested and the cells were pelleted, washed and then stained for flow cytometry evaluation. Degranulation was assessed by flow cytometry using CD107a (a protein normally present on the inner leaves of the lysed particles) and selection on NK cells (CD3-CD16 ⁺ lymphocytes). The percentage of CD107a-positive NK cells was quantified by comparison with a negative control group (isotype control group, unstained cells/FMO). Control cultures (NK cells not cultured in the target cells or NK, target cell co-cultures in the absence of appropriate monoclonal antibodies) were also evaluated; all experiments were repeated three times.

The ADCC assay is performed as follows. Briefly, target cells (Raji or naive CLL) were labeled with 100 μCi ⁵¹ Cr for 4 hours at 37 ° C prior to co-culture with NK cells. The cells were washed, counted and then added three times to a prepared 96-well plate containing 25:1 effector: target (E:T) ratio of treated NK cells. Rituximab (Genentech) was added to the ADCC well at a concentration of 0.1, 1.0 or 10 micrograms/ml, the assay was simply mixed and then centrifuged to collect the cells at the bottom of the well. The natural cytotoxic effect of NK cells was assessed in wells without rituximab. The culture was incubated at 37 ° C for 4 hours and then centrifuged. The supernatant was collected and the ⁵¹ Cr release was measured in liquid scintillation counting. All experiments were repeated three times.

Ibbutinib inhibited rituximab-induced NK cell hormone secretion in a dose-dependent manner (0.1 and 1 μM) (Fig. 32: 48% p=0.018; 72% p=0.002, respectively). At 1 μM, formula (II) Cytokine secretion was not significantly inhibited (Fig. 32: 3.5%). Similarly, Formula (II) had no inhibitory effect on granulation of NK cells stimulated with rituximab (<2%), while Ibufenib reduced degranulation by ~50% (p=0.24, Figure 33). ). Formula (II) had no inhibitory effect, while Ibufenib prevented ~92% of trastuzumab-stimulated NK cytokine release and ~84% of granulation by 1 μM (Figure 30 and Figure 31: ** *p=0.004, **p=0.002).

In Raji cell samples, in vitro NK cell activity against autologous tumor cells was not inhibited by formula (II) added at 1 μM, and cytolysis was observed with rituximab at a fixed E:T ratio. The increase in anti-concentration increases (Fig. 34). A graph emphasizing the difference between formula (II) and ibutinib at 10 μM is shown in Fig. 35. In the primary CLL samples, in vitro NK cell activity against autologous tumor cells was not inhibited by formula (II) added at 1 μM, and cytolysis was observed with rituximab at a fixed E:T ratio. Increased resistance to increase (Figure 36). Conversely, the addition of 1 μM Ibunotetin completely inhibited ADCC, with less than 10% cell lysis at any rituximab concentration compared to cultures without rituximab and in rituximab Does not increase cell lysis in the presence of resistance. The difference between formula (II) and ibufenib was very significant in this assay (p=0.001).

In the ADCC assay using NK cells from healthy donors, antibody-dependent lysis of rituximab-coated Raji cells was not inhibited by formula (II) added at 1 μM (Fig. 34). In these experiments, the addition of 0.1 and 1 micro-crituximab/ml stimulated increased cytolysis compared to low (<20%) natural cytotoxicity in the absence of rituximab. 5 to 8 times. As previously reported, the addition of 1 μM Ibubinib strongly inhibited antibody-dependent lysis of target cells, with less than 20% of cells lysing at all concentrations of rituximab and ADCC not following higher rituximab The concentration of the monoclonal antibody increases. The difference between formula (II) and ibufenib was very significant in this assay (p=0.001).

Ibbutinib is a clinically effective single drug therapy and is combined with rituximab, although ADCC is inhibited in both in vitro and in vivo murine models due to the secondary irreversible binding of Ibupretinib to ITK. The efficacy of therapeutic agents that do not inhibit NK cell function, including formula (II), is superior to ibufitinib before clinical use. The impact of this finding on patients receiving rituximab must be determined in clinical studies because these results provide formula (II) as a better agent than the combination of ibufibrate and antibodies with ADCC as the mechanism of action. The support of the unexpected nature.

Example 5 - BTK Inhibitory Effect of Opitopuzumab on Antibody-Dependent NK Cell Media Cytotoxicity

Previous studies have determined that ibbutinib undesirably antagonizes the rituximab ADCC effect of NK cell mediators. As indicated previously, this may be due to the secondary irreversible binding of Ibufenib to ITK, which is essential for FcR-stimulated NK cell function, including calcium movement, particle release, and overall ADCC. H.E. Kohrt et al., Blood 2014, 123, 1957-60. Ipotinib was also explored for antagonizing the potential of the NK cell-mediated Opitocilizumab (GA-101) ADCC and compared to the effect of Formula (II).

The NK cell degranulation/ADCC assay is performed using a whole blood assay. CLL targets are added to normal donor blood in the presence or absence of different doses of formula (II) and ibutinib. It was then conditioned with anti-CD20 antibody octoprezumab. Ibinidin was used as a control group and two blind BTK inhibitor samples of formula (II) and a second ibufibrate sample were provided to the investigator. The granulation in whole blood is carried out as follows. CLL targets (MEC-1 cells) were expanded in RPMI 1640 medium (Life Technologies, Inc.) with 10% fetal bovine serum (FBS). Use cells grown in geometric progression. On the day of the experiment, 8 ml of blood was taken from a normal volunteer into a test tube containing diazepam to obtain a final concentration of 50 μg/ml. White blood cell (WBC) counts of whole blood were performed. That the MEC-1 cells WBC concentration resuspended in whole blood (for example, when measuring ⁶ × 10 6 WBC / ml, is that the MEC-1 cells at ⁶ × 10 6 cells / ml were resuspended to give a final WBC: MEC The cell ratio of -1 is 1:1). The ibbutinib control group and two blind BTK inhibitors were diluted to a concentration of 200 μM, 20 μM and 2 μM in X-VIVO 15 serum-free hematopoietic cell medium (Lonza Group, Ltd.). A 170 microliter aliquot of untreated whole blood was incubated with 10 microliters of BTK inhibitor or X-VIVO 15 medium for 1 hour in the dish. Cetuximab and octopuzumab (GA-101) were diluted to a concentration of 20 μg/ml in X-VIVO 15 medium. Equal volumes of MEC-1 cells and antibodies were incubated for 5 minutes. After incubation, 20 microliters of MEC-1 cells and antibodies were added to whole blood and BTK inhibitor/X-VIVO 15 medium (final volume of 200 microliters). The sample was placed in a 5% CO ₂ incubator at 37 ° C for 4 hours. Thus, the experimental conditions for a WBC:MEC-1 cell ratio of 1:1 were achieved, and the final agronomic strength of the BTK inhibitor in the assay was 10 μM, 1 μM and 0.1 μM, and the final concentration of the antibody was 1 μg/ml.

After 4 hours, the samples were gently mixed, 50 ml aliquots were removed from each well and placed in a fluorescence activated cell sorting (FACS) test tube. A 20 microliter aliquot of anti-CD56-APC antibody and anti-CD107a-PE antibody were added. The samples were incubated for 20 minutes at room temperature in the dark. A 2 ml aliquot of FACS dissolution solution (BD Biosceinces) was added. The samples were incubated for an additional 5 minutes and then centrifuged at 2000 rpm for 5 minutes. The supernatant was discarded and the cell pellet was resuspended in 500 microliters of PBS. Samples of CD107a ⁺ NK cells (CD56 ⁺ ) were analyzed on a flow cytometer.

The granulation results of NK cells are summarized in Figure 37, n = 3 experiments, which were shown to be pretreated with BTK inhibitor at the indicated concentrations for 1 hour followed by 1 microgram of oxifizumab or cetuximab. The effect of BTK inhibitors on whole blood after 4 hours of MEC-1 stimulation by anti-ml/ml. A strong decrease in the percentage of CD56 ⁺ /CD107a ⁺ NK cells was observed using ibufitinib (as a control group and a blind BTK inhibitor), indicating that ibbutinib undesirably antagonizes NK cells. Conversely, formula (II) unexpectedly shows a very low antagonism against NK cells. These results support the potential synergistic combination of opitolizumab and formula (II) in the treatment of human B cell malignancies.

Example 6 - BTK inhibitory effect on cytotoxicity by systemic NK cell media

The following assay was performed to assess the BTK inhibitory effect of formula (II) on systemic NK killing (non-ADCC kill). The target (K562 cells) does not exhibit MHC class I, so these do not inactivate NK cells. Grown to mid-log (mid-log phase) and the 5 × 10 ⁵ cells in 100 [mu] l at 37 [deg.] C in assay medium (with 10% FCS and penicillin / streptomycin the IMDM) target cells to 100μ Ci ⁵¹ Cr was marked for 1 hour. The cells were washed twice and resuspended in assay medium. A total of 5,000 target cells/slots were used in this assay. The effector cells were resuspended in assay medium, dispensed on a V-bottom 96 well plate and mixed with labeled target cells at an E:T ratio of 40:1. Target cells were incubated in 1% Triton X-100 to determine maximum release. For spontaneous release, the target is incubated in a separate assay medium without an effector. After centrifugation at 1000 rpm for 1 minute, the plates were incubated at 37 ° C for 4 and 16 hours. The supernatant was collected and the ⁵¹ Cr release was measured in a gamma counter. The percentage of specific release was calculated as (experimental release - spontaneous release) / (maximum release - spontaneous release) x 100. The results are shown in Fig. 38.

Example 7 - BTK inhibitory effect on T cells

The following assay was performed to assess the BTK inhibitory effect on T cells using Formula (II). The enriched CD4 ⁺ T cells were plated onto a 24-well plate that had been treated with 250 μl of anti-TCRβ (0.5 μg/ml) in PBS plus anti-CD28 (5 μg/ml) at 37 °C. ML) pre-coated. The cells are then supplemented with a medium containing the BTK inhibitor along with a skewing cytokine as indicated below. Th17 and Treg cultures were grown for 4 days prior to analysis. Cells with offset cytokines (Th17; 20 ng IL-6/ml, 0.5 ng TGF-β/ml, 5 μg IL-4/ml, 5 μg IFN-γ and Treg/ml, 0.5 ng TGF-β/ml, 5 μg IL-4/ml, 5 μg IFN-γ/ml) was maintained for an additional 3 days and supplemented with IL2 as a growth factor.

The results are shown in Figures 39 and 40, and further illustrate the surprising properties of Formula (II) compared to Ibufenib. Since formula (II) lacked activity against Itk and Txk, no adverse effects on the development of Th17 and Treg were observed. Since Ibbutinib inhibited both Itk and Txk, complete inhibition of Th17 cells and increased development of Tregs were observed, which was comparable to the murine Itk/Txk double knockout cells used as a control group.

The effect of ibutinib on CD8 ⁺ T cell survival compared to formula (II) was also assessed. Total T cells were plated onto anti-TCR and anti-CD28 coated wells in the presence of two BTK inhibitors. Natural culture conditions are used which do not polarize T cells into an auxiliary system. Cells were grown for 4 days and then stained with anti-CD4, anti-CD8 and LIVE/DEAD reagents to determine if the drug has a selective effect on CD4 ⁺ or CD8 ⁺ cells. Statistical significance was calculated using the Mann Whitney T-test. The results shown in Figure 41 indicate that higher concentrations of Ibubinib have a strong negative effect on CD8 ⁺ T cell survival, which is not observed at any concentration of Formula (II).

Example 8 - Clinical study of BTK inhibitors in combination with opitolizumab (GA-101) in leukemia/lymphoma

The main objectives of the study are (1) determination of formula (II) and Obito beads The total response rate (ORR) of the combination of mAbs in patients with relapsed or recalcitrant CLL/SLL for 12 months, and (2) the combination of formula (II) and octetuzumab in patients with The 12-month ORR of untreated CLL/SLL patients, and (3) the safety and feasibility of establishing a combination of formula (II) and octopuzumab.

The secondary goals of this study were: (1) to determine the complete response (CR) rate and MRD-negative CR rate in previously untreated and relapsed and recalcitrant CLL using this system; (2) to measure progression-free survival using this system Rate (PFS), time to next treatment (TTNT) and overall survival, (3) baseline analysis of patients enrolled in this trial, including fluorescence in situ hybridization (FISH), stimulated karyotype, Zap-70 methylation and IgV _H mutation status, and indicates the relationship between these biomarkers and ORR or PFS in patients treated with this system; (4) Determination of oral (II) by oral administration Pharmacokinetics (PK); (5) Measure pharmacodynamic (PD) parameters on days 8 and 29 of treatment with formula (II), including BTK drug occupancy, miR changes, and gene expression; To determine the effect of formula (II) on NK cell and T cell function in vivo; (7) by baseline and vertical axis assessment of BTK and PLCG2 mutations at regular tracking intervals and by whole exome sequencing Diagnostic evaluation of relapsing samples to assess the development of resistance in the series; (8) determining the effects of formula (II) on emotional distress and quality of life of patients; and (9) determining the psychological sum of formula (II) To track the reaction and response to therapy covariance.

CLL is the most prevalent form of adult leukemia and has variable clinical processes, many of which do not require treatment for many years and have the same survival rate as the age-matched control group. However, other patients showed an invasion Sexual disease with poor prognosis despite appropriate therapies. Byrd et al., Chronic lymphocytic leukemia. Hematology Am. Soc. Hematol. Educ. Program. 2004, 163-183. Although patients with initial disease do not show a survival advantage with initial treatment, most patients eventually require treatment for their onset of symptoms or diseases of hematocytopenia, and although there is a relatively long period of disease for the initial stage. Life expectancy, but CLL is still an incurable disease. Patients diagnosed with or advanced to advanced disease have an average survival rate of 18 months to 3 years. Unfortunately, such patients with advanced disease are also more resistant to conventional therapies.

The treatment of CLL has progressed significantly over the past few decades, although in the past the use of alkylating agents, the randomized trial with fludarabine and subsequent combinations of fludarabine and cyclophosphamide proved to be higher. Response rate and longer progression-free survival (PFS). O'Brien et al. Advances in the biology and treatment of B-cell chronic lymphocytic leukemia. Blood 1995, 85, 307-18; Rai et al's Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N. Engl. J. Med 2000, 343, 1750-57; Johnson et al. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL.Lancet 1996,347 , 1432-38; Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic Lymphocytic leukemia patients. Blood 2001, 98, 2319-25; Association of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): A randomised controlled trial. Lancet 2007, 370, 230-239; Eichhorst et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006, 107, 885-91. A chimeric anti-CD20 monoclonal antibody rituximab was also introduced for the treatment of CLL. Treatment with a high dose or a strong dose of the single agent rituximab showed efficacy; however, complete response or prolonged remission was rare. O'Brien et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J. Clin. Oncol. 2001, 19, 2165-70; Byrd et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small Lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. Clin. Oncol. 2001, 19, 2533-64. The efficacy of rituximab has been improved by combining it with traditional cytotoxic agents such as fludarabine or fludarabine and cyclophosphamide, which yields a high CR compared to historical controls. Rate and prolonged progression-free survival (PFS). In fact, a large-scale clinical trial reported by the German CLL research team showed that antibody therapy with rituximab added to fludarabine and cyclophosphamide has in patients with untreated CLL. Extend the benefits of PFS and OS. Hallek et al. Addition of rituximab to fludarabine and Cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010, 376, 1164-74. The progress of this inspiring therapy and our response to the disease have been significantly improved and the PFS. However, significantly improved overall survival (OS) and ultimately the cure remains difficult to achieve.

Although chemical immunotherapy based on fludarabine is the standard of care for younger patients, the treatment of older patients is less clear. In the large Phase 2 and 3 trials outlined previously, the mean age was usually in the early 60s, and the average age of patients diagnosed with CLL was 72 years, raising questions about whether these results can be widely used. The entire CLL community. In fact, a randomized phase 3 trial investigating primary CLL therapy in older patients demonstrated that fludarabine was not superior to chlorambucil in patients >65 years of age. Eichhorst et al.'s first line therapy with fludarabine did not provide significant benefit to older patients with advanced chronic lymphocytic leukemia compared to chlorambucil. Blood 2009, 114, 3382-91. This finding was confirmed by a large retrospective study of first-line therapy by the Alliance for Clinical Trials in Oncology, which again demonstrates that fludarabine is no better than benzobutyrate in older patients. Mustard is excellent, but it also shows that adding rituximab to chemotherapy is beneficial, regardless of age. Woyach et al. Impact of age on outcomes after initial therapy with chemotherapy and different chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia: Results of sequential cancer and leukemia group B studies. J. Clin. Oncol. 2013, 31, 440- 7. Two studies evaluated the combination of rituximab and chlorambucil showing that the combination was safe and moderately effective. Hillmen et al. rituximab plus chlorambucil in patients with CD20-positive B-cell chronic lymphocytic leukemia (CLL): Final response analysis of an open-label Phase II Study, ASH Annual Meeting Abstracts, Blood 2010, 116, 697; Foa et al. Phase II study of chlorambucil plus rituximab followed by maintenance versus observation in elderly patients with previously untreated chronic lymphocytic leukemia: Results of the first interim analysis, ASH Annual Meeting Abstracts, Blood 2010, 116, 2462.

Recently introduced a type II glycosylation engineered CD20 monoclonal antibody, octopuzumab. In the Phase 1 trial of CLL previously treated with monotherapy, this antibody has a 62% response rate, including a 1 MRD-negative complete reaction, indicating that this individual antibody may be more likely to be in citrate than rituximab in CLL. active. Morschhauser et al. Phase I study of R05072759 (GA101) in relapsed/refractory chronic lymphocytic leukemia, ASH Annual Meeting Abstracts. Blood, 2009, 114, 884. The German CLL Research Group (GCLLSG) recently completed rituximab and chlorambucil or octetuzumab and chlorambucil relative to chlorambucil alone in untreated CLL Phase 3 trial in patients with significant comorbidities. In this population, octopuzumab and chlorambucil (but not rituximab and chlorambucil) improved the OS beyond the chlorambucil alone (hazard ratio 0.41, p=0.002), and oxifizumab and chlorambucil made PFS improved beyond rituximab and chlorambucil (mean PFS was 26.7 months vs. 14.9 months, p<0.001) ). Goede et al., Binutuzumab plus chlorambucil in patients with CLL and coexisting conditions, N. Engl. J. Med. 2014, 370, 1101-10. Based on these favorable data, the combination of opituzumab and chlorambucil is the first line of treatment for FDA-approved CLL patients.

Many older patients are also treated with a combination of bendamustine plus rituximab (BR). Although BR was not directly compared with chlorambucil and rituximab, the results of the second phase of the trial showed an ORR of 88% with an average event-free survival of 33.9 months and 90.5% of 27 months. OS. Fischer et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: A multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J. Clin. Oncol. 2012, 30, 3209-16. These results apply to >70 years of age and are comparable to those published by chlorambucil and rituximab. Although the results of this system have improved beyond the historical control group, the results are not as good as those observed with younger patients with chemical immunotherapy. Therefore, the optimal treatment for older patients still does not meet the requirements in clinical trials.

In addition, most patients eventually relapse with their disease and often recalculate against existing agents. Patients with relapsed from combined chemical immunotherapy have poor results with subsequent standard therapies. Although the choice of such patients includes Combination of alemtuzumab, bendamustine, high-dose corticosteroids, ovalimumab, and method-based, but none of these therapies are superior to those observed with first-line chemoimmunotherapy Long-term relief. Keating et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002, 99, 3554-61; Bergmann et al. Efficacy of bendamustine in patients with relapsed or refractory chronic Lymphocytic leukemia: results of a phase I/II study of the German CLL Study Group. Haematologica 2005, 90, 1357-64; Thornton PD, Matutes E, Bosanquet AG, etc. High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities .Ann.Hematology 2003, 82, 759-65; Coiffier et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic 1eukemia: A phase 1-2 study.Blood 2008, 111, 1094-1100; Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. T., Lin., 26, pp. -203. Many of these therapies including alemtuzumab and high dose steroids are also associated with significant toxicity and sustained immunosuppression. Lozanski G, Heerema NA, Flinn 1W, etc. Alemtuzumab Is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004,103,3278-81; The efficacy of alemtuzumab for refractory chronic lymphocytic leukemia in relation to cytogenetic abnormalities of p53.Haematologica 2005,90,1435 -36; Thornton et al. High dose methyl prednisolone in refractory chronic lymphocytic leukaemia. Leuk. Lymphoma 1999, 34, 167-70; Bowen et al. Methylprednisolone-rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic 1eukemia including those with unfavorable cytogenetic Features. Leuk Lymphoma 2007, 48, 2412-17; Castro et al. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia 2008, 22, 2048-53.

In the ongoing Phase 1b/2 study, the BTK inhibitor Ibbutinib showed activity in patients with relapsed or recalcitrant CLL. In patients with relapsed or recalcitrant CLL and measurable lymphadenopathy, >50% of lymph node reduction was 89%. The ORR of the 4-month average follow-up period was 48%, due to the absence of symptomatic lymphocytosis, and the ORR improved to 71% in the 26-month longer tracking period in patients receiving the 420 mg dose, an additional 20 % of patients with lymphocytosis (PR-L) achieved partial response. Byrd et al. Activity and tolerability of the Bruton's tyrosine kinase (Btk) inhibitor PCI-32765 in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Interim results of a phase Ib/II study.J.Clin.Oncol .ASCO Annual Meeting Abstracts, 2011, 29, Abstract 6508; Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 2013, 369, 32-42. This lymphocytosis may be associated with release of B cells from the lymph nodes, spleen, and bone marrow microenvironment, which is disrupted by a homeopathic signal or chemoattractant associated with general lymphocyte circulation dynamics. The lymphogastrocytosis of ibufenib was seen within 1-2 weeks of starting treatment, reaching a plateau during the first 2-3 cycles and resolved over time in almost all patients. The duration of lymphocytosis does not appear to be related to the final response depth of the duration of the response. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood 2014, 123, 1810-7. The response to Ibbutinib was not related to high-risk genomic properties, including IgV _H mutation status and del (17p13.1). These relapsed and recalcitrant patients also have a long-term response to this drug, with 76% of PFS and 83% of OS estimated in 26 months. The study also included a group of 31 previously untreated patients. The ORR of the follow-up period of 16.6 months was 71%, with an additional 10% of patients with persistent lymphocytosis; an estimated FFS of 96% for 22 months. This agent is currently undergoing Phase 3 trials in untreated diseases and is currently approved by the FDA for the treatment of relapsing CLL. These data for ibbutinib support the potential benefits of selective BTK inhibition in CLL. However, although BTK is inhibited with high potency, ibbutinib also shows activity against other kinases (such as epidermal growth factor receptor) in vitro, which may be the cause of diarrhea and rash associated with ibufenib. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl. Acad. Sci. USA 2010, 107, 13075-13080. In addition, Ibubinib is a matrix of both cytochrome P450 (CYP) enzymes 3A4/5, which increases the likelihood of drug-drug interaction. Finally, the ITK inhibition found by Ibupotinib has the potential to abolish the NK cell ADCC, making it less effective in combination with monoclonal antibodies. Kohrt et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood 2014, 123, 1957-60. These unfavorable conditions support the development of alternative BTK inhibitors for lymphoma therapy.

In this Phase 1B study, the two groups (relapsed/recalcular and untreated) were evaluated in a largely staggered manner. Six individuals with R/RCLL were first registered as group 1. Once safety has been assessed, the R/R group is expanded to 26 individuals and 6 untreated individuals in Group 2 can be enrolled. Once the safety of Group 2 was established, the group was expanded to 19 individuals.

Formula (II) was administered on day 1 of cycle 1 and twice daily (100 mg BID) until disease progression. Obitozumab Administration is started on the first day of the second cycle by standard administration. The patient received 100 mg IV on the first day of cycle 2. The patient received 900 mg on the second day of cycle 2. The patient received 1000 mg IV on Days 8 and 15 of Cycle 2. The patient received 1000 mg on the first day of each cycle of cycles 3-7. For patients treated with dose value -1, 100 mg was administered on the first day of cycle 2 and 650 mg was administered on the second day of cycle 2. The patient received 750 mg IV on day 8 of cycle 2, and the patient received 750 mg on day 1 of each cycle during periods 3-7. A period beginning within a period of 24 hours (one working day) before and after the first day of the new period defined by the agreement may be accepted.

The inclusion criteria for patient eligibility are as follows: (1) Patients diagnosed with moderate or high-risk CLL (or variant immunophenotype), SLL, or B-PLL with IWCLL 2008 criteria, with: (a) Group 1 : Previously received at least one therapy for their disease; (b) Group 2: previously untreated disease and >65 years old or younger and refused or not used for chemoimmunotherapy; (2) Group 1 The patient may receive the previous ibupotinib (or another BTK inhibitor) as long as the interruption is due to reasons other than the progression of the disease on the on-treatment; (3) all patients must meet the following criteria One of the criteria for active disease requiring therapy: (a) evidence of bone marrow failure as manifested by progression or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia); (b) Thick (under the costal margin > 6 cm), progressive or symptomatic splenomegaly; (c) thick knot (> 10 cm) or progressive or symptomatic lymphadenopathy; (d) systemic symptoms, including the following Either: the limit activity of unconsciously losing 10% or more within 6 months, significant fatigue, after 2 weeks or more >100 .5°F fever without evidence of infection, >1 month of night sweats without evidence of infection; (4) Nodular disease measured by computed tomography (CT). The measurable nodular disease is defined as the largest diameter at the nodule >1 lymph node >1.5 cm; (5) if the patient has CLL evidence that is now only <10% of the large cells in the bone marrow, Qualified for the history of Richter's syndrome; (6) The individual must have appropriate organ function, defined as creatinine <2.5 times normal upper limit (ULN), ALT and AST <3.0 x ULN, and biliary red <2.5 x ULN; (7) platelets > 50 x 10 ⁹ / liter. Platelets in individuals with CLL involving bone marrow > 30 x 10 ⁹ / liter; (8) ANC > 750 / cubic millimeter. ANC > 500 / cubic millimeter in individuals with CLL involving bone marrow; (9) individuals must have ECOG performance status <2; (10) individuals must not lead to life expectancy < 2 years or may confuse toxicity in this study Secondary cancer assessed; (11) the individual must be > 18 years old; (12) the individual must provide informed consent. A signed copy of the consent form will remain in the patient's medical record; (13) the individual must be able to receive outpatient treatment and follow-up at the treatment facility; (14) the individual must end all CLL therapy before the first study is administered>4 week. Allow at least one week of soothing steroids before starting treatment, but must equal the dose of <20 mg of Pressu per day; (15) genital individuals and male individuals with reproductive partners must agree to complete and complete during the study Use effective contraceptive methods within 2 months of their final treatment. Women with a fertility possibility must have a negative β-hCG pregnancy test within 3 days of the first study dose. Female patients who have undergone surgical sterilization or >45 years of age and have menopause for >2 years are exempt from the beta-hCG pregnancy test; (16) the individual must be able to swallow the entire capsule.

The criteria for exclusion of patient eligibility are as follows: (1) Group 1 on prior treatment of CLL, allowing autologous complication of CLL to be treated with steroid or rituximab, however, if rituximab was recently administered For monoclonal antibodies, CD20 must be returned to 10% of CLL cells. Accepts a soothing steroid equivalent to <20 mg of Pressu per day; (2) any life-threatening illness, medical condition, or organ dysfunction that may compromise the patient's safety and interference in the researcher's opinion (II) Absorption or metabolism or the risk of undue risk of research; (3) women who are pregnant or breastfeeding; (4) active cardiovascular disease that is not controlled by medicine or those who have had myocardial infarction in the past 6 months Or individuals with QTc > 480ms; (5) malabsorption syndrome, diseases that significantly affect gastrointestinal function, gastric or small bowel resection or gastric bypass, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete obstruction of the intestine (6) continuous grade 2 toxicity (except for baldness) from previous anticancer therapies (including radiation); (7) major surgery within 4 weeks prior to the first drug study; (8) hemorrhagic quality History (eg, hemophilia, von Willebrand disease); (9) uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura; (10) given in the first drug study History of stroke or intracranial hemorrhage within 6 months before the drug; (11 The anticoagulant effect of warfarin or an equivalent vitamin K antagonist (such as phenylpropanol) is required or accepted within 28 days prior to the first drug study; (12) long-lasting protons are needed Pu inhibitors (such as omeprazole, eomeprazole, lansoprazole, dexlansoprazole, rabeprazole or 泮tora) Azole (pantoprazole)) treatment; (13) Individuals with active infections requiring IV antibiotic/antiviral therapy are not eligible to enter the study until the infection is resolved. Patients who can receive prophylactic antibiotics or antiviral agents; (14) individuals with a history of pneumonia or persistent drug-induced pneumonia; (15) with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) or An active infection of hepatitis B virus (HBV) or any uncontrolled active systemic infection; (16) an individual known to have hepatitis B infection or be positive for hepatitis B core antibody or surface antigen. Patients receiving prophylactic WIG may have false positive hepatitis seropositivity. Patients with positive hepatitis serotypes using WIG must have negative hepatitis B DNA as eligible; (17) individuals with substance abuse or other medical or psychiatric conditions that may confuse research interpretations or influences in the researcher's opinion The ability of the patient to tolerate or complete the study; (18) the individual may not be concurrently involved in another therapeutic clinical trial; (19) the individual who received the live virus vaccination within one month of starting the study drug.

In this study, Formula (II) was administered at 100 mg BID and the second dose was 11-13 hours after the first dose. Obitocilizumab is administered by IV perfusion in an absolute (flat) dose. Obitocilizumab is administered in a single day, except when the patient receives their first dose of opitocilizumab (fractional dose) for two consecutive days in cycle 2 Except: 100 mg on day 1 and 900 mg on day 2. For patients treated with a dose value of -1 (750 mg opiateizumab) - 100 mg on day 1 and 650 mg on day 2. On the day of giving both formula (II) and opitolizumab, the order of study treatment administration was formula (II), It was then followed by at least one hour of octopuzumab. The complete dosing schedule is provided in Table 7.

Anti-CD20 antibodies have a known safety profile including perfusion related reactions (IRR). Anti-CD20 antibodies and in particular opitolizumab can cause severe and life-threatening perfusion reactions. The sequelae of the perfusion response include patient discontinuation of antibody therapy, which results in suboptimal efficacy or increased medical resource depletion, such as hypotensive arsine treatment or prolonged antibody perfusion time. In the initial study of opitolizumab in patients with relapsed/refractory CLL (Bridge 2014, 124, 2196 by Cartron et al), in the first phase, all patients (n=13) experienced IRR (15% of level 3, no grade 4, and 100% of patients experience all grades of AE), with the most common hypotension and fever symptoms. In the second phase of the study, 95% of patients developed IRR, and 60% of cases developed hypotension; 25% of these were grade 3 reactions. In the case of octopuzumab and chlorambucil Of the key trials in previously untreated patients, 69% developed perfusion-related responses, 21% of which were grades 3-4.

Combination of Formula (II) and Oberbitzumab is used in this example for Phase 1b studies in patients with relapsed/refractory or untreated CLL/SLL/PLL The results are as follows. To date, 6 patients have been treated with a combination of formula (II) and opitolizumab in this study. The patient was treated with the formula (II) alone for 1 month, and then the patient received the ibbituzumab on the first day of the cycle 2. To date, 41 doses of omebituzumab have been administered to 6 patients. The number of lymphocytes before the treatment with octoprezumab ranged from 8 to 213 x 10 ⁹ / liter. There are no reports of severe or grade 3-4 IRR cases. Only 2 patients who received octopuzumab had a short delay due to chills and joint pain/tongue, but were able to complete the planned perfusion. The other 3 patients had adverse events within 24 hours of perfusion, all of which were grade 1 (conditions: flushing, palpitations in one patient, rash and eschar and headache). Thus, a month starting with formula (II) will substantially reduce the severity or grade 3-4 IRR, which may lead the combination to higher potency and better tolerance, resulting in reduced medical resource consumption.

<110> Acerta Pharma B.V.

<120> Composition and method for treating chronic lymphocytic leukemia and small lymphocytic leukemia using Bruton's tyrosine kinase (BTK) inhibitor

<140> TW 104120764

<141> 2015-06-19

<150> PCT/IB2015/000645

<151> 2015-01-21

<150> 104115801

<151> 2015-05-18

<150> PCT/US2015/036274

<151> 2015-06-17

<160> 14

<170> PatentIn version 3.5

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Claims (48)

A use of a Bruton's tyrosine kinase (BTK) inhibitor for the manufacture of a medicament for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), wherein the BTK The inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: X is CH or S; Y is C(R ₆ ); Z is CH or a bond; A is CH; B ₁ is N or C (R) ₇ ); B ₂ is N or C(R ₈ ); B ₃ is N or CH; B ₄ is N or CH; R ₁ is R ₁₁ C(=O); R ₂ is (C _1-3 )alkyl R ₃ is (C _1-3 )alkyl; or R ₂ and R ₃ together with the N and C atoms to which they are attached form a (C _3-7 )heterocycloalkyl ring selected from the group consisting of Azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, optionally via one or more of fluorine, hydroxy, (C _1-3 )alkyl or (C _1-3 )alkoxy Substituent; R ₄ is H; R ₅ is H, halogen, cyano, (C _1-4 )alkyl, (C _1-3 )alkoxy, (C _3-6 )cycloalkyl, or such Any alkyl group optionally substituted by one or more halogens; R ₆ is H or (C _1-3 )alkyl; R ₇ is H, halogen or (C _1-3 ) alkoxy; R ₈ is H or (C _1-3 )alkyl; or R ₇ and R ₈ together with the carbon atom to which they are attached form a (C _6-10 )aryl or (C _1-9 )heteroaryl; R ₅ and R ₆ together form (C _3-7) cycloalkenyl or (C _2-6) alkenyl heterocyclyl group, these substituents are each optionally substituted by (C _1-3) alkyl or one or more halo; R ₁₁ Site selected from the group consisting of consisting of the following: (C _2-6) alkenyl and (C _2-6) alkynyl, wherein each alkenyl or alkynyl group optionally selected from the consisting of one or more, Substituent substitution: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl] Amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl and (C _3-7 )heterocycloalkyl; prerequisite B ₁ , 0 to 2 atoms of B ₂ , B ₃ and B ₄ are N. According to the use of the first application of the patent scope, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the use of the first application of the patent scope, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the use of the first application of the patent scope, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the use of the first application of the patent scope, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the use of the first application of the patent scope, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. The use according to any one of claims 1 to 6, wherein the treatment comprises the step of orally administering a dose of the BTK inhibitor once daily, the dose being selected from the group consisting of: 100 mg , 175 mg, 250 mg and 400 mg. The use according to any one of claims 1 to 6, wherein the treatment comprises the step of orally administering a dose of the BTK inhibitor twice daily, the dose being selected from the group consisting of: 100 Mg, 175 mg, 250 mg and 400 mg. The use according to any one of claims 1 to 6, wherein the treatment comprises the step of administering a dose of the BTK inhibitor, the dose being selected from the group consisting of 5 mg, 10 mg, 12.5, 15, 20, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350 , 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg. The use according to any one of claims 1 to 6, wherein after treatment with the BTK inhibitor for a period of time, the CLL or SLL increases mononuclear spheres and NK cells in the peripheral blood, the period being selected from the group consisting of Group: about 14 days, about 28 days, and about 56 days. The use according to any one of claims 1 to 6, wherein the CLL or SLL is selected from the group consisting of IgV _H mutation-negative CLL or SLL, ZAP-70-positive CLL or SLL, CpG3 ZAP-70 CLL or SLL, CD38 positive CLL or SLL, CLL or SLL with 17p13.1 (17p) deletion, CLL or SLL with 11q22.3 (11q) deletion, 11q deletion and no 17p deletion CLL or SLL, CLL or SLL in people who are susceptible to platelet-mediated thrombosis, CLL or SLL in people who are suffering from thrombocytosis, CLL or SLL in people who have platelet-mediated thrombosis, or Their combination. The use according to any one of claims 1 to 6, wherein the treatment further comprises the step of administering a therapeutically effective amount of an anti-CD20 antibody selected from the group consisting of rituximab (rituximab) , opinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and their Fragments, derivatives, conjugates, variants, radioisotope-labeled complexes and biomolecules. The use according to claim 12, wherein the treatment comprises the step of administering a dose of an anti-CD20 antibody selected from the group consisting of 25 mg, 50 mg, 75 mg, 100 mg, 200 Mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg and 2000 mg. The use according to any one of claims 1 to 6, wherein the treatment further comprises administering a therapeutically effective amount of anticoagulant activity or The step of anti-platelet activity of the pharmaceutical ingredient. According to the use of claim 14, wherein the anti-coagulant activity or anti-platelet activity is selected from the group consisting of acenocoumarol, anagrelide, Nagreline hydrochloride, abciximab, alooxiprin, antithrombin, apixaban, argatroban, aspirin, aspirin Prolonged release of dipyridamole, beraprost, betrixaban, bivalirudin, carbasalate calcium, cilostazol , clopidogrel, clopidogrel hydrogen sulphate, clonicromen, dabigatran etexilate, darexaban, dalteparin, dalteparin sodium Defibrotide, dicumarol, diphenadione, dipyridamole, ditazole, desirudin, etoxa Edaoxaban, enoxaparin, enoxaparin sodium, etaiba Peptide (eptifibatide), fondaparinux, fondaparinux, heparin, heparin sodium, heparin calcium, idapainux, idaparin sodium, iloprost, indobufen , lepirudin, low molecular weight heparin, melagatran, nadroparin, otamixaban, parnaparin, phenindione, Phenprofen (phenprocoumon), prasugrel, pyrotoxamine (picotamide), prostacyclin, ramatroban, reviparin, rivaroxaban, sulodexide, terutroban, Truroban sodium, ticagrelor, ticlopidine, ticlopidine hydrochloride, tinzaparin, tinzaparin sodium, tirofiban, tirofiban Rofeban hydrochloride, treprostinil, trifluralin, triflusal, vorapaxar, warfarin, warfarin, ximega Groups (ximelagatran), their salts, solvates, hydrates, and various combinations thereof. A use of a Bruton's tyrosine kinase (BTK) inhibitor for the manufacture of a medicament for the treatment of a hematological malignancy wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: X is CH or S; Y is C(R ₆ ); Z is CH or a bond; A is CH; B ₁ is N or C (R) ₇ ); B ₂ is N or C(R ₈ ); B ₃ is N or CH; B ₄ is N or CH; R ₁ is R ₁₁ C(=O); R ₂ is (C _1-3 )alkyl R ₃ is (C _1-3 )alkyl; or R ₂ and R ₃ together with the N and C atoms to which they are attached form a (C _3-7 )heterocycloalkyl ring selected from the group consisting of Azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, optionally via one or more of fluorine, hydroxy, (C _1-3 )alkyl or (C _1-3 )alkoxy Substituent; R ₄ is H; R ₅ is H, halogen, cyano, (C _1-4 )alkyl, (C _1-3 )alkoxy, (C _3-6 )cycloalkyl or optionally Any alkyl group substituted by one or more halogens; R ₆ is H or (C _1-3 )alkyl; R ₇ is H, halogen or (C _1-3 ) alkoxy; R ₈ is H or (C _{1 -3} )alkyl; or R ₇ and R ₈ together with the carbon atom to which they are attached form a (C _6-10 )aryl or (C _1-9 )heteroaryl; R ₅ and R ₆ together form (C _3-7) cycloalkenyl or (C _2-6) heterocycloalkenyl group, each of these persons optionally substituted by (C _1-3) alkyl or substituted with one or more halo; R ₁₁ is independently Consisting of the following group consisting of: (C _2-6) alkenyl and (C _2-6) alkynyl, wherein each substituted alkenyl or alkynyl group optionally substituted by one or more groups selected from the consisting of Base substitution: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl]amino (C _1-3 ) alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl and (C _3-7 )heterocycloalkyl; prerequisites B ₁ , B ₂ 0 to 2 of B ₃ and B ₄ are N; and wherein the hematological malignancy is selected from the group consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma ( DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B-cell acute lymphoblastic leukemia (B-ALL), Bruton's lymphoma, Walden Waldenström's macroglobulinemia (WM), Bruton's lymphoma, multiple myeloma, and spinal fibrosis. According to the use of claim 16 of the scope of the patent application, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the use of claim 16 of the scope of the patent application, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the use of claim 16 of the scope of the patent application, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the use of claim 16 of the scope of the patent application, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the use of claim 16 of the scope of the patent application, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. The use according to any one of claims 16 to 21, wherein the treatment comprises the step of orally administering a dose of the BTK inhibitor once daily, the dose being selected from the group consisting of: 100 mg , 175 mg, 250 mg and 400 mg. The use according to any one of claims 16 to 21, wherein the treatment comprises the step of orally administering a dose of the BTK inhibitor twice daily, the dose being selected from the group consisting of: 100 Mg, 175 mg, 250 mg and 400 mg. According to any one of the 16th to 21st patent applications And wherein the treatment comprises the step of administering a dose of the BTK inhibitor selected from the group consisting of 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 50 mg , 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 Mg and 500 mg. The use according to any one of claims 16 to 21, wherein after the period of treatment with the BTK inhibitor, the blood malignant disease increases mononuclear cells and NK cells in the peripheral blood, the period selected from the group consisting of Group: About 14 days, about 28 days, and about 56 days. The use according to any one of claims 16 to 21, wherein the NHL is selected from the group consisting of painless NHL and invasive NHL. The use according to any one of claims 16 to 21, wherein the DLBCL is selected from the group consisting of activated B cell-like diffuse large B-cell lymphoma (DLBCL-ABC) and germline center B cell-like diffuse large B-cell lymphoma (DLBCL-GCB). The use according to any one of claims 16 to 21, wherein the MCL is selected from the group consisting of a coat of MCL, a nodular MCL, a diffuse MCL, and a maternal MCL. The use according to any one of claims 16 to 21, wherein the B-ALL is selected from the group consisting of early pre-B-cell B-ALL, pre-B-cell B-ALL and mature B-cell B -ALL. The use according to any one of claims 16 to 21, wherein the Bruton's lymphoma is selected from the group consisting of sporadic Bruton's lymphoma, regional Bruton's lymph. Tumor and human immune deficiency virus-related Bruton's lymphoma. The use according to any one of claims 16 to 21, wherein the multiple myeloma is selected from the group consisting of superdiploid multiple myeloma and non-hyperploid multiple myeloma . The use according to any one of claims 16 to 21, wherein the spinal cord fibrosis is selected from the group consisting of primary spinal fibrosis, spinal fibrosis secondary to erythroblastosis, and Spinal fibrosis secondary to cost-effective thrombocytosis. The use according to any one of claims 16 to 21, wherein the treatment further comprises the step of administering a therapeutically effective amount of an anti-CD20 antibody selected from the group consisting of rituximab (rituximab) , opinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and their Fragments, derivatives, conjugates, variants, radioisotope-labeled complexes and biomolecules. The use according to claim 33, wherein the treatment comprises the step of administering a dose of an anti-CD20 antibody selected from the group consisting of 25 mg, 50 mg, 75 mg, 100 mg, 200 Mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 m Grams, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, and 2000 mg. The use according to any one of claims 16 to 21, wherein the treatment further comprises the step of administering a therapeutically effective amount of a pharmaceutical component of anticoagulant activity or antiplatelet activity. According to the use of claim 35, wherein the anti-coagulant activity or the anti-platelet activity of the pharmaceutical ingredient is selected from the group consisting of acenocoumarol, anagrelide, Nagreline hydrochloride, abciximab, alooxiprin, antithrombin, apixaban, argatroban, aspirin, aspirin Prolonged release of dipyridamole, beraprost, betrixaban, bivalirudin, carbasalate calcium, cilostazol , clopidogrel, clopidogrel hydrogen sulphate, clonicromen, dabigatran etexilate, darexaban, dalteparin, dalteparin sodium Defibrotide, dicumarol, diphenadione, dipyridamole, ditazole, desirudin, etoxa Edaoxaban, enoxaparin, enoxaparin sodium, etaiba Peptide (eptifibatide), fondaparinux, fondaparinux, heparin, heparin sodium, heparin calcium, idapainux, idaparin sodium, iloprost, indobufen Lapti Lepirudin, low molecular weight heparin, melagatran, nadroparin, otamixaban, parnaparin, phenindione, styrene Phenprocoumon, prasugrel, picotamide, prostacyclin, ramatroban, reviparin, rivaroxaban, Sulodexide, terutroban, trubalban, ticagrelor, ticlopidine, ticlopidine hydrochloride, tinzaparin ), tinzaparin sodium, tirofiban, tirofiban hydrochloride, treprostinil, trifluralin, triflusal, vorapaxar ), warfarin, warfarin sodium, ximelagatran, salts, solvates, hydrates thereof, and various combinations thereof. A composition comprising an anti-CD20 antibody and a Bruton's tyrosine kinase (BTK) inhibitor, wherein the anti-CD20 anti-system is selected from the group consisting of rituximab, Obi Tobinizumab (obinutuzumab), atorvamumab (ofatumumab), vittuzumab (tottumumab), tositumomab (ibistumomab), and their fragments, derivatives , conjugates, variants, radioisotope-labeled complexes and biomolecules; and wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, wherein: X is CH, N, O or S; Y is C(R ₆ ), N, O or S; Z is CH, N or a bond; A is CH or N; B ₁ is N or C(R ₇ ); B ₂ is N or C(R ₈ ); B ₃ is N or C(R ₉ ); B ₄ is N or C(R ₁₀ ); R ₁ is R ₁₁ C(O), R ₁₂ S(O), R ₁₃ SO ₂ or (C _1-6 )alkyl optionally substituted by R ₁₄ ; R ₂ is H, ( C _1-3 )alkyl or (C _3-7 )cycloalkyl; R ₃ is H, (C _1-6 )alkyl or (C _3-7 )cycloalkyl; or R ₂ and R ₃ and The N and C atoms are joined together to form (C _3-7 ) optionally substituted with one or more fluorine, hydroxyl, (C _1-3 )alkyl, (C _1-3 ) alkoxy or pendant oxy groups. Heterocycloalkyl; R ₄ is H or (C _1-3 )alkyl; R ₅ is H, halogen, cyano, (C _1-4 )alkyl, (C _1-3 )alkoxy, (C _3-6 ) a cycloalkyl group, optionally substituted with one or more halogens; or R ₅ is (C _6-10 ) aryl or (C _2-6 )heterocycloalkyl; R ₆ is H Or (C _1-3 )alkyl; or R ₅ and R ₆ together may form (C _3-7 )cycloalkenyl or (C _2-6 )heterocyclenyl; each of these optionally passes (C _{1 -3} ) alkyl or one or more halogen substitutions; R ₇ is H, halogen, CF ₃ , (C _1-3 )alkyl or (C _1-3 )alkoxy; R ₈ is H, halogen, CF ₃ , (C _1-3 )alkyl or (C _1-3 )alkoxy; Or R ₇ and R ₈ together with the carbon atom to which they are attached form a (C _6-10 )aryl or (C _1-9 )heteroaryl; R ₉ is H, halo, (C _1-3 )alkyl or (C _1-3 ) alkoxy; R ₁₀ is H, halogen, (C _1-3 )alkyl or (C _1-3 )alkoxy; R _{11 is} independently selected from the group consisting of: ( C _1-6 )alkyl, (C _2-6 )alkenyl and (C _2-6 )alkynyl, each of the alkyl, alkenyl or alkynyl groups optionally optionally via one or more selected from the group consisting of Substitution: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl]amine, (C _1-3 ) alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 ) aryl and (C _3-7 )heterocycloalkyl; or R ₁₁ is (C _1-3 An alkyl-C(O)-S-(C _1-3 )alkyl group; or R ₁₁ is a (C _1-5 )heteroaryl group optionally substituted with one or more groups selected from the group consisting of: Halogen or cyano; R ₁₂ and R _{13 are} independently selected from the group consisting of (C _2-6 )alkenyl and (C _2-6 )alkynyl, optionally singly selected by one or more Substituted from the following group: hydroxyl, (C _{1- 4} ) alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl]amino, (C _1-3 ) alkoxy a (C _3-7 )cycloalkoxy group, a (C _6-10 ) aryl group and a (C _3-7 )heterocycloalkyl group; or a (C _1-5 )heteroaryl group optionally subjected to one or a plurality of groups selected from the group consisting of halogen and cyano; and R _{14 are} independently selected from the group consisting of halogen, cyano, (C _2-6 )alkenyl, and (C _2-6 )alkyne And the alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, (C _1-4 ) Alkylamino, bis[(C _1-4 )alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl, C _1-5 ) Heteroaryl and (C _3-7 )heterocycloalkyl. According to the composition of claim 37, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the composition of claim 37, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the composition of claim 37, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the composition of claim 37, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. According to the composition of claim 37, wherein the BTK inhibitor is: Or a pharmaceutically acceptable salt, solvate or hydrate thereof. The composition according to any one of claims 37 to 42, which comprises the anti-CD20 antibody in an amount between 25 mg and 2000 mg and the BTK inhibitor in an amount between 5 mg and 500 mg. between. The composition according to any one of claims 37 to 42 which comprises the BTK inhibitor in an amount between 25 mg and 125 mg. The composition according to any one of claims 37 to 42, which comprises the BTK inhibitor in an amount selected from the group consisting of 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400 Grams, 425 mg, 450 mg, 475 mg and 500 mg. The composition according to any one of claims 37 to 42, which comprises the anti-CD20 antibody in an amount selected from the group consisting of 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg And 2000 mg. The composition according to any one of claims 37 to 42, further comprising an anticoagulant or an antiplatelet agent, wherein the anticoagulant or antiplatelet agent is selected from the group consisting of chlorine Clopidogrel, prasugrel, ticagrelor, ticlopidine, warfarin, acenocoumarol, dicoumarin ), phenprocoumon, heparin, low molecular weight heparin, fondaparinux and idapainux. The composition according to any one of claims 37 to 42 further comprising at least one pharmaceutically acceptable excipient.