HK1229728A1 - Pharmaceutical composition comprising pyrazine carboxamide compound as active ingredient - Google Patents

Description

Pharmaceutical composition comprising pyrazine carboxamide compound as active ingredient

Technical Field

The present invention relates to a pharmaceutical composition for treating cancer, comprising a pyrazine carboxamide compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Background

BTK (Bruton's tyrosine kinase) is an non-receptor type tyrosine kinase belonging to the Tec kinase family and is a protein with pleckstrin homolog domain, Tec homolog domain, Src homolog 2 domain, Src homolog 3 domain, and kinase domain. BTK is expressed in most hematopoietic cells, not including T cells and plasma cells, and is an essential molecule for B cell production (exp. hematocol. oncol.2014; 3(1):4, and j. hematocol. oncol.2013; 6: 59). In B cells, BTK signals the B cell receptor to downstream phospholipase C γ and causes calcium ion mobilization and activation of the mitogen-activated protein kinase pathway or nuclear factor κ B (Proc. Natl. Acad. Sci. USA.2010; 107(29): 13075-13080).

To date, BTK has been suggested to be involved in the development of B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, acute lymphocytic leukemia and acute myeloid leukemia (exp. Hematol. Oncol. 2014; 3(1):4, and blood.2014; 123(8): 1229-. Furthermore, it has been reported that in initially cultured cells derived from patients with acute myelogenous leukemia, suppression of the expression of BTK by miRNA inhibits cell proliferation, and BTK inhibitors inhibit proliferation of diffuse large B-cell lymphoma cells in which B-cell receptor signaling is activated (blood.2014; 123(8):1207-1213, and Nature.2010; 463: 88-92). Clinical development of BTK inhibitors targeting cancers including follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, and B-cell prolymphocytic leukemia has been conducted, and it was confirmed that BTK inhibitors show some degree of efficacy in patients with these cancers (scand.j.immunol.2013; 78(2): 130-. Furthermore, it is known that the expression of BTK has been confirmed even in a histiocytic lymphoma cell line (J.Immunol.1994; 152(2): 557-565).

These results show that in cancers involving BTK, including leukemias and lymphomas such as cancers in which BTK is overexpressed or activated or in which B cell receptor signaling is activated, BTK is involved in the proliferation of these cancers, and BTK inhibitors may be promising agents for treating these cancers.

JAK3(Janus kinase 3) is an non-receptor type tyrosine kinase belonging to the JAK kinase family and is a protein with a FERM domain, a Src homolog 2 domain, a pseudokinase domain, and a kinase domain (genomebiol. 2004; 5: 253). JAK3 is expressed primarily in hematopoietic cells and interacts with cytokine receptors to deliver signals to downstream STATs (acta. biochim. biophysis. sin.2012; 44(3): 187-196).

To date, JAK3 has been reported to be activation mutated in acute megakaryocytic leukemia, natural killer/T-cell lymphoma, cutaneous T-cell lymphoma, and T-cell acute lymphoblastic leukemia, and JAK3 has been suggested to be involved in the progression of these cancers (Cancer cell.2006; 10:65-75, Cancer discov.2012; 2(7): 591-. Furthermore, JAK inhibitors have been reported to inhibit cell proliferation of acute megakaryocytic leukemia cells, natural killer/T-cell lymphoma cells, and anaplastic large cell lymphoma cells (Cancer cell.2006; 10:65-75, Cancer Discov.2012; 2(7):591-597, and Leukemia.2014; 28: 941-944).

These results show that in cancers involving JAK3, including leukemias and lymphomas such as cancers in which JAK3 is activated mutated or activated, JAK3 is involved in the proliferation of these cancers, and that JAK3 inhibitors may be promising agents for the treatment of these cancers.

ITK (IL2 inducible T cell kinase) is an non-receptor type tyrosine kinase belonging to the Tec kinase family and is a protein with pleckstrin homolog domain, Tec homolog domain, Src homolog 2 domain, Src homolog 3 domain, and kinase domain. ITK is expressed predominantly in T cells and also in mast cells and is responsible for regulating T cell receptor signaling (curr. top. med. chem.2009; 9(8): 690-.

To date, ITK has been reported to be expressed in T cell tumors including cutaneous T cell lymphomas. Furthermore, it has been reported that ITK inhibitors inhibit cell proliferation of T-cell acute lymphoblastic leukemia cells in which ITK is expressed (mol. Pharmacol.2012; 82: 938-947).

These results show that in cancers involving ITK, including leukemias and lymphomas such as cancers in which ITK is activated, ITK is involved in the proliferation of these cancers, and ITK inhibitors may be promising agents for the treatment of these cancers.

It is known that 5- { [ (3R) -1-acryloylpyrrolidin-3-yl ] oxy } -6-ethyl-3- ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrazine-2-carboxamide (hereinafter may be referred to as "compound a") or a pharmaceutically acceptable salt thereof is useful as an active ingredient of a pharmaceutical composition for treating EGFR T790M mutation-positive cancer (patent document 1).

In patent document 1, the compound a or a pharmaceutically acceptable salt thereof is disclosed as a free base in example 54 and as a monomethanesulfonate salt thereof in example 261, and an inhibitory effect against EGFR mutant kinase is demonstrated.

Prior Art

Patent document

Patent document 1: WO2013/108754

Disclosure of Invention

Problems to be solved by the invention

Pharmaceutical compositions for the treatment of cancer are provided, in one instance for the treatment of cancers in which BTK is overexpressed or activated, in another instance for the treatment of cancers in which JAK3 is mutated or activated for activation, and in yet another instance for the treatment of cancers in which ITK is activated.

Means for solving the problems

The present inventors have conducted extensive studies in order to prepare a pharmaceutical composition for the treatment of cancer, and as a result, they have found that a pharmaceutical composition comprising 5- { [ (3R) -1-acryloylpyrrolidin-3-yl ] oxy } -6-ethyl-3- ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a pharmaceutical composition for the treatment of cancer involving one or more kinases among BTK, JAK3 and ITK, thereby completing the present invention.

That is, the present invention relates to:

1. a pharmaceutical composition for treating a cancer involving one or more kinases of BTK, JAK3 and ITK comprising 5- { [ (3R) -1-acryloyl pyrrolidin-3-yl ] oxy } -6-ethyl-3- ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof as an active ingredient.

2.1, wherein the cancer involving one or more of BTK, JAK3 and ITK is a BTK-involving cancer.

3.2, wherein the cancer in which BTK is implicated is a cancer in which BTK is overexpressed or activated.

4.2, wherein the cancer in which BTK is implicated is a cancer in which B cell receptor signaling is activated.

The pharmaceutical composition described in 5.2, wherein the cancer involving BTK is a cancer selected from follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell prolymphocytic leukemia, acute lymphocytic leukemia, histiocytic lymphoma, and acute myelogenous leukemia.

6.5, wherein the cancer in which BTK is implicated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia and/or histiocytic lymphoma.

The pharmaceutical composition described in 7.1, wherein the cancer involving one or more of BTK, JAK3 and ITK is a cancer involving JAK 3.

The pharmaceutical composition described in 8.7, wherein the cancer in which JAK3 is a cancer in which JAK3 is mutated or activated for activation.

The pharmaceutical composition described in 9.7, wherein the cancer in which JAK3 is involved is acute megakaryocytic leukemia and/or anaplastic large cell lymphoma.

10.1, wherein the cancer involving one or more of BTK, JAK3 and ITK is a cancer involving ITK.

11.10, wherein the cancer in which ITK is implicated is a cancer in which ITK is activated.

12.10, wherein the cancer in which ITK is implicated is acute T cell lymphoma and/or lymphoblastic leukemia.

13.1, wherein the cancer involving one or more of BTK, JAK3 and ITK is a cancer involving BTK and JAK 3.

The pharmaceutical composition described in 14.1, wherein the cancer involving one or more of BTK, JAK3 and ITK is a cancer involving BTK and ITK.

15.1, wherein the cancer involving one or more of BTK, JAK3 and ITK is a cancer involving JAK3 and ITK.

16.1, wherein the cancer involving one or more of BTK, JAK3 and ITK is a cancer involving BTK, JAK3 and ITK.

A pharmaceutical composition described in any one of claims 1 to 16, wherein 5- { [ (3R) -1-acryloylpyrrolidin-3-yl ] oxy } -6-ethyl-3- ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof is 5- { [ (3R) -1-acryloylpyrrolidin-3-yl ] oxy } -6-ethyl-3- ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrazine-2-carboxamide monomethanesulfonate salt.

18. Use of compound a or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of cancer involving one or more of BTK, JAK3 and ITK.

19. Use of compound a or a pharmaceutically acceptable salt thereof for the treatment of cancer involving one or more of BTK, JAK3 and ITK.

20. Compound a or a pharmaceutically acceptable salt thereof for use in the treatment of cancer involving one or more of BTK, JAK3 and ITK.

21. A method for treating a cancer involving one or more kinases of BTK, JAK3 and ITK, the method comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention includes an agent for treating a cancer involving one or more of BTK, JAK3 and ITK, comprising compound a or a pharmaceutically acceptable salt thereof; in one instance, an agent for treating a BTK-involved cancer is included, wherein the BTK-involved cancer involving one or more of BTK, JAK3, and ITK is a BTK-involved cancer; in another aspect, an agent for treating a cancer in which BTK is overexpressed or activated; in another aspect, an agent for treating a cancer in which B cell receptor signaling is activated; in another instance, an agent for treating a cancer involving JAK3 is included, wherein the cancer involving one or more of BTK, JAK3, and ITK is a cancer involving JAK 3; in another instance, an agent for treating a cancer in which JAK3 is mutated or activated for activation; in another aspect, an agent for treating a cancer involving ITK is included, wherein the cancer involving one or more of BTK, JAK3, and ITK is a cancer involving ITK; and in yet another instance, agents for treating cancers in which ITK is activated.

Furthermore, the invention relates to the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer involving one or more of BTK, JAK3 and ITK, in one case, for the manufacture of a pharmaceutical composition for the treatment of a cancer involving BTK, in another case, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which BTK is overexpressed or activated, in another case, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which B-cell receptor signaling is activated, in another case, for the manufacture of a pharmaceutical composition for the treatment of a cancer involving JAK3, in another case, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which JAK3 is activated, in another instance, the compound a or a pharmaceutically acceptable salt thereof is used in the manufacture of a pharmaceutical composition for the treatment of cancer involving ITK, and in yet another instance, the compound a or a pharmaceutically acceptable salt thereof is used in the manufacture of a pharmaceutical composition for the treatment of cancer involving ITK; the compound A or a pharmaceutically acceptable salt thereof for use in the treatment of cancer involving one or more of BTK, JAK3 and ITK, in one aspect, the Compound A or a pharmaceutically acceptable salt thereof is used to treat a cancer in which BTK is implicated, in another aspect, the Compound A or a pharmaceutically acceptable salt thereof, is used for the treatment of a cancer in which BTK is overexpressed or activated, in another aspect, the Compound A or a pharmaceutically acceptable salt thereof, is used for the treatment of a cancer in which B cell receptor signaling is activated, in another aspect, the Compound A or a pharmaceutically acceptable salt thereof, is used to treat a cancer involving JAK3, in another aspect, the Compound A or a pharmaceutically acceptable salt thereof, is used for treating a cancer in which JAK3 is mutated or activated for activation, in another aspect, the Compound A or a pharmaceutically acceptable salt thereof, is used to treat a cancer in which ITK is implicated, and in yet another instance, the compound a or a pharmaceutically acceptable salt thereof, is for use in treating a cancer in which ITK is activated; compound A or a pharmaceutically acceptable salt thereof for use in the treatment of cancer involving one or more of BTK, JAK3 and ITK, in one aspect, the Compound A or a pharmaceutically acceptable salt thereof is used to treat a cancer in which BTK is implicated, in another aspect, the Compound A or a pharmaceutically acceptable salt thereof, is used for the treatment of a cancer in which BTK is overexpressed or activated, in another aspect, the Compound A or a pharmaceutically acceptable salt thereof, is used for the treatment of a cancer in which B cell receptor signaling is activated, in another aspect, the Compound A or a pharmaceutically acceptable salt thereof, is used to treat a cancer involving JAK3, in another aspect, the Compound A or a pharmaceutically acceptable salt thereof, is used for treating a cancer in which JAK3 is mutated or activated for activation, in another aspect, the Compound A or a pharmaceutically acceptable salt thereof, is used to treat a cancer in which ITK is implicated, and in yet another instance, the compound a or a pharmaceutically acceptable salt thereof, is for use in treating a cancer in which ITK is activated; and methods for treating a cancer involving one or more of BTK, JAK3, and ITK, comprising administering to a subject an effective amount of compound a, or a pharmaceutically acceptable salt thereof, in one instance, a method for treating a cancer involving BTK, comprising administering to a subject an effective amount of compound a, or a pharmaceutically acceptable salt thereof, in another instance, a method for treating a cancer in which BTK is overexpressed or activated, comprising administering to a subject an effective amount of compound a, or a pharmaceutically acceptable salt thereof, in another instance, a method for treating a cancer in which B-cell receptor signaling is activated, comprising administering to a subject an effective amount of compound a, or a pharmaceutically acceptable salt thereof, in another instance, a method for treating a cancer involving JAK3, comprising administering to a subject an effective amount of compound a, or a pharmaceutically acceptable salt thereof, in another instance, a method for treating a cancer in which JAK3 is mutated or activated by activation, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof, in another instance, a method for treating a cancer in which ITK is implicated, comprising administering to the subject an effective amount of compound a or a pharmaceutically acceptable salt thereof, and in yet another instance, a method for treating a cancer in which ITK is activated, comprising administering to the subject an effective amount of compound a or a pharmaceutically acceptable salt thereof. In addition, the "subject" is a human or another animal in need of such treatment, and in one instance, a human in need of such treatment.

Effects of the invention

Compound a or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, has BTK, JAK3 and ITK inhibitory effects and can be used as an active ingredient in the treatment of cancers involving one or more of BTK, JAK3 and ITK, in one instance, in the treatment of cancers involving BTK, cancers in which BTK is overexpressed or activated, cancers in which B-cell receptor signaling is activated, cancers involving JAK3, cancers in which JAK3 is activated mutated or activated, cancers in which ITK is involved, and/or cancers in which ITK is activated, in another instance, in the treatment of cancers in which BTK is overexpressed or activated, in another instance, in the treatment of cancers in which B-cell receptor signaling is activated, in another instance, in the treatment of cancers in which JAK3 is activated mutated or activated, and in yet another instance, a pharmaceutical composition for treating a cancer in which ITK is activated.

Embodiments for carrying out the invention

Hereinafter, the present invention will be described in detail.

As described above, the chemical name of Compound A is 5- { [ (3R) -1-acryloylpyrrolidin-3-yl ] oxy } -6-ethyl-3- ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrazine-2-carboxamide, which has the chemical structure shown below.

[ chemical formula 1]

Cancer in which BTK is involved means cancer in which BTK is one of the etiologies thereof, and examples thereof include cancer in which BTK is overexpressed or activated and cancer in which B cell receptor signaling is activated. Specific examples thereof include follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell prolymphocytic leukemia, acute lymphocytic leukemia, histiocytic lymphoma and acute myelogenous leukemia, particularly diffuse large B-cell lymphoma, mantle cell lymphoma, acute myelogenous leukemia and histiocytic lymphoma.

Cancer involving JAK3 means cancer in which JAK3 is one of the etiologies thereof, and examples thereof include cancer in which JAK3 is overexpressed or activated and cancer in which JAK3 is activated mutated, such as cancer having the following mutations: the mutation of proline to threonine at position 132, alanine to valine at position 572 and valine to isoleucine at position 722 in JAK3 as defined by GenBank accession NM-000215.3 (Cancer cell.2006; 10:65-75) and includes acute megakaryocytic leukemia and anaplastic large cell lymphoma.

Cancer in which ITK is involved means cancer in which ITK is one of the etiologies, and examples thereof include cancers in which ITK is overexpressed or activated, and include acute T-cell lymphoma and lymphoblastic leukemia.

In addition, in the present specification, "cancer" refers to hematological cancer.

One aspect of the present invention is as follows.

(1-1) a pharmaceutical composition for treating BTK-related cancer, comprising compound a or a pharmaceutically acceptable salt thereof. In one instance, a pharmaceutical composition for treating a cancer in which BTK is overexpressed or activated, comprising compound a or a pharmaceutically acceptable salt thereof. In another aspect, a pharmaceutical composition for treating a cancer in which B cell receptor signaling is activated, comprising compound a or a pharmaceutically acceptable salt thereof.

(1-2) use of compound a or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of BTK-related cancer. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which BTK is overexpressed or activated. In another aspect, the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which B cell receptor signaling is activated.

(1-3) use of compound a or a pharmaceutically acceptable salt thereof for treating BTK-related cancer. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer in which BTK is overexpressed or activated. In another aspect, the use of compound a, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer in which B cell receptor signaling is activated.

(1-4) Compound A or a pharmaceutically acceptable salt thereof for use in the treatment of BTK-related cancers. In one aspect, compound a or a pharmaceutically acceptable salt thereof for use in treating a cancer in which BTK is overexpressed or activated. In another aspect, compound a, or a pharmaceutically acceptable salt thereof, is used for the treatment of a cancer in which B cell receptor signaling is activated.

(1-5) a method for treating BTK-related cancer, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof. In one instance, a method for treating a cancer in which BTK is overexpressed or activated, comprising administering to a subject an effective amount of compound a, or a pharmaceutically acceptable salt thereof. In another aspect, a method for treating a cancer in which B cell receptor signaling is activated, comprising administering to a subject an effective amount of compound a, or a pharmaceutically acceptable salt thereof.

(2-1) a pharmaceutical composition for treating BTK-related cancer comprising compound a monomethanesulfonate salt. In one instance, a pharmaceutical composition for treating a cancer in which BTK is overexpressed or activated, comprising compound a monomethanesulfonate salt. In another aspect, a pharmaceutical composition for treating a cancer in which B cell receptor signaling is activated, comprising compound a monomethanesulfonate salt.

(2-2) use of compound a monomethanesulfonate salt for the manufacture of a pharmaceutical composition for the treatment of BTK-related cancer. In one instance, the use of compound a monomethanesulfonate salt for the manufacture of a pharmaceutical composition for the treatment of a cancer in which BTK is overexpressed or activated. In another aspect, the use of compound a monomesylate salt for the manufacture of a pharmaceutical composition for the treatment of a cancer in which B cell receptor signaling is activated.

(2-3) use of compound a monomethanesulfonate for the treatment of BTK-related cancer. In one instance, the use of compound a monomethanesulfonate salt for the treatment of cancer wherein BTK is overexpressed or activated. In another aspect, the use of compound a monomesylate salt for the treatment of a cancer in which B cell receptor signaling is activated.

(2-4) Compound A monomethanesulfonate salt for use in the treatment of BTK-related cancers. In one instance, compound a monomethanesulfonate is useful for treating cancer in which BTK is overexpressed or activated. In another aspect, compound a monomesylate salt for use in treating a cancer in which B cell receptor signaling is activated.

(2-5) a method for treating a BTK-related cancer, comprising administering to a subject an effective amount of compound a monomethanesulfonate salt. In one instance, a method for treating a cancer in which BTK is overexpressed or activated, comprising administering to a subject an effective amount of compound a monomesylate salt. In another aspect, a method for treating a cancer in which B cell receptor signaling is activated, comprising administering to a subject an effective amount of compound a monomesylate salt.

(3) The pharmaceutical composition disclosed in (1-1) or (2-1), (the use disclosed in (1-2) or (2-2), (the use disclosed in (1-3) or (2-3), (the compound A disclosed in (1-4) or the compound A monomethanesulfonate disclosed in (2-4), or the method of treatment disclosed in (1-5) or (2-5), wherein the cancer in which BTK is implicated, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell prolymphocytic leukemia, acute lymphocytic leukemia, histiocytic lymphoma, or acute myelogenous leukemia.

In another instance, the pharmaceutical composition disclosed in (1-1) or (2-1), (the use disclosed in (1-2) or (2-2), (the use disclosed in (1-3) or (2-3), (compound a disclosed in (1-4) or compound a monomethanesulfonate disclosed in (2-4), or the method of treatment disclosed in (1-5) or (2-5), wherein the cancer in which BTK is implicated, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia, or histiocytic lymphoma.

In another instance, the pharmaceutical composition disclosed in (1-1) or (2-1), (the use disclosed in (1-2) or (2-2), (the use disclosed in (1-3) or (2-3), (compound a disclosed in (1-4) or compound a monomethanesulfonate disclosed in (2-4), or the method of treatment disclosed in (1-5) or (2-5), wherein the cancer in which BTK is implicated, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (1-1) or (2-1), (the use disclosed in (1-2) or (2-2), (the use disclosed in (1-3) or (2-3), (compound a disclosed in (1-4) or compound a monomethanesulfonate disclosed in (2-4), or the method of treatment disclosed in (1-5) or (2-5), wherein the cancer in which BTK is implicated, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is mantle cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (1-1) or (2-1), (the use disclosed in (1-2) or (2-2), (the use disclosed in (1-3) or (2-3), (compound a disclosed in (1-4) or compound a monomethanesulfonate disclosed in (2-4), or the method of treatment disclosed in (1-5) or (2-5), wherein the cancer in which BTK is implicated, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is acute myeloid leukemia.

In another instance, the pharmaceutical composition disclosed in (1-1) or (2-1), (the use disclosed in (1-2) or (2-2), (the use disclosed in (1-3) or (2-3), (compound a disclosed in (1-4) or compound a monomethanesulfonate disclosed in (2-4), or the method of treatment disclosed in (1-5) or (2-5), wherein the cancer in which BTK is implicated, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is a histiocytic lymphoma.

(4-1) a pharmaceutical composition for treating a cancer involving JAK3, comprising compound a or a pharmaceutically acceptable salt thereof. In one instance, a pharmaceutical composition for treating a cancer in which JAK3 is mutated or activated for activation, comprising compound a or a pharmaceutically acceptable salt thereof.

(4-2) use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer involving JAK 3. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which JAK3 is mutated or activated for activation.

(4-3) use of compound a or a pharmaceutically acceptable salt thereof for treating a cancer involving JAK 3. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer in which JAK3 is mutated or activated for activation.

(4-4) Compound A or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer involving JAK 3. In one instance, compound a or a pharmaceutically acceptable salt thereof, for use in treating a cancer in which JAK3 is mutated or activated for activation.

(4-5) a method for treating a cancer involving JAK3, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof. In one instance, a method for treating a cancer in which JAK3 is mutated or activated for activation, comprising administering to a subject an effective amount of compound a, or a pharmaceutically acceptable salt thereof.

(5-1) a pharmaceutical composition for treating a cancer involving JAK3, comprising compound a monomethanesulfonate salt. In one instance, a pharmaceutical composition for treating a cancer in which JAK3 is mutated or activated for activation, comprising compound a monomethanesulfonate.

(5-2) use of compound a monomethanesulfonate for the manufacture of a pharmaceutical composition for the treatment of a cancer involving JAK 3. In one instance, the use of compound a monomesylate salt for the manufacture of a pharmaceutical composition for treating a cancer in which JAK3 is mutated or activated for activation.

(5-3) use of compound a monomethanesulfonate for the treatment of cancer involving JAK 3. In one instance, the use of compound a monomesylate salt for the treatment of a cancer in which JAK3 is mutated or activated for activation.

(5-4) Compound A monomethanesulfonate salt for use in the treatment of cancer involving JAK 3. In one instance, compound a monomesylate salt for use in treating cancer in which JAK3 is mutated or activated for activation.

(5-5) a method for treating a cancer involving JAK3, comprising administering to a subject an effective amount of compound a monomesylate salt. In one instance, a method for treating a cancer in which JAK3 is mutated or activated for activation, comprising administering to a subject an effective amount of compound a monomesylate salt.

(6) The pharmaceutical composition disclosed in (4-1) or (5-1), (the use disclosed in (4-2) or (5-2), (the use disclosed in (4-3) or (5-3), (compound a disclosed in (4-4) or compound a monomethanesulfonate disclosed in (5-4), or the method of treatment disclosed in (4-5) or (5-5), wherein the cancer in which JAK3 is implicated or the cancer in which JAK3 is mutated or activated is acute megakaryocytic leukemia or anaplastic large cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (4-1) or (5-1), (4-2) or (5-2) the use disclosed in (4-3) or (5-3), (4-4) the compound a disclosed in (4-4) or the compound a monomethanesulfonate disclosed in (5-4), or the method of treatment disclosed in (4-5) or (5-5), wherein the cancer in which JAK3 is implicated or the cancer in which JAK3 is mutated or activated for activation is acute megakaryocytic leukemia.

In another instance, the pharmaceutical composition disclosed in (4-1) or (5-1), (4-2) or (5-2) the use disclosed in (4-3) or (5-3), (4-4) the compound a disclosed in (4-4) or the compound a monomethanesulfonate disclosed in (5-4), or the method of treatment disclosed in (4-5) or (5-5), wherein the cancer in which JAK3 is implicated or the cancer in which JAK3 is mutated or activated for activation is anaplastic large cell lymphoma.

(7-1) a pharmaceutical composition for treating cancer involving ITK, comprising compound a or a pharmaceutically acceptable salt thereof. In one instance, a pharmaceutical composition for treating a cancer in which ITK is activated, comprising compound a or a pharmaceutically acceptable salt thereof.

(7-2) use of compound a or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of cancer involving ITK. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which ITK is activated.

(7-3) use of compound a or a pharmaceutically acceptable salt thereof for treating cancer involving ITK. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer in which ITK is activated.

(7-4) Compound A or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in which ITK is implicated. In one instance, compound a or a pharmaceutically acceptable salt thereof, for use in treating a cancer in which ITK is activated.

(7-5) a method for treating cancer involving ITK, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof. In one instance, a method for treating a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a, or a pharmaceutically acceptable salt thereof.

(8-1) a pharmaceutical composition for treating cancer involving ITK, comprising compound a monomethanesulfonate salt. In one instance, a pharmaceutical composition for treating a cancer in which ITK is activated, comprising compound a monomethanesulfonate salt.

(8-2) use of compound a monomethanesulfonate salt for the manufacture of a pharmaceutical composition for the treatment of cancer involving ITK. In one instance, the use of compound a monomethanesulfonate salt for the manufacture of a pharmaceutical composition for the treatment of cancer in which ITK is activated.

(8-3) use of compound a monomethanesulfonate for the treatment of cancer involving ITK. In one instance, the use of compound a monomethanesulfonate salt for the treatment of cancer in which ITK is activated.

(8-4) Compound A monomethanesulfonate salt for use in the treatment of cancer involving ITK. In one instance, compound a monomethanesulfonate salt is useful for treating cancer in which ITK is activated.

(8-5) a method for treating cancer involving ITK, comprising administering to a subject an effective amount of compound a monomethanesulfonate salt. In one instance, a method for treating a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a monomethanesulfonate salt.

(9) The pharmaceutical composition disclosed in (7-1) or (8-1), (the use disclosed in (7-2) or (8-2), (the use disclosed in (7-3) or (8-3), (compound A disclosed in (7-4) or compound A monomethanesulfonate disclosed in (8-4), or the therapeutic method disclosed in (7-5) or (8-5), wherein the cancer in which ITK is involved or in which ITK is activated is acute T-cell lymphoma or lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (7-1) or (8-1), (the use disclosed in (7-2) or (8-2), (the use disclosed in (7-3) or (8-3), (compound a disclosed in (7-4) or compound a monomethanesulfonate disclosed in (8-4), or the method of treatment disclosed in (7-5) or (8-5), wherein the cancer in which ITK is implicated or is activated is acute T-cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (7-1) or (8-1), (the use disclosed in (7-2) or (8-2), (the use disclosed in (7-3) or (8-3), (compound a disclosed in (7-4) or compound a monomethanesulfonate disclosed in (8-4), or the method of treatment disclosed in (7-5) or (8-5), wherein the cancer in which ITK is implicated or is activated is lymphoblastic leukemia.

(10-1) a pharmaceutical composition for treating a cancer involving BTK and JAK3, comprising compound a or a pharmaceutically acceptable salt thereof. In one instance, a pharmaceutical composition for treating a cancer in which BTK is overexpressed or activated and a cancer in which JAK3 is activated mutated or activated, comprising compound a or a pharmaceutically acceptable salt thereof. In another aspect, a pharmaceutical composition for treating a cancer in which B cell receptor signaling is activated and a cancer in which JAK3 is activated by an activating mutation or activation, comprising compound a or a pharmaceutically acceptable salt thereof.

(10-2) use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer involving BTK and JAK 3. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which BTK is overexpressed or activated and a cancer in which JAK3 is activated mutated or activated. In another aspect, the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which B cell receptor signaling is activated and a cancer in which JAK3 is activated by an activating mutation or is activated.

(10-3) use of compound a or a pharmaceutically acceptable salt thereof for treating a cancer involving BTK and JAK 3. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer in which BTK is overexpressed or activated and a cancer in which JAK3 is activated mutated or activated. In another aspect, the use of compound a, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer in which B cell receptor signaling is activated and a cancer in which JAK3 is mutated or activated for activation.

(10-4) Compound A or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer involving BTK and JAK 3. In one instance, compound a or a pharmaceutically acceptable salt thereof, for use in treating a cancer in which BTK is overexpressed or activated and a cancer in which JAK3 is activated mutated or activated. In another aspect, compound a or a pharmaceutically acceptable salt thereof, for use in the treatment of cancers in which B cell receptor signaling is activated and cancers in which JAK3 is activated or is activated,

(10-5) a method for treating a cancer involving BTK and JAK3, comprising administering an effective amount of compound a or a pharmaceutically acceptable salt thereof. In one instance, a method for treating a cancer in which BTK is overexpressed or activated and a cancer in which JAK3 is activated mutated or activated comprising administering an effective amount of compound a or a pharmaceutically acceptable salt thereof. In another aspect, a method for treating a cancer in which B cell receptor signaling is activated and a cancer in which JAK3 is activated or mutated, comprising administering an effective amount of compound a or a pharmaceutically acceptable salt thereof.

(11-1) a pharmaceutical composition for treating a cancer involving BTK and JAK3, comprising compound a monomethanesulfonate salt. In one instance, a pharmaceutical composition for treating a cancer in which BTK is overexpressed or activated and a cancer in which JAK3 is activated mutated or activated, comprising compound a monomethanesulfonate. In another aspect, a pharmaceutical composition for treating a cancer in which B cell receptor signaling is activated and a cancer in which JAK3 is activated by an activating mutation or activation, comprising compound a monomethanesulfonate salt.

(11-2) use of compound a monomethanesulfonate for the manufacture of a pharmaceutical composition for the treatment of cancer involving BTK and JAK 3. In one instance, the use of compound a monomesylate salt for the manufacture of a pharmaceutical composition for treating a cancer in which BTK is overexpressed or activated and a cancer in which JAK3 is activated mutated or activated. In another aspect, the use of compound a monomesylate salt for the manufacture of a pharmaceutical composition for treating a cancer in which B cell receptor signaling is activated and a cancer in which JAK3 is mutated or activated for activation.

(11-3) use of compound a monomethanesulfonate for the treatment of cancer involving BTK and JAK 3. In one instance, the use of compound a monomesylate salt for the treatment of cancer in which BTK is overexpressed or activated and cancer in which JAK3 is activated mutated or activated. In another aspect, the use of compound a monomesylate salt for the treatment of cancer in which B cell receptor signaling is activated and cancer in which JAK3 is mutated or activated for activation.

(11-4) Compound A monomethanesulfonate salt for use in the treatment of cancer involving BTK and JAK 3. In one instance, compound a monomesylate salt for use in treating cancers in which BTK is overexpressed or activated and cancers in which JAK3 is activated mutated or activated. In another instance, compound a monomesylate salt for use in treating cancers in which B cell receptor signaling is activated and cancers in which JAK3 is activated by an activating mutation or activation.

(11-5) a method for treating a cancer involving BTK and JAK3, comprising administering to a subject an effective amount of compound a monomesylate salt. In one instance, a method of treatment for a cancer in which BTK is overexpressed or activated and a cancer in which JAK3 is activated mutated or activated comprising administering to a subject an effective amount of compound a monomesylate salt. In another aspect, a method for treating a cancer in which B cell receptor signaling is activated and a cancer in which JAK3 is activated by an activating mutation or activation, comprising administering to a subject an effective amount of compound a monomesylate salt.

(12) The pharmaceutical composition disclosed in (10-1) or (11-1), (the use disclosed in (10-2) or (11-2), (the use disclosed in (10-3) or (11-3), (the compound A disclosed in (10-4) or the compound A monomethanesulfonate disclosed in (11-4), or the therapeutic method disclosed in (10-5) or (11-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell prolymphocytic leukemia, acute lymphocytic leukemia, histiocytic lymphoma, or acute myelogenous leukemia, and the cancer in which JAK3 is implicated or the cancer in which JAK3 is activated mutated or activated is acute megakaryocytic leukemia or anaplastic large cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (10-1) or (11-1), (10-2) or (11-2), (10-3) or the use disclosed in (11-3), (10-4) or compound a monomethanesulfonate disclosed in (11-4), or the method of treatment disclosed in (10-5) or (11-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia, or histiocytic lymphoma, and the cancer involving JAK3 or the cancer in which JAK3 is activated is mutated or activated is acute megakaryocytic leukemia.

In another instance, the pharmaceutical composition disclosed in (10-1) or (11-1), (10-2) or (11-2), (10-3) or (11-3) or the use disclosed in (10-4) or compound a monomethanesulfonate disclosed in (11-4), or the method of treatment disclosed in (10-5) or (11-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia, or histiocytic lymphoma, and the cancer involving JAK3 or the cancer in which JAK3 is activated is mutated or activated is anaplastic large cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (10-1) or (11-1), (10-2) or (11-2), (10-3) or the use disclosed in (11-3), (10-4) or compound a monomethanesulfonate disclosed in (11-4), or the method of treatment disclosed in (10-5) or (11-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, and the cancer involving JAK3, or the cancer in which JAK3 is mutated or activated is acute megakaryocytic leukemia.

In another instance, the pharmaceutical composition disclosed in (10-1) or (11-1), (10-2) or (11-2), (10-3) or the use disclosed in (11-3), (10-4) or compound a monomethanesulfonate disclosed in (11-4), or the method of treatment disclosed in (10-5) or (11-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, and the cancer involving JAK3, or the cancer in which JAK3 is mutated or activated is anaplastic large B-cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (10-1) or (11-1), (10-2) or (11-2) the use disclosed in (10-3) or (11-3), (10-4) the compound a disclosed in (11-4) or the compound a monomethanesulfonate disclosed in (10-5) or the method of treatment disclosed in (11-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is mantle cell lymphoma, and the cancer involving JAK3 or the cancer in which JAK3 is activated mutated or activated is acute megakaryocytic leukemia.

In another instance, the pharmaceutical composition disclosed in (10-1) or (11-1), (10-2) or (11-2), the use disclosed in (10-3) or (11-3), compound a disclosed in (10-4) or compound a monomesylate disclosed in (11-4), or the method of treatment disclosed in (10-5) or (11-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is mantle cell lymphoma, and the cancer involving JAK3, or the cancer in which JAK3 is activated mutated or activated is anaplastic large cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (10-1) or (11-1), (10-2) or (11-2), (10-3) or (11-3) or the use disclosed in (10-4) or compound a monomesylate disclosed in (11-4), or the method of treatment disclosed in (10-5) or (11-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is acute myeloid leukemia, and the cancer involving JAK3, or the cancer in which JAK3 is mutated or activated is acute megakaryocytic leukemia.

In another instance, the pharmaceutical composition disclosed in (10-1) or (11-1), (10-2) or (11-2), (10-3) or (11-3) or the use disclosed in (10-4) or compound a monomethanesulfonate disclosed in (11-4), or the method of treatment disclosed in (10-5) or (11-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is acute myeloid leukemia, and the cancer involving JAK3 or the cancer in which JAK3 is activated is mutated or activated is anaplastic large cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (10-1) or (11-1), (10-2) or (11-2), the use disclosed in (10-3) or (11-3), compound a disclosed in (10-4) or compound a monomesylate disclosed in (11-4), or the method of treatment disclosed in (10-5) or (11-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is histiocytic lymphoma, and the cancer involving JAK3, or the cancer in which JAK3 is activated, is acute megakaryocytic leukemia.

Further, in another case, the pharmaceutical composition disclosed in (10-1) or (11-1), (the use disclosed in (10-2) or (11-2), (the use disclosed in (10-3) or (11-3), (the compound a disclosed in (10-4) or the compound a monomethanesulfonate disclosed in (11-4), or the method of treatment disclosed in (10-5) or (11-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is histiocytic lymphoma, and the cancer involving JAK3, or the cancer in which JAK3 is activated, is mutated or activated, is anaplastic large cell lymphoma.

(13-1) a pharmaceutical composition for treating a cancer involving BTK and ITK, comprising compound a or a pharmaceutically acceptable salt thereof. In one instance, a pharmaceutical composition for treating a cancer in which BTK is overexpressed or activated and a cancer in which ITK is activated, comprising compound a or a pharmaceutically acceptable salt thereof. In another aspect, a pharmaceutical composition for treating a cancer in which B cell receptor signaling is activated and a cancer in which ITK is activated, comprising compound a or a pharmaceutically acceptable salt thereof.

(13-2) use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer involving BTK and ITK. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which BTK is overexpressed or activated and a cancer in which ITK is activated. In another aspect, the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which B cell receptor signaling is activated and a cancer in which ITK is activated.

(13-3) use of compound a or a pharmaceutically acceptable salt thereof for treating a cancer involving BTK and ITK. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer in which BTK is overexpressed or activated and a cancer in which ITK is activated. In another aspect, the use of compound a, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer in which B cell receptor signaling is activated and a cancer in which ITK is activated.

(13-4) Compound A or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer involving BTK and ITK. In one instance, compound a or a pharmaceutically acceptable salt thereof, is useful for treating cancers in which BTK is overexpressed or activated and cancers in which ITK is activated. In another aspect, compound a, or a pharmaceutically acceptable salt thereof, for use in treating a cancer in which B cell receptor signaling is activated and a cancer in which ITK is activated.

(13-5) a method for treating a cancer involving BTK and ITK, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof. In one instance, a method for treating a cancer in which BTK is overexpressed or activated and a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof. In another aspect, a method for treating a cancer in which B cell receptor signaling is activated and a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof.

(14-1) a pharmaceutical composition for treating a cancer involving BTK and ITK comprising compound a monomethanesulfonate salt. In one instance, a pharmaceutical composition for treating a cancer in which BTK is overexpressed or activated and a cancer in which ITK is activated, comprising compound a monomethanesulfonate salt. In another aspect, a pharmaceutical composition for treating a cancer in which B cell receptor signaling is activated and a cancer in which ITK is activated, comprising compound a monomethanesulfonate salt.

(14-2) use of compound a monomethanesulfonate salt for the manufacture of a pharmaceutical composition for the treatment of cancer involving BTK and ITK. In one instance, the use of compound a monomethanesulfonate salt for the manufacture of a pharmaceutical composition for the treatment of a cancer in which BTK is overexpressed or activated and ITK is activated. In another aspect, the use of compound a monomesylate salt for the manufacture of a pharmaceutical composition for treating a cancer in which B cell receptor signaling is activated and ITK is activated.

(14-3) use of compound a monomethanesulfonate for the treatment of cancer involving BTK and ITK. In one instance, the use of compound a monomethanesulfonate salt for the treatment of cancer wherein BTK is overexpressed or activated and cancer wherein ITK is activated. In another aspect, the use of compound a monomesylate salt for the treatment of a cancer in which B cell receptor signaling is activated and a cancer in which ITK is activated.

(14-4) Compound A monomethanesulfonate salt for use in the treatment of cancer involving BTK and ITK. In one instance, compound a monomethanesulfonate is useful for treating cancers in which BTK is overexpressed or activated and cancers in which ITK is activated. In another aspect, compound a monomesylate salt for use in treating a cancer in which B cell receptor signaling is activated and a cancer in which ITK is activated.

(14-5) a method for treating a cancer involving BTK and ITK, comprising administering to a subject an effective amount of compound a monomethanesulfonate salt. In one instance, a method for treating a cancer in which BTK is overexpressed or activated and a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a monomethanesulfonate salt. In another aspect, a method for treating a cancer in which B cell receptor signaling is activated and a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a monomesylate salt.

(15) The pharmaceutical composition disclosed in (13-1) or (14-1), (the use disclosed in (13-2) or (14-2), (the use disclosed in (13-3) or (14-3), (the compound A disclosed in (13-4) or the compound A monomethanesulfonate disclosed in (14-4), or the therapeutic method disclosed in (13-5) or (14-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell prolymphocytic leukemia, acute lymphocytic leukemia, histiocytic lymphoma, or acute myelogenous leukemia, and the cancer in which ITK is implicated or activated is acute T cell lymphoma or lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (13-1) or (14-1), (13-2) or (14-2), the use disclosed in (13-3) or (14-3), compound a disclosed in (13-4) or compound a monomethanesulfonate disclosed in (14-4), or the method of treatment disclosed in (13-5) or (14-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia, or histiocytic lymphoma, and the cancer in which ITK is involved or the cancer in which ITK is activated is acute T-cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (13-1) or (14-1), (13-2) or (14-2), the use disclosed in (13-3) or (14-3), compound a disclosed in (13-4) or compound a monomethanesulfonate disclosed in (14-4), or the method of treatment disclosed in (13-5) or (14-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia, or histiocytic lymphoma, and the cancer in which ITK is involved or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (13-1) or (14-1), (13-2) or (14-2), the use disclosed in (13-3) or (14-3), compound a disclosed in (13-4) or compound a monomethanesulfonate disclosed in (14-4), or the method of treatment disclosed in (13-5) or (14-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is acute T-cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (13-1) or (14-1), (13-2) or (14-2), the use disclosed in (13-3) or (14-3), compound a disclosed in (13-4) or compound a monomethanesulfonate disclosed in (14-4), or the method of treatment disclosed in (13-5) or (14-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (13-1) or (14-1), (13-2) or (14-2), the use disclosed in (13-3) or (14-3), compound a disclosed in (13-4) or compound a monomesylate disclosed in (14-4), or the method of treatment disclosed in (13-5) or (14-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is mantle cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (13-1) or (14-1), (13-2) or (14-2), the use disclosed in (13-3) or (14-3), compound a disclosed in (13-4) or compound a monomethanesulfonate disclosed in (14-4), or the method of treatment disclosed in (13-5) or (14-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is mantle cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (13-1) or (14-1), (13-2) or (14-2), the use disclosed in (13-3) or (14-3), compound a disclosed in (13-4) or compound a monomethanesulfonate disclosed in (14-4), or the method of treatment disclosed in (13-5) or (14-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is acute myeloid leukemia, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (13-1) or (14-1), (13-2) or (14-2), the use disclosed in (13-3) or (14-3), compound a disclosed in (13-4) or compound a monomesylate disclosed in (14-4), or the method of treatment disclosed in (13-5) or (14-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is acute myeloid leukemia, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (13-1) or (14-1), (13-2) or (14-2), the use disclosed in (13-3) or (14-3), compound a disclosed in (13-4) or compound a monomesylate salt disclosed in (14-4), or the method of treatment disclosed in (13-5) or (14-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is histiocytic lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma.

Further, in another case, the pharmaceutical composition disclosed in (13-1) or (14-1), (13-2) or (14-2), the use disclosed in (13-3) or (14-3), the compound a disclosed in (13-4) or the compound a monomethanesulfonate salt disclosed in (14-4), or the therapeutic method disclosed in (13-5) or (14-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is histiocytic lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

(16-1) a pharmaceutical composition for treating a cancer involving JAK3 and ITK, comprising compound a or a pharmaceutically acceptable salt thereof. In one instance, a pharmaceutical composition for treating a cancer in which JAK3 is mutated or activated for activation and a cancer in which ITK is activated, comprising compound a or a pharmaceutically acceptable salt thereof.

(16-2) use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer involving JAK3 and ITK. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which JAK3 is activated by an activating mutation or activation and a cancer in which ITK is activated.

(16-3) use of compound a, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer involving JAK3 and ITK. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer in which JAK3 is mutated or activated for activation and a cancer in which ITK is activated.

(16-4) Compound A or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer involving JAK3 and ITK. In one instance, compound a or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer in which JAK3 is mutated or activated for activation and a cancer in which ITK is activated.

(16-5) a method for treating a cancer involving JAK3 and ITK, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof. In one instance, a method for treating a cancer in which JAK3 is mutated or activated for activation and a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof.

(17-1) a pharmaceutical composition for treating a cancer involving JAK3 and ITK, comprising compound a monomethanesulfonate salt. In one instance, a pharmaceutical composition for treating a cancer in which JAK3 is mutated or activated for activation and a cancer in which ITK is activated, comprising compound a monomethanesulfonate salt.

(17-2) use of compound a monomethanesulfonate for the manufacture of a pharmaceutical composition for the treatment of cancers involving JAK3 and ITK. In one instance, the use of compound a monomesylate salt for the manufacture of a pharmaceutical composition for the treatment of a cancer in which JAK3 is activated by an activating mutation or activation and a cancer in which ITK is activated.

(17-3) use of compound a monomethanesulfonate for the treatment of cancers involving JAK3 and ITK. In one instance, the use of compound a monomesylate salt for the treatment of JAK 3-activated mutant or activated cancer and ITK-activated cancer.

(17-4) Compound A monomethanesulfonate salt for use in the treatment of cancers involving JAK3 and ITK. In one instance, compound a monomesylate salt for use in treating cancers in which JAK3 is mutated or activated for activation and cancers in which ITK is activated.

(17-5) a method for treating a cancer involving JAK3 and ITK, comprising administering to a subject an effective amount of compound a monomesylate salt. In one instance, a method for treating a cancer in which JAK3 is activated by an activating mutation or activation and a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a monomesylate salt.

(18) The pharmaceutical composition disclosed in (16-1) or (17-1), (16-2) or (17-2), the use disclosed in (16-3) or (17-3), compound a disclosed in (16-4) or compound a monomethanesulfonate disclosed in (17-4), or the method of treatment disclosed in (16-5) or (17-5), wherein the cancer involving JAK3 or the cancer in which JAK3 is activated is mutated or activated is acute megakaryocytic leukemia or anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is acute T-cell lymphoma or lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (16-1) or (17-1), (16-2) or (17-2), the use disclosed in (16-3) or (17-3), compound a disclosed in (16-4) or compound a monomesylate disclosed in (17-4), or the method of treatment disclosed in (16-5) or (17-5), wherein the cancer involving JAK3 or the cancer in which JAK3 is mutated or activated for activation is acute megakaryocytic leukemia, and the cancer involving ITK or the cancer in which ITK is activated is acute T-cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (16-1) or (17-1), (16-2) or (17-2), the use disclosed in (16-3) or (17-3), compound a disclosed in (16-4) or compound a monomesylate disclosed in (17-4), or the method of treatment disclosed in (16-5) or (17-5), wherein the cancer involving JAK3 or the cancer in which JAK3 is mutated or activated for activation is acute megakaryocytic leukemia, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (16-1) or (17-1), (16-2) or (17-2), the use disclosed in (16-3) or (17-3), compound a disclosed in (16-4) or compound a monomesylate disclosed in (17-4), or the method of treatment disclosed in (16-5) or (17-5), wherein the cancer involving JAK3 or the cancer in which JAK3 is mutated or activated for activation is anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma.

Further, in another case, the pharmaceutical composition disclosed in (16-1) or (17-1), (16-2) or (17-2), the use disclosed in (16-3) or (17-3), compound a disclosed in (16-4) or compound a monomethanesulfonate disclosed in (17-4), or the method of treatment disclosed in (16-5) or (17-5), wherein the cancer involving JAK3 or the cancer in which JAK3 is activated mutated or activated is anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

(19-1) a pharmaceutical composition for treating a cancer involving BTK, JAK3 and ITK, comprising compound a or a pharmaceutically acceptable salt thereof. In one instance, a pharmaceutical composition for treating a cancer in which BTK is overexpressed or activated, a cancer in which JAK3 is activated by an activating mutation or activated, and a cancer in which ITK is activated, comprising compound a or a pharmaceutically acceptable salt thereof. In another aspect, a pharmaceutical composition for treating a cancer in which B cell receptor signaling is activated, a cancer in which JAK3 is activated or is activated, and a cancer in which ITK is activated, comprising compound a or a pharmaceutically acceptable salt thereof.

(19-2) use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer involving BTK, JAK3 and ITK. In one instance, the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which BTK is overexpressed or activated, a cancer in which JAK3 is mutated or activated for activation, and a cancer in which ITK is activated. In another aspect, the use of compound a, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment of a cancer in which B cell receptor signaling is activated, a cancer in which JAK3 is mutated or activated for activation, and a cancer in which ITK is activated.

(19-3) use of compound a or a pharmaceutically acceptable salt thereof for treating a cancer involving BTK, JAK3 and ITK. In one instance, the use of compound a or a pharmaceutically acceptable salt thereof, for the treatment of a cancer in which BTK is overexpressed or activated, a cancer in which JAK3 is mutated or activated for activation, and a cancer in which ITK is activated. In another aspect, the use of compound a, or a pharmaceutically acceptable salt thereof, for the treatment of a cancer in which B cell receptor signaling is activated, a cancer in which JAK3 is mutated or activated for activation, and a cancer in which ITK is activated.

(19-4) Compound A or a pharmaceutically acceptable salt thereof for use in the treatment of cancers involving BTK, JAK3 and ITK. In one instance, compound a or a pharmaceutically acceptable salt thereof, for use in treating a cancer in which BTK is overexpressed or activated, a cancer in which JAK3 is activated by an activating mutation or activation, and a cancer in which ITK is activated. In another instance, compound a or a pharmaceutically acceptable salt thereof, is used in the treatment of a cancer in which B cell receptor signaling is activated, a cancer in which JAK3 is activated by an activating mutation or activation, and a cancer in which ITK is activated.

(19-5) a method for treating a cancer involving BTK, JAK3 and ITK, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof. In one instance, a method for treating a cancer in which BTK is overexpressed or activated, a cancer in which JAK3 is activated or mutated or activated, and a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof. In another aspect, a method for treating a cancer in which B cell receptor signaling is activated, a cancer in which JAK3 is activated or is activated, and a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof.

(20-1) a pharmaceutical composition for treating a cancer involving BTK, JAK3 and ITK, comprising compound a monomethanesulfonate salt. In one instance, a pharmaceutical composition for treating a cancer in which BTK is overexpressed or activated, a cancer in which JAK3 is activated by an activating mutation or activated, and a cancer in which ITK is activated, comprising compound a monomesylate salt. In another aspect, a pharmaceutical composition for treating a cancer in which B cell receptor signaling is activated, a cancer in which JAK3 is activated or is activated, and a cancer in which ITK is activated, comprising compound a monomesylate salt.

(20-2) use of compound a monomethanesulfonate for the manufacture of a pharmaceutical composition for the treatment of cancer involving BTK, JAK3 and ITK. In one instance, the use of compound a monomesylate salt for the manufacture of a pharmaceutical composition for treating a cancer in which BTK is overexpressed or activated, a cancer in which JAK3 is mutated or activated for activation, and a cancer in which ITK is activated. In another aspect, the use of compound a monomesylate salt for the manufacture of a pharmaceutical composition for treating a cancer in which B cell receptor signaling is activated, a cancer in which JAK3 is mutated or activated for activation, and a cancer in which ITK is activated.

(20-3) use of compound a monomethanesulfonate for the treatment of cancer involving BTK, JAK3 and ITK. In one instance, the use of compound a monomesylate salt for the treatment of cancer in which BTK is overexpressed or activated, JAK3 is mutated or activated for activation, and ITK is activated. In another aspect, the use of compound a monomesylate salt for the treatment of a cancer in which B cell receptor signaling is activated, a cancer in which JAK3 is activated by an activating mutation or activation, and a cancer in which ITK is activated.

(20-4) Compound A monomethanesulfonate for use in the treatment of cancers involving BTK, JAK3, and ITK. In one instance, compound a monomethanesulfonate is useful for treating cancers in which BTK is overexpressed or activated, cancers in which JAK3 is activated by an activating mutation or activation, and cancers in which ITK is activated. In another instance, compound a monomesylate salt for use in treating a cancer in which B cell receptor signaling is activated, a cancer in which JAK3 is activated by an activating mutation or activation, and a cancer in which ITK is activated.

(20-5) a method for treating a cancer involving BTK, JAK3 and ITK, comprising administering to a subject an effective amount of compound a monomethanesulfonate salt. In one instance, a method for treating a cancer in which BTK is overexpressed or activated, a cancer in which JAK3 is activated or activated by an activating mutation, and a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a monomesylate salt. In another aspect, a method for treating a cancer in which B cell receptor signaling is activated, a cancer in which JAK3 is activated or is activated, and a cancer in which ITK is activated, comprising administering to a subject an effective amount of compound a monomesylate salt.

(21) The pharmaceutical composition disclosed in (19-1) or (20-1), (the use disclosed in (19-2) or (20-2), (the use disclosed in (19-3) or (20-3), (the cancer disclosed in (19-4) or the compound A monomethanesulfonate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell prolymphocytic leukemia, acute lymphocytic leukemia, histiocytic lymphoma, or acute myelogenous leukemia, the cancer in which JAK3 is implicated or the cancer in which JAK3 is activated mutated or activated is acute megakaryocytic leukemia or anaplastic large cell lymphoma, and the cancer in which ITK is implicated or activated is acute T cell lymphoma or lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), (19-3) or the use disclosed in (20-3), (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia, or histiocytic lymphoma, the cancer involving JAK3 or the cancer in which JAK3 is activated mutated or activated is acute megakaryocytic leukemia or anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma or lymphoblastic lymphoma And (4) sexual leukemia.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (the use disclosed in (19-2) or (20-2), (the use disclosed in (19-3) or (20-3), (compound A disclosed in (19-4) or compound A monomethanesulfonate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer in which BTK is implicated, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia, or histiocytic lymphoma, the cancer in which JAK3 is implicated or in which JAK3 is mutated or activated is acute megakaryocytic leukemia, and the cancer in which ITK is implicated or activated is acute T cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (the use disclosed in (19-2) or (20-2), (the use disclosed in (19-3) or (20-3), (compound A disclosed in (19-4) or compound A monomethanesulfonate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer in which BTK is implicated, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia, or histiocytic lymphoma, the cancer in which JAK3 is implicated or in which JAK3 is mutated or activated is acute megakaryocytic leukemia, and the cancer in which ITK is implicated or activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (the use disclosed in (19-2) or (20-2), (the use disclosed in (19-3) or (20-3), (compound A disclosed in (19-4) or compound A monomethanesulfonate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer in which BTK is implicated, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia, or histiocytic lymphoma, the cancer in which JAK3 is implicated or in which JAK3 is mutated or activated for activation is anaplastic large cell lymphoma, and the cancer in which ITK is implicated or activated is acute T cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (the use disclosed in (19-2) or (20-2), (the use disclosed in (19-3) or (20-3), (compound A disclosed in (19-4) or compound A monomethanesulfonate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer in which BTK is implicated, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia, or histiocytic lymphoma, the cancer in which JAK3 is implicated or in which JAK3 is mutated or activated for activation is anaplastic large cell lymphoma, and the cancer in which ITK is implicated or activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, the cancer involving JAK3, or the cancer in which JAK3 is mutated or activated is acute megakaryocytic leukemia, and the cancer involving ITK or the cancer in which ITK is activated is acute T-cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), (19-3) or the use disclosed in (20-3), (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, the cancer involving JAK3, or the cancer in which JAK3 is mutated or activated for activation is acute megakaryocytic leukemia, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, the cancer involving JAK3, or the cancer in which JAK3 is mutated or activated is anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), (19-3) or the use disclosed in (20-3), (19-4) or compound a monomesylate salt disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is diffuse large B-cell lymphoma, the cancer involving JAK3, or the cancer in which JAK3 is mutated or activated is anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is mantle cell lymphoma, the cancer involving JAK3, or the cancer in which JAK3 is activated is mutated or activated is acute megakaryocytic leukemia, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is mantle cell lymphoma, the cancer involving JAK3 or the cancer in which JAK3 is activated is mutated or activated is acute megakaryocytic leukemia, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is mantle cell lymphoma, the cancer involving JAK3 or the cancer in which JAK3 is activated is mutated or activated is anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is mantle cell lymphoma, the cancer involving JAK3 or the cancer in which JAK3 is activated is mutated or activated is anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is acute myeloid leukemia, the cancer involving JAK3, or the cancer in which JAK3 is mutated or activated is acute megakaryocytic leukemia, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is acute myeloid leukemia, the cancer involving JAK3, or the cancer in which JAK3 is mutated or activated is acute megakaryocytic leukemia, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is acute myeloid leukemia, the cancer involving JAK3, or the cancer in which JAK3 is mutated or activated is anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is acute myeloid leukemia, the cancer involving JAK3, or the cancer in which JAK3 is mutated or activated is anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is histiocytic lymphoma, the cancer involving JAK3, or the cancer in which JAK3 is activated mutated or activated is acute megakaryocytic leukemia, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is histiocytic lymphoma, the cancer involving JAK3, or the cancer in which JAK3 is activated, is acute megakaryocytic leukemia, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is histiocytic lymphoma, the cancer involving JAK3, or the cancer in which JAK3 is activated mutated or activated is anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is acute T cell lymphoma.

In another instance, the pharmaceutical composition disclosed in (19-1) or (20-1), (19-2) or (20-2), the use disclosed in (19-3) or (20-3), compound a disclosed in (19-4) or compound a monomesylate disclosed in (20-4), or the method of treatment disclosed in (19-5) or (20-5), wherein the cancer involving BTK, the cancer in which BTK is overexpressed or activated, or the cancer in which B cell receptor signaling is activated is histiocytic lymphoma, the cancer involving JAK3, or the cancer in which JAK3 is activated, is anaplastic large cell lymphoma, and the cancer involving ITK or the cancer in which ITK is activated is lymphoblastic leukemia.

Compound a or a pharmaceutically acceptable salt thereof can be obtained according to the method disclosed in the above-mentioned patent document 1(WO2013/108754) or a modification method thereof.

Further, "pharmaceutically acceptable salts of compound a" means acid addition salts of compound a, and examples thereof include acid addition salts of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutaminic acid. Further, "a pharmaceutically acceptable salt of compound a" includes a solvate of compound a, specifically, for example, a hydrate or an ethanolate, and also includes an acid addition salt of compound a.

Furthermore, examples of "compound a or a pharmaceutically acceptable salt thereof" include compound a (free base) in one instance and compound a monomethanesulfonate in another instance.

The pharmaceutical composition containing compound a or a pharmaceutically acceptable salt thereof can be prepared according to a method commonly used in the art using excipients commonly used in the art, i.e., excipients for pharmaceutical preparations, carriers for pharmaceutical preparations, and the like.

The administration of the pharmaceutical composition may be oral administration by tablets, pills, capsules, granules, powders and liquids, or parenteral administration by injection such as intra-articular, intravenous and intramuscular injections, suppositories, transdermal liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, inhalants and the like.

As solid compositions for oral administration, tablets, powders and granules are used. In such solid compositions, one or more active ingredients are mixed with at least one inactive excipient. In conventional manner, the composition may contain inactive additives such as lubricants, disintegrants, stabilizers and dissolution aids. The tablets or pills may be coated with sugar or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like. The liquid compositions contain a common inert diluent such as pure water or ethanol, and also contain adjuvants such as dissolution aids, wetting and suspending agents, sweetening, flavoring, perfuming or preservative agents.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. The aqueous solvent includes, for example, distilled water for injection or physiological saline. Examples of non-aqueous solvents include alcohols such as ethanol. Such compositions may also contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents or dissolution aids. They are sterilized, for example, by filtration through a filter which retains the bacteria, by blending with a bactericide or by irradiation. In addition, they can also be used by preparing sterile solid compositions and dissolving or suspending in sterile water or sterile solvent for injection before use.

Generally, for oral administration, the daily dose is from about 0.001mg/kg to 100mg/kg, preferably from 0.01mg/kg to 30mg/kg, more preferably from 0.1 to 10mg/kg body weight, administered in one portion or in 2 to 4 separate portions. In the case of intravenous administration, the daily dose is from about 0.0001mg/kg to 10mg/kg body weight, suitably administered once daily or twice daily or more. Further, the transmucosal pharmaceutical agent is administered at a dose of about 0.001mg/kg to 100mg/kg of body weight once a day or twice or more a day. The dose is appropriately determined depending on the individual in consideration of symptoms, age, sex, and the like.

The pharmaceutical composition of the present invention contains 0.01 to 99% by weight, and in one case 0.01 to 50% by weight of compound a or a pharmaceutically acceptable salt thereof as an active ingredient, although it varies depending on the administration route, dosage form, administration site, or type of excipient or additive.

The pharmaceutical compositions of the invention may be used in combination with a variety of different therapeutic agents believed to be effective against cancer, particularly cancers involving one or more of JAK3 and ITK. The combined preparations may be administered simultaneously or separately and consecutively or at desired time intervals. The formulations to be administered simultaneously may be mixtures or may be prepared separately. Specifically, examples of agents that may be used in combination herein include anti-CD 20 monoclonal antibodies such as rituximab, alkylating agents such as cyclophosphamide and ifosfamide, antineoplastic agents such as doxorubicin, cisplatin, methotrexate, anthracyclines and lenalidomide, microtubule polymerization inhibitors such as vincristine, corticosteroids such as prednisone, prednisolone and dexamethasone, antimetabolites such as bendamustine, kinase inhibitors such as imatinib and dasatinib, cytokine agents such as interferons, antibiotics such as mitoxantrone and bleomycin, and asparaginase.

Detailed Description

Examples

The pharmacological effects of the pharmaceutical composition of the present invention are demonstrated by the following examples. Further, compound a monomethanesulfonate (hereinafter referred to as "test compound B") was used as compound a or a pharmaceutically acceptable salt thereof in the following examples. In each example, the concentration of test compound B was calculated from the concentration of compound a in free form.

Example 1 evaluation of BTK kinase inhibitory Activity

BTK kinase inhibitory activity was assessed using QSS assistance BTK _ MSA kit (Carna Bioscience).

Test compound B was dissolved in dimethyl sulfoxide (DMSO) to prepare a solution at 100-fold concentration compared to the final concentration. The solution was also diluted 25-fold with the attached assay buffer to obtain a test compound B solution. In addition, BTK kinase attached to the kit was used for the reaction.

mu.L of a 4-fold concentrated test compound B solution prepared using the above assay buffer and 10. mu.L of a 2-fold concentrated BTK kinase solution were mixed in the wells of a 384-well plate and left to undergo a reaction at room temperature for 30 minutes. To this was added 5. mu.L of 4-fold concentration of substrate peptide/ATP/MgCl₂The solution was reacted at room temperature for 1 hour. The substrate peptide was present at a final concentration of 1000nM, ATP at a final concentration of 1mM, MgCl₂Used at a final concentration of 5 mM. Subsequently, 60. mu.L of the following stop buffer was added thereto to stop the reaction. BTK kinase activity was calculated by quantifying the product conversion obtained from the substrate peptide peak height and the product (phosphorylated substrate peptide) peak height using LabChip EZ Reader II (PerkinElmer).

For data analysis, inhibition was calculated from the average conversion of wells tested for the corresponding test compound B by defining the average conversion of control wells including all reaction components as 0% inhibition and defining the average conversion of background wells including all reaction components except BTK kinase as 100% inhibition. Determination of IC by non-linear regression on the basis of the concentration of test compound B and of the profile derived from the inhibition₅₀The value is obtained.

As a result, compound B was tested with an IC of 0.17nM₅₀The values inhibit BTK kinase activity.

Example 2 evaluation of proliferation inhibition Using human diffuse Large B-cell lymphoma cell line OCI-Ly10 cells

OCI-Ly10 is a cell line derived from human diffuse large B-cell lymphoma, a B-cell malignancy, and BTK dependency has been confirmed (Nature.2010; 463: 88-92). Human diffuse large B-cell lymphoma cell line OCI-Ly10 cells (University Health Network) cultured in Iscove's modified Dulbecco's medium (Sigma) containing 20% bovine serum were seeded into 96-well plates. On the same day, a DMSO solution of test compound B at a final concentration of 0.1nM to 1. mu.M or DMSO only (DMSO group) was added thereto, and cells were incubated at 37 ℃ and 5% CO₂The cells were cultured for 3 days. Subsequently, a cell counting reagent (CellTiter-Glo) was used^TMLuminescent Cell viatilityassay (Promega)) measures the number of cells. The cell proliferation inhibition rate was calculated by setting the measurement values in the DMSO group as 0% inhibition and the measurement values in the DSMO group on the cell inoculation day as 100% inhibition.

As a result, test compound B was administered with GI of 1.0nM₅₀The value inhibited proliferation of OCI-Ly10 cells.

Example 3 evaluation of proliferation inhibition Using human mantle cell lymphoma cell line Rec-1 cells

Rec-1 is a Cell line derived from human mantle Cell lymphoma, a B-Cell malignancy, and BTK expression and phosphorylation have been confirmed (Cell Oncol.2011; 34: 141-153). Human mantle cell lymphoma cell line Rec-1 cells (American type culture Collection, CRL-3004) cultured in RPMI1640 medium (Sigma) containing 10% bovine serum were seeded in 96-well plates. The following day, to which a DMSO solution of test compound B was added at a final concentration of 1nM to 10. mu.M or DMSO only (DMSO group), cells were incubated at 37 ℃ and 5% CO₂The cells were cultured for 3 days. Subsequently, a cell counting reagent (CellTiter-Glo) was used^TMLuminescent Cell Viability Assay (Promega)) measures Cell number. The cell proliferation inhibition rate was calculated by setting the measurement value in the DMSO group as 0% inhibition and the measurement value in the well containing only the medium without seeded cells as 100% inhibition.

As a result, compound B was tested with an IC of 68nM₅₀The values inhibit proliferation of Rec-1 cells.

Example 4 evaluation of proliferation inhibition of KG-1 cells using the human acute myeloid leukemia cell line

KG-1 is a cell line derived from human acute myeloid leukemia, and BTK expression has been confirmed (J.Immunol.1994; 152(2): 557-565). Human acute myeloid leukemia cell line KG-1 cells (American Type Culture Collection, CCL-246) cultured in RPMI1640 medium (Sigma) containing 10% bovine serum were seeded in 96-well plates. The following day, to which a DMSO solution of test compound B was added at a final concentration of 1nM to 10. mu.M or DMSO only (DMSO group), cells were incubated at 37 ℃ and 5% CO₂The cells were cultured for 3 days. Subsequently, a cell counting reagent (CellTiter-Glo) was used^TMLuminescent Cell Viability Assay (Promega)) measures Cell number. The cell proliferation inhibition rate was calculated by setting the measurement value in the DMSO group as 0% inhibition and the measurement value in the well containing only the medium without seeded cells as 100% inhibition.

As a result, test compound B had an IC of 38nM₅₀The values inhibit the proliferation of KG-1 cells.

Example 5 evaluation of proliferation inhibition Using the human acute myeloid leukemia cell line MV4-11 cells

MV4-11 is a cell line derived from human acute myeloid leukemia, and BTK expression has been confirmed (mol. CellProteomics.2009; 8(7): 1751-. Will contain 10 percentHuman acute myeloid leukemia cell line MV4-11 cells (American Type culture collection, CRL-9591) cultured in Iscove's modified Dulbecco's medium (Sigma) in bovine serum were seeded in 96-well plates. The following day, to which a DMSO solution of test compound B was added at a final concentration of 1nM to 10. mu.M or DMSO only (DMSO group), cells were incubated at 37 ℃ and 5% CO₂The cells were cultured for 3 days. Subsequently, a cell counting reagent (CellTiter-Glo) was used^TMLuminescent Cell Viability Assay (Promega)) measures Cell number. The cell proliferation inhibition rate was calculated by setting the measurement value in the DMSO group as 0% inhibition and the measurement value in the well containing only the medium without seeded cells as 100% inhibition.

As a result, test compound B was tested with an IC of 10nM₅₀The values inhibited the proliferation of MV4-11 cells.

Example 6 evaluation of proliferation inhibition Using the human histiocytic lymphoma cell line U-937 cells

U-937 is a cell line derived from human histiocytic lymphoma, and BTK expression has been confirmed (J.Immunol.1994; 152(2): 557-565). Human histiocytic lymphoma cell line U-937 cells (Sumitomo Dainippon Pharma co., Ltd.) cultured in RPMI1640 medium (Sigma) containing 10% bovine serum were seeded in 96-well plates. On the same day, a DMSO solution of test compound B at a final concentration of 1nM to 10. mu.M or DMSO only (DMSO group) was added thereto, and cells were incubated at 37 ℃ and 5% CO₂The cells were cultured for 3 days. Subsequently, a cell counting reagent (CellTiter-Glo) was used^TMLuminescent Cell Viability Assay (Promega)) measures Cell number. The cell proliferation inhibition rate was calculated by setting the measurement value in the DMSO group as 0% inhibition and the measurement value in the well containing only the medium without seeded cells as 100% inhibition.

As a result, compound B was tested with an IC of 63nM₅₀The values inhibit proliferation of U-937 cells.

Example 7 antitumor evaluation in OCI-Ly10 subcutaneous xenograft mouse model

Human diffuse large B-cell lymphoma cell line OCI-Ly10 cells were implanted subcutaneously into the back of immunodeficient mice (nod. cb17-Prkdc scid/J, male, 4 week old (Charles River Laboratories Japan, Inc.) to create an OCI-Ly10 subcutaneous xenograft mouse model. Mice grouped on the basis of tumor volume were administered either 0.5% methylcellulose (control group: 10 mL/kg/day, QD, po (n ═ 4)) or test compound B (test compound B administration group: 30 or 100 mg/kg/day, in 0.5% methylcellulose suspension, QD, po (n ═ 4)). Tumor volume was assessed as a function of time.

As a result, in the control group, the size was 188mm on the day of initiation of the administration³Increased to 520mm after 14 days³The size of (2). Meanwhile, in the test compound B administration group of 30 mg/kg/day, the size was 190mm on the day of start of administration³Reduced to 50mm after 14 days³The size of (2). Furthermore, in the test compound B administration group at 100 mg/kg/day, the size of the tumor volume was from 184mm³Reduced to 22mm³。

Example 8 assessment of JAK3 kinase inhibitory Activity

JAK3 kinase inhibitory activity was assessed using QSS assistance JAK3_ MSA kit (Carna Bioscience).

Test compound B was dissolved in dimethyl sulfoxide (DMSO) to prepare a solution at a concentration 100-fold higher than the test concentration. The solution was also diluted 25-fold with the attached assay buffer to obtain a test compound B solution. In addition, JAK3 kinase attached to the kit was used for the reaction.

mu.L of a 4-fold concentrated test compound B solution prepared using the above assay buffer and 10. mu.L of a 2-fold concentrated JAK3 kinase solution were mixed in the well of a 384-well plate and incubated at room temperatureFor 30 minutes. To this was added 5. mu.L of 4-fold concentration of substrate peptide/ATP/MgCl₂The solution was reacted at room temperature for 1 hour. The substrate peptide was at a final concentration of 1. mu.M, ATP at a final concentration of 1mM, MgCl₂Used at a final concentration of 5 mM. Subsequently, 60. mu.L of the following stop buffer was added thereto to stop the reaction. JAK3 kinase activity was calculated by quantifying the product conversion obtained from the substrate peptide peak height and the product (phosphorylated substrate peptide) peak height using LabChip EZ Reader II (PerkinElmer).

For data analysis, inhibition was calculated from the average conversion of wells tested for the corresponding test compound B by defining the average conversion of control wells including all reaction components as 0% inhibition and defining the average conversion of background wells including all reaction components except JAK3 kinase as 100% inhibition. Determination of IC by non-linear regression on the basis of the concentration of test compound B and of the profile derived from the inhibition₅₀The value is obtained.

As a result, compound B was tested with an IC of 0.44nM₅₀Values inhibit JAK3 kinase activity.

Example 9 evaluation of proliferation inhibition Using human Interdegenerating Large cell lymphoma cell line SU-DHL-1 cells

SU-DHL-1 is a cell line derived from human anaplastic large cell lymphoma, and activation of JAK3 has been confirmed (Leukemia.2014; 28: 941-. Human anaplastic large cell lymphoma cell line SU-DHL-1 cells (American Type Culture Collection, CRL-2955) cultured in RPMI1640 medium (Sigma) containing 10% bovine serum were seeded into 96-well plates. On the same day, a DMSO solution of test compound B at a final concentration of 1nM to 10. mu.M or DMSO only (DMSO group) was added thereto, and cells were incubated at 37 ℃ and 5% CO₂The cells were cultured for 4 days. Subsequently, a cell counting reagent (CellTiter-Glo) was used^TMLuminescent Cell Viability Assay (Promega)) measures Cell number. By setting the measurements in the DMSO group to 0% inhibition and will contain only cultures without seeded cellsThe cell proliferation inhibition rate was calculated by setting the measurement value in the wells of the nutrient group as 100% inhibition.

As a result, compound B was tested with an IC of 120nM₅₀The values inhibit the proliferation of SU-DHL-1 cells.

Example 10 evaluation of proliferation inhibition Using human anaplastic Large cell lymphoma cell line KARPAS-299 cells

KARPAS-299 is a cell line derived from human anaplastic large cell lymphoma, and activation of JAK3 has been confirmed (oncogene.2002; 21: 1038-. Human anaplastic large cell lymphoma cell line KARPAS-299 cells (DSMZ, ACC31) cultured in RPMI1640 medium (Sigma) containing 10% bovine serum were seeded into 96-well plates. On the same day, a DMSO solution of test compound B at a final concentration of 1nM to 10. mu.M or DMSO only (DMSO group) was added thereto, and cells were incubated at 37 ℃ and 5% CO₂The cells were cultured for 3 days. Subsequently, a cell counting reagent (CellTiter-Glo) was used^TMLuminescent Cell Viability Assay (Promega)) measures Cell number. The cell proliferation inhibition rate was calculated by setting the measurement value in the DMSO group as 0% inhibition and the measurement value in the well containing only the medium without seeded cells as 100% inhibition.

As a result, test compound B had an IC of 250nM₅₀The values inhibit proliferation of KARPAS-299 cells.

Example 11 evaluation of proliferation inhibition Using CMK cells of human acute megakaryocytic leukemia cell line

CMK is a cell line derived from human acute megakaryocytic leukemia, and activation of JAK3 has been confirmed (Cancer cell.2006; 10: 65-75). Human acute megakaryocytic leukemia cell line CMK cells (DSMZ, ACC392) cultured in RPMI1640 medium (Sigma) containing 20% bovine serum and 2mM glutamine were seeded into 96-well plates. On the same day, an assay was added to it at a final concentration of 1nM to 10. mu.MDMSO solutions of Compound B or DMSO only (DMSO group) were added and cells were incubated at 37 ℃ and 5% CO₂The cells were cultured for 4 days. Subsequently, a cell counting reagent (CellTiter-Glo) was used^TMLuminescent Cell Viability Assay (Promega)) measures Cell number. The cell proliferation inhibition rate was calculated by setting the measurement value in the DMSO group as 0% inhibition and the measurement value in the well containing only the medium without seeded cells as 100% inhibition.

As a result, compound B was tested with an IC of 110nM₅₀The values inhibit the proliferation of CMK cells.

Example 12 evaluation of ITK kinase inhibitory Activity

ITK kinase inhibitory activity was assessed using a mobility change assay system.

Test compound B was dissolved in dimethyl sulfoxide (DMSO) to prepare a solution at a concentration 100-fold higher than the test concentration. The solution was also diluted 25-fold with assay buffer (20mM HEPES, 0.01% Triton X-100, 1mM DTT, pH7.5) to obtain a test substance solution.

mu.L of a 4-fold concentrated test compound B solution prepared using the above assay buffer and 10. mu.L of a 2-fold concentrated ITK kinase solution were mixed in the wells of a 384-well plate and incubated at room temperature for 30 minutes. To this was added 5. mu.L of a 4-fold concentration of substrate PEPTIDE (Srctide, PEPTIDE insertion, INC. # AD-995)/ATP/MgCl₂The solution was reacted at room temperature for 1 hour. The substrate peptide was at a final concentration of 1000nM, ATP at a final concentration of 1000. mu.M, MgCl₂Used at a final concentration of 5 mM. Then, 60. mu.L of a stop buffer (127mM HEPES, 0.01% Triton X-100, 26.7mM EDTA, 1% DMSO, pH7.5) was added thereto to stop the reaction. ITK kinase activity was calculated by quantifying the product conversion obtained from the substrate peptide peak height and the product (phosphorylated substrate peptide) peak height using LabChip3000 (PerkinElmer).

For data analysis, inhibition was calculated from the average conversion of wells tested for the corresponding test compound B by defining the average conversion of control wells including all reaction components as 0% inhibition and defining the average conversion of background wells including all reaction components except for ITK kinase as 100% inhibition.

As a result, the% inhibition of ITK kinase activity by test compound B was 29.5% and 92.6% at 1nM and 10nM, respectively.

Example 13 evaluation of proliferation inhibition Using human acute T-cell lymphoma cell line Jurkat 6.1E cells

Jurkat 6.1E is a cell line derived from human acute T-cell lymphoma, and ITK expression has been confirmed (mol. Pharmacol.2012; 82: 938-947). Human acute T cell lymphoma cell line Jurkat 6.1E cells (European Collection of CellCulturs, 88042803) cultured in RPMI1640 medium (Sigma) containing 10% bovine serum were seeded into 96-well plates. On the same day, a DMSO solution of test compound B at a final concentration of 1nM to 10. mu.M or DMSO only (DMSO group) was added thereto, and cells were incubated at 37 ℃ and 5% CO₂The cells were cultured for 4 days. Subsequently, a cell counting reagent (CellTiter-Glo) was used^TMLuminescent Cell Viability Assay (Promega)) measures Cell number. The cell proliferation inhibition rate was calculated by setting the measurement value in the DMSO group as 0% inhibition and the measurement value in the well containing only the medium without seeded cells as 100% inhibition.

As a result, compound B was tested with an IC of 940nM₅₀Values inhibit proliferation of Jurkat 6.1E cells.

Example 14 evaluation of proliferation inhibition Using human lymphoblastic leukemia cell line MOLT-4 cells

MOLT-4 is a cell line derived from human lymphoblastic leukemia, and ITK expression has been confirmed (mol. Pharmacol.2012; 82: 938-947). The cells were cultured in RPMI1640 medium (Sigma) containing 10% bovine serum) The cultured human lymphoblastic leukemia cell line MOLT-4 cells (European Collection of cell cultures, 85011413) were seeded into 96-well plates. On the same day, a DMSO solution of test compound B at a final concentration of 1nM to 10. mu.M or DMSO only (DMSO group) was added thereto, and cells were incubated at 37 ℃ and 5% CO₂The cells were cultured for 4 days. Subsequently, a cell counting reagent (CellTiter-Glo) was used^TMLuminescent Cell Viability Assay (Promega)) measures Cell number. The cell proliferation inhibition rate was calculated by setting the measurement value in the DMSO group as 0% inhibition and the measurement value in the well containing only the medium without seeded cells as 100% inhibition.

As a result, test compound B had an IC of 410nM₅₀The values inhibit proliferation of MOLT-4 cells.

From the above results, it was confirmed that compound a or a pharmaceutically acceptable salt thereof inhibits the activity of BTK, JAK3 and ITK kinases, and it was shown that compound a or a pharmaceutically acceptable salt thereof can be expected to be used as an active ingredient of a pharmaceutical composition for treating cancers involving one or more kinases among BTK, JAK3 and ITK. Specifically, it was confirmed that compound a or a pharmaceutically acceptable salt thereof has an effect on the proliferation of OCI-Ly10 cells which are a diffuse large B-cell lymphoma cell line, Rec-1 cells which are a mantle cell lymphoma cell line, KG-1 cells and MV4-11 cells which are an acute myelogenous leukemia cell line, U-937 cells which are a histiocytic lymphoma cell line, SU-DHL-1 and KARPAS-299 cells which are anaplastic large cell lymphoma cell lines, CMK cells which are an acute megakaryocytic leukemia cell line, Jurkat 6.1E cells which are an acute T cell lymphoma cell line, and MOLT-4 cells which are lymphoblastic leukemia cell lines, and that compound a or a pharmaceutically acceptable salt thereof has an effect on cancers involving one or more kinases among BTK, JAK3, and ITK. Furthermore, compound a monomethanesulfonate showed significant antitumor activity and regression in a dose-dependent manner, even in a mouse model xenografted subcutaneously with the diffuse large B-cell lymphoma cell line OCI-Ly10 cells.

Industrial applicability

Compound a or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, is expected to have BTK inhibitory effect, JAK3 inhibitory effect and ITK inhibitory effect, and can be used as an active ingredient of a pharmaceutical composition for the treatment of cancers involving one or more of BTK, JAK3 and ITK, which are cancers in which BTK is overexpressed or activated in one case, B-cell receptor signaling is activated in another case, JAK3 is activated by mutation or activation in another case, and ITK is activated in another case.

Claims (21)

1. A pharmaceutical composition for treating a cancer involving one or more kinases of BTK, JAK3 and ITK comprising 5- { [ (3R) -1-acryloyl pyrrolidin-3-yl ] oxy } -6-ethyl-3- ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof as an active ingredient.

2. The pharmaceutical composition of claim 1, wherein the cancer involving one or more of BTK, JAK3, and ITK is a cancer involving BTK.

3. The pharmaceutical composition of claim 2, wherein the cancer in which BTK is implicated is a cancer in which BTK is overexpressed or activated.

4. The pharmaceutical composition of claim 2, wherein the cancer in which BTK is implicated is a cancer in which B cell receptor signaling is activated.

5. The pharmaceutical composition of claim 2, wherein the cancer in which BTK is implicated is a cancer selected from follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell prolymphocytic leukemia, acute lymphocytic leukemia, histiocytic lymphoma, and acute myelogenous leukemia.

6. The pharmaceutical composition according to claim 5, wherein the cancer in which BTK is implicated is diffuse large B-cell lymphoma, mantle cell lymphoma, acute myeloid leukemia, and/or histiocytic lymphoma.

7. The pharmaceutical composition of claim 1, wherein the cancer involving one or more of BTK, JAK3, and ITK is a cancer involving JAK 3.

8. The pharmaceutical composition of claim 7, wherein the cancer in which JAK3 is a JAK3 activating mutation or activation cancer.

9. The pharmaceutical composition according to claim 7, wherein the cancer in which JAK3 is involved is acute megakaryocytic leukemia and/or anaplastic large cell lymphoma.

10. The pharmaceutical composition of claim 1, wherein the cancer involving one or more of BTK, JAK3, and ITK is a cancer involving ITK.

11. The pharmaceutical composition according to claim 10, wherein the cancer in which ITK is implicated is a cancer in which ITK is activated.

12. The pharmaceutical composition according to claim 10, wherein the cancer in which ITK is implicated is acute T-cell lymphoma and/or lymphoblastic leukemia.

13. The pharmaceutical composition of claim 1, wherein the cancer involving one or more of BTK, JAK3, and ITK is a cancer involving BTK and JAK 3.

14. The pharmaceutical composition of claim 1, wherein the cancer involving one or more of BTK, JAK3, and ITK is a cancer involving BTK and ITK.

15. The pharmaceutical composition of claim 1, wherein the cancer involving one or more of BTK, JAK3, and ITK is a cancer involving JAK3 and ITK.

16. The pharmaceutical composition of claim 1, wherein the cancer involving one or more of BTK, JAK3, and ITK is a cancer involving BTK, JAK3, and ITK.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein 5- { [ (3R) -1-acryloylpyrrolidin-3-yl ] oxy } -6-ethyl-3- ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof is 5- { [ (3R) -1-acryloylpyrrolidin-3-yl ] oxy } -6-ethyl-3- ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } amino) pyrazine-2-carboxamide monomethanesulfonate salt.

18. Use of compound a or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of cancer involving one or more of BTK, JAK3 and ITK.

19. Use of compound a or a pharmaceutically acceptable salt thereof for the treatment of cancer involving one or more of BTK, JAK3 and ITK.

20. Compound a or a pharmaceutically acceptable salt thereof for use in the treatment of cancer involving one or more of BTK, JAK3 and ITK.

21. A method for treating a cancer involving one or more kinases of BTK, JAK3 and ITK, the method comprising administering to a subject an effective amount of compound a or a pharmaceutically acceptable salt thereof.