JP2012116777A - Baff binding inhibitor comprising pyrrolopyrimidine derivative as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound that inhibits binding of BAFF to a BR3 receptor and is useful as a medicine having excellent prevention and treatment effects on autoimmune diseases and a pharmaceutical composition containing the same.SOLUTION: The compound is represented by general formula (1) [wherein ring A is a nitrogen-containing heterocyclic ring; m is an integer of 0-2], a salt thereof or a solvate thereof. The pharmaceutical composition comprises the compound.

Description

  The present invention relates to a pyrrolopyrimidine derivative useful as an inhibitor for binding of BAFF to the BR3 receptor. More specifically, the present invention relates to a pyrrolopyrimidine derivative useful as a preventive and / or therapeutic agent for autoimmune diseases, an acquired immune deficiency syndrome or a preventive and / or therapeutic agent for cancer.

  The immune mechanism in the living body is originally a biological defense mechanism for recognizing and eliminating foreign antigenic proteins such as bacteria, viruses or tumors. A specific reaction to a foreign antigen occurs, producing a specific antibody or cytotoxic T With cell activation. In these acquired immunity, B cells play a central role through humoral immunity, and produce specific antibodies against foreign antigens to eliminate foreign antigens (Non-patent Document 1). However, in an autoimmune disease, an excessive reaction to a self antigen occurs, which is accompanied by autoantibody production and T cell activation. In autoimmune diseases such as rheumatoid arthrhitis (RA) and systemic lupus Erythematosus (SLE) with autoimmune reaction in the background, production of autoreactive B cells and autoantibodies is enhanced. Therefore, many studies have been conducted on elucidation of mechanisms that control maturation and activation of B cells and antibody production.

  B cells are derived from bone marrow hematopoietic stem cells and are a group of cells that express immunoglobulin on the cell surface, occupy about 10 to 30% of peripheral blood lymphocytes, and are mediated by B cell receptors (BCR) in the spleen. In response to antigen stimulation or activation stimulation from T cells, the cells differentiate into immunoglobulin-producing cells (plasma cells). Activated B cells produce inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), and via costimulatory molecules such as CD40 expressed on the cell surface. To activate T cells. Thus, B cells are greatly involved not only as autoantibody-producing cells but also as functions of antigen-presenting cells, and pathogenesis of autoimmune diseases through crosstalk with cytokine-producing cells and T cells. It has been made clear. Furthermore, monoclonal antibodies against CD20, a CD antigen specific to B cells (Rituximab, Rituxan, rituximab, Non-Patent Document 2) are clinically confirmed to be effective in improving symptoms of B-cell non-Hodgkin lymphoma, RA or SLE. There is a great expectation for the treatment of autoimmune diseases targeting B cells.

  Recently, BAFF (B cell activating factor belonging to TNF superfamily) has been discovered as a B cell survival and maturation factor (Non-patent Document 3, Patent Document 1). BAFF is also known as BLyS, TALL-1, THANK, zTNF4, TNFSF13B, or Kay ligand (see Patent Document 1), and is positioned as a member of the superfamily of TNF-alpha, an inflammatory cytokine. BAFF exists as a precursor protein on the surface of monocytes, macrophages, and dendritic cells, and is stimulated by interferon-gamma (IFN-gamma), LPS (lipopolysaccharide) or interleukin-10 (IL-10). Its expression is enhanced (Non-Patent Document 4). BAFF undergoes processing by furin-type protease to become secreted, and this activated BAFF protein forms a homotrimer, and similarly binds to a receptor expressed on the surface of the B cell as a trimer (non-reactive). Patent Document 5). The main effect of BAFF on B cells is to induce Bcl-2, which acts antagonistically to apoptosis, and induces B cell activation such as prolonging survival of B cells and enhancing production of IgM, which is an immunoglobulin. Increases overproduction of autoantibodies (Non-patent Document 6). The intracellular signal is due to the transcription factor NF-kappaB2 / p100 being processed into p52 (Non-patent Document 7). BAFF transgenic mice have been confirmed to have enlarged lymph nodes or spleen, hyperplasia of B cells in the tissue, and a severe autoimmune disease-like phenotype (Non-patent Documents 8 and 9). On the other hand, almost no mature B cells were observed in BAFF knockout mice, and lack of humoral immune response has been reported (Non-patent Document 10).

  From the phenotypes of these BAFF transgenic mice and BAFF knockout mice, it can be considered that they are deeply involved in autoimmune diseases accompanied by B cell activation. The possibility of application to treatment of various autoimmune diseases is shown in the review by Matsushita et al., SLE, Sjogren's syndrome, RA, systemic sclerosis (SSc), multiple sclerosis (Multiple Sclerosis: MS), application to antitumor agents such as non-classifiable immunodeficiency (CVID) and non-Hodgkin's lymphoma (Non-Patent Document 11). In patients with acquired immune deficiency syndrome (AIDS), blood T cells decrease, B cells increase and immunoglobulin production increases, and expression of BAFF protein on the surface of B cells increases. This suggests that BAFF and its receptor are involved in the progression of AIDS pathology (Non-patent Document 12).

  Examples of receptors for BAFF include BCMA (B Cell Maturation Antigen, also known as TNFRSF17, Non-Patent Document 13), TACI (Transmembrane Activator and CAML-Interactor, also known as TNFRSF13B, Non-Patent Document 14), and BR3 (also known as TNFSFR13C, BAFF Receptor, BAFF). -R may be abbreviated as -R.3 types of transmembrane proteins of Non-Patent Document 15) have been reported, and these receptors are members of the TNF receptor superfamily as well as ligands. Among these, APRIL (A Proliferation Inducing Ligand), which is one of TNF family members, binds to BCMA and TACI as a ligand (Non-patent Document 16). Among these three receptors, it is suggested that the action of BAFF on B cells is mainly mediated by BR3 (Non-patent Document 15). As in the case of BAFF-deficient mice, BR3 knockout mice have phenotypes such as deletion of mature B cells and a decrease in immunoglobulin production ability (Non-patent Document 17). In WySnJ mice, the importance of BAFF and BR3 in the maturation process of B cells has been suggested, such as a marked decrease in the number of peripheral B cells (Non-patent Document 18).

  In recent years, for the treatment of autoimmune diseases such as RA, biopharmaceuticals such as a specific antibody of the target protein or a soluble receptor using the receptor of the target protein have been developed. One TNF-alpha soluble receptor protein preparation, Enbrel (Etanercept, Non-Patent Document 19), has been used for RA treatment. Similarly, development of a specific antibody against BAFF or a soluble receptor protein using its receptor has been promoted, and it has been developed for the treatment of autoimmune diseases and other diseases associated with B cells. (Non-Patent Document 6). For example, belimumab (Lymphostat), an anti-human BAFF antibody, has been tested against SLE (Non-patent Document 20), and Atacicept, a TACI-Fc fusion protein, has also been tested in SLE patients for the purpose of inhibiting BAFF. (Non-patent document 21). In addition, the relationship between the survival rate of non-Hodgkin's lymphoma patients and the blood BAFF concentration has been suggested (Non-patent Document 22), and the development of a therapeutic method targeting BAFF is also expected in diseases other than autoimmune diseases. Furthermore, the development of BR3-Fc, which is a soluble receptor, has also been promoted for the purpose of controlling B cell activation (Non-patent Document 23).

  As mentioned above, targeting BAFF and its receptor, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, multiple sclerosis, autoimmune diseases such as unclassifiable immunodeficiency, acquired immune deficiency Development of biologics such as anti-BAFF antibody and BR3-Fc protein is underway as a treatment for anti-tumor agents such as Syndrome and non-Hodgkin's lymphoma. There are no reports of molecular compounds, and only a partial peptide of BR3 protein has been reported (Non-patent Document 24, Patent Document 2). Further, as described above, at least three types of receptors to which BAFF binds are known. Of these, the BR3 receptor is the only BAFF-specific receptor and is thought to mainly transmit the BAFF signal.

  On the other hand, compounds having a pyrrolopyrimidine skeleton are effective in treating cancer, rheumatism and the like based on MEK inhibitory action (Patent Document 3, Patent Document 4), treating cancer based on HSP inhibition (Patent Document 5), and progesterone action. Treatment of infertility based on (Patent Document 6), treatment of various diseases including inflammatory diseases based on CRF inhibitory action (Patent Document 7), and the like are disclosed. However, the compounds of any literature differ from the compounds of the present invention in the combination of substituents on the pyrrolopyrimidine ring. In any of the documents, there is no description or suggestion regarding the binding inhibitory action of BAFF on the BR3 receptor.

WO99 / 12964 pamphlet WO2005 / 005462 pamphlet WO2008 / 067481 pamphlet WO2008 / 157179 pamphlet WO2007 / 035963 pamphlet JP-T-2002-541259 Japanese Translation of National Publication No. 09-504520

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  An object of the present invention is to contain a novel compound that inhibits the binding of BAFF to the BR3 receptor and is excellent in the preventive and therapeutic effects of autoimmune diseases and the like, or the preventive and / or therapeutic effects of cancer, and the like. It is to provide a pharmaceutical composition.

  As described above, BAFF binding inhibitors are being developed in biologics such as anti-BAFF antibodies and BR3-Fc receptors, but there have been no reports of low molecular weight compounds. As described above, at least three types of receptors to which BAFF binds are known, and it is also suggested that the BR3 receptor is the most important. As a result of intensive studies, the present inventors have found that a pyrrolopyrimidine derivative represented by the following general formula (1) inhibits this BAFF-BR3 binding, and completed the present invention.

That is, the present invention relates to the following inventions.
[1] The following general formula (1):

[Wherein ring A represents the following formula:

A group selected from: (wherein B represents —CH ₂ —, —O— or —NH—, R ⁴ represents a (C _1-6 alkyl) amino group, (C _3-6 cycloalkyl) amino; A group, a pyridinyl group, or a 2-oxopyrrolidinyl group, L represents the formula — (CH ₂ ) _p —, —CH ₂ C (O) —, or —C (O) CH ₂ —, n Represents an integer of 0 to 2, o represents an integer of 1 to 3, and p represents an integer of 0 to 3).
R ¹ and R ² may be the same or different from each other, and each represents a hydrogen atom or a C _1-6 alkyl group,
R ³ represents a C _3-6 cycloalkyl group, a C _6-10 aryl group _optionally substituted with a halogen atom, or a (C _6-10 aryl) C _1-6 alkyl group,
m shows the integer of 0-2. ]
Or a salt thereof, or a solvate thereof.

[2] The compound represented by the general formula (1) is
7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) azepan-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [2-{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2-one,
1- {2- (4-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- (2- [3-{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2-one,
1- {2- (2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- (2- [4-{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} azepan-1-yl] -2-oxoethyl) pyrrolidine -2-one,
4- {2- (azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperazin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
4- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} ethyl] morpholine,
7-benzyl-5,6-dimethyl-4- {2- (pyrrolidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-cyclopropylacetamide,
N-cyclopropyl-2- (4-[{7- (4-fluorophenyl) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy] piperidin-1-yl Acetamide,
2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isopropylacetamide,
N- (sec-butyl) -2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] acetamide ,
1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine -2-one and
From the group consisting of 2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isobutylacetamide The compound according to the above [1], which is at least one selected compound, or a salt thereof, or a solvate thereof.

[3] A pharmaceutical composition comprising the compound according to [1] or [2], or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
[4] The pharmaceutical composition according to [3] above, wherein the pharmaceutical composition is for the prevention and / or treatment of a disease associated with inhibition of binding of BAFF to BR3 receptor.
[5] An inhibitor of binding of BAFF to BR3 receptor comprising the compound according to [1] or [2], or a salt thereof, or a solvate thereof as an active ingredient.
[6] A prophylactic and / or therapeutic agent for autoimmune diseases comprising the compound according to [1] or [2] above, or a salt thereof, or a solvate thereof as an active ingredient.
[7] Prevention and / or the above-mentioned [6], wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, multiple sclerosis, or unclassifiable immunodeficiency Therapeutic agent.
[8] A preventive and / or therapeutic agent for acquired immune deficiency syndrome, comprising the compound according to [1] or [2], or a salt thereof, or a solvate thereof as an active ingredient.
[9] A prophylactic and / or therapeutic agent for non-Hodgkin's lymphoma comprising the compound according to [1] or [2], or a salt thereof, or a solvate thereof as an active ingredient.
[10] The non-Hodgkin lymphoma is a precursor B cell lymphoblastic lymphoma, chronic B lymphocytic leukemia, precursor cell leukemia, small lymphocytic lymphoma, lymphoplasma cell lymphoma, immunocytoma, mantle cell lymphoma, The prophylactic and / or therapeutic agent according to [9] above, which is follicular lymphoma, marginal lymphoma, hairy cell leukemia, plasmacytoma, plasma cell myeloma, diffuse large cell lymphoma or Burkitt lymphoma.

[11] Prevention of autoimmune disease, acquired immune deficiency syndrome or non-Hodgkin's lymphoma by administering an effective amount of the compound represented by the general formula (1) or a salt thereof, or a solvate thereof to a patient And / or treatment methods.
[12] The compound represented by the general formula (1), or a salt thereof, or a solvation thereof for producing a preventive and / or therapeutic agent for autoimmune disease, acquired immunodeficiency syndrome or non-Hodgkin lymphoma Use of things.
[13] The compound represented by the general formula (1), a salt thereof, or a solvate thereof for use in the prevention and / or treatment of autoimmune disease, acquired immune deficiency syndrome or non-Hodgkin lymphoma .

  The compound represented by the general formula (1) of the present invention, a salt thereof, or a solvate thereof has an activity of inhibiting the binding of BAFF to the BR3 receptor, and inhibits the binding of BAFF to the BR3 receptor. It is useful as a prophylactic and / or therapeutic agent for diseases related to the disease, such as autoimmune diseases, acquired immune deficiency syndrome or cancer. Further, the compound represented by the general formula (1) of the present invention, or a salt thereof, or a solvate thereof is a low molecular weight compound and can be administered orally unlike a soluble protein of the BAFF receptor. The present invention provides a novel preventive and / or therapeutic agent for diseases associated with inhibition of binding of BAFF to a BR3 receptor that can be administered orally.

FIG. 1 shows the results of testing the inhibitory action of BAFF on the induction of IL-6 production by the compounds of the present invention.

Hereinafter, the present invention will be described in detail.
The definitions of terms in the present invention are as follows.

  As used herein, non-Hodgkin lymphoma is a malignant lymphoma other than Hodgkin lymphoma, such as a Revised European American Lymphoma (REAL) classification. (For example, Harris et al., Blood, 84 (5), 1361-1392 (1994), Mizoguchi et al., History of Medicine, Hematology Ver.2, Biomedical Publishing, 303-307 (1998)) reference). Examples of the non-Hodgkin lymphoma of the present invention include B cell lymphoma (precursor B-lymphoblastic leukemia), chronic B lymphocytic leukemia, progenitor leukemia. (B-cell prolymphocytic leukemia), B-cell small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, immunocytoma, Mantle cell lymphoma, follicular Lymphoma (follicle center lymphoma), marginal zone B-cell lymphoma, hairy cell leukemia, plasmacytoma, plasma cell myeloma, diffuse large cell Lymphoma (Diffuse Large B-cell lymphoma), Burkitt's lymphoma, etc.), T-cell lymphoma, or NK-cell lymphoma (T-cell chronic lymphocytic leukerni) a), T-cell prolymphocytic leukemia, T-cell Large granular lymphocyte leukemia, NK-cell Large granular lymphocyte leukemia, bacteria Mycosis fungoides, Sezary syndrome, Peripheral T-cell lymphomas, Angioimmunoblastic T-cell lymphoma, Angiocentric lymphoma ), Intestinal T-cell lymphoma, adult T-cell lymphoma, anaplastic large cell lymphoma, and the like.

As used herein, “C _1-6 alkyl group” means a straight or branched hydrocarbon group having 1 to 6 carbon atoms, preferably a saturated chain hydrocarbon group. The “C _1-6 alkyl group” is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, Examples include n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, isohexyl group and the like. In the present specification, the definition of “C _1-6 alkyl” is also used in “(C _1-6 alkyl) amino group” and “(C _6-10 aryl) C _1-6 alkyl group”. These are also synonymous with the above-mentioned “C _1-6 alkyl”.

As used herein, “(C _1-6 alkyl) amino group” includes an amino group mono- or di-substituted with the above-mentioned C _1-6 alkyl group. For example, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, n-pentylamino group, isopentyl Examples thereof include linear or branched alkylamino groups having 1 to 6 carbon atoms such as an amino group, neopentylamino group, n-hexylamino group, and isohexylamino group.

As used herein, “C _3-6 cycloalkyl” refers to a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms. Examples of “C _3-6 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

In the present specification, examples of the “(C _3-6 cycloalkyl) amino group” include amino groups substituted with the above-mentioned “C _3-6 cycloalkyl”. Examples of the “(C _3-6 cycloalkyl) amino group” include (cycloalkyl) amino groups having 3 to 6 carbon atoms such as cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group and the like. It is done.

As used herein, “C _6-10 aryl group” refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples of the “C _6-10 aryl group” include a phenyl group, a naphthyl group, an azulenyl group, and the like. In this specification, “C _6-10 aryl group _optionally substituted with a halogen atom” and “(C _6-10 aryl) C _1-6 alkyl group” are also defined as “C _6-10 aryl”. Are used, and “C _6-10 aryl” in these definitions is also as defined above. Moreover, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

As used herein, “(C _6-10 aryl) C _1-6 alkyl group” refers to C _1-6 alkyl substituted with one or more of the above-mentioned “C _6-10 aryl groups”. Groups. Examples of the “(C _6-10 aryl) C _1-6 alkyl group” include a benzyl group, a phenethyl group, a phenylpropyl group, a phenylbutyl group, a phenylpentyl group, a phenylhexyl group, a naphthylmethyl group, and a naphthylethyl group. Naphthylpropyl group, naphthylbutyl group, azulenylmethyl group, azulenylethyl group, azulenylpropyl group, azulenylbutyl group and the like.

Examples of the “C _6-10 aryl group _optionally substituted with a halogen atom” include a C _6-10 aryl group substituted with one or more halogen atoms. Examples of the C _6-10 aryl group substituted with one or more halogen atoms include a halogen-substituted phenyl group, a halogen-substituted naphthyl group, a halogen-substituted azulenyl group, and the like. More preferably, the 4-position is a halogen atom. Examples thereof include a substituted phenyl group.

In the general formula (1), the “C _1-6 alkyl group” in R ¹ and R ² is preferably a C _1-4 alkyl group, and more preferably a methyl group.

In General Formula (1), the “C _3-6 cycloalkyl group” in R ³ is preferably a C _5-6 cycloalkyl group, and more preferably a cyclopentyl group.

In general formula (1), the “C _6-10 aryl group which may be substituted with a halogen atom” in R ³ is preferably a phenyl group or a 4-fluorophenyl group.

In the general formula (1), the “(C _6-10 aryl) C _1-6 alkyl group” in R ³ is preferably a phenyl-substituted C _1-6 alkyl group, and more preferably a benzyl group.

In the general formula (1), the “(C _1-6 alkyl) amino group” in R ⁴ is preferably a (C _1-4 alkyl) amino group, and an isopropylamino group, an isobutylamino group, or a sec-butylamino group is More preferred.

In General Formula (1), the “(C _3-6 cycloalkyl) amino group” in R ⁴ is preferably a (C _3-4 cycloalkyl) amino group, and more preferably a cyclopropylamino group.

Specific examples of the pyrrolopyrimidine derivative represented by the general formula (1) of the present invention include the following compounds.
7-Benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine (Example 1);
1- (2- [4-{(7-Benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one Example 2);
7-Benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine (Example 3);
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine (Example 4);
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine (Example 5);
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine (Example 6);
7-Benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine (Example 7);
7-Benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine (Example 8);
7-Benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) azepan-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine (Example 9);
1- (2- [2-{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2-one (Example 10);

1- {2- (4-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one (Example 11);
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one (Example 12);
1- {2- (3-[{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one (Example 13);
1- (2- [3-{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2-one (Example 14);
1- {2- (2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one (Example 15);
1- (2- [4-{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} azepan-1-yl] -2-oxoethyl) pyrrolidine -2-one (Example 16);
4- {2- (azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine (Example 17);
7-benzyl-5,6-dimethyl-4- {2- (piperidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine (Example 18);
7-Benzyl-5,6-dimethyl-4- {2- (piperazin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine (Example 19);
4- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} ethyl] morpholine (Example 20);

7-Benzyl-5,6-dimethyl-4- {2- (pyrrolidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine (Example 21);
7-Benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine (Example 22);
2- [4-{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-cyclopropylacetamide (Examples) 23);
N-cyclopropyl-2- (4-[{7- (4-fluorophenyl) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy] piperidin-1-yl Acetamide (Example 24);
2- [4-{(7-Cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isopropylacetamide (Example 25) );
N- (sec-butyl) -2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] acetamide (Example 26);
1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine -2-one (Example 27); and
2- [4-{(7-Cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isobutylacetamide (Example 28) ).

  Examples of the pyrrolopyrimidine derivative represented by the general formula (1) of the present invention, or a salt thereof, or a solvate thereof include not only the pyrrolopyrimidine derivative of the present invention, but also a pharmaceutically acceptable salt thereof, Hydrates and solvates, and substances having crystalline polymorphs, and substances that become prodrugs of these substances. Moreover, when it has an asymmetric carbon atom, not only a racemate but an optically active substance is included.

  As a salt acceptable as a pyrrolopyrimidine derivative represented by the general formula (1) of the present invention, specifically, when the compound is treated as a basic compound, an inorganic acid (for example, hydrochloric acid, hydrobromic acid, Acid addition salts with hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (for example, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.). On the other hand, when treating a compound as an acidic compound, inorganic salts (for example, sodium salt, potassium salt, lithium salt, barium salt, calcium salt, magnesium salt, etc.) and the like can be mentioned.

  Examples of solvates of the pyrrolopyrimidine derivative represented by the general formula (1) of the present invention and pharmaceutically acceptable salts thereof include hydrates and various solvates (for example, solvates with alcohols such as ethanol). Product).

  The pyrrolopyrimidine derivative represented by the general formula (1) of the present invention is produced with reference to known methods described in JP-A-8-53454, Heterocycles, 39 (1), 345-356 (1994), etc. can do. For example, although it can manufacture by the method shown to the following reaction process drawing, or the method according to this, it is not limited to these. Moreover, you may perform each reaction, protecting a functional group as needed. The protection and deprotection conditions can be carried out with reference to commonly used methods (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

(Method A) Compound 1a can be produced by the following method.
[Reaction Process Diagram 1]

[Wherein, R ¹ , R ² , R ⁴ , L, m, and o have the same meanings as defined above, R ³ represents a C _3-6 cycloalkyl group, (C _6-10 aryl) C _1-6 Represents an alkyl group, P ¹ represents an amino-protecting group (benzyl group, benzyloxycarbonyl group, tert-butoxycarbonyl group, etc.), X ¹ and X ² represent a leaving group such as a halogen atom, L ^1, - _{(CH 2) q} - indicates, q represents an integer of 0 to 2. ]

[Step 1] Compound (4) can be produced by reacting compound (2) with compound (3) in a solvent in the presence of a base. In this step, the amount of compound (3) is not particularly limited. For example, 1.0 to 1.5 equivalents can be used for the reaction with respect to compound (2). Although the quantity of a base is not specifically limited, For example, 1.0-1.5 equivalent can be used for reaction with respect to a compound (2). The solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; diethyl ether, diisopropyl ether, tetrahydrofuran And ethers such as dioxane and ethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane and 1,2-dichloromethane. The base is not particularly limited. For example, pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 -Organic bases such as diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine Inorganic bases such as lithium hydride, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate Can be used. Although the reaction temperature in this process changes with the raw materials and solvent to be used, it is -20-100 degreeC normally, and reaction time is 10 minutes-2 days normally.

[Step 2] Compound (6) can be produced by reacting compound (4) with compound (5) in a solvent in the presence of a base. In this step, the amount of compound (5) is not particularly limited. For example, 1.2 to 1.8 equivalents can be used for the reaction with respect to compound (4). Although the quantity of a base is not specifically limited, For example, 1.2-1.8 equivalent can be used for reaction with respect to compound (4). The solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; diethyl ether, diisopropyl ether, tetrahydrofuran And ethers such as dioxane and ethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane and 1,2-dichloromethane. The base is not particularly limited. For example, pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 -Organic bases such as diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine Inorganic bases such as lithium hydride, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate Can be used. The reaction temperature in this step varies depending on the raw materials and solvents used, but is usually 0 to 100 ° C., and the reaction time is usually 30 minutes to 24 hours.

[Step 3] Compound a protective group P ¹ (6) is deprotected, it is possible to produce the compound (7). The methods and conditions for the deprotection varies depending on the kind of protecting group P ^1. For example, benzyl group and benzyloxycarbonyl group can be deprotected by catalytic hydrogenation, and tert-butoxycarbonyl group can be deprotected by acid. , Inc.).

[Step 4] Compound (1a) can be produced by subjecting compound (7) and aldehyde compound (8) to a reductive amination reaction in a solvent in the presence of a reducing agent. In this step, the amount of compound (8) is not particularly limited. For example, 1.0 to 1.5 equivalents can be used for the reaction with respect to compound (7). Although the quantity of a reducing agent is not specifically limited, For example, 2.0-4.0 equivalent can be used for reaction with respect to a compound (7). The solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; diethyl ether, diisopropyl ether, tetrahydrofuran And ethers such as dioxane and ethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane and 1,2-dichloromethane. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. In addition, an organic acid such as acetic acid may be used for pH adjustment in order to promote the formation of imine and accelerate the reaction. Furthermore, organic bases such as pyridine, triethylamine, diisopropylethylamine, diisopropylpentylamine, and trimethylamine may coexist in the reaction. Although the reaction temperature in this process changes with the raw materials and solvent to be used, it is -20-100 degreeC normally, and reaction time is 10 minutes-2 days normally.

  Compound (1a) can be produced by reacting compound (7) with carboxylic acid compound (9) in a solvent using a condensing agent. In this step, for the purpose of accelerating the reaction, a base or a condensation accelerator may coexist in addition to the condensing agent. In this step, the amount of compound (9) is not particularly limited. For example, 1.0 to 1.5 equivalents can be used for the reaction with respect to compound (7). Although the quantity of a condensing agent is not specifically limited, For example, 1.0-1.5 equivalent can be used for reaction with respect to a compound (7). Although the quantity of a base is not specifically limited, For example, 2.0-2.5 equivalent can be used for reaction with respect to a compound (7). The solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; diethyl ether, diisopropyl ether, tetrahydrofuran And ethers such as dioxane and ethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; and acetates such as methyl acetate and ethyl acetate. The condensing agent is not particularly limited, but N, N′-dicyclohexylcarbodiimide (DCC), N, N′-diisopropylcarbodiimide (DIPCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSCI) ), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl) and the like. The base is not particularly limited. For example, pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 -Organic bases such as diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine Inorganic bases such as lithium hydride, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate Can be used. The condensation accelerator is not particularly limited, but 4-dimethylaminopyridine (DMAP), 1-hydroxy-7-azobenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-3,4- Dihydro-4-oxo-1,2,3-benzotriazole (HODhbt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), pentafluorophenol (HOPfp), N-hydroxyphthalimide (HOPht) ), N-hydroxysuccinimide (HOSu) and the like. The reaction temperature in this step varies depending on the raw materials and the solvent to be used, but is usually 0 to 100 ° C., and the reaction time is usually 30 minutes to 24 hours.

(Method B) The production intermediate (4) can also be produced by the method shown in FIG.
[Reaction Process Diagram 2]

[Wherein R ¹ , R ² and R ⁴ have the same meaning as defined above, and R ³ represents a C _3-6 cycloalkyl group, a C _6-10 aryl group _optionally substituted with a halogen atom, (C _6-10 aryl) represents a C _1-6 alkyl group, R ⁵ represents a C _1-6 alkyl group, and X ¹ represents a leaving group such as a halogen atom. ]

[Step 5] Compound (12) can be produced by reacting compound (10) with compound (11) in a solvent in the presence of a base. The solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; diethyl ether, diisopropyl ether, tetrahydrofuran Ethers such as dioxane and ethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; and alcohols such as methanol and ethanol. The base is not particularly limited. For example, pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 -Organic bases such as diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine Inorganic bases such as lithium hydride, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; Sodium methoxide, sodium ethoxide, potassium methoxide, potassium It can be used metal alcoholates such as Tokishido. The reaction temperature in this step varies depending on the raw materials and the solvent to be used, but is usually 0 to 120 ° C., and the reaction time is usually 30 minutes to 24 hours.

[Step 6] Compound (4) can be produced by reacting compound (12) with a halogenating reagent in a solvent in the presence of a base. Examples of the halogenating reagent include phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, thionyl chloride, oxalyl chloride, a combination of triphenylphosphine and carbon tetrachloride or carbon tetrabromide. The solvent is not particularly limited, but examples thereof include halogenated alkyl solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, acetic acid. Ester solvents such as ethyl, nitrile solvents such as acetonitrile and propionitrile, dimethylformamide and the like can be used alone or in combination. Moreover, when using phosphorus oxychloride etc. as a halogenating reagent, it can be used as a solvent and reagent. The reaction temperature in this step varies depending on the raw materials and the solvent to be used, but is usually 0 to 120 ° C., and the reaction time is usually 30 minutes to 24 hours.

(Method C) Compound 1b can be produced by the following method.
[Reaction Process Diagram 3]

[Step 7] Compound (1b) can be produced by reacting compound (4) with compound (13) in a solvent in the presence of a base. In this step, the amount of compound (13) is not particularly limited. For example, 1.0 to 1.7 equivalents can be used for the reaction with respect to compound (4). Although the quantity of a base is not specifically limited, For example, 2.0-2.5 equivalent can be used for reaction with respect to a compound (4). The solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; diethyl ether, diisopropyl ether, tetrahydrofuran And ethers such as dioxane and ethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane and 1,2-dichloromethane. The base is not particularly limited. For example, pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 -Organic bases such as diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octene (DABCO), triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine Inorganic bases such as lithium hydride, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate Can be used. The reaction temperature in this step varies depending on the raw materials and the solvent to be used, but is usually 0 to 100 ° C., and the reaction time is usually 30 minutes to 24 hours.

In addition, in accordance with this method, instead of compound (13), compound (1a) can also be produced by using a compound in which P ¹ part of compound (5) is -LR ^4. . For details of this method, refer to Examples described later.

  Intermediates and target products obtained in the above reactions are necessary for purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.

  Furthermore, various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between the isomers. For example, a racemic mixture is obtained by a general racemic resolution method such as a method of optically resolving a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. Can lead to optically pure isomers. Further, the diastereomeric mixture can be divided by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

The inhibitor for binding of BAFF to the BR3 receptor of the present invention, or the preventive and / or therapeutic agent for autoimmune diseases is a pyrrolopyrimidine derivative represented by the general formula (1), a salt thereof, or a solvate thereof. It is contained as an active ingredient and can be used as a pharmaceutical composition. In that case, the compound of the present invention may be used alone, but it is usually used in combination with a pharmaceutically acceptable carrier and / or diluent.
The pharmaceutical composition of the present invention is used for the prevention and / or treatment of diseases associated with inhibition of binding of BAFF to BR3 receptor, such as autoimmune diseases, acquired immune deficiency syndrome, and / or non-Hodgkin lymphoma. Can be used. The autoimmune disease in the present invention is not particularly limited as long as it is a disease related to inhibition of binding of BAFF to BR3 receptor. For example, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, Examples include multiple sclerosis and non-classifiable immunodeficiency.
The acquired immune deficiency syndrome is not particularly limited as long as it is a disease related to inhibition of binding of BAFF to the BR3 receptor, and examples thereof include HIV. Further, the non-Hodgkin lymphoma is not particularly limited as long as it is a disease related to inhibition of the binding of BAFF to the BR3 receptor, and the non-Hodgkin lymphoma described above is preferable. Lymphoma, chronic B lymphocytic leukemia, progenitor leukemia, small lymphocytic lymphoma, lymphoid plasma cell lymphoma, immunocytoma, mantle cell lymphoma, follicular lymphoma, marginal lymphoma, hairy cell leukemia, plasmacytoma, Plasma cell myeloma, diffuse large cell lymphoma, Burkitt lymphoma and the like are more preferred.

  The administration route is not particularly limited, but can be appropriately selected depending on the purpose of treatment. For example, any of oral preparations, injections, suppositories, inhalants and the like may be used. Pharmaceutical compositions suitable for these dosage forms can be produced by utilizing known preparation methods.

  When preparing an oral solid preparation, the compound represented by the general formula (1) is a pharmaceutically acceptable excipient, and further, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, and a corrigent. After adding a flavoring agent, tablets, coated tablets, granules, powders, capsules and the like can be produced using conventional methods. The additive may be one commonly used in the art. Examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol. Examples of the corrigent include sucrose, orange peel, citric acid, tartaric acid and the like.

  When an oral liquid preparation is prepared, a liquid medicine, syrup preparation is added to the compound represented by the general formula (1) by adding a corrigent, a buffer, a stabilizer, a corrigent and the like using a conventional method. An elixir or the like can be produced. As the corrigent, those mentioned above may be used. Examples of the buffer include sodium citrate. Examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing an injection, a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the compound represented by the general formula (1), and a conventional method is used. Subcutaneous, intramuscular and intravenous injections can be manufactured. Examples of the pH adjuster and buffer include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA (sodium edetate), thioglycolic acid, thiolactic acid, and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

  When preparing a suppository, a known suppository carrier such as polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride, etc., and a surfactant (for example, , Tween (registered trademark)) and the like can be added and then manufactured using a conventional method.

  In addition to the above, it is possible to appropriately prepare a preferable preparation using a conventional method.

  The dose of the pyrrolopyrimidine derivative represented by the general formula (1) of the present invention varies depending on age, body weight, symptom, dosage form, number of administrations, etc., but is usually a compound represented by the general formula (1) for adults. It is preferable that 0.1 mg to 1000 mg per day, preferably 1 mg to 1000 mg, more preferably 1 mg to 500 mg be orally or parenterally administered in one or several divided doses.

EXAMPLES The present invention will be described more specifically with reference to examples and test examples below, but the present invention is not limited to these examples. In addition, the symbol used in the following Example shows the following meaning.
s: singlet
d: Doublet
t: triplet
m: multiplet
J: coupling constant
Hz: Hertz
CDCl ₃ : deuterated chloroform
¹ H-NMR: proton nuclear magnetic resonance IR: infrared absorption spectrum THF: tetrahydrofuran DMSO: dimethyl sulfoxide WSC · HCl: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride HOBt · H ₂ O: 1-hydroxy Benzotriazole monohydrate

In addition, the term “Rt” used in the present specification means the LC-MS retention time (unit: minute) associated with the compound. Unless otherwise stated, the LC-MS method used to obtain the reported retention time is as follows:
Equipment used: Surveyor MSQ (Thermo Finnigan, USA)
Column: Waters Xterra MS C18 culumn (30x2.1mm, 3.5μm)
Gradient: 100% [water + 0.1% formic acid] to 5% [water + 0.1% formic acid] and 95% acetonitrile (2.5 minutes) to 100% [water + 0.1% formic acid] (1.5 minutes) Total 4.0 minutes Flow rate: 1.5 mL / min Detection: Photodiode array detector 190-800 nm
Ionization method: Atmospheric pressure chemical ionization detection method: Evaporative light scattering detection MS detection range: 45-1000D
Injection volume: 2 μL

[Example 1]
Preparation of 7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine a) 7-Benzyl- 4-Chloro-7H-pyrrolo [2,3-d] pyrimidine was prepared.

  100 mg (0.65 mmol) of commercially available 4-chloro-7H-pyrrolo [2,3-d] pyrimidine is dissolved in 2 mL of anhydrous THF, and 31 mg (0.72 mmol) of sodium hydride (NaH) (55% mineral oil mixture) under an argon atmosphere. And stirred at room temperature for 30 minutes. After confirming that foaming of the reaction solution had subsided, 122 mg (0.72 mmol) of benzyl bromide (BnBr) was added. The mixture was stirred at room temperature overnight. The reaction solution was poured into 20 mL of water and extracted with chloroform (5 mL × 4). The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained oil was purified with SNAP10 (Biotage) (hexane-ethyl acetate), and 135 mg (yield 85%) of 7-benzyl-4-chloro-7H-pyrrolo [2,3-d] pyrimidine was obtained as colorless crystals. Obtained as a powder.

¹ H-NMR (CDCl ₃ ) δ: 5.46 (2H, s), 6.62 (1H, d, J = 3.6 Hz), 7.18-7.25 (3H, m), 7.28-7.38 (3H, m), 8.67 (1H , s).

b) Tert-butyl 4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidine-1-carboxylate was prepared by the following reaction.

  Dissolve 62 mg (0.31 mmol) of tert-butyl-4-hydroxy-1-piperidinecarboxylate in 1 mL of anhydrous THF and add 13 mg (0.31 mmol) of sodium hydride (NaH) (55% mineral oil mixture) under an argon atmosphere at room temperature. For 20 minutes. After confirming that foaming of the reaction solution had subsided, 50 mg (0.21 mmol) of 7-benzyl-4-chloro-7H-pyrrolo [2,3-d] pyrimidine obtained in a) above was added in 1 mL of anhydrous THF. The solution was added. The solution was directly stirred at room temperature for 1 hour, and further stirred in an oil bath at 80 ° C. for 2 hours. After cooling, the reaction solution was poured into 15 mL of water and extracted with ethyl acetate (10 mL × 3). The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained oil was purified with SNAP10 (hexane-ethyl acetate) manufactured by Biotage, and tert-butyl-4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy. } Obtained 97 mg of piperidine-1-carboxylate as a red oil.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.75-1.91 (2H, m), 1.98-2.12 (2H, m), 3.27-3.40 (2H, m), 5.43 (2H, s) , 5.50-5.53 (1H, m), 6.54 (1H, d, J = 3.6 Hz), 7.01 (1H, d, J = 3.3 Hz), 7.16-7.23 (2H, m), 7.27-7.33 (3H, m ), 8.46 (1H, s).

c) 7-Benzyl-4- (piperidin-4-yloxy) -7H-pyrrolo [2,3-d] pyrimidine hydrochloride was prepared by the following reaction.

  Dissolve 97 mg of tert-butyl-4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidine-1-carboxylate obtained in b) above in 1 mL of ethyl acetate. 1 mL of 4N hydrochloric acid-ethyl acetate solution was added. When the obtained solution was stirred at room temperature, a white solid was precipitated in 30 minutes. The solution was further stirred overnight at room temperature. The obtained solid was collected by filtration, washed with ethyl acetate, dried under reduced pressure, and then 7 mg of 2-benzyl-4- (piperidin-4-yloxy) -7H-pyrrolo [2,3-d] pyrimidine hydrochloride (2 Step total yield: 99%) was obtained as a white solid.

¹ H-NMR (DMSO-D ₆ ) δ: 1.86-2.04 (2H, m), 2.12-2.27 (2H, m), 3.05-3.36 (4H, m), 5.44 (2H, s), 5.47-5.57 ( 1H, m), 6.59 (1H, d, J = 3.3 Hz), 7.19-7.33 (5H, m), 7.56 (1H, d, J = 3.6 Hz), 8.42 (1H, s).

d) The desired 7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine was prepared by the following reaction.

  7-Benzyl-4- (piperidin-4-yloxy) -7H-pyrrolo [2,3-d] pyrimidine hydrochloride 17 mg (0.05 mmol) and nicotinaldehyde 7 mg (0.065 mmol) obtained in c) above were used. To 0.5 mL of dichloromethane, 20 mg (0.2 mmol) of triethylamine and a catalytic amount of acetic acid were added, and the mixture was stirred at room temperature for 30 minutes. To the obtained solution, 32 mg (0.15 mmol) of sodium triacetoxyborohydride was added, and the mixture was further stirred at room temperature for 2 hours. The obtained solution was poured into 20 mL of water and extracted with chloroform (10 mL × 3). The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil was purified with SNAP10 (chloroform-methanol) manufactured by Biotage, and 7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [ 20 mg (yield: 100%) of 2,3-d] pyrimidine was obtained as a colorless transparent oil. The obtained oily substance was dissolved in ethyl acetate, 4N hydrochloric acid-ethyl acetate solution was added to cause white precipitation, filtered and washed with ethyl acetate, 7-benzyl-4-[{1- (pyridine-3- 20 mg of (Ilmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine hydrochloride was obtained as a white solid.

¹ H-NMR (DMSO-D ₆ , vt. 80) δ: 2.10-2.26 (2H, m), 2.27-2.41 (2H, m), 3.10-3.52 (4H, m), 4.43 (2H, s), 5.43 (2H, s), 5.48-5.59 (1H, m), 6.56 (1H, s), 7.19-7.35 (5H, m), 7.45 (1H, d, J = 3.6 Hz), 7.62 (1H, dd, J = 8.1, 5.1 Hz), 8.31 (1H, d, J = 8.2 Hz), 8.39 (1H, s), 8.71 (1H, d, J = 4.6 Hz), 8.91 (1H, s).

[Example 2]
1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine- 2-one was produced.

7.9 mg (0.055 mmol) of 2- (2-oxopyrrolidin-1-yl) acetic acid was dissolved in 0.5 mL of dichloromethane, and 11.5 mg (0.06 mmol) of WSC · HCl, 11.5 mg of HOBt · H ₂ O ( 0.075 mmol) was added. To this was added 17.2 mg (0.05 mmol) of 7-benzyl-4- (piperidin-4-yloxy) -7H-pyrrolo [2,3-d] pyrimidine hydrochloride and 12.6 mg (0.13 mmol) of triethylamine. And stirred at room temperature for 90 minutes. The reaction solution was poured into 20 mL of water and extracted with chloroform (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil was purified with SNAP10 (chloroform-methanol) manufactured by Biotage, and 1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) was obtained. 17 mg (78% yield) of oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one were obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.82-2.00 (2H, m), 2.01-2.16 (4H, m), 2.45 (2H, t, J = 8.1 Hz), 3.40-3.65 (4H, m), 3.69 -3.82 (1H, m), 3.87-4.00 (1H, m), 4.15 (2H, d, J = 1.3 Hz), 5.43 (2H, s), 5.54-5.63 (1H, m), 6.54 (1H, d , J = 3.6 Hz), 7.02 (1H, d, J = 3.6 Hz), 7.20 (2H, dd, J = 7.4, 1.8 Hz), 7.27-7.35 (3H, m), 8.46 (1H, s).

[Example 3]
Preparation of 7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine

a) 280 mg (1.0 mmol) of 7-benzyl-4-chloro-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine produced by the method described in JP-A-8-53454 and tert 302 mg (1.5 mmol) of butyl-2- (hydroxymethyl) pyrrolidine-1-carboxylate was dissolved in 5 mL of tetrahydrofuran. Then, 80 mg (2.0 mmol) of 60% sodium hydride was added to the solution, and reacted at 60 ° C. for 1 hour. After cooling, 50 mL of water was added to the reaction solution, and extracted with dichloromethane (5 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) and tert-butyl-2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] Pyrimidin-4-yl) oxy} methyl] pyrrolidine-1-carboxylate 140 mg (32%) was obtained as a white solid.

b) tert-butyl-2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidine- obtained in a) above 109 mg (0.25 mmol) of 1-carboxylate was dissolved in 3 mL of dioxane, 6 mL of 16% hydrochloric acid / dioxane was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, the residue was washed with hexane, and 7-benzyl-5,6-dimethyl-4- (pyrrolidin-2-ylmethoxy) -7H-pyrrolo [2,3-d] pyrimidine hydrochloride 106 mg (95 %) As a white solid.

c) 45 mg (0.12 mmol) of 7-benzyl-5,6-dimethyl-4- (pyrrolidin-2-ylmethoxy) -7H-pyrrolo [2,3-d] pyrimidine hydrochloride obtained in b) above was added to dichloromethane. Dissolve in 5 mL, add 20 mg (0.18 mmol) of pyridine-3-carbaldehyde, 0.042 mL (0.24 mmol) of N, N-diisopropylethylamine, and 50 mg (0.24 mmol) of sodium triacetoxyborohydride at room temperature. Stir for 11 hours. To the reaction solution was added 25 mL of 10% aqueous potassium carbonate solution, and the mixture was extracted with 20 mL of dichloromethane. The organic layer was washed with 25 mL of water and concentrated under reduced pressure. The residue was purified by HPLC (reverse phase, Betasil C18, 250 × 21.2) to give 34.9 mg (50%) of the title compound as a colorless oil.
Rt = 1.58 min MS found [M + H] ⁺ = 428

[Example 4-9]
The compounds shown in Table 1 below were obtained in the same manner as in Example 3. Table 1 shows the chemical structural formula, name, and physical properties of the compound of Example 4-9.

[Example 10]
1- (2- [2-{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2-one production

  7-benzyl-5,6-dimethyl-4- (pyrrolidin-2-ylmethoxy) -7H-pyrrolo [2,3-d] pyrimidine hydrochloride 45 mg (0.12 mmol) obtained in b) of Example 3 above Was dissolved in 5 mL of acetonitrile, 26 mg (0.18 mmol) of (2-oxo-pyrrolidin-1-yl) acetic acid, 31 mg (0.24 mmol) of diisopropylethylamine, 2- (1H-benzotriazol-1-yl) -1, 60 mg (0.18 mmol) of 1,3,3-tetramethyluronium tetrafluoroborate was added and stirred overnight at room temperature. To the reaction solution was added 25 mL of 10% aqueous potassium carbonate solution, and the mixture was extracted with dichloromethane (15 mL × 2). The obtained organic layer was washed with 25 mL of water and concentrated under reduced pressure. The residue was purified by HPLC (reverse phase, Betasil C18, 250 × 21.2) to give 22.7 mg (37%) of the title compound as a colorless oil.

Rt = 2.10min
MS found [M + H] ⁺ = 462

[Examples 11-16]
The compounds shown in Table 2 below were obtained in the same manner as in Example 10. Table 2 shows the chemical structural formulas, names, and physical property values of the compounds of Examples 11-16.

[Example 17]
Preparation of 4- {2- (azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine

  280 mg (1.0 mmol) of 2-benzyl-4-chloro-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine produced by the method described in JP-A-8-53454 and 2- ( Azepan-1-yl) ethanol (215 mg, 1.5 mmol) was dissolved in tetrahydrofuran (5 mL), 60% sodium hydride (80 mg, 2.0 mmol) was added, and the mixture was reacted at 60 ° C. for 1 hour. After cooling, 50 mL of water was added to the reaction solution, and extracted with dichloromethane (5 mL × 2). The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1), and 4- (2- (azepan-1-yl) ethoxy) -7-benzyl-5,6-dimethyl-7H-pyrrolo [ 38 mg (19%) of 2,3-d] pyrimidine was obtained as a colorless oil.

Rt = 1.64min
MS found [M + H] ⁺ = 379

[Example 18-21]
The compounds shown in Table 3 below were obtained in the same manner as in Example 17. Table 3 shows the chemical structural formulas, names, and physical property values of the compounds of Example 18-21.

[Examples 22 to 28]
The compounds shown in Table 4, Table 5 and Table 6 below were obtained in the same manner as in Example 17. The compound in which R ³ is a 4-fluorophenyl group (Example 24) is 4-chloro-7- (4-fluorophenyl) -5,6 supplied as a chemical library compound from Aurora Fine Chemicals. Prepared from dimethyl-7H-pyrrolo [2,3-d] pyrimidine. In addition, a compound in which R ³ is a cyclopentyl group (Examples 25 to 28) is a compound represented by 7-cyclopentyl-5,6-dimethyl-3H-pyrrolo described in Liebigs Ann., (9), 1485-505 (1986). Prepared from 2,3-d] pyrimidin-4 (7H) -one. Table 4-6 shows the chemical structural formulas, names, and physical property values of the compounds of Examples 22-28.

[Test Example 1] Binding inhibition test of BAFF and BR3 receptor 1) Establishment of BR3-expressing cells Raji cell-derived RNA, which is a human B cell culture strain, with reference to the sequence described in GenBank Accession No. AF373846 The full length was obtained from the obtained product by RT-PCR and subcloned into a cloning vector pBlueScript II vector (Stratagen). Subsequently, the same gene was inserted into a pEAK10 vector (EdgeBio), which is a vector for mammalian cell expression, and E. coli strain DH5α (TOYOBO) was transformed to obtain a clone. CHO-K1 cells, an epithelial cell line, were transfected. CHO-K1 cells were subcultured using Nutrient Mixture Ham's F-12 medium (Sigma) containing 10% fetal bovine serum, penicillin, and streptomycin. After obtaining a puromycin drug-resistant cell clone, expression of BR3 protein was confirmed by flow cytometry using a mouse anti-human BR3 antibody (Abcam) and a FITC-labeled anti-mouse IgG antibody (Prozyme).

2) Binding test The ligand-receptor binding test was performed as follows. For fluorescently labeled BAFF, recombinant human BAFF (PeproTech) labeled with FMAT Blue labeling kit (Applied Biosystems) was used. BR3-expressing CHO-K1 cells were seeded at 1.0 × 10 ⁴ in a 96 well black clear microtiter plate and cultured overnight in a CO ₂ incubator. After removing the medium, 20 mM Hepes buffer (pH 7.4), Hank's Balanced Salt Solution (Sigma) (containing 0.1% BSA, 0.1% NaN ₃ , 0.08% CHAPS) was used as a reaction solution. After adding the test compound and labeled BAFF in this order, the affinity between the fluorescently labeled BAFF and the BR3 receptor of the expressed cells after standing for 6 hours at 25 ° C. in the dark using a fluorescence detector FMAT8200CDS (Applied Biosystems) Detected. The 50% inhibition concentration (IC ₅₀ value) of each test compound was measured with the maximum reaction of only the fluorescently labeled BAFF as 100%. EC ₅₀ values were calculated using a statistical analysis program, SAS preclinical package Ver 5.0 (SAS institute Japan Co., Tokyo).

3) Results The results of the above binding test are shown in Table 7 below.

  In particular, Compound 17 and Compound 27 were found to have excellent BAFF binding inhibitory activity against the BR3 receptor. Moreover, also about the compound which was not described in Table 7, many compounds had inhibitory activity of 40% or more at 25 micromol. From the above, it was confirmed that the compound of the present invention has a strong binding inhibitory action of BAFF and BR3 receptor, and it can be used for treatment and / or prevention of various diseases related to inhibition of binding of BAFF to BR3 receptor. It was confirmed to be effective.

[Test Example 2] Inhibitory effect on the induction of IL-6 (interleukin 6) production by BAFF Human monocytic leukemia cell line THP-1 cells (Bioresource Bank; obtained from Japanese Collection of Research Bioresource) were obtained from 10% fetal bovine serum ( Cells were seeded at 2.5 × 10 ⁵ cells / mL in a 24-well plate (Corning) in a PRMI-1640 medium (ATCC) containing JRH Biosciences). IFNγ (interferon γ; manufactured by BD Pharmingen) was added to a final concentration of 200 ng / mL and cultured at 37 ° C. in a 5% CO ₂ environment. After 4 days of culture, each culture solution was removed, the cells were washed twice with the medium, and the medium containing recombinant human soluble BAFF (manufactured by Chemicon) with a final concentration of 2 μg / mL was added. The compound of Example 27 (compound 27) was added to a final concentration of 5, 10 μg / mL, and the culture was continued under the same conditions. After culturing for 4 days, the culture supernatant was recovered, and the amount of IL-6 in the supernatant was quantified by ELISA. For the ELISA method, mouse anti-human IL-6 antibody (BD Pharmingen), biotin-labeled anti-human IL-6 antibody (BD Pharmingen) and HRP-labeled streptavidin (BD Pharmingen) were used.

FIG. 1 shows IL-6 production-enhancing effect and BAFF stimulation by BAFF stimulation (when “BAFF” in FIG. 1 is +) of IFNγ-treated THP-1 cells (“IFNγ priming” in FIG. 1 is +). 1 shows the effect of the compound of Example 27 (Compound 27) (in FIG. 1, the case where Compound 27 is not added is indicated by-, and the case where it is added is indicated by a numerical value) on the production of IL-6. As shown in FIG. 1, IL-6 production in THP-1 cells was enhanced by adding BAFF after IFNγ treatment, and IL-6 production by BAFF stimulation was suppressed in a dose-dependent manner by the addition of Example 27 compound. It was done. From the above, it was confirmed that the compound of the present invention has a strong BAFF inhibitory action, and it was confirmed that it is effective for the treatment and / or prevention of the above-mentioned various diseases.
(In the figure, + indicates that the object is added to the medium, and − indicates that the object is not added to the medium. In the case of 5 μM, there is a significant difference at P <0.05. 10 μM In case of P <0.01, there is a significant difference.)

  The present invention for the first time finds that the pyrrolopyrimidine derivative represented by the general formula (1) or a salt thereof, or a solvate thereof has an excellent BAFF and BR3 receptor binding inhibitory activity. The present invention provides a preventive and / or therapeutic agent for low molecular weight autoimmune diseases, acquired immune deficiency syndrome or non-Hodgkin lymphoma that can be administered. The present invention provides a preventive and / or therapeutic agent for a new autoimmune disease, acquired immune deficiency syndrome or non-Hodgkin lymphoma that can be administered orally with a low molecular weight, and is useful in the pharmaceutical industry. Has availability.

Claims (7)

The following general formula (1):
[Wherein ring A is represented by the following formula:
A group selected from: wherein B represents —CH ₂ —, —O— or —NH—, R ⁴ represents a (C _1-6 alkyl) amino group, (C _3-6 cycloalkyl); An amino group, a pyridinyl group, or a 2-oxopyrrolidinyl group, L represents a formula — (CH ₂ ) _p —, —CH ₂ C (O) —, or —C (O) CH ₂ —; n represents an integer of 0 to 2, o represents a natural number of 1 to 3, and p represents an integer of 0 to 3).
R ¹ and R ² may be the same or different from each other and each represents a hydrogen atom or a C _1-6 alkyl group,
R ³ represents a C _3-6 cycloalkyl group, a C _6-10 aryl group _optionally substituted with a halogen atom, a (C _6-10 aryl) C _1-6 alkyl group,
m shows the integer of 0-2. ]
Or a salt thereof, or a solvate thereof. The compound represented by the general formula (1) is
7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) azepan-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [2-{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2-one,
1- {2- (4-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- (2- [3-{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2-one,
1- {2- (2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- (2- [4-{(7-Benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} azepan-1-yl] -2-oxoethyl) pyrrolidine -2-one,
4- {2- (azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperazin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
4- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} ethyl] morpholine,
7-benzyl-5,6-dimethyl-4- {2- (pyrrolidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-cyclopropylacetamide,
N-cyclopropyl-2- (4-[{7- (4-fluorophenyl) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy] piperidin-1-yl Acetamide,
2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isopropylacetamide,
N- (sec-butyl) -2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] acetamide ,
1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine -2-one and
From the group consisting of 2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isobutylacetamide The compound according to claim 1, which is at least one selected compound, or a salt thereof, or a solvate thereof.   A pharmaceutical composition comprising the compound according to claim 1 or 2, or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.   A binding inhibitor of BAFF for BR3 receptor comprising the compound according to claim 1 or 2 or a salt thereof, or a solvate thereof as an active ingredient.   Prevention and / or prevention of autoimmune disease, acquired immune deficiency syndrome, and / or non-Hodgkin's lymphoma comprising the compound according to claim 1 or 2 or a salt thereof, or a solvate thereof as an active ingredient Therapeutic agent.   The prophylactic and / or therapeutic agent according to claim 5, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, multiple sclerosis, or unclassifiable immunodeficiency.   Non-Hodgkin lymphoma is a precursor B cell lymphoblastic lymphoma, chronic B lymphocytic leukemia, progenitor leukemia, small lymphocytic lymphoma, lymphoplasma cell lymphoma, immunocytoma, mantle cell lymphoma, follicular lymphoma, The prophylactic and / or therapeutic agent according to claim 5, which is marginal lymphoma, hairy cell leukemia, plasmacytoma, plasma cell myeloma, diffuse large cell lymphoma or Burkitt lymphoma.