Title of Invention	IMMUNOSUPPRESSIVE AGENT AND ANTI-TUMOR AGENT COMPRISING HETEROCYCLIC COMPOUND AS ACTIVE INGREDIENT
Abstract	A novel immunosuppressive agent, more specifically an immunosuppressive agent comprising, as an active ingredient, a heterocyclic compound represented by the general formula (I) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof; a novel heterocyclic compound represented by the general formula (II) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof; and use of the compound or salt as an antitumor agent.

Title of Invention

IMMUNOSUPPRESSIVE AGENT AND ANTI-TUMOR AGENT COMPRISING HETEROCYCLIC COMPOUND AS ACTIVE INGREDIENT

Abstract

A novel immunosuppressive agent, more specifically an immunosuppressive agent comprising, as an active ingredient, a heterocyclic compound represented by the general formula (I) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof; a novel heterocyclic compound represented by the general formula (II) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof; and use of the compound or salt as an antitumor agent.

Full Text	SPECIFICATION IMMUNOSUPPRESSIVE AGENT AND ANTI-TUMOR AGENT COMPRISING HETEROCYCLIC COMPOUND AS ACTIVE INGREDIENT TECHNICAL FIELD [0001] The present invention relates to novel immunosuppressive agents, and more specifically immunosuppressive agents comprising heterocyclic compounds of a specific structure as effective ingredients. The present invention also relates to novel chemical compounds among the above heterocyclic compounds, and further to the use of such novel compounds as antitumor agents. BACKGROUND ART [0002] In general, as disorders for which immunosuppressive agents may be used, mention may be made of a number of autoimmune diseases such as rejection after transplantation of organs or tissues, graft versus host disease after bone-marrow transplantation, inflammatory bowel diseases such as ulcerative colitis or Crohn disease, inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis, inflammatory or allergenic respiratory disorders such as chronic obstructive pulmonary disease or asthma, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren syndrome, or the like. In addition, immunosuppressive agents such as cyclophosphamide or methotrexate are employed also in the treatment of hematologic neoplasms such as multiple myeloma, malignant lymphoma, leukemia or the like. Furthermore, immunosuppressive agents may also be employed in combination with antibiotics in the case of the treatment of disorders characterized by an enhanced immune function associated with infection such as sepsis (Non-Patent Document 1). Thus, a number of immunosuppressive agents are presently utilized as therapeutic agents for the above-mentioned disorders in clinical practice. However, as it now stands, there still remain many problems to be improved due to a failure to obtain a sufficient therapeutic effect and an unexpected occurrence of side effects. [0003] A variety of cells such as T, B lymphocytes and factors are known to be involved in the inducement of the immune response. Since cyclosporin and tacrolimus, which are presently used for organ transplantation or the like, are restricted in their efficacy to T cells, there is a need for immunosuppressive agents which serve as agents for acting on 1 more extensive immune mechanisms, with less side effects in clinical applications, and acting simultaneously on a variety of cells involved in the disorders. Here, "a variety of cells involved in the disorders" are not limited to immune cells, i.e., T cells, B cells, monocytes, macrophages, NK cells, NKT cells, dendritic cells, neutrophils, basophils, eosinophils, mast cells or the like. They should include cells in which functions are affected by humoral factors released from immune cells or membrane receptors on the immune cells. Examples of these cells include, but are not limited to platelets, vascular endothelial cells, synoviocytes, osteoclasts, osteoblasts, chondrocytes, tracheal epithelial cells, or the like. In addition, in the case where the humoral factors are autoantibodies, cells expressing target antigens are also included. [0004] Regarding benzimidazole ring-substituted s-triazine [1,3,5-triazine] derivatives and pyrimidine derivatives, the present inventors have studied their cytostatic activity on solid tumors, and have performed synthesis of a great number of such compounds as well as verification of the relationship between antitumor activity and chemical structure (see Patent Documents 1, 2, 3, 4 and 5). [0005] In particular, s-triazine derivatives and pyrimidine derivatives having a specific substituent at position 2 of the benzimidazole ring were found to exhibit an enhanced cytostatic activity on solid tumors (see Patent Documents 3, 4 and 5). The processes for the production of such derivatives are described in these patent documents, but are not limited to these, and various reactions such as alkylation, alkylcarbonylation or the like may be induced in the final products to employ the resultant as final compounds. Non-Patent Document 1: T. Munster et.al. Clin. Exp. Rheumatol., 17 (Suppl. 18): S29-S36 (1999); Patent Document 1: WO 99/05138 pamphlet Patent Document 2: WO 00/43385 pamphlet Patent Document 3: WO 02/088112 pamphlet Patent Document 4: WO 2004/037812 pamphlet Patent Document 5: WO 2005/095389 pamphlet PROBLEMS TO BE SOLVED BY THE INVENTION [0006] The present inventors demonstrated that the above compounds specifically inhibited phosphatidylinositol 3-kinase (PI3K) activity (Non-Patent Document 2). PI3K is an enzyme that phosphorylates phosphatidylinositol (PI) on the cell membrane, classified into three subfamilies according to structures and its substrate specificity. Among these, 2 the compounds of the present invention specifically inhibit class I PI3K. Class I PI3K phosphorylates PI, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5- biphosphate to produce phosphatidylinositol 3-phosphate, phosphatidylinositol 3,4- biphosphate, and phosphatidylinositol 3,4,5-triphosphate, respectively. Phosphatidylinositol 3,4,5-triphosphate thus produced serves as an intracellular second messenger. Class I PI3K is expressed in various cells, and exhibits a wide spectrum of functions such as cell proliferation, cell survival, glucose transport, cytoskeleton regulation and the like. In PI3K gene-knockout animals, development of B cells, T cells or the like and signal transduction are obstructed. Furthermore, the degranulation of mast cells and migration of leukocytes are also obstructed (Non-Patent Document 3). [0007] It is known that B cell proliferation by lipopolysaccharides (LPS) or anti-IgM antibodies is inhibited by wortmannin or LY294002, PI3K inhibitors (Non-Patent Document 4). Furthermore, wortmannin inhibits T cell proliferation induced by anti-CD3 antibodies and anti-CD28 antibodies (Non-Patent Document 5). [0008] Hematologic neoplasms are characterized by a spontaneous enhancement of cell division and an inhibition of apoptosis of the immune cells. However, abnormalities of PI3K cascades such as reduction of PTEN proteins that dephosphorylate phosphatidylinositol 3,4,5-triphosphate and enhancement of Akt phosphorylation have been reported (Non-Patent Document 6). Furthermore, it was demonstrated that the inhibition of PI3K may result in the inhibition of the cell division and the induction of apoptosis of various hematologic neoplasms (e.g., Non-Patent Document 7). [0009] Rheumatoid arthritis is a disorder characterized by immune abnormalities and hypertrophy of synovial tissues. It is known that the hypertrophy of synovial tissues results from proliferation and inhibition of apoptosis of synoviocytes. In inflamed synovial tissues of patients with rheumatoid arthritis, the levels of phosphorylated Akt were increased due to the activation of PI3K (Non-Patent Document 8). Moreover, it was revealed that proliferation and inhibition of apoptosis of synoviocytes were normalized by the inhibition of PI3K in vitro study (Non-Patent Document 9). [0010] However, wortmannin and LY294002 have not been put to clinical use due to their toxicity. Furthermore, although a lot of candidates that have therapeutic potential for a wide spectrum of disorders such as inflammations, cancers and others have been developed to take advantage of PI3K's inhibitory property, none has been put to clinical use. Thus, there is a need for immunosuppressive agents which normalize the 3 hyperfunctioning of PI3K in various cells involved in disorder of immune system without exhibiting any toxicity to living subjects. Non-Patent Document 2: S. Yaguchi et al., 96th Annual Meeting of the AACR, Anaheim, CA, USA. April 16-20,2005, #1691. Non-Patent Document 3: R. Wetzker and C. Rommel, Current Pharmaceutical Design, 2004, 10, 1915-1922 Non-Patent Document 4: A. C. Donahue and D. A. Fruman, J. Immunol. 2003, 170, 5851- 5860 Non-Patent Document 5: S. G. Ward et al., Eur J Immunol. 1995, 25, 526-532 Non-Patent Document 6: P. Workmann, Biochem. Soc. Trans. 2004, 32, 393-396 Non-Patent Document 7: S. Uddin et al., Biochem. Biophys. Res. Commun. 2004, 320, 932-938 Non-Patent Document 8: H. Zhang et al., Arthritis Rheum 2001, 44,1555-1567 Non-Patent Document 9: T. Miyashita et al., Biochem Biophys Res Commun 2003, 312, 397-404 MEANS TO SOLVE THE PROBLEMS [0011] In view of the foregoing, the present inventors have conducted extensive research on the heterocyclic compounds disclosed in Patent Documents 1, 2, 3, 4 and 5 on the assumption that some might be useful for the disorders for which immunosuppressive agents are used, such as for autoimmune diseases, organ transplantation, allergic diseases, hematologic neoplasm, sepsis or the like. As a result, they found that the heterocyclic compounds represented by the following general formula (I) are effective, arriving at completion of the present invention. [0012] Thus, one aspect of the present invention provides an immunosuppressive agent comprising as an effective ingredient a heterocyclic compound represented by the general Formula (I): 4 wherein, X represents a nitrogen atom or CH; both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1- C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl); or a pharmaceutically acceptable salt thereof. [0013] Here, one embodiment provides an immunosuppressive agent wherein in Formula (I), either of R1 or R2 is a hydroxyl group. Another embodiment provides an immunosuppressive agent wherein in Formula (I), either of R1 or R2 is a hydroxyl group, and R3 is a difluoromethyl. A further embodiment provides an immunosuppressive agent wherein in Formula (I), both of R1 and R2 are hydrogens, and R3 is a difluoromethyl. A further embodiment provides an immunosuppressive agent wherein in Formula (I), R6 is a 4-acetylpiperazine. 5 [0014] In the foregoing, the disorders to be treated may be rejection and graft versus host diseases, inflammatory bowel diseases such as ulcerative colitis or Crohn disease, inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis; inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma or Sjogren syndrome; hematological neoplasms such as malignant lymphoma, multiple myeloma, chronic leukemia, acute leukemia, or myelocytic leukemia; sepsis, fulminant hepatitis and the like. [0015] Here, one embodiment provides a PI3K inhibitor wherein in Formula (I), either of R1 or R2 is a hydroxyl group. Another embodiment provides a PI3K inhibitor wherein in Formula (I), either of R1 or R2 is a hydroxyl group, and R3 is a difluoromethyl. A further embodiment provides a PI3K inhibitor wherein in Formula (I), both of R1 and R2 are hydrogens, and R3 is a difluoromethyl. Furthermore, a PI3K inhibitor wherein in Formula (I), R6 is a 4-acetylpiperazine is provided. [0016] In the foregoing, the disorders to be treated may be rejection and graft versus host diseases, inflammatory bowel diseases such as ulcerative colitis or Crohn disease, inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis; inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma or Sjogren syndrome; hematological neoplasms such as malignant lymphoma, multiple myeloma, chronic leukemia, or acute leukemia; sepsis, fulminant hepatitis and the like. [0017] Among the heterocyclic compounds of Formula (I) which are used in the immunosuppressive agents in accordance with the present invention, some compounds are novel in their structures. Thus, in another aspect, the present invention provides a heterocyclic compound represented by the general Formula (II): wherein, 6 n represents 0-2; X represents a nitrogen atom or CH; Y represents -(CH2)n1-, wherein n1 is 1-2; R1 and R2, both or either, represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; R7 represents a hydrogen atom, a C1-C6 alkyl group, a formyl, a C1-C6 hydroxyalkyl, a C1- C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, or a substituted carbamoyl; or a pharmaceutically acceptable salt thereof. [0018] Here, in the above Formula (II), R7 may represent a hydrogen atom or a C1-C6 alkyl group; R6 may represent a hydrogen atom or a C1-C6 alkyl group. Examples include: 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-morpholino-1,3,5- triazine; 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3- dimethylmorpholino)-1,3,5-triazine; 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3- dimethylmorpholino)-1,3,5 -triazine; 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2- dimethylmorpholino)-l,3,5-triazine; 4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-6- morpholino-1,3,5-triazine; 4-(4-acetylpiperazin-l-yl)-2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-6-morpholino- 1,3,5-triazine; 4-(4-acetylpiperazin-1 -yl)-2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino-1,3,5- triazine; 4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6- morpholinopyrimidine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(cis-2,3- dimethylmorpholino)pyrimidine; 7 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3- dimethylmorpholino)pyrimidine; 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2- dimethylmorpholino)pyrimidine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-6- morpholinopyrimidine; 4-(4-acetylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6- morpholinopyrimidine; 4-(4-acetylpiperazin-1 -yl)-2-(2-hydroxymethylbenzimidazol-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- morpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- (cis-2,3-dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- (trans-2,3-dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-1 -yl]-6- (2,2-dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoyl- piperazin)-1 -yl] -6-morpholino-1,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)- l-yl]-6-morpholino-l,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- morpholino-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- (cis-2,3-dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- (trans-2,3-dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- (2,2-dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoyl- piperazin)-1 -yl] -6-morpholinopyrimidine; 8 2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)- 1-yl]-6-morpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-1 -yl]-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-morpholino- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cis-2,3- dimethylmorpholino-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(trans-2,3- dimethylmorpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-(2,2- dimethylmorpholino)-1,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6- morpholino-l,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6- morpholino-1,3,5-triazine; 4-[4-(2-furoyl)piperazin-1 -yl]-2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cis-2,3- dimethylmorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-(trans-2,3 - dimethylmorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(2-furoyl)piperazin-1 -yl]-6-(2,2- dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6- morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6- morpholinopyrimidine; 4-[4-(2-furoyl)piperazin-l-yl]-2-(2-hydroxymethylbenzimidazol-l-yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5- triazine; 9 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3- dimethylmorpholino)-1,3,5-triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3- dimethylmorpholino)-l,3,5-triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2- dimethylmorpholino)-1,3,5-triazine; 4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-6- morpholino-1,3,5-triazine; 4-(4-acetonylpiperazin-l-yl)-2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-6- morpholino-1,3,5 -triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-hydroxymethylbenzimidazol-l-yl)-6-morpholino-l,3,5- triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3- dimethylmorpholino)pyrimidine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3- dimethylmorpholino)pyrimidine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2- dimethylmorpholino)pyrimidine; 4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6- morpholinopyrimidinn; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)-1,3,5- triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino-6-(4- propionylpiperazin-1 -yl)-l ,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino-6-(4- propionylpiperazin-l-yl)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino-6-(4- propionylpiperazin-1 -yl)-1,3,5-triazine; 10 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin- l-yl)-l,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)-l,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino-6-(4- propionylpiperazin-1 -yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino-6-(4- propionylpiperazin-1 -yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino-6-(4- propionylpiperazin-1 -yl)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin- l-yl)pyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)pyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazin-1 -yl)-6-morpholino- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(cis-2,3 - dimethylmorpholino)-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(trans-2,3 - dimethylmorpholino)-1,3,5 -triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(2,2- dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholino-1,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholino-l,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-morpholino- 1,3,5-triazine; 11 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(cis-2,3- dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(trans-2,3- dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(2,2- dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(cis-2,3- dimethylmorpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(trans-2,3- dimethylmorpholino-1,3,5 -triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(2,2- dimethylmorpholino-1,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] - 6-morpholino-l ,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6- morpholino-1,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-[4-(3-hydroxypropyl)piperazi-1 -yl]-6- morpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(cis-2,3- dimethylmorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(trans-2,3 - dimethylmorpholinopyrimidine; 12 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(2,2- dimethylmorpholinopyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] - 6-morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(cis-2,3 - dimethylmorpholino)-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans- 2,3-dimethylmorpholino)-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(2,2- dimethylmorpholino)-1,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)- 6-morpholino-1,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholino-l,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(cis-2,3- dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans- 2,3-dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(2,2- dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)- 6-morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholinopyrimidine; 13 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-morpholino-6-(5-oxo-l,4-diazepan-l-yl)-l,3,5- triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-morpholino-6-(3-oxopiperazin-l-yl)-l,3,5- triazine; and 2-(2-difluoromethylbenzimidazol-l-yl)-6-(3,5-dioxopiperazin-l-yl)-4-morpholino-l,3,5- triazine. [0019] Furthermore, the present inventors have found novel uses as antitumor agents for the novel compounds represented by the above Formula (II). Thus, a further embodiment relates to an antitumor agent comprising a compound of Formula (II) as an effective ingredient. The disorders of interest may include, but are not limited to, lung cancer, prostate cancer, breast cancer, colon cancer, gastric cancer, pancreatic cancer, liver cancer, esophageal cancer, brain tumor, ovarian cancer, uterine cancer, malignant melanoma, renal cancer, head and neck cancer, skin cancer, bladder cancer, osteogenic sarcoma, biliary tract cancer, vulvar cancer, testicular neoplasm, penile cancer, colorectal cancer, mediastinal neoplasm, urothelial carcinoma, choriocarcinoma, soft tissue sarcoma, thyroid cancer, parathyroid cancer, adrenal cancer, malignant pheochromocytoma, germ cell tumor and the like. [0020] Furthermore, the present invention relates to the following various embodiments. The present invention relates to a method for immunosuppression comprising administering to a mammal a therapeutically effective amount of a heterocyclic compound represented by the general Formula (I): wherein, X represents a nitrogen atom or CH; 14 both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difiuoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1- C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl); or a pharmaceutically acceptable salt thereof. Here, in one embodiment, in Formula (I), either of R1 or R2 is hydroxyl group. In another embodiment, in Formula (I), either of R1 or R2 is hydroxyl group, and R3 is difiuoromethyl. In a further embodiment, in Formula (I), both of R1 and R2 are hydrogens, and R3 is difiuoromethyl. In a further embodiment, in Formula (I), R6 is 4- acetylpiperazine. Furthermore, as the disorders to be treated, mention can be made of rejection and graft versus host disease; inflammatory bowel diseases such as ulcerative colitis or Crohn disease; inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis; inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren syndrome, or the like; hematologic neoplasms such as malignant lymphoma, multiple myeloma, chronic leukemia, acute leukemia or the like; sepsis, fulminant hepatitis and the like. [0021] Yet another embodiment relates to a method for treating tumors comprising administering to a patient a therapeutically effective amount of a heterocyclic compound represented by the general Formula (II): 15 wherein, n represents 0-2; X represents a nitrogen atom or CH; Y represents -(CH2)n1-, wherein n1 is 1-2; R1 and R2, both or either, represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; R7 represents a hydrogen atom, a C1-C6 alkyl group, a formyl, a C1-C6 hydroxyalkyl, a C1- C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, or a substituted carbamoyl; or a pharmaceutically acceptable salt thereof. [0022] In yet another embodiment, the present invention relates to an immunosuppressive composition comprising a therapeutically effective amount of a heterocyclic compound represented by the general Formula (II): wherein, n represents 0-2; X represents a nitrogen atom or CH; Y represents -(CH2)n1-, wherein n1 is 1-2; 16 R1 and R2, both or either, represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; R7 represents a hydrogen atom, a C1-C6 alkyl group, a formyl, a C1-C6 hydroxyalkyl, a C1- C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, or a substituted carbamoyl; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In a yet further embodiment, the invention relates to a composition, in particular a pharmaceutical composition, and more preferably an antitumor composition, comprising a therapeutically effective amount of a heterocyclic compound represented by the general Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [0023] Furthermore, the present invention relates to the following various embodiments. The present invention relates to a PI3K inhibition method comprising administering to a mammal a therapeutically effective amount of a heterocyclic compound represented by the general Formula (I): wherein, X represents a nitrogen atom or CH; both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; 17 R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1- C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl); or a pharmaceutically acceptable salt thereof. Here, in one embodiment, in Formula (I), either of R1 or R2 is hydroxyl group. In another embodiment, in Formula (I), either of R1 or R2 is hydroxyl group, and R3 is difiuoromethyl. In a further embodiment, in Formula (I), both of R1 and R2 are hydrogens, and R3 is difiuoromethyl. In a further embodiment, in Formula (I), R6 is 4- acety lpiperazine. Furthermore, as the disorders to be treated, mention can be made of rejection and graft versus host disease; inflammatory bowel diseases such as ulcerative colitis or Crohn disease; inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis; inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjagren syndrome, or the like; hematologic neoplasms such as malignant lymphoma, multiple myeloma, chronic leukemia, acute leukemia or the like; sepsis, fulminant hepatitis and the like. [0024] In yet another embodiment, the present invention relates to a PI3K inhibitory composition comprising a therapeutically effective amount of a heterocyclic compound represented by Formula (I): 18 wherein, X represents a nitrogen atom or CH; both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1- C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl); or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In a yet further embodiment, the invention relates to a composition, in particular a pharmaceutical composition, and more preferably a PI3K inhibitory composition, comprising a therapeutically effective amount of a heterocyclic compound represented by the general Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [0025] Furthermore, the present invention relates to use of a heterocyclic compound represented by Formula (I): 19 wherein, X represents a nitrogen atom or CH; both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difiuoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1- C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl); or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of immune diseases, or as an immunosuppressive agent. Here, in one embodiment, in Formula (I), either of R1 or R2 is hydroxyl group. In another embodiment, in Formula (I), either of R1 or R2 is hydroxyl group, and R3 is difiuoromethyl. In a further embodiment, in Formula (I), both of R1 and R2 are hydrogens, and R3 is difiuoromethyl. In a further embodiment, in Formula (I), R6 is a 4- acetylpiperazine. 20 Furthermore, as the disorders to be treated, mention can be made of rejection and graft versus host disease; inflammatory bowel diseases such as ulcerative colitis or Crohn disease; inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis; inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren syndrome, or the like; hematologic neoplasms such as malignant lymphoma, multiple myeloma, chronic leukemia, acute leukemia or the like; sepsis, fulminant hepatitis and the like. [0026] In yet another embodiment, the present invention relates to use of a heterocyclic compound represented by the general Formula (II): wherein, n represents 0-2; X represents a nitrogen atom or CH; Y represents -(CH2)n1-, wherein n1 is 1-2; R1 and R2, both or either, represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; R7 represents a hydrogen atom, a C1-C6 alkyl group, a formyl, a C1-C6 hydroxyalkyl, a C1- C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, or a substituted carbamoyl; or a pharmaceutically acceptable salt thereof in the manufacture of a composition for threatment of tumors. In yet another embodiment, the present invention relates to use of a heterocyclic compound represented by Formula (I): 21 wherein, X represents a nitrogen atom or CH; both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1- C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl); or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the inhibition of PI3K or as a PI3K inhibition agent. Here, in one embodiment, in Formula (I), either of R1 or R2 is hydroxyl group. In another embodiment, in Formula (I), either of R1 or R2 is hydroxyl group, and R3 is difluoromethyl. In a further embodiment, in Formula (I), both of R1 and R2 are hydrogens, and R3 is difluoromethyl. In a further embodiment, in Formula (I), R6 is a 4- acetylpiperazine. 22 Furthermore, as the disorders to be treated, mention can be made of rejection and graft versus host disease; inflammatory bowel diseases such as ulcerative colitis or Crohn disease; inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis; inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren syndrome, or the like; hematologic neoplasms such as malignant lymphoma, multiple myeloma, chronic leukemia, acute leukemia or the like; sepsis, fulminant hepatitis and the like. Yet other embodiments, modes and features of the present invention will be apparent to those skilled in the art in view of the detailed description below. EFFECT OF THE INVENTION [0027] The agents of the invention are effective for the prevention or treatment of the disorders attributable to the hyperfunctioning of PI3K such as autoimmne diseases, organ transplantation, allergenic or inflammatory disorders, hematologic neoplasms, sepsis, and treatment of tumors. BRIEF EXPLANATION OF THE DRAWINGS [0028] [Figure 1] Diagrams showing the effects of test substances on the upregulation of CD 69 expression and CD 40L expression on human peripheral blood mononuclear cells induced by anti-human CD3 antibody and anti-human CD28 antibody. [Figure 2] Graph depicting a comparison between test substance-treated group and control group on the volume change in hind paw of rats after the onset of arthritis. [Figure 3] Graph depicting a comparison between test substance-treated group and control group on the change in arthritis score after the onset of arthritis. [Figure 4] Graph depicting a comparison between test substance-treated group and control group in a human B lymphoma xenografted model. BEST MODES FOR CARRYING OUT THE PRESENT INVENTION [0029] The heterocyclic compound for use in the present invention is the one represented by the general Formula (I): 23 wherein, X represents a nitrogen atom or CH; both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1- C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl); or its pharmaceutically acceptable salt. [0030] In the above formula, "C1-C6" without any limitation means a group having 1 to 6 carbon atoms. "C1-C6 alkyl" includes alkyl groups of linear or branched chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl and the like. "C1- C6 alkoxy" includes alkoxy groups with linear or branched chain, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, seobutoxy, n-pentyloxy, n- hexyloxy and the like. "Hydroxy C1-C6 alkyl" means those groups having a hydroxyl group bonded to any of the carbon atoms of the group defined by the above "C1-C6 alkyl". 24 When the above heterocyclic compound has an asymmetric carbon atom in its structure, isomers from the asymmetric carbon atom and their mixture (racemic compounds) exist, and any such compounds are to be included among the compounds of the present invention. [0031] Furthermore, the heterocyclic compounds that are used as effective ingredients of the present invention may be in the form of an acid addition salt as a pharmaceutically acceptable salt. Appropriate acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, hydrobromides, nitrates, phosphates or the like, and organic acid salts such as acetates, oxalates, propionates, glycollates, lactates, pyruvates, malonates, succinates, maleates, fumarates, malates, tartrates, citrates, benzoates, cinnamates, methane sulfonates, benzene sulfonates, p-toluene sulfonates, salicylates or the like. [0032] The compounds which can be used as the effective ingredients of the present invention include, but are not limited to, the following heterocyclic compounds: [0033] 2-(2-Methylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 1) [0034] 2-(Benzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-l,3,5- triazine (Compound 2) [0035] 4,6-Dimorpholino-2-(2-hydroxymethylbenzimidazol-l-yl)-l,3,5-triazine (Compound 3) [0036] 2-(2-Difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 4) [0037] 2-(2-Aminobenzimidazol-l-yl)-4,6-dimorpholinopyrimidine (Compound 5) [0038] 2-(2-Aminobenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 6) [0039] 2-(2-Difluoromethylbenzimidazol-l-yl)-4-piperidino-6-morpholino-l,3,5-triazine (Compound 7) [0040] 2-(6-Amino-2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino)- 6-morpholino-l,3,5-triazine (Compound 8) [0041] 2-(2-Difluoromethyl-6-ethoxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 9) [0042] 2-(2-Difluoromethyl-4-methylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 10) [0043] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-morpholino-6-(2,6- dimethylmorpholino)pyrimidine (Compound 11) [0044] 2-(2-Difluoromethyl-5-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 12) 25 [0045] 2-(6-Amino-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6- morpholino-l,3,5-triazine (Compound 13) [0046] 2-(4-Amino-2-difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 14) [0047] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 15) [0048] 2-(2-Difluoromethyl-6-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 16) [0049] 2-(5-Amino-2-difluoromethylbenzimidazol-1-yl)-4,6-di(2,6-dimethyl- morpholino)pyrimidine (Compound 17) [0050] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4,6-dimorpholinopyrimidine (Compound 18) [0051] 2-(6-Amino-4-chloro-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethyl- morpholino)-6-morpholino-l,3,5-triazine (Compound 19) [0052] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethyl- pyrrolidin-l-yl)-6-morpholino-l,3,5-triazine (Compound 20) [0053] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2,2-dimethylmorpholino)-6- morpholinopyrimidine (Compound 21) [0054] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(3,3-dimethylmorpholino)-6- morpholinopyrimidine (Compound 22) [0055] 2-(2-Difluoromethyl-5-methoxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5- triazine (Compound 23) [0056] 2-(2-Difluoromethyl-4-methoxybenzimidazol-l-yl)-4-(cis-2,6-dimethyl- morpholino)-6-morpholinopyrimidine (Compound 24) [0057] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5-oxo-1,4-diazepan-1 - yl)-l,3,5-triazine (Compound 25) [0058] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-(4-hydroxypiperizin-1 -yl)-6- morpholino-l,3,5-triazine (Compound 26) [0059] 2-(2-Difluoromethylbenzimidazol-l-yl)-4-[4-(2-hydroxyethyl)piperazin-l-yl]-6- morpholino-l,3,5-triazine (Compound 27) [0060] 4-(4-Acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino- 1,3,5-triazine (Compound 28) [0061] 2-(2-Difluoromethylbenzimidazol-l-yl)-4-(4-benzylcarbonylpiperazin-l-yl)-6- morpholino-l,3,5-triazine (Compound 29) 26 [0062] 4-(4-Acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6- morpholino-l,3,5-triazine (Compound 30) [0063] 2-(2-Difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6- morpholino-l,3,5-triazine (Compound 31) [0064] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)- l-yl]-6-morpholino-l,3,5-triazine (Compound 32) [0065] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-(4-methoxylacetylpiperazin-1 -yl)-6- morpholino-l,3,5-triazine (Compound 33) [0066] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholino-l,3,5-triazine (Compound 34) [0067] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)-l,3,5-triazine (Compound 35) [0068] 2-(2-Difluoromethyl-4-methoxybenzimidazol-1 -yl)-4-(2,2-dimethylmorpholino)-6- morpholinopyrimidine (Compound 36) [0069] 2-(2-Difluoromethyl-4-methoxybenzimidazol-l-yl)-4-(cis-2,3-dimethyl- morpholino)-6-morpholinopyrimidine (Compound 37) [0070] 2-(2-Difluoromethyl-4-ethoxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6- morpholinopyrimidine (Compound 38) [0071] As will be demonstrated in Examples to be hereinafter described, the agents of the present invention inhibit the activation of T cells and B cells induced by Con A, LPS, anti- IgM antibody, anti-CD3 antibody + anti-CD28 antibody, thereby exhibiting PI3K inhibitory action on the immune cells. Thus, the drugs of the present invention can be used in the treatment and prevention of disorders of immune system attributable to the hyperfunctioning of PI3K. [0072] As disorders of immune system attributable to the hyperfunctioning of PI3K, mention may be made of: autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjegren syndrome, or the like; organ dysfunction associated with autoimmune diseases such as uveitis, glomerulonephritis, thyroiditis, pancreatitis, bone destruction or the like; rejection after transplantation of tissues, graft versus host disease after bone-marrow transplantation; inflammatory bowel diseases such as ulcerative colitis or Crohn disease; inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis; inflammatory or allergenic respiratory disorders such as chronic obstructive pulmonary disease or asthma; allergenic conjunctivitis or rhinitis; hematologic neoplasm originated from immune cells, such as B-cell lymphoma, T-cell 27 lymphoma, myeloid leukemia or the like; sepsis triggered by infection with gram-negative bacteria or coronavirus, severe acute respiratory syndrome, fulminant hepatitis or the like. [0073] While the agents of the present invention can be applied to mammals such as humans, dogs, cats, rabbits, hamsters, rats, mice or the like, the administration regimen, formulation and dosage for application to humans will be particularly explained below. [0074] The agents of the present invention may be administered orally or parenterally, and tablets, coated-tablets, powdered drugs, granules, capsules, microcapsules, syrups or the like may be used as the dosage form for oral administration whereas eye drops, inhalants, injectable form (including lyophilizates for injection which are to be dissolved upon application), suppositories, poultices or the like may be used as the dosage form for parenteral administration. The formulation of these dosage forms may be effected using pharmaceutically acceptable excipients, binders, lubricants, disintegrants, suspending agents, emulsifiers, preservatives, stabilizing agents and dispersants, such as lactose, sucrose, starch, dextrin, crystalline cellulose, kaolin, calcium carbonate, talc, magnesium stearate, distilled water or saline. [0075] When used in oral dosage forms, the dosages of the effective ingredient will differ depending on the symptoms, age, weight or the like of the patient, but a daily dose of 10- 500 mg may be administered in 2-3 portions for an adult weighing 60 kg. In addition, the dosages will also differ depending on the symptoms of the patient in the case of ophthalmic solutions, inhalation to lungs or the nasal cavity, and injection to inflamed articular cavities, but a daily dose of 1-100 µg may be administered in 2-3 portions for an adult. EXAMPLES [0076] PRODUCTION EXAMPLES Some examples of the heterocyclic compounds represented by the general Formula (I) were produced according to the processes disclosed in the examples of Patent Documents 3, 4 and 5, and described below. [0077] The synthesis was preformed with reference to Patent Documents 1-3. [0078] Production Example 1 2-(2-Methylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 1) Melting point: 218-20°C (Decomposed) NMR(CDCl3)δ: 3.03 (3 H, s), 3.7-3.9 (16H, m), 7.2-7.4 (2H, m), 7.7-7.8 (1H, m), 8.1-8.3 (lH,m) 28 MS m/z:381(M+) [0079] Production Example 2 2-(Benzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-l,3,5-triazine (Compound 2) Melting point: 147-150 °C NMR(CDCl3) δ: 1.1-1.5(6H, m), 2.7-3.0(lH, m), 3.4-3.6(lH, m), 3.7-4.0(8H, m), 4.1- 4.3(1H, m), 4.4-4.7(2H, m), 7.3-7.4(2H, m), 7.7-7.9(lH, m), 8.3-8.4(lH, m), 8.98(1H, s). [0080] Production Example 3 4,6-Dimorpholino-2-(2-hydroxymethylbenzimidazol-l-yl)-l,3,5-triazine (Compound 3) Melting point: 208-210 °C (Decomposed) NMR(CDC13) δ: 3.7-3.9(16H, m), 4.59(1H, t, J=6Hz), 5.15(2H, d, J=7Hz),7.2-7.4(2H, m), 7.7-7.8(lH, m), 8.3-8.4( lH, m) MS m/z : 397(M+) [0081] Production Example 4 2-(2-Difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 4) Melting point: 211-214 °C NMR(CDC13)δ: 3.79(8H, t, J=4Hz), 3.88(8H, t, J=4Hz), 7.3-7.4(2H, m), 7.56(1H, t, J=53Hz), 7.88(1H, d, J=7Hz), 8.32(1H, d, J=7Hz). MS m/z: 417(M+) [0082] Production Example 5 2-(2-Aminobenzimidazol-l -yl)-4,6-dimorpholinopyrimidine (Compound 5) Melting point: 237-239 °C NMR(CDCl3)δ: 3.59(8H, t, J=5Hz), 3.84(8H, t, J=5Hz), 5.46(1H, s), 6.65(2H, brs), 7.06(lH, t, J=7Hz), 7.18(1H, t, J=7Hz), 7.37(1H, d, J=7Hz), 8.1(1H, d, 7Hz) MSm/z:381(M+) [0083] Production Example 6 2-(2-Aminobenzimidazol-1 -yl)-4,6-dimorpholino-1,3,5-triazine (Compound 6) Melting point: 298-300 °C (Decomposed) NMR(CDCl3)δ: 3.7-3.9(16H, m), 6.74(2H, brs), 7.05(lH, t, J=7Hz), 7.20(1H, t, J=7Hz), 7.39(1H, d, J=7Hz), 8.20(1H, d, 7Hz) MS m/z : 382(M+) [0084] Production Example 7 2-(2-Difluoromethylbenzimidazol-l-yl)-4-piperidino-6-morpholino-l,3,5-triazine (Compound 7) 29 Melting point: 190-192 °C NMR(CDCl3)δ: 1.5-1.8(6H, m), 3.7-3.9(12H, m), 7.3-7.5(2H, m), 7.61(1H, t, J=54Hz), 7.90(1H, d, J=8Hz), 8.34(1H, d, 8Hz) MSm/z : 415(M+) [0085] Production Example 8 2-(6-Amino-2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino)-6- morpholino-l,3,5-triazine (Compound 8) Melting point: 220-222 °C (Decomposed) NMR(CDCl3)δ: 1.22(3H, d, J=9Hz), 1.26(3H, d, J=9Hz), 3.1-3.4(1H, m), 3.5-4.1(11H, m), 4.3-4.5(lH, m), 4.5-4.7(lH, m), 6.77(1H, dd, J=2Hz, J=9Hz), 7.49(1H, t, J=54Hz), 7.62(1H, d, J=9Hz), 7.64(1H, d, J=2Hz). MSm/z: 460(M+) [0086] Production Example 9 2-(2-Difluoromethyl-6-ethoxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 9) Melting point: 222-224 °C NMR(CDC13)δ: 1.46(3H, t, J=7Hz), 3.7-3.9(16H, m), 4.08(2H, q, J=7Hz), 7.00(lH, dd, J=9Hz, 3Hz), 7.52(1H, t, J=54Hz), 7.74(1H, d, J=9Hz), 7.89(1H, d, J=3Hz). MSm/z : 461(M+) [0087] Production Example 10 2-(2-Difluoromethyl-4-methylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 10) Melting point: 259-260 °C NMR(CDCl3)δ: 2.72(3H, s), 3.7-3.9(16H, m), 7.1-7.5(2H, m), 7.56(1H, t, J=54Hz), 8.15(lH,d,8Hz) MSm/z : 431(M+) [0088] Production Example 11 2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(2,6- dimethylmorpholino)pyrimidine (Compound 11) Melting point: 265-267 °C 1H NMR(CDCl3)δ: 3.7-3.9(16 H, m), 3.86 (3 H , s), 7.02 (1 H , dd, J = 3, 9 Hz,), 7.52 (1 H, t, J = 53 Hz,), 7.75 (1 H , d, J = 9 Hz,),7.91 (1 H, d, J = 3Hz,),. MS m/z 447 (M+). [0089] Production Example 12 30 2-(2-Difluoromethyl-5-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 12) Melting point: 272-274 °C NMR(CDC13)δ: 3.7-3.9(16H, m), 7.26-7.29(2H, m), 7.54(1H, t, J=54Hz), 8.20(1H, d, 8Hz) MS m/z: 433(M+) [0090] Example 13 2-(6-Amino-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6- morpholino-l,3,5-triazine (Compound 13) Melting point: 226-227 °C (Decomposed) NMR(CDCl3)δ: 1.28(6H, s), 3.6-3.8(14H, m), 6.7-6.8(lH, m), 7.2-7.7(3H, m). MS m/z: 460(M+) [0091] Example 14 2-(4-Amino-2-difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 14) Melting point: 214-216 °C (Decomposed) NMR(CDCl3)δ: 3.7-3.9(16H, m), 4.48(2H, brs), 6.63(1H, d, J=8Hz), 7.21(1H, t, J=8Hz), 7.55(1H, t, J=54Hz), 7.64(1H, d, J=8Hz). MS m/z: 432(M+) [0092] Production Example 15 2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 15) Melting point: >250 °C NMR(DMSO-d6)δ: 3.70-3.90(16H,m), 6.76(1H, d, J=8Hz), 7.73(1H, t, J=8Hz), 7.70(1H, t, J=54Hz), 7.74(1H, d, J=8Hz),10.24 (1H, brs) MS m/z: 433 [0093] Production Example 16 2-(2-Difluoromethyl-6-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 16) Melting point: >250 °C NMR(DMSO-d6)δ: 3.70-3.90(16H,m), 6.86(lH,d,J=8Hz), 7.61(lH,d,J=8Hz), 7.70(lH,t,J=54Hz), 7.73(lH,s), 9.81 (lH,brs) MS m/z: 433 [0094] Production Example 17 31 2-(5-Amino-2-difluoromethylbenzimidazol-l-yl)-4,6-di(2,6-dimethylmorpholino)- pyrimidine (Compound 17) Melting point: 157-160 °C NMR(CDCl3)δ: 1.30(6H, d, J=9Hz), 2.6-2.8(4H, m), 3.6-4.2(8H, m), 5.45(1H, s), 6.7- 6.8(1H, m), 7.5-7.7(2H, m), 7.42(1H, t, J=53Hz) MS m/z: 487(M+) [0095] Production Example 18 2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4,6-dimorpholinopyrimidine (Compound 18) Melting point: >250 °C NMR(DMSO-d6)δ: 3.60-3.80(16H,m), 5.98(lH,s), 6.72(lH,d,J=8Hz), 7.22(lH,t,J=8Hz), 7.62(1H, d,J=8Hz) ,7.65(lH,t,J=54Hz), 10.17 (lH,brs) MS m/z: 432 [0096] Production Example 19 2-(6-Amino-4-chloro-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6- morpholino-l,3,5-triazine (Compound 19) (1) 6-Amino-4-chloro-2-difluoromethylbenzimidazole (500 mg, 2.3 mmol) was dissolved in acetone (50 ml), 2,4-dichloro-6-morpholino-l,3,5-triazine (542 mg, 2.3 mmol) was added at -15°C, and potassium carbonate (500 mg) was further added. After having elevated the temperature gradually to room temperature, the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under vacuum, and the residue was purified by silica gel column chromatography (n-hexane : ethyl acetate =1 : 4) to afford 2-(6-amino-4-chloro-2-difluoromethylbenzimidazol-1 -yl)-4-chloro-6-morpholino- 1,3,5-triazine (272 mg, yield 28%). (2) 2-(6-Amino-4-chloro-2-difluoromethylbenzimidazol-1 -yl)-4-chloro-6-morpholino- 1,3,5-triazine (150 mg, 0.36 mmol) thus obtained was dissolved in DMF (6ml), 2,2- dimethylmorpholine hydrochloride (150 mg, 1.0 mmol) was added thereto at -15°C, and potassium carbonate (500 mg) was further added. After stirring at room temperature overnight, water was added to the reaction mixture, which was extracted with ethyl acetate several times, washed with brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under vacuum, the residue was purified by silica gel column chromatography (n-hexane : ethyl acetate = 1 : 2) to give the title compound as colorless crystals (130 mg, yield 73%). Melting point: 238 °C (Decomposed) 32 NMR (CDCl3)δ: 1.27 (6H, s), 3.68 (2H, s), 3.7-3.9 (12H, m), 6.82 (1H, d, J =2.3Hz), 7.42 (1H, dt, J =9.6Hz, J =53Hz), 7.50 (1H, d, J =2.3Hz) MS m / z: 494 (M +) [0097] Production Example 20 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethylpyrrolidin-1 -yl)-6- morpholino-l,3,5-triazine (Compound 20) Melting point: 245 °C (Decomposed) NMR (CDCl3)δ: 1.9-2.1(4H, m), 3.5-4.0(12H, m), 4.7-4.8(lH, m), 5.1-5.3(1H, m), 6.89(1H, d, J=9Hz), 7.30(1H, t, J=9Hz), 7.50(1H, brs), 7.55(1H, t, J=54Hz), 7.83(1H, d, J=9Hz). MS m/z: 447(M+) [0098] Production Example 21 2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6- morpholinopyrimidine (Compound 21) Melting point: 185-187 °C NMR (CDCl3)δ: 1.29(6H, s), 3.48(2H, s), 3.59-3.64(6H, m), 3.81-3.87(6H, m), 5.47(1H, s), 6.86(1H, m), 7.26-7.32(lH, m), 7.49(1H, t, J=53Hz), 7.72(1H, d, 8Hz) MS m/z : 460(M+) [0099] Production Example 22 2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-(3,3-dimethylmorpholino)-6- morpholinopyrimidine (Compound 22) Melting point: 204-206 °C NMR (CDCl3)δ: 1.48(6H, s), 3.50(2H, s), 3.6-3.8(6H, m), 3.8-4.0(6H, m), 5.76(1H, s), 6.68(1H, d, J=7Hz), 7.29(1H, d, J=7Hz), 7.49(1H, t, J=54Hz), 7.66(1H, d, 7Hz) MS m/z : 460(M+) [00100] Production Example 23 2-(2-Difluoromethyl-5-methoxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 23) Melting points: 206-207 °C NMR((CD3)2CO) δ: 1.17 (6H, d, J=6Hz), 2.5-2.8(4H, m), 3.6-4.4(10H, m), 5.95(1H, s), 6.77(1H, d, J=8Hz), 7.23(1H, t, J=8Hz), 7.66(1H, t, J=53Hz), 7.75(1H, d, J=8Hz), 8.9(1H, s) MS m/z 447 (M+) [00101] Production Example 24 33 2-(2-Difluoromethyl-4-methoxybenzimidazol-l-yl)-4-(cis-2,6-dimethylmorpholino)-6- morpholinopyrimidine (Compound 24) (1) 2-Difluoromethyl-4-methoxybenzimidazole (9.03 g, 45.6 mmol) was dissolved in DMF (100 ml), 60% NaH (1.82 g, 45.6 mmol) was added, and stirred for 30 minutes. The reaction mixture was added to a solution obtained by dissolving 2,4,6-trichloropyrimidine (15.7 g, 92.1 mmol) into DMF (100 ml) while cooling with ice, and stirred on an ice bath for 30 minutes and further at room temperature for 2 hours. Water was added to the reaction mixture, precipitated crystals were filtered, and washed well with hexane and ether, then air-dried to afford 2-(2-difluoromethyl-4-methoxybenzimidazol-l-yl)-4,6- dichloropyrimidine (12.3g, yield 78%). (2) 2-(2-Difluoromethyl-4-methoxybenzimidazol-l-yl)-4,6-dichloropyrimidine (12.3 g, 35.7 mmol) thus obtained was dissolved in DMF (150 ml), cis-2,6-dimethylmorpholine (6.63 ml, 53.7 mmol) was added at room temperature, and potassium carbonate (7.35 g) was further added. After stirring at room temperature for 30 minutes, water was added to the reaction mixture, extracted with ethyl acetate several times, washed with brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under vacuum, the residue was washed sufficiently with hexane, and then successively with ether, and then air-dried to give 4-chloro-2-(2-difluoromethyl-4-methoxybenzimidazol-l-yl)-6-(cis- 2,6-dimethyl-morpholino)pyrimidine (14.4 g, yield 95%). (3) Morpholine (275 ml, 3.15 mol) was added to 4-chloro-2-(2-difluoromethyl-4- methoxybenzimidazol-l-yl)-6-(cis-2,6-dimethylmorpholino)pyrimidine (14.4 g, 34 mmol) thus obtained, and stirred at room temperature for 30 minutes and further at 80°C for 30 minutes. Water was added to the reaction solution, and the precipitated crystals were filtered, and washed well successively with hexane, ether and ethyl acetate, then air-dried to afford 2-(2-difluoromethyl-4-methoxybenzimidazol-1 -yl)-4-(cis-2,6-dimethyl- morpholino)-6-morpholinopyrimidine (13.7 g, yield 86%). Melting point: 180-181 °C NMR(CDCl3) δ: 1.28(6H, d, J=6Hz), 2.6-2.7(2H, m), 3.6-3.7(6H, m), 3.80-3.86(4H, m), 4.04(3H, s), 4.10-4.14(2H, m), 5.49(1H, s), 6.78(1H, d, J=8Hz), 7.32(1H, d, J=8Hz), 7.41(1H, t, J-52Hz), 7.77(1H, d, J=8Hz) MS m/z: 474(M+) [00102] Production Example 25 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5-oxo-1,4-diazepan-1 -yl)-1,3,5- triazine (Compound 25) 34 Melting point: 235-37 °C 1H NMR(CDCl3) δ: 2.7-2.8 (2H, m), 3.4-3.5 (2H, m), 3.8-4.2 (12H, m), 5.97 (1H, brs), 7.2-7.5 (2 H, m), 7.52 (1 H, t, J = 54Hz), 7.8-8.0 (1 H, m) 8.2-8.4 (1 H ,m). MS m/z 444 (M+) [00103] Production Example 26 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-(4-hydroxypiperizin-1 -yl)-6-morpholino-1,3,5- triazine (Compound 26) Melting point: 219-21 °C 1HNMR(CDCl3) δ: 3.4-3.5 (2H, m), 3.7-4.1 (16H, m), 7.3-7.5 (2 H, m), 7.59 (1 H, t, J = 50Hz), 7.8-8.0 (1 H, m) 8.3-8.4 (1 H ,m). MS m/z 431 (M+). [00104] Production Example 27 2-(2-Difluoromethylbenzimidazol-1 -yl)-4- [4-(2-hydroxyethyl)piperazin-1 -yl] -6- morpholino-l,3,5-triazine (Compound 27) Melting point: 174-77 °C 1H NMR(CDCl3) δ: 2.6-2.7 (8H, m), 3.6-3.9 (12H, m), 3.91 (1H, br) 7.3-7.5 (2 H, m), 7.58 (1 H, t, J = 54Hz), 7.9-8.0 (1 H, m) 8.3-8.4 (1 H ,m). MS m/z 460 (M+). Refer to Patent Document 4. [00105] Production Example 28 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethylpyrrolidin-1 -yl)-6- morpholinopyrimidine (947) (1) 4-rert-Butyldimethylsilyloxy-2-difluoromethylbenzimidazole (1.49 g, 5.0 mmol) was dissolved in DMF (10 ml), 2,4,6-trichloropyrimidine (0.91 g, 5.0 mmol) was added at room temperature, potassium carbonate (0.55 g) was further added, and the mixture was stirred for 5 hours. Water was added to the reaction mixture, extracted with ethyl acetate several times, washed with brine, and then dried over anhydrous magnesium sulfate. After the solvent was evaporated under vacuum, the residue was purified by silica gel column chromatography (n-hexane : ethyl acetate = 8 : 1) to give 2-(4-tert-buthyldimethylsilyloxy- 2-difluoromethylbenzimidazol-l-yl)-4,6-dichloropyrimidine (1.12 g, yield 50%). (2) 2-(4-tertButhyldimethylsilyloxy-2-difluoromethylbenzimidazol-1 -yl)-4,6- dichloropyrimidine (386 mg, 0.87 mmol) thus obtained was dissolved in DMF (6 ml), 2- pyrrolidine methanol (0.13 ml, 1.3 mmol) was added at room temperature, and potassium carbonate (179 mg) was further added. After the mixture was stirred at room temperature 35 for 30 minutes, water was added to the reaction mixture, extracted with ethyl acetate several times, washed with brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under vacuum, the residue was purified by silica gel column chromatography (n-hexane : ethyl acetate =1 : 1) to give 2-(4-tert-buthyldimethylsilyloxy- 2-difluoromethylbenzimidazol-1 -yl)-4-(2-hydroxy-methylpyrrolidin-1 -yl)-6- chloropyrimidine (291 mg, yield 64%). (3) Morpholine (4.4 g, 50 mmol) was added to 2-(4-tert-buthyldimethylsilyloxy-2- difluoromethylbenzimidazol-1 -yl)-4-(2-hydroxymethyl-pyrrolidin-1 -yl)-6- chloropyrimidine (281 mg, 0.54 mmol) thus obtained, and the mixture was stirred at room temperature for 9 hours. Water was added to the reaction mixture, extracted with ethyl acetate several times, washed with brine, and then dried over anhydrous magnesium sulfate. After the solvent was evaporated under vacuum, the residue was purified by silica gel column chromatography (n-hexane : ethyl acetate = 2 : 3) to obtain 2-(4-tert- bumyldimethylsilyloxy-2-difluoromethylbenzimidazol-l-yl)-4-(2-hydroxy- methylpyrrolidin-l-yl)-6-morpholinopyrimidine (216 mg, yield 72%). 2-(4-tert-Buthyldimethylsilyloxy-2-difluoromethyl-benzimidazol-l-yl)-4-(2- hydroxymethylpyrrolidin-l-yl)-6-morpholinopyrimidine (213 mg, 0.38 mmol) was dissolved in anhydrous THF (7 ml), tetra-n-butylammonium fluoride (0.4 ml) (1M THF solution) was added at room temperature, and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, extracted with ethyl acetate several times, washed with brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under vacuum, the residue was purified by silica gel column chromatography (n-hexane : ethyl acetate = 1 : 4) to obtain the title compound as colorless crystals (101 mg, yield 60%). Melting point: 195-198°C NMR(CDCl3)δ: 2.0-2.1(4H, m), 3.4-4.0(12H, m), 4.0-4.1(lH, m), 4.3-4.4(lH, m), 5.36(1H, s), 6.85(1H, d, J=8Hz), 7.28(1H, t, J=8Hz), 7.58(1H, brs), 7.58(1H, t, J=54Hz), 7.73(1H, d, J=8Hz). MSm/z: 446(M+) The production was effected with reference to Patent Document 4. [00106] Production Example 29 2-(5,6-Dimethyl-2-difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (ZSTK705) Melting point: 217-220°C 36 1H NMR (CDCl3) δ: 2.39 (3H, s), 2.40 (3H, s), 3.7-3.9 (16H, m), 7.53 (1 H, t, J = 54Hz), 7.62 (lH, s) 8.12 (lH, s). MS m/z 445 (M+). [00107] Production Example 30 2-(6-Amino-4-chloro-2-difluoromethylbenzimidazol-l-yl)-4-(2-hydroxymethylpyrrolidin- 1-yl )-6-morpholino-l,3,5-triazine (STK922) Melting point: 256°C (Decomposed) NMR(CD3OD-CDCl3(1:1)) δ: 1.9-2.2(4H, m), 3.68(2H, s), 3.5-4.0(llH, m), 4.39(1H, brs), 6.84(1H, d, J=2.1Hz), 7.58(1H, t, J=53Hz), 7.64(1H, d, J=2.1Hz). MS m/z: 480(M+) [00108] Production Example 31 2-(4-Chloro-2-difluoromethyl-5-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5- triazine (STK894) Melting point: >250°C NMR(CDC13)δ: 3.7-3.9(16H, m), 5.63(1H, s), 7.15(1H, d, J=9Hz), 7.51(1H, t, J=53Hz), 8.14(lH,d,J=9Hz). MS m/z: 467(M+) [00109] Production Example 32 Synthesis of 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6- morpholino-l,3,5-triazine (Compound 28) A mixture of 6-chloro-2-(2-difmoromethylbenzimidazol-l-yl)-4-morpholino-l,3,5- triazine (3.66 g, 10 mmol), 1-acetylpiperazine (1.40 g, 11 mmol), potassium carbonate (1.38 g, 10 mmol) and DMF (30 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by silica gel column to obtain 4-(4-acetylpiperazin-l-yl)-2-(2- difluoromethylbenzimidazol-l-yl)-6-morpholino-l,3,5-triazine (4.08 g, 9.0 mmol) in a yield of 90% as colorless crystals. Naturally, triazine or pyrimidine derivatives bearing such piperazine groups may also be synthesized according to the following schemes. For example, a mixture of 6-chloro-2-(2-difluoromethylbenzimidazol-l-yl)-4- morpholino-l,3,5-triazine (3.66 g, 10 mmol), piperazine (3.45 g, 40 mmol), and acetone (50 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and precipitated crystals were filtered, and washed with methanol to afford 2- 37 (2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(piperazin-1 -yl)-1,3,5-triazine (3.87 g, 9.3 mmol) in a yield of 93% as colorless crystals. 1H NMR (CDCl3) δ: 3.8-4.1 (16H, m), 7.3-7.5 (2 H, m), 7.59 (1 H, t, J = 54Hz), 7.9-8.0 (1 H, m) 8.3-8.4 (1 H, m). MSm/z416(M+). Acetyl chloride (0.14 ml, 2.0 mmol) was added dropwise to a mixture of 2-(2- difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(piperazin-1 -yl)-1,3,5 -triazine (417 mg, 1.0 mmol) and THF (10 ml). The reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was poured into water, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated under vaccum, and the residue was purified by silica gel column to give the target compound 4-(4- acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5 -triazine (354 mg, 7.7 mmol) in a yield of 77% as colorless crystals. Melting point: 223°C 1H NMR (CDCl3) 8: 2.18 (3 H, s), 3.6-4.0 (16H, m), 7.3-7.5 (2 H, m), 7.55 (1 H, t, J = 53.5 Hz), 7.9-8.0 (1 H, m) 8.3-8.4 (1 H ,m). MS m/z 458 (M+). The following compounds were manufactured in a manner similar to Production Example 34. [00110] Production Example 33 2-(2-Difluoromethylbenzimidazol-l-yl)-6-(4-formylpiperazin-l-yl)-4-morpholino-l,3,5- triazine Melting point: 228-30°C 1H NMR (CDCl3) δ: 3.8-4.1 (16H, m), 7.2-7.5 (2 H, m), 7.54 (1 H, t, J = 54Hz), 7.8-8.0 (1 H, m), 8.17 (1H, s), 8.3-8.4 (1 H ,m). MS m/z 444 (M+). [00111] Production Example 34 2-(2-Difluoromethylbenzimidazol-l-yl)-4-morpholino-6-(3-oxopiperazin-l-yl)-l,3,5- triazine Melting point: 255-57°C lH NMR (CDCl3) δ: 3.5-3.9 (14H, m), 6.48 (1H, brs), 7.2-7.5 (2 H, m), 7.59 (1 H, t, J = 54Hz), 7.8-7.9(1 H, m) 8.2-8.4 (1 H ,m). MS m/z 430(M+). [00112] Production Example 35 38 2-(2-Difluoromethylbenzimidazol-l-yl)-6-(3,5-dioxopiperazin-l-yl)-4-morpholino-l,3,5- triazine Melting point: 230-32°C 1H NMR (CDCl3) δ: 3.5-3.9 (12H, m), 7.2-7.5 (2 H, m), 7.59 (1 H, t, J = 55Hz), 7.9-8.0 (1 H, m) 8.3-8.4 (1 H ,m). MS m/z 444 (M+). [00113] Production Example 36 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-(4-benzylcarbonylpiperazin-1 -yl)-6- morpholino-l,3,5-triazine (Compound 29) (STK1515) Melting point: 178-181°C 1H NMR (CDCl3) δ: 3.81 (2 H , s), 3.5-3.9(16 H, m), 7.2-7.5(7 H, m), 7.52 (1 H, t, J = 54 Hz,), 7.89 (1 H , d, J = 8 Hz,),8.30 (1 H , d, J = 8 Hz,). MS m/z 534 (M+). [00114] Production Example 37 4-(4-Acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5- triazine (Compound 30) (STK01529) Melting point: 79-81°C NMR (CDCl3-d1)δ: 2.19 (3H, s) ,2.60(2H,s), 3.70-4.00(16H,m), 7.30-7.50(2H,m), 7.57(1 H,t,J=54Hz), 7.90(1H, d ,J=8Hz),8.33(lH, d ,J=8Hz) MS m/z: 472 [00115] Production Example 38 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-[4-(2-furoyl)piperazin-1 -yl]-6-morpholino- 1,3,5-triazine (Compound 31) (STK01531) Melting point: 220-222°C NMR (CDCl3-d1)δ: 3.80-4.00(16H,m), 6.53(1H, d ,J=2Hz), 7.01(lH, d ,J=2Hz), 7.30- 7.60(4H,m),7.80(lH, d, J=8Hz), 8.34(1H, d, J=8Hz) MS m/z : 510 [00116] Production Example 39 2-(2-Difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin-l-yl)-6- morpholino-l,3,5-triazine (Compound 32) (STK01539) Melting point: 203-205°C NMR (CDCl3-d1)δ: 2.90(6H,s),3.30-3.40(4H,m),3.80-4.00(12H,m), 7.30-7.40(2H,m), 7.56(lH,t,J=54Hz), 7.89(1H, d, 8Hz),8.34 (1H, d, 8Hz) 39 MS m/z : 487 [00117] Production Example 40 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-(4-methoxylacetylpiperazin-1 -yl)-6- morpholino-l,3,5-triazine (Compound 33) (STK01540) Melting point: 72-75°C NMR (CDCl3-d1)δ: 3.46(3H, s), 3.60-4.00(16H,s), 4.17 (2H, s) 7.30-7.50(2H,m), 7.55(lH,t,J=54Hz), 7.90(1H, d, J=8Hz), 8.34(1H, d, J=8Hz) MS m/z: 488 [00118] Production Example 41 2-(2-Difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazin-1 -yl] -6- morpholino-l,3,5-triazine (Compound 34) (STK01541) NMR (CDCl3-d1) δ: 1.17 (2H, m) ,2.60-2.70(4H, m), 4.70 (lH,brs) 3.50-4.00(16H,m), 7.30-7.50(2H,m), 7.56(lH,t,J=54Hz), 7.90(1H, d, J=8Hz),8.33(lH, d, J=8Hz) MS m/z: 474 [00119] Production Example 42 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)- 1,3,5-triazine (Compound 35) (STK01542) Melting point: 198-202°C NMR (CDCl3-d1) δ: 1.20 (3H, t,J=7Hz) ,2.42(2H, q ,J=7Hz), 3.50-4.00(16H,m), 7.30- 7.50(2H,m), 7.56(lH,t,J=54Hz), 7.90(1H, d, J=8Hz),8.33(lH, d, J=8Hz) MS m/z: 472 [00120] Production Example 43 2-(2-Difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6- morpholino-l,3,5-triazine(STK01553) Melting point: 255-260°C NMR (CDCl3-d1) δ: 3.59(4H,brs), 3.76(3H,s),3.70-3.95(12H,s), 7.30-7.50(2H,m), 7.55(1 H,t,J=54Hz), 7.9O(1H, d, J=8Hz),8.34(lH, d, J=8Hz) MS m/z: 474 [00121] The following were produced in the same manner as in Production Example 24. Production Example 44 2-(2-Difluoromethyl-4-methoxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6- morpholinopyrimidine (Compound 36) Melting point: 166-168°C 40 NMR (CDCl3) δ: 1.30(6H, s), 3.49(2H, s), 3.4-3.9(12H, m), 4.05(3H, s), 5.47(1H, s), 6.79(1H, d, J=8Hz), 7.32(1H, t, J=8Hz), 7.41(1H, t, J=54Hz), 7.78(1H, d, J=8Hz). MSm/z: 474(M+) [00122] Production Example 45 2-(2-Difluoromethyl-4-methoxybenzimidazol-1 -yl)-4-(cis-2,3 -dimethylmorpholino)-6- morpholinopyrimidine (Compound 37) Melting point: 176-178°C NMR (CDCl3) δ: 1.20(3H, d, J=5Hz), 1.22(3H, d, J=5Hz), 3.6-3.7(lH, m), 3.6-4.1(13H, m), 4.05(3H, s), 5.47(1H, s), 6.79(1H, d, J=8Hz), 7.32(1H, t, J=8Hz), 7.42(1H, t, J=53Hz), 7.78(1H, d, J=8Hz). MS m/z: 474(M+) [00123] Production Example 46 2-(2-Difluoromethyl-4-ethoxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6- morpholinopyrimidine (Compound 38) Melting point: 114-116°C NMR (CDCl3) δ: 1.56(3H, t, J=7Hz), 3.49(2H, s), 3.5-3.9(12H, m), 4.32(2H, q, J=7Hz), 5.47(1H, s), 6.78(1H, d, J=8Hz), 7.30(1H, t, J=8Hz), 7.41(1H, t, J=53Hz), 7.76(1H, d, J=8Hz). MS m/z: 488(M+) [00124] Drug Efficacy Assays Next, the assay protocols for pharmacological effects and toxicity of the heterocyclic compounds represented by the general Formula (I) and their results will be hereinafter described. Here, the compound number for each test substances corresponds to the compound number assigned to each of the above heterocyclic compounds. [00125] Assay Example 1 Mitogen Response Inhibititory Activity Spleen cells (2 x 106 cells/mL) prepared from C57BL/6N female mice (8 weeks old, purchased from Charles River Laboratories Japan Inc.) were suspended in RPMI 1640 medium (containing 10% fetal bovine serum, 10 mM HEPES, 1 mM pyruvic acid, 4.5 g/L glucose, 100 units/mL penicillin, and 0.1 mg/mL streptomycin), and seeded in wells of a 96 well plate at 0.225 mL per well. Serial dilutions of test substances were added to respective wells, and then concanavalin A (Con A, 3 µg/mL), lipopolysaccharide (LPS, 100 µg/mL), or an anti-mouse IgM antibody (100 µg/mL) were added. Thereafter, they 41 were incubated under conditions of carbon dioxide 5 % at a temperature 37°C for 3 days. Next, Alamar Blue solution was added at 50 µL per 150 µL, and after having cultured for one day, the fluorescence intensity at 590 nm using an excitation wavelength of 530 nm was determined by Cytoflour 4000 (Applied Biosystems). As a result, as shown in Table 1, it was revealed that s-triazine analogs inhibit proliferation of mouse spleen cells induced by Con A, LPS, or an anti-IgM antibody. [00126] [Table 1] Test Compounds Inhibition of Con A response Inhibition of LPS response Inhibition of Anti-IgM antibody response Compound 1 + + nd Compound 2 + + + Compound 3 + + nd Compound 4 ++ ++ ++ Compound 5 + + + Compound 6 + + + Compound 7 + + + Compound 8 ++ + ++ Compound 9 ++ ++ ++ Compound 10 + ± + Compound 12 ++ ++ ++ Compound 13 ++ ++ ++ Compound 17 + ± + Compound 19 ++ ++ nd Compound 20 +++ +++ +++ Compound 21 +++ +++ +++ Compound 22 +++ +++ +++ Compound 24 + + + Compound 25 ++ + nd Compound 26 +++ ++ nd Compound 27 +++ + nd Compound 28 +++ ++ nd 42 [00127] Assay Example 2 Proliferation Inhibition Assay for Human Peripheral Blood Mononuclear Cells 43 4 mL of blood collected from healthy subjects was placed on 3 mL of MonoPoly Resolving Medium, and after centrifugation, the mononuclear cell (PBMC) fraction was collected. After washing with saline, PBMC (1 x 105 cells/mL) was suspended in RPMI 1640 medium (containing 10% fetal bovine serum, 10 mM HEPES, 1 mM pyruvic acid, and 4.5 g/L glucose). Next, after having added an anti-CD28 antibody (1 µg/mL) to the suspension, they were seeded on an anti-human CD3 T cell activation plate (BD Bioscience) at a capacity of 0.135 mL per well. Then, serial dilutions of test substances were added to respective wells, and incubated under conditions of carbon dioxide 5 % at a temperature 37°C. After 3 days, Alamar Blue solution was added at 50 µL per well, and after incubation for one day, a fluorescence intensity at 590 nm using an excitation wavelength of 530 nm was determined by Cytoflour 4000 (Applied Biosystems). As a result, as shown in Table 2, it was revealed that s-triazine analogs inhibit the growth of human T cells induced by an anti-CD3 antibody and an anti-CD28 antibody. [00128] [Table 2] [00129] Assay Example 3 Activation Inhibition Assay for Human Peripheral Blood Mononuclear Cells In accordance with the method of Assay Example 2, PBMC (2 x 106 cells/mL) was isolated from human peripheral blood, suspended in RPMI 1640 medium (containing 10% fetal bovine serum, 10 mM HEPES, 1 mM pyruvic acid, and 4.5 g/L glucose), and seeded in wells of a 96 well plate at 0.225 mL per well. The test substances were added to respective wells, and then an anti-CD3 antibody (2 µg/mL) and an anti-CD28 antibody (1 µg/mL) were added. Then, after incubation under conditions of carbon dioxide 5% at a temperature 37°C for 6 hours, the expressions of CD40L and CD69, activation markers, were analysed by flow cytometry. As a result, when the cells were stimulated by both an anti-CD3 antibody and an anti-CD28 antibody, CD40L was expressed on 14.4% of PBMC, which was also CD4 positive. However, the proportion of the cells which expressed CD40L decreased when the cells had been treated with test substances (ZSTK474: 4.9%; 913: 3.7%, 1213: 3.6%). Although CD69 was expressed on 28.8% (CD4-positive) and 50.9% (CD4-negative) of PBMC, the proportions of CD4-positive cells (ZSTK 474: 18.8%, 913: 10.1%, 1213:17.7%) and CD4-negative cells (ZSTK 474: 17.7%, 913: 10.5%, 1213: 22.4%) which expressed CD69 decreased when the cells had been treated with test substances. Thus, the s-triazine analogs were shown to inhibit the activation of lymphocytes (Figure 1). [00130] Assay Example 4 Adjuvant-Induced Arthritis Inhibitory Action Lyophilized Mycobacterium butyricum suspended in Freund's incomplete adjuvant was intradermally administered to the base of the tail of Lewis male rats (7 weeks old, purchased from Charles River Laboratories Japan Inc.) to induce adjuvant-induced arthritis. Then, 10 days after the induction of the adjuvant-induced arthritis, the test substances suspended in 0.5% hydroxypropylcellulose (HPC) were orally administered on consecutive days. Furthermore, after the onset of the arthritis, the volume of the hind paw was measured using a hindpaw edema volume measuring apparatus (TK105, Physio-Tech). As a result, for the test substances, as shown in Figure 2, a statistically significant 44 (analysis of variance, Dunnett's test P after day 14 was confirmed for the present model study. [00131] Assay Example 5 Collagen-Induced Arthritis Inhibitory Action Bovine type II collagen suspended in Freund's complete adjuvant was intradermally administered to the base of tail of DBA1 male mice (7 weeks old, purchased from Charles River Laboratories Japan Inc.) on day 1 and day 21. Then, from day 28 when 50% of the mice developed arthritis, the test substances suspended in 0.5% hydroxypropylcellulose (HPC) were orally administered on consecutive days. Here, the efficacy was evaluated by scoring the arthritis. Specifically, for each paw, the degree of arthritis was evaluated according to: no symptoms: 0; redness or swelling of one joint: 1; redness or swelling for two or more joints: 2; redness or swelling over the entire paw: 3; and maximum redness or swelling over the entire paw: 4. As a result, it was revealed that ZSTK474 inhibited the progression of the collagen-induced arthritis in a dose-dependent manner. For the group administered 50 or 100 mg/kg of the above compound, after day 30, a statistically significant efficacy was recognized (Dunnett's test P administered 50 mg/kg of the above compound, the conditions were exacerbated after day 40, and no significant difference was recognized in comparison with the control group after day 44 (Figure 3). [00132] Assay Example 6 Inhibition Assay for Proliferation of Rabbit Synoviocyte Rabbit synoviocytes HIG-82 suspended in HAM medium (containing 10% fetal bovine serum, 25 mM HEPES, and 0.1 mg/mL kanamycin) (with 4 x 104 cells/mL) were seeded in wells of a 96 well plate at 0.135 mL per well. Then, 15 p.L of each of serial dilutions of test substances was added to a respective well, and incubated under conditions of carbon dioxide 5 % at a temperature 37°C. Alamar Blue solution was added at 50 µL per well on day 0 and day 3, and incubated for one day, and thereafter fluorescence intensity at 590 nm using an excitation wavelength of 530 nm was determined by Cytoflour 4000 (Applied Biosystems). As shown in Table 3, it was demonstrated that s- triazine analogs inhibited cell division of rabbit synoviocytes. 45 [00133] [Table 3] [00134] Assay Example 7 Allogeneic Mixed Lymphocyte Reaction Spleen cells prepared from C57BL/6N female mice (8-10 weeks old, purchased from Charles River Laboratories Japan Inc.) and peripheral lymph node mononuclear cells prepared from BALB/c female mice (8-10 weeks old, purchased from Charles River Laboratories Japan Inc.) were used as stimulator cells and responder cells, respectively. The respective cells were suspended in RPMI 1640 medium (containing 10% fetal bovine serum, 100 units/mL penicillin, and 0.1 mg/mL streptomycin) (with 2 x 106 cells/mL). Then, the stimulator cells (50 uL) treated with mitomycin C (50 mg/mL, 30 minutes) were added to the responder cells (100 uL). Thereafter, serial dilutions of test substances were added to respective wells, and incubated under conditions of carbon dioxide 5% at 37°C for 86 hours. Finally, the cell proliferation was examined using a BrdU cell proliferation kit (Calbiochem). As a result, as shown in Table 4, it was found that the s-triazine analogs inhibited the allogeneic mixed lymphocyte reaction. [00135] [Table 4] 46 [00136] Assay Example 8 Proliferation Inhibitory Activity on Hematologic Neoplasm Cells Daudi cells (5 x 105 cells/mL), Jurkat cells (5 x 105 cells/mL), THP-1 cells (5 x 105 cells/mL), U 937 cells (5 x 105 cells/mL), and HL 60 cells (5 x 105 cells/mL) suspended in RPMI 1640 medium (containing 10 % fetal bovine serum, 10 mM HEPES, 1mM pyruvic acid, 4.5 g/L glucose, 100 units/mL penicillin, and 0.1 mg/mL streptomycin) were seeded in 96 well plates at a capacity of 0.135 mL per well. Serial dilutions of test substances were added to respective wells at 15 µL/well, and incubated under conditions of carbon dioxide 5 % at 37°C for 3 days. Thereafter, Alamar Blue solution was added at 50 µL, and after incubation for one day, the fluorescence intensity at 590 run using an excitation wavelength of 530 nm was determined by Cytoflour 4000 (Applied Biosystems). As a result, as shown in Table 5, it was revealed that s-triazine analogs inhibited the proliferation of hematologic neoplasm cells. 47 [00137] [Table 5] [00138] Assay Example 9 Therapeutic Action on Human B Lymphoma Xenografted Model Daudi cells (1 x 107 cells/mL) cultured in RPMI 1640 medium (containing 10 % fetal bovine serum, 10 mM HEPES, lmM pyruvic acid, 4.5 g/L glucose, 100 units/mL penicillin, and 0.1 mg/mL streptomycin) were implanted subcutaneously in the chests of 8 week-old NOD/SCID mice. After day 20 when the tumor had grown to the volume of about 800 mm3, Compound 8 (400 mg/kg) was administered orally. As a result, as shown in Figure 4, the increase in tumor volume in the present model was inhibited. [00139] Assay Example 10 Fulminant Hepatitis Model BALB/c male mice (7 weeks old, purchased from Charles River Laboratories Japan Inc.) were used in the experiment. After having orally administered the test substances suspended in 5 % HPC, galactosamine (800 mg/kg) and LPS (110 µg/kg) were intraperitoneally administered. Then, survival rates at 72 hours after administration were obtained. As a result, as shown in Table 6, the test substances improved the survival rate due to galactosamine and LPS. [00140] [Table 6] 48 [00141] Assay Example 11 Toxicologic Test for Single Oral Administration A single oral dose toxicity of typical heterocyclic compounds was examined using SD male rats (6 weeks old, weight 162-188 g), and as a result, for Compound 8, no examples of death were recognized even with 1200 mg/kg, and for Compound 14, LD50 was 600- 900 mg/kg. [00142] Assay Example 12 Ames Test Using 5 strains of Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2uvrA, the test substances (Compound 8, Compound 10, Compound 12 and Compound 14) were tested for their mutagenesis according to a preincubation method. As a result, with or without metabolic activation due to S-9, even in 5000 µg/flat plate (maxium dose), no increase was observed in the colony number of reverse mutation in any tested strains, so mutagenesis was negative. Accordingly, in addition to in vivo tests such as rat adjuvant induced arthritis assay, mouse collagen induced arthritis assay, human B-lymphoma xenografted model, fulminant hepatitis inhibition assay and toxicologic test for single oral administration, s-triazine analogs were found to be safer compounds. [00143] The agents of the present invention inhibit the response to T cells and B cells induced by Con A, LPS, anti-IgM antibody, anti-CD3 antibody + anti-CD28 antibody, thereby exhibiting PI3K inhibitory action on immune cells. Specifically, the drugs of the present invention can be used in the treatment and prevention of disorders of immune system attributable to the hyperfunctioning of PI3K. As disorders of immune system attributable to the hyperfunctioning of PI3K, mention may be made of: autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren 49 syndrome, or the like; organ dysfunction associated with autoimmune diseases such as uveitis, glomerulonephritis, thyroiditis, pancreatitis, bone destruction or the like; rejection after transplantation of tissues, graft versus host disease after bone-marrow transplantation; inflammatory bowel diseases such as ulcerative colitis or Crohn disease; inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis; inflammatory or allergenic respiratory disorders such as chronic obstructive pulmonary disease or asthma; allergenic conjunctivitis or rhinitis; hematologic neoplasm originated from immune cells, such as B-cell lymphoma, T-cell lymphoma, myeloid leukemia or the like; sepsis triggered by infection to gram-negative bacteria or coronavirus, severe acute respiratory syndrome, fulminant hepatitis or the like. [00144] Assay Example 13 Test for Measuring Blood Level A pharmacokinetic study was performed using 6 week-old BDF1 male mice. The test substances were mixed with hydroxylpropylcellulose (low-molecular weight form) [HPC(L)] in 2.5-fold of the drug weight, and dissolved in dichloromethane. The solventwas evaporated to dryness. To make the dosing formation, the residue was suspended in distilled water to prepare the drug level of 20 mg/mL. The test compounds were administered compulsorily and orally at a dose of 200 mg/kg to the mice that had been starved for 16 hours. One hour after the administration, blood was collected from the orbits of two mice to obtain serum. Internal standards solution and 1 ml of distilled water were added to 100 µL of serum thus obtained, and then extracted with diethylether. The solvent was evaporated under vacuum, and the residue was resolved with eluent to provide samples for the HPLC measurement. HPLC was performed by using reversed-phase type column, and acetonitrile-phosphate buffer (pH 2.5) was used as the eluent. Using regression curves (Y=aX+b) obtained from the standards, the drug levels in the sample serum were calculated. Their results are shown in Table 7 below. 50 [00145] [Table 7] As shown in the above test results, the compounds of the present invention having an acyl group at position 4 of the piperazine ring exhibited high blood levels quickly, one hour after the administration, as compared with the known control compounds 2, 3 and 9. [00146] Assay Example 14 Proliferation Inhibitory Activity on Solid Tumor Cells Used in the test were MCF-7 cells which were established from human breast cancer and were cultured routinely under the conditions of 37°C and 5% CO2, in MEM medium supplemented with 10 % fetal calf serum, 25 mM of HEPES and 0.1 mg/ml kanamycin. The MCF-7 cells in a logarithmic growth phase were treated with trypsin/EDTA to prepare single cell suspension adjusted to 4.0 x 104 cells/ml in MEM medium (supplemented with 10 % fetal calf serum, 25 mM of HEPES and 0.1 mg/ml kanamycin). Test compounds were dissolved in DMSO and diluted with RPMI 1640 medium (supplemented with 10 % fetal calf serum, 25 mM of HEPES and 0.1 mg/ml kanamycin) to a concentration of 2.0 x 10-4 to 2.0 x 10-9M. The cell suspension was filled in a 96-wells microplate at a rate of 0.1 ml per well and was cultured for 24 hours so as to make the cells to adhere to the microplate. Then, it was added with 0.1 ml of the sample solution and cultured at 37°C for 72 hours in 5% CO2. 50 % Growth inhibition concentrations (GI50 µM) were calculated from growth inhibitions at various sample concentrations. The results are as shown in Table 8. In the foregoing, when the cells other than MCF-7 are used, instead of adding 10 % fetal bovine serum, the following media were used, and the following single cell suspensions were prepared. PC-3 prostate cancer cells: 10% fetal bovine serum in F12K medium, single cell suspension of 2 x 104 cells; A549 lung cancer cells: 10% fetal bovine serum in DMEM medium, single cell suspension of 1.5 xl04 cells; WiDr colon cancer cells: 10% fetal bovine serum in MEM medium, single cell suspension of3xl04 cells; 51 B16F10 melanoma cells: 10% fetal bovine serum in RPMI 1640 medium, single cell suspension of 1 x 104 cells; Compound 25 0.27 3.21 0.92 0.99 0.98 Compound 27 0.31 4.63 1.32 1.12 1.14 Compound 28 0.27 2.66 1.27 0.83 1.21 Compound 29 0.32 3.93 2.58 1.32 0.70 Compound 30 0.77 3.32 3.74 1.52 0.41 Compound 31 0.32 1.51 1.43 0.65 0.05 Compound 32 0.38 2.14 1.33 0.83 Compound 33 0.51 2.91 1.46 1.05 Compound 34 0.55 2.91 2.07 1.38 0.14 Compound 35 0.73 2.84 2.10 1.22 0.10 INDUSTRIAL APPLICABILITY [00148] The agents of the present invention can be used for the prevention or treatment of disorders of immune system involving in PI3K, such as autoimmune diseases, organ transplantation, allergic or inflammatory diseases, hematologic neoplasm, sepsis or the like. Furthermore, they can be used for the treatment of solid tumors. Moreover, they can be used as PI3K inhibitors for the treatment of a variety of disorders. 52 Claims 1. An immunosuppressive agent comprising as an effective ingredient a heterocyclic compound represented by Formula (I): wherein, X represents a nitrogen atom or CH; both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1- C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano (optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being optionally substituted with a substituent selected from the group consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, a substituted carbamoyl); or a pharmaceutically acceptable salt thereof. 2. The immunosuppressive agent according to Claim 1, wherein either of R1 or R2 is a hydroxyl group. 53 3. The immunosuppressive agent according to Claim 1 or 2, wherein either of R1 or R2 is a hydroxyl group, and R3 is a difluoromethyl. 4. The immunosuppressive agent according to Claim 1, wherein both of R1 and R2 are hydrogens, and R3 is a difluoromethyl. 5. The immunosuppressive agent according to any one of Claims 1 to 4, wherein R6 is a 4-acetylpiperazine. 6. The imminosuppressive agent according to Claim 1, wherein said heterocyclic compound is selected from the group consisting of: 2-(2-methylbenzimidazol-1 -yl)-4,6-dimorpholino-1,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4,6-dimorpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-morpholino-6-(piperazin-l-yl)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5 -oxo-1,4-diazepan-1 -yl)-1,3,5- triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(3 -oxopiperazin-1 -yl)-1,3,5 - triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-6-(4-formylpiperazin-1 -yl)-4-morpholino-1,3,5- triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-6-(3,5-dioxopiperazin-l-yl)-4-morpholino-l,3,5- triazine; 2-(benzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-morpholino-6-piperidino-l,3,5-triazine; 2-(6-amino-2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino)-6- morpholino-1,3,5-triazine; 2-(2-difluoromethyl-6-ethoxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine; 2-(2-difluoromethyl-4-methylbenzimidazol-l-yl)-4,6-dimorpholino-l,3)5-triazine; 2-(2-difluoromethyl-5-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine; 2-(2-aminobenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine; 2-(6-amino-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6- morpholino-1,3,5-triazine; 54 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethylpyrrolidin-1 -yl)-6- morpholino-l,3,5-triazine; 2-(2-methylbenzimidazol-1 -yl)-4,6-dimorpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-l-yl)-4,6-dimorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(piperazin-1 -yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5 -oxo-1,4-diazepan-1 - yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-morpholino-6-(3-oxopiperazin-l-yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-1-yl)-6-(4-formylpiperazin-1-yl)-4- morpholinopyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6- morpholinopyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-(3,3-dimethylmorpholino)-6- morpholinopyrimidine; 2-(2-aminobenzimidazol-1 -yl)-4,6-dimorpholinopyrimidine; 2-(2-difluoromethyl-4-methoxybenzimidazol-l-yl)-4-(2,6-dimethylmorpholino)-6- morpholinopyrimidine; or 2-(5-ammo-2-difluoromethylbenzimidazol-l-yl)-4,6-di(2,6- dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(2-hydroxymethylpyrrolidin-1-yl)-6- morpholinopyrimidine; 2-(6-amino-4-chrolo-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6- morpholino-1,3,5-triazine; 2-(6-amino-4-chrolo-2-difluoromethylbenzimidazol-l-yl)-4-[methyl(l-methylpiperidin-4- yl)amino]-6-morpholino-l,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethylpyrrolidin-1 -yl)-6- morpholino-1,3,5-triazine; 2-(4-chrolo-2-difluoromethyl-5 -hydroxybenzimidazol-1 -yl)-4,6-dimorpholino-1,3,5- triazine; 2-(5,6-dimethyl-2-difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5- triazine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(cz.y-2,3 - dimethylmorpholino)-l,3,5-triazine; 55 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(trans-2,3- dimethylmorpholino)-l,3,5-triazine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2- dimethylmorpholino)-l,3,5-triazine; 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-6- morpholino-1,3,5-triazine; 4-(4-acetylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6-morpholino- 1,3,5-triazine; 4-(4-acetylpiperazin-1 -yl)-2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino-1,3,5- triazine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6- morpholinopyrimidine; 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3- dimethy lmorpholino)pyrimidine; 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3- dimethylmorpholino)pyrimidine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2- dimethylmorpholino)pyrimidine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-6- morpholinopyrimidine; 4-(4-acetylpiperazin-l-yl)-2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-6- morpholinopyrimidine; 4-(4-acetylpiperazin-1 -yl)-2-(2-hydroxymethylbenzimidazol-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- morpholino-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- (cis-2,3-dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- (trans-2,3-dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- (2,2-dimethylmorpholino)-1,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(N,N- dimethylcarbamoylpiperazin)-1 -yl]-6-morpholino-1,3,5-triazine; 56 2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)- l-yl]-6-morpholino-l,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- morpholino-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-1 -yl]-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- (cis-2,3-dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- (trans-2,3 -dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- (2,2-dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(N,N- dimethylcarbamoylpiperazin)-l-yl]-6-morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)- 1 -yl] -6-morpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-morpholino- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cw-2,3- dimethylmorpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-(trans-2,3 - dimethylmorpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-(2,2- dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-[4-(2-furoyl)piperazin-1 -yl]-6- morpholino-1,3,5 -triazine; 2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6- morpholino-l,3,5-triazine; 4- [4-(2-furoyl)piperazin-1 -yl] -2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6- morpholinopyrimidine; 57 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cis-2,3- dimethylmorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(trans-2,3- dimethylmorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(2,2- dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6- morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6- morpholinopyrimidine; 4-[4-(2-furoyl)piperazin-1 -yl]-2-(2-hydroxymethylbenzimidazol-1 -yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5- triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3- dimethylmorpholino)-1,3,5-triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3- dimethylmorpholino)-l,3,5-triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2- dimethylmorpholino)-1,3,5-triazine; 4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethy-4-hydroxybenzimidazol-1-yl)-6- morpholino)-l ,3,5-triazine; 4-(4-acetonylpiperazin-1-yl)-2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-6- morpholino-1,3,5-triazine; 4-(4-acetonylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-morpholino-1,3,5- triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(cis-2,3 - dimethylmorpholino)pyrimidine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3- dimethylmorpholino)pyrimidine; 4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2- dimethylmorpholino)pyrimidine; 58 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-l-yl)-2-(2-hydroxymethylbenzimidazol-l-yl)-6- morpholinopyrimidinne; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)-1,3,5- triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino)-6-(4- propionylpiperazin-1 -yl)-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino)-6-(4- propionylpiperazin-1 -yl)-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-(4- propionylpiperazin-1 -yl)-1,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin- l-yl)-l,3,5-triazine; 2-(4-aniino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)-l,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1-yl)-4-morpholino-6-(4-propionylpiperazin-1-yl)- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino-6-(4- propionylpiperazin-1 -yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino-6-(4- propionylpiperazin-1 -yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino-6-(4- propionylpiperazin-1 -yl)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin- l-yl)pyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)pyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)pyrimidine; 59 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazin-1 -yl)-6-morpholino- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazin-l-yl)-6-(cis-2,3- dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazin-l-yl)-6-(trans-2,3- dimethylmorpholino)-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazin-1 -yl)-6-(2,2- dimethylmorpholino)-1,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazin-1 -yl)-6- morpholino-1,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazin-1 -yl)-6- morpholino-1,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-morpholino- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(cis-2,3- dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(trans-2,3- dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(2,2- dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholino-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(cis-2,3 - dimethylmorpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(trans-2,3- dimethylmorpholino-1,3,5 -triazine; 60 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(2,2- dimethylmorpholino-l,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] - 6-morpholino-l,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholino-1,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholino-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(cis-2,3- dimethylmorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(trans-2,3- dimethylmorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(2,2- dimethylmorpholinopyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] - 6-morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6- morpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-[4-(3-hydroxypropyl)piperazi-1 -yl]-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxycarbonylpiperazin-l-yl)-6-(cis-2,3- dimetylmorpholino)-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans- 2,3-dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(2,2- dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)- 6-morpholino-l,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxycarbonylpiperazin-l-yl)-6- morpholino-1,3,5-triazine; 61 2-(2-hydroxymethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6- morpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(cis-2,3 - dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans- 2,3-dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxycarbonylpiperazin-l-yl)-6-(2,2- dimethy lmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)- 6-morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5-oxo-1,4-diazepan-1 -yl)-1,3,5- triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(3 -oxopiperazin-1 -yl)-1,3,5 - triazine; and 2-(2-difluoromethylbenzimidazol-1 -yl)-6-(3,5-dioxopiperazin-1 -yl)-4-morpholino-1,3,5- triazine. 7. The immunosuppressive agent according to Claim 1, wherein the heterocyclic compound is selected from the group consisting of: 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethylpyrrolidin-1 -yl)-6- morpholino-1,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6- morpholinopyrimidine; and 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(3,3 -dimethylmorpholino)-6- morpholinopyrimidine. 8. The immunosuppressive agent according to Claim 1, wherein the heterocyclic compound is selected from the group consisting of: 62 2-(2-difluoromethylbenzimidazol-1 -yl)-4,6-dimorpholino-1,3,5-triazine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6- morpholinopyrimidine; and 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5- triazine. 9. The immunosuppressive agent according to any one of Claims 1 to 8, wherein the disorder of interest is rejection or graft versus host disease; an inflammatory bowel disease such as ulcerative colitis or Crohn disease; an inflammatory or allergenic skin disease such as psoriasis or atopic dermatitis; an inflammatory or allergenic respiratory disorder such as obstructive pulmonary disease or asthma; autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma or Sjogren syndrome; malignant lymphoma, multiple myeloma, leukemia; sepsis, fulminant hepatitis or the like. 10. A heterocyclic compound represented by the general Formula (II): wherein, n represents 0-2; X represents a nitrogen atom or CH; Y represents -(CH2)n1-, wherein n1 is 1-2; R1 and R2, both or either, represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a cyano group; R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6 alkylamino group, a methyl or a hydroxymethyl group; R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group; 63 R7 represents a hydrogen atom, a C1-C6 alkyl group, a formyl, a C1-C6 hydroxyalkyl, a C1- C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, or a substituted carbamoyl; or a pharmaceutically acceptable salt thereof. 11. The compound according to Claim 10, wherein the heterocyclic compound is: 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5- triazine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(cis-2,3- dimethylmorpholino)-l,3,5-triazine; 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3- dimethylmorpholino)-l,3,5-triazine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2- dimethylmorpholino)-l,3,5-triazine; 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-6- morpholino-1,3,5-triazine; 4-(4-acetylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6-morpholino- 1,3,5-triazine; 4-(4-acetylpiperazin-1 -yl)-2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino-1,3,5- triazine; 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6- morpholinopyrimidine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(cis-2,3- dimethylmorpholino)pyrimidine; 4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3- dimethylmorpholino)pyrimidine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2- dimethylmorpholino)pyrimidine; 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-6- morpholinopyrimidine; 4-(4-acetylpiperazin-l-yl)-2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-6- morpholinopyrimidine; 4-(4-acetylpiperazin-l-yl)-2-(2-hydroxymethylbenzimidazol-l-yl)-6- morpholinopyrimidine; 64 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- morpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- (cis-2,3-dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- (trans-2,3-dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- (2,2-dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(N,N- dimethylcarbamoylpiperazin)-1 -yl] -6-morpholino-1,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)- l-yl]-6-morpholino-l,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- morpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-1 -yl]-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- (cis-2,3-dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- (trans-2,3-dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6- (2,2-dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(N,N- dimethylcarbamoylpiperazin)-l-yl]-6-morpholinopyrimidine; 2-(4-arnino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)- 1 -yl] -6-morpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(2-furoyl)piperazin-1 -yl]-6-morpholino- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cis-2,3- dimethylmorpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(2-furoyl)piperazin-1 -yl]-6-(trans-2,3- dimethylmorpholino-l,3,5-triazine; 65 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(2,2- dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6- morpholino-1,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6- morpholino-1,3,5-triazine; 4- [4-(2-furoyl)piperazin-1 -yl] -2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cis-2,3- dimethylmorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-(trans-2,3 - dimethy lmorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(2,2- dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6- morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6- morpholinopyrimidine; 4-[4-(2-furoyl)piperazin-l-yl]-2-(2-hydroxymethylbenzimidazol-l-yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5 - triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3- dimethylmorpholino)-l,3,5-triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3- dimethylmorpholino)-1,3,5-triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2- dimethylmorpholino)-1,3,5-triazine; 4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-6- morpholino-1,3,5-triazine; 4-(4-acetonylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6- morpholino-1,3,5-triazine; 66 4-(4-acetonylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-morpholino-1,3,5- triazine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3- dimethylmorpholino)pyrimidine; 4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3- dimethylmorpholino)pyrimidine; 4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2- dimethy lmorpholino)pyrimidine; 4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6- morpholinopyrimidine; 4-(4-acetonylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6- morpholinopyrimidinne; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)-1,3,5- triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(cis-2,3 -dimethylmorpholino)-6-(4- propionylpiperazin-1 -yl)-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(trans-2,3 -dimethylmorpholino)-6-(4- propionylpiperazin-1 -yl)-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-(4- propionylpiperazin-1 -yl)-1,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin- l-yl)-l,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)-l,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino-6-(4- propionylpiperazin-1 -yl)pyrimidine; 67 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(trans-2,3 -dimethylmorpholino-6-(4- propionylpiperazin-1 -yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino-6-(4- propionylpiperazin-1 -yl)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin- l-yl)pyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)pyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 - yl)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-morpholino- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(cis-2,3- dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(trans-2,3- dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(2,2- dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(4-methoxyacetylpiperazi-1-yl)-6- morpholino-1,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholino-1,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-morpholino- 1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazi-1-yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(cis-2,3- dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(trans-2,3- dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(2,2- dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6- morpholinopyrimidine; 68 2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazi-1-yl)-6- morpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazi-1-yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(cis-2,3 - dimethylmorpholino-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(trans-2,3- dimethylmorpholino-1,3,5 -triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(2,2- dimethylmorpholino-1,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] - 6-morpholino-l,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholino-1,3,5 -triazine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholino-1,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(cis-2,3- dimethylmorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(trans-2,3 - dimethylmorpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(2,2- dimethy lmorpholinopyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] - 6-morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholino-1,3,5 -triazine; 69 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(cis-2,3 - dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans- 2,3-dimethylmorpholino)-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxycarbonylpiperazin-l-yl)-6-(2,2- dimethylmorpholino)-1,3,5-triazine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1-yl)- 6-morpholino-l ,3,5-triazine; 2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholino-1,3,5-triazine; 2-(2-hydroxymethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6- morpholino-l,3,5-triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxycarbonylpiperazin-l-yl)-6-(cis-2,3- dimethy lmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans- 2,3-dimethylmorpholino)pyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(2,2- dimethylmorpholino)pyrimidine; 2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)- 6-morpholinopyrimidine; 2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholinopyrimidine; 2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6- morpholinopyrimidine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5-oxo-1,4-diazepan-1-yl)-1,3,5- triazine; 2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(3 -oxopiperazin-1 -yl)-1,3,5- triazine; and 2-(2-difluoromethylbenzimidazol-l-yl)-6-(3,5-dioxopiperazin-l-yl)-4-morpholino-l,3,5- triazine. 70 12. An antitumor agent comprising as an effective ingredient a compound according to either of Claims 10 or 11. 71 A novel immunosuppressive agent, more specifically an immunosuppressive agent comprising, as an active ingredient, a heterocyclic compound represented by the general formula (I) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof; a novel heterocyclic compound represented by the general formula (II) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof; and use of the compound or salt as an antitumor agent.

Full Text

SPECIFICATION
IMMUNOSUPPRESSIVE AGENT AND ANTI-TUMOR AGENT COMPRISING
HETEROCYCLIC COMPOUND AS ACTIVE INGREDIENT
TECHNICAL FIELD
[0001] The present invention relates to novel immunosuppressive agents, and more
specifically immunosuppressive agents comprising heterocyclic compounds of a specific
structure as effective ingredients. The present invention also relates to novel chemical
compounds among the above heterocyclic compounds, and further to the use of such
novel compounds as antitumor agents.
BACKGROUND ART
[0002] In general, as disorders for which immunosuppressive agents may be used,
mention may be made of a number of autoimmune diseases such as rejection after
transplantation of organs or tissues, graft versus host disease after bone-marrow
transplantation, inflammatory bowel diseases such as ulcerative colitis or Crohn disease,
inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis,
inflammatory or allergenic respiratory disorders such as chronic obstructive pulmonary
disease or asthma, rheumatoid arthritis, systemic lupus erythematosus, scleroderma,
Sjogren syndrome, or the like. In addition, immunosuppressive agents such as
cyclophosphamide or methotrexate are employed also in the treatment of hematologic
neoplasms such as multiple myeloma, malignant lymphoma, leukemia or the like.
Furthermore, immunosuppressive agents may also be employed in combination with
antibiotics in the case of the treatment of disorders characterized by an enhanced immune
function associated with infection such as sepsis (Non-Patent Document 1).
Thus, a number of immunosuppressive agents are presently utilized as therapeutic
agents for the above-mentioned disorders in clinical practice. However, as it now stands,
there still remain many problems to be improved due to a failure to obtain a sufficient
therapeutic effect and an unexpected occurrence of side effects.
[0003] A variety of cells such as T, B lymphocytes and factors are known to be involved
in the inducement of the immune response. Since cyclosporin and tacrolimus, which are
presently used for organ transplantation or the like, are restricted in their efficacy to T
cells, there is a need for immunosuppressive agents which serve as agents for acting on
1

more extensive immune mechanisms, with less side effects in clinical applications, and
acting simultaneously on a variety of cells involved in the disorders.
Here, "a variety of cells involved in the disorders" are not limited to immune cells, i.e.,
T cells, B cells, monocytes, macrophages, NK cells, NKT cells, dendritic cells, neutrophils,
basophils, eosinophils, mast cells or the like. They should include cells in which functions
are affected by humoral factors released from immune cells or membrane receptors on the
immune cells. Examples of these cells include, but are not limited to platelets, vascular
endothelial cells, synoviocytes, osteoclasts, osteoblasts, chondrocytes, tracheal epithelial
cells, or the like. In addition, in the case where the humoral factors are autoantibodies,
cells expressing target antigens are also included.
[0004] Regarding benzimidazole ring-substituted s-triazine [1,3,5-triazine] derivatives and
pyrimidine derivatives, the present inventors have studied their cytostatic activity on solid
tumors, and have performed synthesis of a great number of such compounds as well as
verification of the relationship between antitumor activity and chemical structure (see
Patent Documents 1, 2, 3, 4 and 5).
[0005] In particular, s-triazine derivatives and pyrimidine derivatives having a specific
substituent at position 2 of the benzimidazole ring were found to exhibit an enhanced
cytostatic activity on solid tumors (see Patent Documents 3, 4 and 5). The processes for
the production of such derivatives are described in these patent documents, but are not
limited to these, and various reactions such as alkylation, alkylcarbonylation or the like
may be induced in the final products to employ the resultant as final compounds.
Non-Patent Document 1: T. Munster et.al. Clin. Exp. Rheumatol., 17 (Suppl. 18): S29-S36
(1999);
Patent Document 1: WO 99/05138 pamphlet
Patent Document 2: WO 00/43385 pamphlet
Patent Document 3: WO 02/088112 pamphlet
Patent Document 4: WO 2004/037812 pamphlet
Patent Document 5: WO 2005/095389 pamphlet
PROBLEMS TO BE SOLVED BY THE INVENTION
[0006] The present inventors demonstrated that the above compounds specifically
inhibited phosphatidylinositol 3-kinase (PI3K) activity (Non-Patent Document 2). PI3K is
an enzyme that phosphorylates phosphatidylinositol (PI) on the cell membrane, classified
into three subfamilies according to structures and its substrate specificity. Among these,
2

the compounds of the present invention specifically inhibit class I PI3K. Class I PI3K
phosphorylates PI, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-
biphosphate to produce phosphatidylinositol 3-phosphate, phosphatidylinositol 3,4-
biphosphate, and phosphatidylinositol 3,4,5-triphosphate, respectively.
Phosphatidylinositol 3,4,5-triphosphate thus produced serves as an intracellular second
messenger. Class I PI3K is expressed in various cells, and exhibits a wide spectrum of
functions such as cell proliferation, cell survival, glucose transport, cytoskeleton
regulation and the like. In PI3K gene-knockout animals, development of B cells, T cells
or the like and signal transduction are obstructed. Furthermore, the degranulation of mast
cells and migration of leukocytes are also obstructed (Non-Patent Document 3).
[0007] It is known that B cell proliferation by lipopolysaccharides (LPS) or anti-IgM
antibodies is inhibited by wortmannin or LY294002, PI3K inhibitors (Non-Patent
Document 4). Furthermore, wortmannin inhibits T cell proliferation induced by anti-CD3
antibodies and anti-CD28 antibodies (Non-Patent Document 5).
[0008] Hematologic neoplasms are characterized by a spontaneous enhancement of cell
division and an inhibition of apoptosis of the immune cells. However, abnormalities of
PI3K cascades such as reduction of PTEN proteins that dephosphorylate
phosphatidylinositol 3,4,5-triphosphate and enhancement of Akt phosphorylation have
been reported (Non-Patent Document 6). Furthermore, it was demonstrated that the
inhibition of PI3K may result in the inhibition of the cell division and the induction of
apoptosis of various hematologic neoplasms (e.g., Non-Patent Document 7).
[0009] Rheumatoid arthritis is a disorder characterized by immune abnormalities and
hypertrophy of synovial tissues. It is known that the hypertrophy of synovial tissues
results from proliferation and inhibition of apoptosis of synoviocytes. In inflamed
synovial tissues of patients with rheumatoid arthritis, the levels of phosphorylated Akt
were increased due to the activation of PI3K (Non-Patent Document 8). Moreover, it was
revealed that proliferation and inhibition of apoptosis of synoviocytes were normalized by
the inhibition of PI3K in vitro study (Non-Patent Document 9).
[0010] However, wortmannin and LY294002 have not been put to clinical use due to their
toxicity. Furthermore, although a lot of candidates that have therapeutic potential for a
wide spectrum of disorders such as inflammations, cancers and others have been
developed to take advantage of PI3K's inhibitory property, none has been put to clinical
use. Thus, there is a need for immunosuppressive agents which normalize the
3

hyperfunctioning of PI3K in various cells involved in disorder of immune system without
exhibiting any toxicity to living subjects.
Non-Patent Document 2: S. Yaguchi et al., 96th Annual Meeting of the AACR,
Anaheim, CA, USA. April 16-20,2005, #1691.
Non-Patent Document 3: R. Wetzker and C. Rommel, Current Pharmaceutical Design,
2004, 10, 1915-1922
Non-Patent Document 4: A. C. Donahue and D. A. Fruman, J. Immunol. 2003, 170, 5851-
5860
Non-Patent Document 5: S. G. Ward et al., Eur J Immunol. 1995, 25, 526-532
Non-Patent Document 6: P. Workmann, Biochem. Soc. Trans. 2004, 32, 393-396
Non-Patent Document 7: S. Uddin et al., Biochem. Biophys. Res. Commun. 2004, 320,
932-938
Non-Patent Document 8: H. Zhang et al., Arthritis Rheum 2001, 44,1555-1567
Non-Patent Document 9: T. Miyashita et al., Biochem Biophys Res Commun 2003, 312,
397-404
MEANS TO SOLVE THE PROBLEMS
[0011] In view of the foregoing, the present inventors have conducted extensive research
on the heterocyclic compounds disclosed in Patent Documents 1, 2, 3, 4 and 5 on the
assumption that some might be useful for the disorders for which immunosuppressive
agents are used, such as for autoimmune diseases, organ transplantation, allergic diseases,
hematologic neoplasm, sepsis or the like. As a result, they found that the heterocyclic
compounds represented by the following general formula (I) are effective, arriving at
completion of the present invention.
[0012] Thus, one aspect of the present invention provides an immunosuppressive agent
comprising as an effective ingredient a heterocyclic compound represented by the general
Formula (I):
4

wherein,
X represents a nitrogen atom or CH;
both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a
pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is
optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1-
C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen
at position 4 being optionally substituted with a substituent selected from the group
consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl,
an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano
(optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being
optionally substituted with a substituent selected from the group consisting of a formyl, a
C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a
benzylcarbonyl, and a substituted carbamoyl);
or a pharmaceutically acceptable salt thereof.
[0013] Here, one embodiment provides an immunosuppressive agent wherein in Formula
(I), either of R1 or R2 is a hydroxyl group. Another embodiment provides an
immunosuppressive agent wherein in Formula (I), either of R1 or R2 is a hydroxyl group,
and R3 is a difluoromethyl. A further embodiment provides an immunosuppressive agent
wherein in Formula (I), both of R1 and R2 are hydrogens, and R3 is a difluoromethyl. A
further embodiment provides an immunosuppressive agent wherein in Formula (I), R6 is a
4-acetylpiperazine.
5

[0014] In the foregoing, the disorders to be treated may be rejection and graft versus host
diseases, inflammatory bowel diseases such as ulcerative colitis or Crohn disease,
inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis;
inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or
asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus,
scleroderma or Sjogren syndrome; hematological neoplasms such as malignant lymphoma,
multiple myeloma, chronic leukemia, acute leukemia, or myelocytic leukemia; sepsis,
fulminant hepatitis and the like.
[0015] Here, one embodiment provides a PI3K inhibitor wherein in Formula (I), either of
R1 or R2 is a hydroxyl group. Another embodiment provides a PI3K inhibitor wherein in
Formula (I), either of R1 or R2 is a hydroxyl group, and R3 is a difluoromethyl. A further
embodiment provides a PI3K inhibitor wherein in Formula (I), both of R1 and R2 are
hydrogens, and R3 is a difluoromethyl. Furthermore, a PI3K inhibitor wherein in Formula
(I), R6 is a 4-acetylpiperazine is provided.
[0016] In the foregoing, the disorders to be treated may be rejection and graft versus host
diseases, inflammatory bowel diseases such as ulcerative colitis or Crohn disease,
inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis;
inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or
asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus,
scleroderma or Sjogren syndrome; hematological neoplasms such as malignant lymphoma,
multiple myeloma, chronic leukemia, or acute leukemia; sepsis, fulminant hepatitis and
the like.
[0017] Among the heterocyclic compounds of Formula (I) which are used in the
immunosuppressive agents in accordance with the present invention, some compounds are
novel in their structures. Thus, in another aspect, the present invention provides a
heterocyclic compound represented by the general Formula (II):

wherein,
6

n represents 0-2;
X represents a nitrogen atom or CH;
Y represents -(CH2)n1-, wherein n1 is 1-2;
R1 and R2, both or either, represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
R7 represents a hydrogen atom, a C1-C6 alkyl group, a formyl, a C1-C6 hydroxyalkyl, a C1-
C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, or a
substituted carbamoyl;
or a pharmaceutically acceptable salt thereof.
[0018] Here, in the above Formula (II), R7 may represent a hydrogen atom or a C1-C6
alkyl group; R6 may represent a hydrogen atom or a C1-C6 alkyl group. Examples include:
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-morpholino-1,3,5-
triazine;
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3-
dimethylmorpholino)-1,3,5-triazine;
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3-
dimethylmorpholino)-1,3,5 -triazine;
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2-
dimethylmorpholino)-l,3,5-triazine;
4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-6-
morpholino-1,3,5-triazine;
4-(4-acetylpiperazin-l-yl)-2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-6-morpholino-
1,3,5-triazine;
4-(4-acetylpiperazin-1 -yl)-2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino-1,3,5-
triazine;
4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-
morpholinopyrimidine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(cis-2,3-
dimethylmorpholino)pyrimidine;
7

4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3-
dimethylmorpholino)pyrimidine;
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2-
dimethylmorpholino)pyrimidine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-6-
morpholinopyrimidine;
4-(4-acetylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6-
morpholinopyrimidine;
4-(4-acetylpiperazin-1 -yl)-2-(2-hydroxymethylbenzimidazol-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
morpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
(cis-2,3-dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
(trans-2,3-dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-1 -yl]-6-
(2,2-dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoyl-
piperazin)-1 -yl] -6-morpholino-1,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-
l-yl]-6-morpholino-l,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
morpholino-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
(cis-2,3-dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
(trans-2,3-dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
(2,2-dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoyl-
piperazin)-1 -yl] -6-morpholinopyrimidine;
8

2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-
1-yl]-6-morpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-1 -yl]-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-morpholino-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cis-2,3-
dimethylmorpholino-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(trans-2,3-
dimethylmorpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-(2,2-
dimethylmorpholino)-1,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-
morpholino-l,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-
morpholino-1,3,5-triazine;
4-[4-(2-furoyl)piperazin-1 -yl]-2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cis-2,3-
dimethylmorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-(trans-2,3 -
dimethylmorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(2-furoyl)piperazin-1 -yl]-6-(2,2-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-
morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-
morpholinopyrimidine;
4-[4-(2-furoyl)piperazin-l-yl]-2-(2-hydroxymethylbenzimidazol-l-yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5-
triazine;
9

4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3-
dimethylmorpholino)-1,3,5-triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3-
dimethylmorpholino)-l,3,5-triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2-
dimethylmorpholino)-1,3,5-triazine;
4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-6-
morpholino-1,3,5-triazine;
4-(4-acetonylpiperazin-l-yl)-2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-6-
morpholino-1,3,5 -triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-hydroxymethylbenzimidazol-l-yl)-6-morpholino-l,3,5-
triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3-
dimethylmorpholino)pyrimidine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3-
dimethylmorpholino)pyrimidine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2-
dimethylmorpholino)pyrimidine;
4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-
morpholinopyrimidinn;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)-1,3,5-
triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino-6-(4-
propionylpiperazin-1 -yl)-l ,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino-6-(4-
propionylpiperazin-l-yl)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino-6-(4-
propionylpiperazin-1 -yl)-1,3,5-triazine;
10

2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin-
l-yl)-l,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)-l,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino-6-(4-
propionylpiperazin-1 -yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino-6-(4-
propionylpiperazin-1 -yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino-6-(4-
propionylpiperazin-1 -yl)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin-
l-yl)pyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)pyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazin-1 -yl)-6-morpholino-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(cis-2,3 -
dimethylmorpholino)-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(trans-2,3 -
dimethylmorpholino)-1,3,5 -triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(2,2-
dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholino-1,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholino-l,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-morpholino-
1,3,5-triazine;
11

2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(cis-2,3-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(trans-2,3-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(2,2-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(cis-2,3-
dimethylmorpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(trans-2,3-
dimethylmorpholino-1,3,5 -triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(2,2-
dimethylmorpholino-1,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -
6-morpholino-l ,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-
morpholino-1,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-[4-(3-hydroxypropyl)piperazi-1 -yl]-6-
morpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(cis-2,3-
dimethylmorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(trans-2,3 -
dimethylmorpholinopyrimidine;
12

2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(2,2-
dimethylmorpholinopyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -
6-morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(cis-2,3 -
dimethylmorpholino)-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans-
2,3-dimethylmorpholino)-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(2,2-
dimethylmorpholino)-1,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-
6-morpholino-1,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholino-l,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(cis-2,3-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans-
2,3-dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(2,2-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-
6-morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholinopyrimidine;
13

2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-morpholino-6-(5-oxo-l,4-diazepan-l-yl)-l,3,5-
triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-morpholino-6-(3-oxopiperazin-l-yl)-l,3,5-
triazine; and
2-(2-difluoromethylbenzimidazol-l-yl)-6-(3,5-dioxopiperazin-l-yl)-4-morpholino-l,3,5-
triazine.
[0019] Furthermore, the present inventors have found novel uses as antitumor agents for
the novel compounds represented by the above Formula (II). Thus, a further embodiment
relates to an antitumor agent comprising a compound of Formula (II) as an effective
ingredient. The disorders of interest may include, but are not limited to, lung cancer,
prostate cancer, breast cancer, colon cancer, gastric cancer, pancreatic cancer, liver cancer,
esophageal cancer, brain tumor, ovarian cancer, uterine cancer, malignant melanoma, renal
cancer, head and neck cancer, skin cancer, bladder cancer, osteogenic sarcoma, biliary
tract cancer, vulvar cancer, testicular neoplasm, penile cancer, colorectal cancer,
mediastinal neoplasm, urothelial carcinoma, choriocarcinoma, soft tissue sarcoma, thyroid
cancer, parathyroid cancer, adrenal cancer, malignant pheochromocytoma, germ cell
tumor and the like.
[0020] Furthermore, the present invention relates to the following various embodiments.
The present invention relates to a method for immunosuppression comprising
administering to a mammal a therapeutically effective amount of a heterocyclic compound
represented by the general Formula (I):

wherein,
X represents a nitrogen atom or CH;
14

both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difiuoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a
pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is
optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1-
C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen
at position 4 being optionally substituted with a substituent selected from the group
consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl,
an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano
(optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being
optionally substituted with a substituent selected from the group consisting of a formyl, a
C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a
benzylcarbonyl, and a substituted carbamoyl);
or a pharmaceutically acceptable salt thereof.
Here, in one embodiment, in Formula (I), either of R1 or R2 is hydroxyl group. In
another embodiment, in Formula (I), either of R1 or R2 is hydroxyl group, and R3 is
difiuoromethyl. In a further embodiment, in Formula (I), both of R1 and R2 are hydrogens,
and R3 is difiuoromethyl. In a further embodiment, in Formula (I), R6 is 4-
acetylpiperazine.
Furthermore, as the disorders to be treated, mention can be made of rejection and
graft versus host disease; inflammatory bowel diseases such as ulcerative colitis or Crohn
disease; inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis;
inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or
asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, Sjogren syndrome, or the like; hematologic neoplasms such as malignant
lymphoma, multiple myeloma, chronic leukemia, acute leukemia or the like; sepsis,
fulminant hepatitis and the like.
[0021] Yet another embodiment relates to a method for treating tumors comprising
administering to a patient a therapeutically effective amount of a heterocyclic compound
represented by the general Formula (II):
15

wherein,
n represents 0-2;
X represents a nitrogen atom or CH;
Y represents -(CH2)n1-, wherein n1 is 1-2;
R1 and R2, both or either, represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
R7 represents a hydrogen atom, a C1-C6 alkyl group, a formyl, a C1-C6 hydroxyalkyl, a C1-
C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, or a
substituted carbamoyl;
or a pharmaceutically acceptable salt thereof.
[0022] In yet another embodiment, the present invention relates to an immunosuppressive
composition comprising a therapeutically effective amount of a heterocyclic compound
represented by the general Formula (II):

wherein,
n represents 0-2;
X represents a nitrogen atom or CH;
Y represents -(CH2)n1-, wherein n1 is 1-2;
16

R1 and R2, both or either, represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
R7 represents a hydrogen atom, a C1-C6 alkyl group, a formyl, a C1-C6 hydroxyalkyl, a C1-
C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, or a
substituted carbamoyl; or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier. In a yet further embodiment, the invention relates to
a composition, in particular a pharmaceutical composition, and more preferably an
antitumor composition, comprising a therapeutically effective amount of a heterocyclic
compound represented by the general Formula (II) or a pharmaceutically acceptable salt
thereof and a pharmaceutically acceptable carrier.
[0023] Furthermore, the present invention relates to the following various embodiments.
The present invention relates to a PI3K inhibition method comprising administering to a
mammal a therapeutically effective amount of a heterocyclic compound represented by the
general Formula (I):

wherein,
X represents a nitrogen atom or CH;
both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
17

R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a
pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is
optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1-
C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen
at position 4 being optionally substituted with a substituent selected from the group
consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl,
an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano
(optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being
optionally substituted with a substituent selected from the group consisting of a formyl, a
C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a
benzylcarbonyl, and a substituted carbamoyl);
or a pharmaceutically acceptable salt thereof.
Here, in one embodiment, in Formula (I), either of R1 or R2 is hydroxyl group. In
another embodiment, in Formula (I), either of R1 or R2 is hydroxyl group, and R3 is
difiuoromethyl. In a further embodiment, in Formula (I), both of R1 and R2 are hydrogens,
and R3 is difiuoromethyl. In a further embodiment, in Formula (I), R6 is 4-
acety lpiperazine.
Furthermore, as the disorders to be treated, mention can be made of rejection and
graft versus host disease; inflammatory bowel diseases such as ulcerative colitis or Crohn
disease; inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis;
inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or
asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, Sjagren syndrome, or the like; hematologic neoplasms such as malignant
lymphoma, multiple myeloma, chronic leukemia, acute leukemia or the like; sepsis,
fulminant hepatitis and the like.
[0024] In yet another embodiment, the present invention relates to a PI3K inhibitory
composition comprising a therapeutically effective amount of a heterocyclic compound
represented by Formula (I):
18

wherein,
X represents a nitrogen atom or CH;
both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a
pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is
optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1-
C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen
at position 4 being optionally substituted with a substituent selected from the group
consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl,
an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano
(optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being
optionally substituted with a substituent selected from the group consisting of a formyl, a
C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a
benzylcarbonyl, and a substituted carbamoyl);
or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In
a yet further embodiment, the invention relates to a composition, in particular a
pharmaceutical composition, and more preferably a PI3K inhibitory composition,
comprising a therapeutically effective amount of a heterocyclic compound represented by
the general Formula (II) or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
[0025] Furthermore, the present invention relates to use of a heterocyclic compound
represented by Formula (I):
19

wherein,
X represents a nitrogen atom or CH;
both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difiuoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a
pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is
optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1-
C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen
at position 4 being optionally substituted with a substituent selected from the group
consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl,
an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano
(optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being
optionally substituted with a substituent selected from the group consisting of a formyl, a
C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a
benzylcarbonyl, and a substituted carbamoyl);
or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the
treatment of immune diseases, or as an immunosuppressive agent.
Here, in one embodiment, in Formula (I), either of R1 or R2 is hydroxyl group. In
another embodiment, in Formula (I), either of R1 or R2 is hydroxyl group, and R3 is
difiuoromethyl. In a further embodiment, in Formula (I), both of R1 and R2 are hydrogens,
and R3 is difiuoromethyl. In a further embodiment, in Formula (I), R6 is a 4-
acetylpiperazine.
20

Furthermore, as the disorders to be treated, mention can be made of rejection and
graft versus host disease; inflammatory bowel diseases such as ulcerative colitis or Crohn
disease; inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis;
inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or
asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, Sjogren syndrome, or the like; hematologic neoplasms such as malignant
lymphoma, multiple myeloma, chronic leukemia, acute leukemia or the like; sepsis,
fulminant hepatitis and the like.
[0026] In yet another embodiment, the present invention relates to use of a heterocyclic
compound represented by the general Formula (II):
wherein,
n represents 0-2;
X represents a nitrogen atom or CH;
Y represents -(CH2)n1-, wherein n1 is 1-2;
R1 and R2, both or either, represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
R7 represents a hydrogen atom, a C1-C6 alkyl group, a formyl, a C1-C6 hydroxyalkyl, a C1-
C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, or a
substituted carbamoyl;
or a pharmaceutically acceptable salt thereof in the manufacture of a composition for
threatment of tumors.
In yet another embodiment, the present invention relates to use of a heterocyclic
compound represented by Formula (I):
21

wherein,
X represents a nitrogen atom or CH;
both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a
pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is
optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1-
C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen
at position 4 being optionally substituted with a substituent selected from the group
consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl,
an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano
(optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being
optionally substituted with a substituent selected from the group consisting of a formyl, a
C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a
benzylcarbonyl, and a substituted carbamoyl);
or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the
inhibition of PI3K or as a PI3K inhibition agent.
Here, in one embodiment, in Formula (I), either of R1 or R2 is hydroxyl group. In
another embodiment, in Formula (I), either of R1 or R2 is hydroxyl group, and R3 is
difluoromethyl. In a further embodiment, in Formula (I), both of R1 and R2 are hydrogens,
and R3 is difluoromethyl. In a further embodiment, in Formula (I), R6 is a 4-
acetylpiperazine.
22

Furthermore, as the disorders to be treated, mention can be made of rejection and
graft versus host disease; inflammatory bowel diseases such as ulcerative colitis or Crohn
disease; inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis;
inflammatory or allergenic respiratory disorders such as obstructive pulmonary diseases or
asthma; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, Sjogren syndrome, or the like; hematologic neoplasms such as malignant
lymphoma, multiple myeloma, chronic leukemia, acute leukemia or the like; sepsis,
fulminant hepatitis and the like.
Yet other embodiments, modes and features of the present invention will be
apparent to those skilled in the art in view of the detailed description below.
EFFECT OF THE INVENTION
[0027] The agents of the invention are effective for the prevention or treatment of the
disorders attributable to the hyperfunctioning of PI3K such as autoimmne diseases, organ
transplantation, allergenic or inflammatory disorders, hematologic neoplasms, sepsis, and
treatment of tumors.
BRIEF EXPLANATION OF THE DRAWINGS
[0028] [Figure 1] Diagrams showing the effects of test substances on the upregulation
of CD 69 expression and CD 40L expression on human peripheral blood mononuclear
cells induced by anti-human CD3 antibody and anti-human CD28 antibody.
[Figure 2] Graph depicting a comparison between test substance-treated group and
control group on the volume change in hind paw of rats after the onset of arthritis.
[Figure 3] Graph depicting a comparison between test substance-treated group and
control group on the change in arthritis score after the onset of arthritis.
[Figure 4] Graph depicting a comparison between test substance-treated group and
control group in a human B lymphoma xenografted model.
BEST MODES FOR CARRYING OUT THE PRESENT INVENTION
[0029] The heterocyclic compound for use in the present invention is the one represented
by the general Formula (I):
23

wherein,
X represents a nitrogen atom or CH;
both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a
pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is
optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1-
C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen
at position 4 being optionally substituted with a substituent selected from the group
consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl,
an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano
(optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being
optionally substituted with a substituent selected from the group consisting of a formyl, a
C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a
benzylcarbonyl, and a substituted carbamoyl);
or its pharmaceutically acceptable salt.
[0030] In the above formula, "C1-C6" without any limitation means a group having 1 to 6
carbon atoms. "C1-C6 alkyl" includes alkyl groups of linear or branched chain, such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl and the like. "C1-
C6 alkoxy" includes alkoxy groups with linear or branched chain, such as methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, seobutoxy, n-pentyloxy, n-
hexyloxy and the like. "Hydroxy C1-C6 alkyl" means those groups having a hydroxyl
group bonded to any of the carbon atoms of the group defined by the above "C1-C6 alkyl".
24

When the above heterocyclic compound has an asymmetric carbon atom in its
structure, isomers from the asymmetric carbon atom and their mixture (racemic
compounds) exist, and any such compounds are to be included among the compounds of
the present invention.
[0031] Furthermore, the heterocyclic compounds that are used as effective ingredients of
the present invention may be in the form of an acid addition salt as a pharmaceutically
acceptable salt. Appropriate acid addition salts include inorganic acid salts such as
hydrochlorides, sulfates, hydrobromides, nitrates, phosphates or the like, and organic acid
salts such as acetates, oxalates, propionates, glycollates, lactates, pyruvates, malonates,
succinates, maleates, fumarates, malates, tartrates, citrates, benzoates, cinnamates,
methane sulfonates, benzene sulfonates, p-toluene sulfonates, salicylates or the like.
[0032] The compounds which can be used as the effective ingredients of the present
invention include, but are not limited to, the following heterocyclic compounds:
[0033] 2-(2-Methylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 1)
[0034] 2-(Benzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-l,3,5-
triazine (Compound 2)
[0035] 4,6-Dimorpholino-2-(2-hydroxymethylbenzimidazol-l-yl)-l,3,5-triazine
(Compound 3)
[0036] 2-(2-Difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 4)
[0037] 2-(2-Aminobenzimidazol-l-yl)-4,6-dimorpholinopyrimidine (Compound 5)
[0038] 2-(2-Aminobenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 6)
[0039] 2-(2-Difluoromethylbenzimidazol-l-yl)-4-piperidino-6-morpholino-l,3,5-triazine
(Compound 7)
[0040] 2-(6-Amino-2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino)-
6-morpholino-l,3,5-triazine (Compound 8)
[0041] 2-(2-Difluoromethyl-6-ethoxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 9)
[0042] 2-(2-Difluoromethyl-4-methylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 10)
[0043] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-morpholino-6-(2,6-
dimethylmorpholino)pyrimidine (Compound 11)
[0044] 2-(2-Difluoromethyl-5-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 12)
25

[0045] 2-(6-Amino-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-
morpholino-l,3,5-triazine (Compound 13)
[0046] 2-(4-Amino-2-difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 14)
[0047] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 15)
[0048] 2-(2-Difluoromethyl-6-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 16)
[0049] 2-(5-Amino-2-difluoromethylbenzimidazol-1-yl)-4,6-di(2,6-dimethyl-
morpholino)pyrimidine (Compound 17)
[0050] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4,6-dimorpholinopyrimidine
(Compound 18)
[0051] 2-(6-Amino-4-chloro-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethyl-
morpholino)-6-morpholino-l,3,5-triazine (Compound 19)
[0052] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethyl-
pyrrolidin-l-yl)-6-morpholino-l,3,5-triazine (Compound 20)
[0053] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2,2-dimethylmorpholino)-6-
morpholinopyrimidine (Compound 21)
[0054] 2-(2-Difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(3,3-dimethylmorpholino)-6-
morpholinopyrimidine (Compound 22)
[0055] 2-(2-Difluoromethyl-5-methoxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-
triazine (Compound 23)
[0056] 2-(2-Difluoromethyl-4-methoxybenzimidazol-l-yl)-4-(cis-2,6-dimethyl-
morpholino)-6-morpholinopyrimidine (Compound 24)
[0057] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5-oxo-1,4-diazepan-1 -
yl)-l,3,5-triazine (Compound 25)
[0058] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-(4-hydroxypiperizin-1 -yl)-6-
morpholino-l,3,5-triazine (Compound 26)
[0059] 2-(2-Difluoromethylbenzimidazol-l-yl)-4-[4-(2-hydroxyethyl)piperazin-l-yl]-6-
morpholino-l,3,5-triazine (Compound 27)
[0060] 4-(4-Acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-
1,3,5-triazine (Compound 28)
[0061] 2-(2-Difluoromethylbenzimidazol-l-yl)-4-(4-benzylcarbonylpiperazin-l-yl)-6-
morpholino-l,3,5-triazine (Compound 29)
26

[0062] 4-(4-Acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-
morpholino-l,3,5-triazine (Compound 30)
[0063] 2-(2-Difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-
morpholino-l,3,5-triazine (Compound 31)
[0064] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-
l-yl]-6-morpholino-l,3,5-triazine (Compound 32)
[0065] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-(4-methoxylacetylpiperazin-1 -yl)-6-
morpholino-l,3,5-triazine (Compound 33)
[0066] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholino-l,3,5-triazine (Compound 34)
[0067] 2-(2-Difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)-l,3,5-triazine (Compound 35)
[0068] 2-(2-Difluoromethyl-4-methoxybenzimidazol-1 -yl)-4-(2,2-dimethylmorpholino)-6-
morpholinopyrimidine (Compound 36)
[0069] 2-(2-Difluoromethyl-4-methoxybenzimidazol-l-yl)-4-(cis-2,3-dimethyl-
morpholino)-6-morpholinopyrimidine (Compound 37)
[0070] 2-(2-Difluoromethyl-4-ethoxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-
morpholinopyrimidine (Compound 38)
[0071] As will be demonstrated in Examples to be hereinafter described, the agents of the
present invention inhibit the activation of T cells and B cells induced by Con A, LPS, anti-
IgM antibody, anti-CD3 antibody + anti-CD28 antibody, thereby exhibiting PI3K
inhibitory action on the immune cells. Thus, the drugs of the present invention can be
used in the treatment and prevention of disorders of immune system attributable to the
hyperfunctioning of PI3K.
[0072] As disorders of immune system attributable to the hyperfunctioning of PI3K,
mention may be made of: autoimmune diseases such as rheumatoid arthritis, systemic
lupus erythematosus, scleroderma, Sjegren syndrome, or the like; organ dysfunction
associated with autoimmune diseases such as uveitis, glomerulonephritis, thyroiditis,
pancreatitis, bone destruction or the like; rejection after transplantation of tissues, graft
versus host disease after bone-marrow transplantation; inflammatory bowel diseases such
as ulcerative colitis or Crohn disease; inflammatory or allergenic skin diseases such as
psoriasis or atopic dermatitis; inflammatory or allergenic respiratory disorders such as
chronic obstructive pulmonary disease or asthma; allergenic conjunctivitis or rhinitis;
hematologic neoplasm originated from immune cells, such as B-cell lymphoma, T-cell
27

lymphoma, myeloid leukemia or the like; sepsis triggered by infection with gram-negative
bacteria or coronavirus, severe acute respiratory syndrome, fulminant hepatitis or the like.
[0073] While the agents of the present invention can be applied to mammals such as
humans, dogs, cats, rabbits, hamsters, rats, mice or the like, the administration regimen,
formulation and dosage for application to humans will be particularly explained below.
[0074] The agents of the present invention may be administered orally or parenterally, and
tablets, coated-tablets, powdered drugs, granules, capsules, microcapsules, syrups or the
like may be used as the dosage form for oral administration whereas eye drops, inhalants,
injectable form (including lyophilizates for injection which are to be dissolved upon
application), suppositories, poultices or the like may be used as the dosage form for
parenteral administration. The formulation of these dosage forms may be effected using
pharmaceutically acceptable excipients, binders, lubricants, disintegrants, suspending
agents, emulsifiers, preservatives, stabilizing agents and dispersants, such as lactose,
sucrose, starch, dextrin, crystalline cellulose, kaolin, calcium carbonate, talc, magnesium
stearate, distilled water or saline.
[0075] When used in oral dosage forms, the dosages of the effective ingredient will differ
depending on the symptoms, age, weight or the like of the patient, but a daily dose of 10-
500 mg may be administered in 2-3 portions for an adult weighing 60 kg. In addition, the
dosages will also differ depending on the symptoms of the patient in the case of
ophthalmic solutions, inhalation to lungs or the nasal cavity, and injection to inflamed
articular cavities, but a daily dose of 1-100 µg may be administered in 2-3 portions for an
adult.
EXAMPLES
[0076] PRODUCTION EXAMPLES
Some examples of the heterocyclic compounds represented by the general Formula (I)
were produced according to the processes disclosed in the examples of Patent Documents
3, 4 and 5, and described below.
[0077] The synthesis was preformed with reference to Patent Documents 1-3.
[0078] Production Example 1
2-(2-Methylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 1)
Melting point: 218-20°C (Decomposed)
NMR(CDCl3)δ: 3.03 (3 H, s), 3.7-3.9 (16H, m), 7.2-7.4 (2H, m), 7.7-7.8 (1H, m), 8.1-8.3
(lH,m)
28

MS m/z:381(M+)
[0079] Production Example 2
2-(Benzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-l,3,5-triazine
(Compound 2)
Melting point: 147-150 °C
NMR(CDCl3) δ: 1.1-1.5(6H, m), 2.7-3.0(lH, m), 3.4-3.6(lH, m), 3.7-4.0(8H, m), 4.1-
4.3(1H, m), 4.4-4.7(2H, m), 7.3-7.4(2H, m), 7.7-7.9(lH, m), 8.3-8.4(lH, m), 8.98(1H, s).
[0080] Production Example 3
4,6-Dimorpholino-2-(2-hydroxymethylbenzimidazol-l-yl)-l,3,5-triazine (Compound 3)
Melting point: 208-210 °C (Decomposed)
NMR(CDC13) δ: 3.7-3.9(16H, m), 4.59(1H, t, J=6Hz), 5.15(2H, d, J=7Hz),7.2-7.4(2H, m),
7.7-7.8(lH, m), 8.3-8.4( lH, m)
MS m/z : 397(M+)
[0081] Production Example 4
2-(2-Difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine (Compound 4)
Melting point: 211-214 °C
NMR(CDC13)δ: 3.79(8H, t, J=4Hz), 3.88(8H, t, J=4Hz), 7.3-7.4(2H, m), 7.56(1H, t,
J=53Hz), 7.88(1H, d, J=7Hz), 8.32(1H, d, J=7Hz).
MS m/z: 417(M+)
[0082] Production Example 5
2-(2-Aminobenzimidazol-l -yl)-4,6-dimorpholinopyrimidine (Compound 5)
Melting point: 237-239 °C
NMR(CDCl3)δ: 3.59(8H, t, J=5Hz), 3.84(8H, t, J=5Hz), 5.46(1H, s), 6.65(2H, brs),
7.06(lH, t, J=7Hz), 7.18(1H, t, J=7Hz), 7.37(1H, d, J=7Hz), 8.1(1H, d, 7Hz)
MSm/z:381(M+)
[0083] Production Example 6
2-(2-Aminobenzimidazol-1 -yl)-4,6-dimorpholino-1,3,5-triazine (Compound 6)
Melting point: 298-300 °C (Decomposed)
NMR(CDCl3)δ: 3.7-3.9(16H, m), 6.74(2H, brs), 7.05(lH, t, J=7Hz), 7.20(1H, t, J=7Hz),
7.39(1H, d, J=7Hz), 8.20(1H, d, 7Hz)
MS m/z : 382(M+)
[0084] Production Example 7
2-(2-Difluoromethylbenzimidazol-l-yl)-4-piperidino-6-morpholino-l,3,5-triazine
(Compound 7)
29

Melting point: 190-192 °C
NMR(CDCl3)δ: 1.5-1.8(6H, m), 3.7-3.9(12H, m), 7.3-7.5(2H, m), 7.61(1H, t, J=54Hz),
7.90(1H, d, J=8Hz), 8.34(1H, d, 8Hz)
MSm/z : 415(M+)
[0085] Production Example 8
2-(6-Amino-2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino)-6-
morpholino-l,3,5-triazine (Compound 8)
Melting point: 220-222 °C (Decomposed)
NMR(CDCl3)δ: 1.22(3H, d, J=9Hz), 1.26(3H, d, J=9Hz), 3.1-3.4(1H, m), 3.5-4.1(11H, m),
4.3-4.5(lH, m), 4.5-4.7(lH, m), 6.77(1H, dd, J=2Hz, J=9Hz), 7.49(1H, t, J=54Hz),
7.62(1H, d, J=9Hz), 7.64(1H, d, J=2Hz).
MSm/z: 460(M+)
[0086] Production Example 9
2-(2-Difluoromethyl-6-ethoxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 9)
Melting point: 222-224 °C
NMR(CDC13)δ: 1.46(3H, t, J=7Hz), 3.7-3.9(16H, m), 4.08(2H, q, J=7Hz), 7.00(lH, dd,
J=9Hz, 3Hz), 7.52(1H, t, J=54Hz), 7.74(1H, d, J=9Hz), 7.89(1H, d, J=3Hz).
MSm/z : 461(M+)
[0087] Production Example 10
2-(2-Difluoromethyl-4-methylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 10)
Melting point: 259-260 °C
NMR(CDCl3)δ: 2.72(3H, s), 3.7-3.9(16H, m), 7.1-7.5(2H, m), 7.56(1H, t, J=54Hz),
8.15(lH,d,8Hz)
MSm/z : 431(M+)
[0088] Production Example 11
2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(2,6-
dimethylmorpholino)pyrimidine (Compound 11)
Melting point: 265-267 °C
1H NMR(CDCl3)δ: 3.7-3.9(16 H, m), 3.86 (3 H , s), 7.02 (1 H , dd, J = 3, 9 Hz,), 7.52 (1
H, t, J = 53 Hz,), 7.75 (1 H , d, J = 9 Hz,),7.91 (1 H, d, J = 3Hz,),.
MS m/z 447 (M+).
[0089] Production Example 12
30

2-(2-Difluoromethyl-5-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 12)
Melting point: 272-274 °C
NMR(CDC13)δ: 3.7-3.9(16H, m), 7.26-7.29(2H, m), 7.54(1H, t, J=54Hz), 8.20(1H, d,
8Hz)
MS m/z: 433(M+)
[0090] Example 13
2-(6-Amino-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-
morpholino-l,3,5-triazine (Compound 13)
Melting point: 226-227 °C (Decomposed)
NMR(CDCl3)δ: 1.28(6H, s), 3.6-3.8(14H, m), 6.7-6.8(lH, m), 7.2-7.7(3H, m).
MS m/z: 460(M+)
[0091] Example 14
2-(4-Amino-2-difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 14)
Melting point: 214-216 °C (Decomposed)
NMR(CDCl3)δ: 3.7-3.9(16H, m), 4.48(2H, brs), 6.63(1H, d, J=8Hz), 7.21(1H, t, J=8Hz),
7.55(1H, t, J=54Hz), 7.64(1H, d, J=8Hz).
MS m/z: 432(M+)
[0092] Production Example 15
2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 15)
Melting point: >250 °C
NMR(DMSO-d6)δ: 3.70-3.90(16H,m), 6.76(1H, d, J=8Hz), 7.73(1H, t, J=8Hz), 7.70(1H,
t, J=54Hz), 7.74(1H, d, J=8Hz),10.24 (1H, brs)
MS m/z: 433
[0093] Production Example 16
2-(2-Difluoromethyl-6-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 16)
Melting point: >250 °C
NMR(DMSO-d6)δ: 3.70-3.90(16H,m), 6.86(lH,d,J=8Hz), 7.61(lH,d,J=8Hz),
7.70(lH,t,J=54Hz), 7.73(lH,s), 9.81 (lH,brs)
MS m/z: 433
[0094] Production Example 17
31

2-(5-Amino-2-difluoromethylbenzimidazol-l-yl)-4,6-di(2,6-dimethylmorpholino)-
pyrimidine (Compound 17)
Melting point: 157-160 °C
NMR(CDCl3)δ: 1.30(6H, d, J=9Hz), 2.6-2.8(4H, m), 3.6-4.2(8H, m), 5.45(1H, s), 6.7-
6.8(1H, m), 7.5-7.7(2H, m), 7.42(1H, t, J=53Hz)
MS m/z: 487(M+)
[0095] Production Example 18
2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4,6-dimorpholinopyrimidine
(Compound 18)
Melting point: >250 °C
NMR(DMSO-d6)δ: 3.60-3.80(16H,m), 5.98(lH,s), 6.72(lH,d,J=8Hz), 7.22(lH,t,J=8Hz),
7.62(1H, d,J=8Hz) ,7.65(lH,t,J=54Hz), 10.17 (lH,brs)
MS m/z: 432
[0096] Production Example 19
2-(6-Amino-4-chloro-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-
morpholino-l,3,5-triazine (Compound 19)
(1) 6-Amino-4-chloro-2-difluoromethylbenzimidazole (500 mg, 2.3 mmol) was
dissolved in acetone (50 ml), 2,4-dichloro-6-morpholino-l,3,5-triazine (542 mg, 2.3
mmol) was added at -15°C, and potassium carbonate (500 mg) was further added. After
having elevated the temperature gradually to room temperature, the mixture was stirred at
room temperature for 5 hours. The solvent was evaporated under vacuum, and the residue
was purified by silica gel column chromatography (n-hexane : ethyl acetate =1 : 4) to
afford 2-(6-amino-4-chloro-2-difluoromethylbenzimidazol-1 -yl)-4-chloro-6-morpholino-
1,3,5-triazine (272 mg, yield 28%).
(2) 2-(6-Amino-4-chloro-2-difluoromethylbenzimidazol-1 -yl)-4-chloro-6-morpholino-
1,3,5-triazine (150 mg, 0.36 mmol) thus obtained was dissolved in DMF (6ml), 2,2-
dimethylmorpholine hydrochloride (150 mg, 1.0 mmol) was added thereto at -15°C, and
potassium carbonate (500 mg) was further added. After stirring at room temperature
overnight, water was added to the reaction mixture, which was extracted with ethyl acetate
several times, washed with brine, and dried over anhydrous magnesium sulfate. After the
solvent was evaporated under vacuum, the residue was purified by silica gel column
chromatography (n-hexane : ethyl acetate = 1 : 2) to give the title compound as colorless
crystals (130 mg, yield 73%).
Melting point: 238 °C (Decomposed)
32

NMR (CDCl3)δ: 1.27 (6H, s), 3.68 (2H, s), 3.7-3.9 (12H, m), 6.82 (1H, d, J =2.3Hz), 7.42
(1H, dt, J =9.6Hz, J =53Hz), 7.50 (1H, d, J =2.3Hz)
MS m / z: 494 (M +)
[0097] Production Example 20
2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethylpyrrolidin-1 -yl)-6-
morpholino-l,3,5-triazine (Compound 20)
Melting point: 245 °C (Decomposed)
NMR (CDCl3)δ: 1.9-2.1(4H, m), 3.5-4.0(12H, m), 4.7-4.8(lH, m), 5.1-5.3(1H, m),
6.89(1H, d, J=9Hz), 7.30(1H, t, J=9Hz), 7.50(1H, brs), 7.55(1H, t, J=54Hz), 7.83(1H, d,
J=9Hz).
MS m/z: 447(M+)
[0098] Production Example 21
2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-
morpholinopyrimidine (Compound 21)
Melting point: 185-187 °C
NMR (CDCl3)δ: 1.29(6H, s), 3.48(2H, s), 3.59-3.64(6H, m), 3.81-3.87(6H, m), 5.47(1H,
s), 6.86(1H, m), 7.26-7.32(lH, m), 7.49(1H, t, J=53Hz), 7.72(1H, d, 8Hz)
MS m/z : 460(M+)
[0099] Production Example 22
2-(2-Difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-(3,3-dimethylmorpholino)-6-
morpholinopyrimidine (Compound 22)
Melting point: 204-206 °C
NMR (CDCl3)δ: 1.48(6H, s), 3.50(2H, s), 3.6-3.8(6H, m), 3.8-4.0(6H, m), 5.76(1H, s),
6.68(1H, d, J=7Hz), 7.29(1H, d, J=7Hz), 7.49(1H, t, J=54Hz), 7.66(1H, d, 7Hz)
MS m/z : 460(M+)
[00100] Production Example 23
2-(2-Difluoromethyl-5-methoxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(Compound 23)
Melting points: 206-207 °C
NMR((CD3)2CO) δ: 1.17 (6H, d, J=6Hz), 2.5-2.8(4H, m), 3.6-4.4(10H, m), 5.95(1H, s),
6.77(1H, d, J=8Hz), 7.23(1H, t, J=8Hz), 7.66(1H, t, J=53Hz), 7.75(1H, d, J=8Hz), 8.9(1H,
s)
MS m/z 447 (M+)
[00101] Production Example 24
33

2-(2-Difluoromethyl-4-methoxybenzimidazol-l-yl)-4-(cis-2,6-dimethylmorpholino)-6-
morpholinopyrimidine (Compound 24)
(1) 2-Difluoromethyl-4-methoxybenzimidazole (9.03 g, 45.6 mmol) was dissolved in
DMF (100 ml), 60% NaH (1.82 g, 45.6 mmol) was added, and stirred for 30 minutes. The
reaction mixture was added to a solution obtained by dissolving 2,4,6-trichloropyrimidine
(15.7 g, 92.1 mmol) into DMF (100 ml) while cooling with ice, and stirred on an ice bath
for 30 minutes and further at room temperature for 2 hours. Water was added to the
reaction mixture, precipitated crystals were filtered, and washed well with hexane and
ether, then air-dried to afford 2-(2-difluoromethyl-4-methoxybenzimidazol-l-yl)-4,6-
dichloropyrimidine (12.3g, yield 78%).
(2) 2-(2-Difluoromethyl-4-methoxybenzimidazol-l-yl)-4,6-dichloropyrimidine (12.3 g,
35.7 mmol) thus obtained was dissolved in DMF (150 ml), cis-2,6-dimethylmorpholine
(6.63 ml, 53.7 mmol) was added at room temperature, and potassium carbonate (7.35 g)
was further added. After stirring at room temperature for 30 minutes, water was added to
the reaction mixture, extracted with ethyl acetate several times, washed with brine, and
dried over anhydrous magnesium sulfate. After the solvent was evaporated under vacuum,
the residue was washed sufficiently with hexane, and then successively with ether, and
then air-dried to give 4-chloro-2-(2-difluoromethyl-4-methoxybenzimidazol-l-yl)-6-(cis-
2,6-dimethyl-morpholino)pyrimidine (14.4 g, yield 95%).
(3) Morpholine (275 ml, 3.15 mol) was added to 4-chloro-2-(2-difluoromethyl-4-
methoxybenzimidazol-l-yl)-6-(cis-2,6-dimethylmorpholino)pyrimidine (14.4 g, 34 mmol)
thus obtained, and stirred at room temperature for 30 minutes and further at 80°C for 30
minutes. Water was added to the reaction solution, and the precipitated crystals were
filtered, and washed well successively with hexane, ether and ethyl acetate, then air-dried
to afford 2-(2-difluoromethyl-4-methoxybenzimidazol-1 -yl)-4-(cis-2,6-dimethyl-
morpholino)-6-morpholinopyrimidine (13.7 g, yield 86%).
Melting point: 180-181 °C
NMR(CDCl3) δ: 1.28(6H, d, J=6Hz), 2.6-2.7(2H, m), 3.6-3.7(6H, m), 3.80-3.86(4H, m),
4.04(3H, s), 4.10-4.14(2H, m), 5.49(1H, s), 6.78(1H, d, J=8Hz), 7.32(1H, d, J=8Hz),
7.41(1H, t, J-52Hz), 7.77(1H, d, J=8Hz)
MS m/z: 474(M+)
[00102] Production Example 25
2-(2-Difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5-oxo-1,4-diazepan-1 -yl)-1,3,5-
triazine (Compound 25)
34

Melting point: 235-37 °C
1H NMR(CDCl3) δ: 2.7-2.8 (2H, m), 3.4-3.5 (2H, m), 3.8-4.2 (12H, m), 5.97 (1H, brs),
7.2-7.5 (2 H, m), 7.52 (1 H, t, J = 54Hz), 7.8-8.0 (1 H, m) 8.2-8.4 (1 H ,m).
MS m/z 444 (M+)
[00103] Production Example 26
2-(2-Difluoromethylbenzimidazol-1 -yl)-4-(4-hydroxypiperizin-1 -yl)-6-morpholino-1,3,5-
triazine (Compound 26)
Melting point: 219-21 °C
1HNMR(CDCl3) δ: 3.4-3.5 (2H, m), 3.7-4.1 (16H, m), 7.3-7.5 (2 H, m), 7.59 (1 H, t, J =
50Hz), 7.8-8.0 (1 H, m) 8.3-8.4 (1 H ,m).
MS m/z 431 (M+).
[00104] Production Example 27
2-(2-Difluoromethylbenzimidazol-1 -yl)-4- [4-(2-hydroxyethyl)piperazin-1 -yl] -6-
morpholino-l,3,5-triazine (Compound 27)
Melting point: 174-77 °C
1H NMR(CDCl3) δ: 2.6-2.7 (8H, m), 3.6-3.9 (12H, m), 3.91 (1H, br) 7.3-7.5 (2 H, m),
7.58 (1 H, t, J = 54Hz), 7.9-8.0 (1 H, m) 8.3-8.4 (1 H ,m).
MS m/z 460 (M+).
Refer to Patent Document 4.
[00105] Production Example 28
2-(2-Difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethylpyrrolidin-1 -yl)-6-
morpholinopyrimidine (947)
(1) 4-rert-Butyldimethylsilyloxy-2-difluoromethylbenzimidazole (1.49 g, 5.0 mmol)
was dissolved in DMF (10 ml), 2,4,6-trichloropyrimidine (0.91 g, 5.0 mmol) was added at
room temperature, potassium carbonate (0.55 g) was further added, and the mixture was
stirred for 5 hours. Water was added to the reaction mixture, extracted with ethyl acetate
several times, washed with brine, and then dried over anhydrous magnesium sulfate. After
the solvent was evaporated under vacuum, the residue was purified by silica gel column
chromatography (n-hexane : ethyl acetate = 8 : 1) to give 2-(4-tert-buthyldimethylsilyloxy-
2-difluoromethylbenzimidazol-l-yl)-4,6-dichloropyrimidine (1.12 g, yield 50%).
(2) 2-(4-tertButhyldimethylsilyloxy-2-difluoromethylbenzimidazol-1 -yl)-4,6-
dichloropyrimidine (386 mg, 0.87 mmol) thus obtained was dissolved in DMF (6 ml), 2-
pyrrolidine methanol (0.13 ml, 1.3 mmol) was added at room temperature, and potassium
carbonate (179 mg) was further added. After the mixture was stirred at room temperature
35

for 30 minutes, water was added to the reaction mixture, extracted with ethyl acetate
several times, washed with brine, and dried over anhydrous magnesium sulfate. After the
solvent was evaporated under vacuum, the residue was purified by silica gel column
chromatography (n-hexane : ethyl acetate =1 : 1) to give 2-(4-tert-buthyldimethylsilyloxy-
2-difluoromethylbenzimidazol-1 -yl)-4-(2-hydroxy-methylpyrrolidin-1 -yl)-6-
chloropyrimidine (291 mg, yield 64%).
(3) Morpholine (4.4 g, 50 mmol) was added to 2-(4-tert-buthyldimethylsilyloxy-2-
difluoromethylbenzimidazol-1 -yl)-4-(2-hydroxymethyl-pyrrolidin-1 -yl)-6-
chloropyrimidine (281 mg, 0.54 mmol) thus obtained, and the mixture was stirred at room
temperature for 9 hours. Water was added to the reaction mixture, extracted with ethyl
acetate several times, washed with brine, and then dried over anhydrous magnesium
sulfate. After the solvent was evaporated under vacuum, the residue was purified by silica
gel column chromatography (n-hexane : ethyl acetate = 2 : 3) to obtain 2-(4-tert-
bumyldimethylsilyloxy-2-difluoromethylbenzimidazol-l-yl)-4-(2-hydroxy-
methylpyrrolidin-l-yl)-6-morpholinopyrimidine (216 mg, yield 72%).
2-(4-tert-Buthyldimethylsilyloxy-2-difluoromethyl-benzimidazol-l-yl)-4-(2-
hydroxymethylpyrrolidin-l-yl)-6-morpholinopyrimidine (213 mg, 0.38 mmol) was
dissolved in anhydrous THF (7 ml), tetra-n-butylammonium fluoride (0.4 ml) (1M THF
solution) was added at room temperature, and the mixture was stirred for 30 minutes.
Water was added to the reaction mixture, extracted with ethyl acetate several times,
washed with brine, and dried over anhydrous magnesium sulfate. After the solvent was
evaporated under vacuum, the residue was purified by silica gel column chromatography
(n-hexane : ethyl acetate = 1 : 4) to obtain the title compound as colorless crystals (101 mg,
yield 60%).
Melting point: 195-198°C
NMR(CDCl3)δ: 2.0-2.1(4H, m), 3.4-4.0(12H, m), 4.0-4.1(lH, m), 4.3-4.4(lH, m),
5.36(1H, s), 6.85(1H, d, J=8Hz), 7.28(1H, t, J=8Hz), 7.58(1H, brs), 7.58(1H, t, J=54Hz),
7.73(1H, d, J=8Hz).
MSm/z: 446(M+)
The production was effected with reference to Patent Document 4.
[00106] Production Example 29
2-(5,6-Dimethyl-2-difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine
(ZSTK705)
Melting point: 217-220°C
36

1H NMR (CDCl3) δ: 2.39 (3H, s), 2.40 (3H, s), 3.7-3.9 (16H, m), 7.53 (1 H, t, J = 54Hz),
7.62 (lH, s) 8.12 (lH, s).
MS m/z 445 (M+).
[00107] Production Example 30
2-(6-Amino-4-chloro-2-difluoromethylbenzimidazol-l-yl)-4-(2-hydroxymethylpyrrolidin-
1-yl )-6-morpholino-l,3,5-triazine (STK922)
Melting point: 256°C (Decomposed)
NMR(CD3OD-CDCl3(1:1)) δ: 1.9-2.2(4H, m), 3.68(2H, s), 3.5-4.0(llH, m), 4.39(1H,
brs), 6.84(1H, d, J=2.1Hz), 7.58(1H, t, J=53Hz), 7.64(1H, d, J=2.1Hz).
MS m/z: 480(M+)
[00108] Production Example 31
2-(4-Chloro-2-difluoromethyl-5-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-
triazine (STK894)
Melting point: >250°C
NMR(CDC13)δ: 3.7-3.9(16H, m), 5.63(1H, s), 7.15(1H, d, J=9Hz), 7.51(1H, t, J=53Hz),
8.14(lH,d,J=9Hz).
MS m/z: 467(M+)
[00109] Production Example 32
Synthesis of 4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-
morpholino-l,3,5-triazine (Compound 28)
A mixture of 6-chloro-2-(2-difmoromethylbenzimidazol-l-yl)-4-morpholino-l,3,5-
triazine (3.66 g, 10 mmol), 1-acetylpiperazine (1.40 g, 11 mmol), potassium carbonate
(1.38 g, 10 mmol) and DMF (30 ml) was stirred at room temperature for 16 hours. The
reaction mixture was poured into water, and extracted with dichloromethane. The extract
was dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was
purified by silica gel column to obtain 4-(4-acetylpiperazin-l-yl)-2-(2-
difluoromethylbenzimidazol-l-yl)-6-morpholino-l,3,5-triazine (4.08 g, 9.0 mmol) in a
yield of 90% as colorless crystals.
Naturally, triazine or pyrimidine derivatives bearing such piperazine groups may also
be synthesized according to the following schemes.
For example, a mixture of 6-chloro-2-(2-difluoromethylbenzimidazol-l-yl)-4-
morpholino-l,3,5-triazine (3.66 g, 10 mmol), piperazine (3.45 g, 40 mmol), and acetone
(50 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured
into water, and precipitated crystals were filtered, and washed with methanol to afford 2-
37

(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(piperazin-1 -yl)-1,3,5-triazine (3.87
g, 9.3 mmol) in a yield of 93% as colorless crystals.
1H NMR (CDCl3) δ: 3.8-4.1 (16H, m), 7.3-7.5 (2 H, m), 7.59 (1 H, t, J = 54Hz), 7.9-8.0 (1
H, m) 8.3-8.4 (1 H, m).
MSm/z416(M+).
Acetyl chloride (0.14 ml, 2.0 mmol) was added dropwise to a mixture of 2-(2-
difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(piperazin-1 -yl)-1,3,5 -triazine (417 mg,
1.0 mmol) and THF (10 ml). The reaction mixture was stirred at room temperature for 22
hours. The reaction mixture was poured into water, and extracted with dichloromethane.
The extract was dried over anhydrous sodium sulfate, concentrated under vaccum, and the
residue was purified by silica gel column to give the target compound 4-(4-
acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5 -triazine
(354 mg, 7.7 mmol) in a yield of 77% as colorless crystals.
Melting point: 223°C
1H NMR (CDCl3) 8: 2.18 (3 H, s), 3.6-4.0 (16H, m), 7.3-7.5 (2 H, m), 7.55 (1 H, t, J =
53.5 Hz), 7.9-8.0 (1 H, m) 8.3-8.4 (1 H ,m).
MS m/z 458 (M+).
The following compounds were manufactured in a manner similar to Production
Example 34.
[00110] Production Example 33
2-(2-Difluoromethylbenzimidazol-l-yl)-6-(4-formylpiperazin-l-yl)-4-morpholino-l,3,5-
triazine
Melting point: 228-30°C
1H NMR (CDCl3) δ: 3.8-4.1 (16H, m), 7.2-7.5 (2 H, m), 7.54 (1 H, t, J = 54Hz), 7.8-8.0 (1
H, m), 8.17 (1H, s), 8.3-8.4 (1 H ,m).
MS m/z 444 (M+).
[00111] Production Example 34
2-(2-Difluoromethylbenzimidazol-l-yl)-4-morpholino-6-(3-oxopiperazin-l-yl)-l,3,5-
triazine
Melting point: 255-57°C
lH NMR (CDCl3) δ: 3.5-3.9 (14H, m), 6.48 (1H, brs), 7.2-7.5 (2 H, m), 7.59 (1 H, t, J =
54Hz), 7.8-7.9(1 H, m) 8.2-8.4 (1 H ,m).
MS m/z 430(M+).
[00112] Production Example 35
38

2-(2-Difluoromethylbenzimidazol-l-yl)-6-(3,5-dioxopiperazin-l-yl)-4-morpholino-l,3,5-
triazine
Melting point: 230-32°C
1H NMR (CDCl3) δ: 3.5-3.9 (12H, m), 7.2-7.5 (2 H, m), 7.59 (1 H, t, J = 55Hz), 7.9-8.0 (1
H, m) 8.3-8.4 (1 H ,m).
MS m/z 444 (M+).
[00113] Production Example 36
2-(2-Difluoromethylbenzimidazol-1 -yl)-4-(4-benzylcarbonylpiperazin-1 -yl)-6-
morpholino-l,3,5-triazine (Compound 29)
(STK1515)
Melting point: 178-181°C
1H NMR (CDCl3) δ: 3.81 (2 H , s), 3.5-3.9(16 H, m), 7.2-7.5(7 H, m), 7.52 (1 H, t, J = 54
Hz,), 7.89 (1 H , d, J = 8 Hz,),8.30 (1 H , d, J = 8 Hz,).
MS m/z 534 (M+).
[00114] Production Example 37
4-(4-Acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5-
triazine (Compound 30) (STK01529)
Melting point: 79-81°C
NMR (CDCl3-d1)δ: 2.19 (3H, s) ,2.60(2H,s), 3.70-4.00(16H,m), 7.30-7.50(2H,m),
7.57(1 H,t,J=54Hz), 7.90(1H, d ,J=8Hz),8.33(lH, d ,J=8Hz)
MS m/z: 472
[00115] Production Example 38
2-(2-Difluoromethylbenzimidazol-1 -yl)-4-[4-(2-furoyl)piperazin-1 -yl]-6-morpholino-
1,3,5-triazine (Compound 31) (STK01531)
Melting point: 220-222°C
NMR (CDCl3-d1)δ: 3.80-4.00(16H,m), 6.53(1H, d ,J=2Hz), 7.01(lH, d ,J=2Hz), 7.30-
7.60(4H,m),7.80(lH, d, J=8Hz), 8.34(1H, d, J=8Hz)
MS m/z : 510
[00116] Production Example 39
2-(2-Difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin-l-yl)-6-
morpholino-l,3,5-triazine (Compound 32) (STK01539)
Melting point: 203-205°C
NMR (CDCl3-d1)δ: 2.90(6H,s),3.30-3.40(4H,m),3.80-4.00(12H,m), 7.30-7.40(2H,m),
7.56(lH,t,J=54Hz), 7.89(1H, d, 8Hz),8.34 (1H, d, 8Hz)
39

MS m/z : 487
[00117] Production Example 40
2-(2-Difluoromethylbenzimidazol-1 -yl)-4-(4-methoxylacetylpiperazin-1 -yl)-6-
morpholino-l,3,5-triazine (Compound 33) (STK01540)
Melting point: 72-75°C
NMR (CDCl3-d1)δ: 3.46(3H, s), 3.60-4.00(16H,s), 4.17 (2H, s) 7.30-7.50(2H,m),
7.55(lH,t,J=54Hz), 7.90(1H, d, J=8Hz), 8.34(1H, d, J=8Hz)
MS m/z: 488
[00118] Production Example 41
2-(2-Difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazin-1 -yl] -6-
morpholino-l,3,5-triazine (Compound 34) (STK01541)
NMR (CDCl3-d1) δ: 1.17 (2H, m) ,2.60-2.70(4H, m), 4.70 (lH,brs) 3.50-4.00(16H,m),
7.30-7.50(2H,m), 7.56(lH,t,J=54Hz), 7.90(1H, d, J=8Hz),8.33(lH, d, J=8Hz)
MS m/z: 474
[00119] Production Example 42
2-(2-Difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)-
1,3,5-triazine (Compound 35) (STK01542)
Melting point: 198-202°C
NMR (CDCl3-d1) δ: 1.20 (3H, t,J=7Hz) ,2.42(2H, q ,J=7Hz), 3.50-4.00(16H,m), 7.30-
7.50(2H,m), 7.56(lH,t,J=54Hz), 7.90(1H, d, J=8Hz),8.33(lH, d, J=8Hz)
MS m/z: 472
[00120] Production Example 43
2-(2-Difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-
morpholino-l,3,5-triazine(STK01553)
Melting point: 255-260°C
NMR (CDCl3-d1) δ: 3.59(4H,brs), 3.76(3H,s),3.70-3.95(12H,s), 7.30-7.50(2H,m),
7.55(1 H,t,J=54Hz), 7.9O(1H, d, J=8Hz),8.34(lH, d, J=8Hz)
MS m/z: 474
[00121] The following were produced in the same manner as in Production Example 24.
Production Example 44
2-(2-Difluoromethyl-4-methoxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-
morpholinopyrimidine (Compound 36)
Melting point: 166-168°C
40

NMR (CDCl3) δ: 1.30(6H, s), 3.49(2H, s), 3.4-3.9(12H, m), 4.05(3H, s), 5.47(1H, s),
6.79(1H, d, J=8Hz), 7.32(1H, t, J=8Hz), 7.41(1H, t, J=54Hz), 7.78(1H, d, J=8Hz).
MSm/z: 474(M+)
[00122] Production Example 45
2-(2-Difluoromethyl-4-methoxybenzimidazol-1 -yl)-4-(cis-2,3 -dimethylmorpholino)-6-
morpholinopyrimidine (Compound 37)
Melting point: 176-178°C
NMR (CDCl3) δ: 1.20(3H, d, J=5Hz), 1.22(3H, d, J=5Hz), 3.6-3.7(lH, m), 3.6-4.1(13H,
m), 4.05(3H, s), 5.47(1H, s), 6.79(1H, d, J=8Hz), 7.32(1H, t, J=8Hz), 7.42(1H, t, J=53Hz),
7.78(1H, d, J=8Hz).
MS m/z: 474(M+)
[00123] Production Example 46
2-(2-Difluoromethyl-4-ethoxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-
morpholinopyrimidine (Compound 38)
Melting point: 114-116°C
NMR (CDCl3) δ: 1.56(3H, t, J=7Hz), 3.49(2H, s), 3.5-3.9(12H, m), 4.32(2H, q, J=7Hz),
5.47(1H, s), 6.78(1H, d, J=8Hz), 7.30(1H, t, J=8Hz), 7.41(1H, t, J=53Hz), 7.76(1H, d,
J=8Hz).
MS m/z: 488(M+)
[00124] Drug Efficacy Assays
Next, the assay protocols for pharmacological effects and toxicity of the heterocyclic
compounds represented by the general Formula (I) and their results will be hereinafter
described. Here, the compound number for each test substances corresponds to the
compound number assigned to each of the above heterocyclic compounds.
[00125] Assay Example 1
Mitogen Response Inhibititory Activity
Spleen cells (2 x 106 cells/mL) prepared from C57BL/6N female mice (8 weeks
old, purchased from Charles River Laboratories Japan Inc.) were suspended in RPMI 1640
medium (containing 10% fetal bovine serum, 10 mM HEPES, 1 mM pyruvic acid, 4.5 g/L
glucose, 100 units/mL penicillin, and 0.1 mg/mL streptomycin), and seeded in wells of a
96 well plate at 0.225 mL per well. Serial dilutions of test substances were added to
respective wells, and then concanavalin A (Con A, 3 µg/mL), lipopolysaccharide (LPS,
100 µg/mL), or an anti-mouse IgM antibody (100 µg/mL) were added. Thereafter, they
41

were incubated under conditions of carbon dioxide 5 % at a temperature 37°C for 3 days.
Next, Alamar Blue solution was added at 50 µL per 150 µL, and after having cultured for
one day, the fluorescence intensity at 590 nm using an excitation wavelength of 530 nm
was determined by Cytoflour 4000 (Applied Biosystems). As a result, as shown in Table
1, it was revealed that s-triazine analogs inhibit proliferation of mouse spleen cells induced
by Con A, LPS, or an anti-IgM antibody.
[00126] [Table 1]

Test Compounds Inhibition of
Con A response Inhibition of LPS
response Inhibition of Anti-IgM
antibody response
Compound 1 + + nd
Compound 2 + + +
Compound 3 + + nd
Compound 4 ++ ++ ++
Compound 5 + + +
Compound 6 + + +
Compound 7 + + +
Compound 8 ++ + ++
Compound 9 ++ ++ ++
Compound 10 + ± +
Compound 12 ++ ++ ++
Compound 13 ++ ++ ++
Compound 17 + ± +
Compound 19 ++ ++ nd
Compound 20 +++ +++ +++
Compound 21 +++ +++ +++
Compound 22 +++ +++ +++
Compound 24 + + +
Compound 25 ++ + nd
Compound 26 +++ ++ nd
Compound 27 +++ + nd
Compound 28 +++ ++ nd
42

[00127] Assay Example 2
Proliferation Inhibition Assay for Human Peripheral Blood Mononuclear Cells
43
4 mL of blood collected from healthy subjects was placed on 3 mL of MonoPoly
Resolving Medium, and after centrifugation, the mononuclear cell (PBMC) fraction was
collected. After washing with saline, PBMC (1 x 105 cells/mL) was suspended in RPMI
1640 medium (containing 10% fetal bovine serum, 10 mM HEPES, 1 mM pyruvic acid,
and 4.5 g/L glucose). Next, after having added an anti-CD28 antibody (1 µg/mL) to the
suspension, they were seeded on an anti-human CD3 T cell activation plate (BD
Bioscience) at a capacity of 0.135 mL per well. Then, serial dilutions of test substances
were added to respective wells, and incubated under conditions of carbon dioxide 5 % at a
temperature 37°C. After 3 days, Alamar Blue solution was added at 50 µL per well, and
after incubation for one day, a fluorescence intensity at 590 nm using an excitation
wavelength of 530 nm was determined by Cytoflour 4000 (Applied Biosystems). As a
result, as shown in Table 2, it was revealed that s-triazine analogs inhibit the growth of
human T cells induced by an anti-CD3 antibody and an anti-CD28 antibody.
[00128] [Table 2]

[00129] Assay Example 3
Activation Inhibition Assay for Human Peripheral Blood Mononuclear Cells
In accordance with the method of Assay Example 2, PBMC (2 x 106 cells/mL) was
isolated from human peripheral blood, suspended in RPMI 1640 medium (containing 10%
fetal bovine serum, 10 mM HEPES, 1 mM pyruvic acid, and 4.5 g/L glucose), and seeded
in wells of a 96 well plate at 0.225 mL per well. The test substances were added to
respective wells, and then an anti-CD3 antibody (2 µg/mL) and an anti-CD28 antibody (1
µg/mL) were added. Then, after incubation under conditions of carbon dioxide 5% at a
temperature 37°C for 6 hours, the expressions of CD40L and CD69, activation markers,
were analysed by flow cytometry. As a result, when the cells were stimulated by both an
anti-CD3 antibody and an anti-CD28 antibody, CD40L was expressed on 14.4% of PBMC,
which was also CD4 positive. However, the proportion of the cells which expressed
CD40L decreased when the cells had been treated with test substances (ZSTK474: 4.9%;
913: 3.7%, 1213: 3.6%). Although CD69 was expressed on 28.8% (CD4-positive) and
50.9% (CD4-negative) of PBMC, the proportions of CD4-positive cells (ZSTK 474:
18.8%, 913: 10.1%, 1213:17.7%) and CD4-negative cells (ZSTK 474: 17.7%, 913: 10.5%,
1213: 22.4%) which expressed CD69 decreased when the cells had been treated with test
substances. Thus, the s-triazine analogs were shown to inhibit the activation of
lymphocytes (Figure 1).
[00130] Assay Example 4
Adjuvant-Induced Arthritis Inhibitory Action
Lyophilized Mycobacterium butyricum suspended in Freund's incomplete adjuvant
was intradermally administered to the base of the tail of Lewis male rats (7 weeks old,
purchased from Charles River Laboratories Japan Inc.) to induce adjuvant-induced
arthritis. Then, 10 days after the induction of the adjuvant-induced arthritis, the test
substances suspended in 0.5% hydroxypropylcellulose (HPC) were orally administered on
consecutive days. Furthermore, after the onset of the arthritis, the volume of the hind paw
was measured using a hindpaw edema volume measuring apparatus (TK105, Physio-Tech).
As a result, for the test substances, as shown in Figure 2, a statistically significant
44

(analysis of variance, Dunnett's test P after day 14 was confirmed for the present model study.
[00131] Assay Example 5
Collagen-Induced Arthritis Inhibitory Action
Bovine type II collagen suspended in Freund's complete adjuvant was intradermally
administered to the base of tail of DBA1 male mice (7 weeks old, purchased from Charles
River Laboratories Japan Inc.) on day 1 and day 21. Then, from day 28 when 50% of the
mice developed arthritis, the test substances suspended in 0.5% hydroxypropylcellulose
(HPC) were orally administered on consecutive days. Here, the efficacy was evaluated by
scoring the arthritis. Specifically, for each paw, the degree of arthritis was evaluated
according to: no symptoms: 0; redness or swelling of one joint: 1; redness or swelling for
two or more joints: 2; redness or swelling over the entire paw: 3; and maximum redness or
swelling over the entire paw: 4. As a result, it was revealed that ZSTK474 inhibited the
progression of the collagen-induced arthritis in a dose-dependent manner. For the group
administered 50 or 100 mg/kg of the above compound, after day 30, a statistically
significant efficacy was recognized (Dunnett's test P administered 50 mg/kg of the above compound, the conditions were exacerbated after day
40, and no significant difference was recognized in comparison with the control group
after day 44 (Figure 3).
[00132] Assay Example 6
Inhibition Assay for Proliferation of Rabbit Synoviocyte
Rabbit synoviocytes HIG-82 suspended in HAM medium (containing 10% fetal
bovine serum, 25 mM HEPES, and 0.1 mg/mL kanamycin) (with 4 x 104 cells/mL) were
seeded in wells of a 96 well plate at 0.135 mL per well. Then, 15 p.L of each of serial
dilutions of test substances was added to a respective well, and incubated under conditions
of carbon dioxide 5 % at a temperature 37°C. Alamar Blue solution was added at 50 µL
per well on day 0 and day 3, and incubated for one day, and thereafter fluorescence
intensity at 590 nm using an excitation wavelength of 530 nm was determined by
Cytoflour 4000 (Applied Biosystems). As shown in Table 3, it was demonstrated that s-
triazine analogs inhibited cell division of rabbit synoviocytes.
45
[00133] [Table 3]

[00134] Assay Example 7
Allogeneic Mixed Lymphocyte Reaction
Spleen cells prepared from C57BL/6N female mice (8-10 weeks old, purchased from
Charles River Laboratories Japan Inc.) and peripheral lymph node mononuclear cells
prepared from BALB/c female mice (8-10 weeks old, purchased from Charles River
Laboratories Japan Inc.) were used as stimulator cells and responder cells, respectively.
The respective cells were suspended in RPMI 1640 medium (containing 10% fetal bovine
serum, 100 units/mL penicillin, and 0.1 mg/mL streptomycin) (with 2 x 106 cells/mL).
Then, the stimulator cells (50 uL) treated with mitomycin C (50 mg/mL, 30 minutes) were
added to the responder cells (100 uL). Thereafter, serial dilutions of test substances were
added to respective wells, and incubated under conditions of carbon dioxide 5% at 37°C
for 86 hours. Finally, the cell proliferation was examined using a BrdU cell proliferation
kit (Calbiochem). As a result, as shown in Table 4, it was found that the s-triazine analogs
inhibited the allogeneic mixed lymphocyte reaction.
[00135] [Table 4]
46

[00136] Assay Example 8
Proliferation Inhibitory Activity on Hematologic Neoplasm Cells
Daudi cells (5 x 105 cells/mL), Jurkat cells (5 x 105 cells/mL), THP-1 cells (5 x 105
cells/mL), U 937 cells (5 x 105 cells/mL), and HL 60 cells (5 x 105 cells/mL) suspended in
RPMI 1640 medium (containing 10 % fetal bovine serum, 10 mM HEPES, 1mM pyruvic
acid, 4.5 g/L glucose, 100 units/mL penicillin, and 0.1 mg/mL streptomycin) were seeded
in 96 well plates at a capacity of 0.135 mL per well. Serial dilutions of test substances
were added to respective wells at 15 µL/well, and incubated under conditions of carbon
dioxide 5 % at 37°C for 3 days. Thereafter, Alamar Blue solution was added at 50 µL, and
after incubation for one day, the fluorescence intensity at 590 run using an excitation
wavelength of 530 nm was determined by Cytoflour 4000 (Applied Biosystems). As a
result, as shown in Table 5, it was revealed that s-triazine analogs inhibited the
proliferation of hematologic neoplasm cells.
47
[00137] [Table 5]

[00138] Assay Example 9
Therapeutic Action on Human B Lymphoma Xenografted Model
Daudi cells (1 x 107 cells/mL) cultured in RPMI 1640 medium (containing 10 % fetal
bovine serum, 10 mM HEPES, lmM pyruvic acid, 4.5 g/L glucose, 100 units/mL
penicillin, and 0.1 mg/mL streptomycin) were implanted subcutaneously in the chests of 8
week-old NOD/SCID mice. After day 20 when the tumor had grown to the volume of
about 800 mm3, Compound 8 (400 mg/kg) was administered orally. As a result, as shown
in Figure 4, the increase in tumor volume in the present model was inhibited.
[00139] Assay Example 10
Fulminant Hepatitis Model
BALB/c male mice (7 weeks old, purchased from Charles River Laboratories Japan
Inc.) were used in the experiment. After having orally administered the test substances
suspended in 5 % HPC, galactosamine (800 mg/kg) and LPS (110 µg/kg) were
intraperitoneally administered. Then, survival rates at 72 hours after administration were
obtained. As a result, as shown in Table 6, the test substances improved the survival rate
due to galactosamine and LPS.
[00140] [Table 6]
48

[00141] Assay Example 11
Toxicologic Test for Single Oral Administration
A single oral dose toxicity of typical heterocyclic compounds was examined using SD
male rats (6 weeks old, weight 162-188 g), and as a result, for Compound 8, no examples
of death were recognized even with 1200 mg/kg, and for Compound 14, LD50 was 600-
900 mg/kg.
[00142] Assay Example 12
Ames Test
Using 5 strains of Salmonella typhimurium TA98, TA100, TA1535, TA1537 and
Escherichia coli WP2uvrA, the test substances (Compound 8, Compound 10, Compound
12 and Compound 14) were tested for their mutagenesis according to a preincubation
method. As a result, with or without metabolic activation due to S-9, even in 5000 µg/flat
plate (maxium dose), no increase was observed in the colony number of reverse mutation
in any tested strains, so mutagenesis was negative. Accordingly, in addition to in vivo
tests such as rat adjuvant induced arthritis assay, mouse collagen induced arthritis assay,
human B-lymphoma xenografted model, fulminant hepatitis inhibition assay and
toxicologic test for single oral administration, s-triazine analogs were found to be safer
compounds.
[00143] The agents of the present invention inhibit the response to T cells and B cells
induced by Con A, LPS, anti-IgM antibody, anti-CD3 antibody + anti-CD28 antibody,
thereby exhibiting PI3K inhibitory action on immune cells. Specifically, the drugs of the
present invention can be used in the treatment and prevention of disorders of immune
system attributable to the hyperfunctioning of PI3K. As disorders of immune system
attributable to the hyperfunctioning of PI3K, mention may be made of: autoimmune
diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren
49

syndrome, or the like; organ dysfunction associated with autoimmune diseases such as
uveitis, glomerulonephritis, thyroiditis, pancreatitis, bone destruction or the like; rejection
after transplantation of tissues, graft versus host disease after bone-marrow
transplantation; inflammatory bowel diseases such as ulcerative colitis or Crohn disease;
inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis;
inflammatory or allergenic respiratory disorders such as chronic obstructive pulmonary
disease or asthma; allergenic conjunctivitis or rhinitis; hematologic neoplasm originated
from immune cells, such as B-cell lymphoma, T-cell lymphoma, myeloid leukemia or the
like; sepsis triggered by infection to gram-negative bacteria or coronavirus, severe acute
respiratory syndrome, fulminant hepatitis or the like.
[00144] Assay Example 13
Test for Measuring Blood Level
A pharmacokinetic study was performed using 6 week-old BDF1 male mice. The test
substances were mixed with hydroxylpropylcellulose (low-molecular weight form)
[HPC(L)] in 2.5-fold of the drug weight, and dissolved in dichloromethane. The
solventwas evaporated to dryness. To make the dosing formation, the residue was
suspended in distilled water to prepare the drug level of 20 mg/mL. The test compounds
were administered compulsorily and orally at a dose of 200 mg/kg to the mice that had
been starved for 16 hours. One hour after the administration, blood was collected from the
orbits of two mice to obtain serum. Internal standards solution and 1 ml of distilled water
were added to 100 µL of serum thus obtained, and then extracted with diethylether. The
solvent was evaporated under vacuum, and the residue was resolved with eluent to provide
samples for the HPLC measurement. HPLC was performed by using reversed-phase type
column, and acetonitrile-phosphate buffer (pH 2.5) was used as the eluent. Using
regression curves (Y=aX+b) obtained from the standards, the drug levels in the sample
serum were calculated. Their results are shown in Table 7 below.
50
[00145] [Table 7]

As shown in the above test results, the compounds of the present invention having an
acyl group at position 4 of the piperazine ring exhibited high blood levels quickly, one
hour after the administration, as compared with the known control compounds 2, 3 and 9.
[00146] Assay Example 14
Proliferation Inhibitory Activity on Solid Tumor Cells
Used in the test were MCF-7 cells which were established from human breast
cancer and were cultured routinely under the conditions of 37°C and 5% CO2, in MEM
medium supplemented with 10 % fetal calf serum, 25 mM of HEPES and 0.1 mg/ml
kanamycin. The MCF-7 cells in a logarithmic growth phase were treated with
trypsin/EDTA to prepare single cell suspension adjusted to 4.0 x 104 cells/ml in MEM
medium (supplemented with 10 % fetal calf serum, 25 mM of HEPES and 0.1 mg/ml
kanamycin). Test compounds were dissolved in DMSO and diluted with RPMI 1640
medium (supplemented with 10 % fetal calf serum, 25 mM of HEPES and 0.1 mg/ml
kanamycin) to a concentration of 2.0 x 10-4 to 2.0 x 10-9M.
The cell suspension was filled in a 96-wells microplate at a rate of 0.1 ml per well
and was cultured for 24 hours so as to make the cells to adhere to the microplate. Then, it
was added with 0.1 ml of the sample solution and cultured at 37°C for 72 hours in 5% CO2.
50 % Growth inhibition concentrations (GI50 µM) were calculated from growth
inhibitions at various sample concentrations. The results are as shown in Table 8.
In the foregoing, when the cells other than MCF-7 are used, instead of adding 10 %
fetal bovine serum, the following media were used, and the following single cell
suspensions were prepared.
PC-3 prostate cancer cells: 10% fetal bovine serum in F12K medium, single cell
suspension of 2 x 104 cells;
A549 lung cancer cells: 10% fetal bovine serum in DMEM medium, single cell suspension
of 1.5 xl04 cells;
WiDr colon cancer cells: 10% fetal bovine serum in MEM medium, single cell suspension
of3xl04 cells;

51
B16F10 melanoma cells: 10% fetal bovine serum in RPMI 1640 medium, single cell
suspension of 1 x 104 cells;

Compound 25
0.27 3.21 0.92 0.99 0.98
Compound 27 0.31 4.63 1.32 1.12 1.14
Compound 28 0.27 2.66 1.27 0.83 1.21
Compound 29 0.32 3.93 2.58 1.32 0.70
Compound 30 0.77 3.32 3.74 1.52 0.41
Compound 31 0.32 1.51 1.43 0.65 0.05
Compound 32 0.38 2.14 1.33 0.83 Compound 33 0.51 2.91 1.46 1.05 Compound 34 0.55 2.91 2.07 1.38 0.14
Compound 35 0.73 2.84 2.10 1.22 0.10
INDUSTRIAL APPLICABILITY
[00148] The agents of the present invention can be used for the prevention or treatment of
disorders of immune system involving in PI3K, such as autoimmune diseases, organ
transplantation, allergic or inflammatory diseases, hematologic neoplasm, sepsis or the
like. Furthermore, they can be used for the treatment of solid tumors. Moreover, they can
be used as PI3K inhibitors for the treatment of a variety of disorders.
52

Claims
1. An immunosuppressive agent comprising as an effective ingredient a heterocyclic
compound represented by Formula (I):

wherein,
X represents a nitrogen atom or CH;
both or either of R1 and R2 represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
R6 represents a morpholino (optionally substituted with one or two C1-C6 alkyl groups), a
pyrrolidinyl (optionally substituted with a hydroxy C1-C6 alkyl), a piperidino (which is
optionally substituted with one or two oxygen atoms, a hydroxyl group, a formyl, or a C1-
C6 alkyl), a piperazinyl (optionally substituted with one or two oxygen atoms, the nitrogen
at position 4 being optionally substituted with a substituent selected from the group
consisting of a formyl, a C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl,
an aromatic carbonyl, a benzylcarbonyl, and a substituted carbamoyl), or a 1,4-diazepano
(optionally substituted with one or two oxygen atoms, the nitrogen at position 4 being
optionally substituted with a substituent selected from the group consisting of a formyl, a
C1-C6 hydroxyalkyl, a C1-C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a
benzylcarbonyl, a substituted carbamoyl);
or a pharmaceutically acceptable salt thereof.
2. The immunosuppressive agent according to Claim 1, wherein either of R1 or R2 is a
hydroxyl group.
53

3. The immunosuppressive agent according to Claim 1 or 2, wherein either of R1 or
R2 is a hydroxyl group, and R3 is a difluoromethyl.
4. The immunosuppressive agent according to Claim 1, wherein both of R1 and R2 are
hydrogens, and R3 is a difluoromethyl.
5. The immunosuppressive agent according to any one of Claims 1 to 4, wherein R6 is
a 4-acetylpiperazine.
6. The imminosuppressive agent according to Claim 1, wherein said heterocyclic
compound is selected from the group consisting of:
2-(2-methylbenzimidazol-1 -yl)-4,6-dimorpholino-1,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4,6-dimorpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-morpholino-6-(piperazin-l-yl)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5 -oxo-1,4-diazepan-1 -yl)-1,3,5-
triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(3 -oxopiperazin-1 -yl)-1,3,5 -
triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-6-(4-formylpiperazin-1 -yl)-4-morpholino-1,3,5-
triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-6-(3,5-dioxopiperazin-l-yl)-4-morpholino-l,3,5-
triazine;
2-(benzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-morpholino-6-piperidino-l,3,5-triazine;
2-(6-amino-2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino)-6-
morpholino-1,3,5-triazine;
2-(2-difluoromethyl-6-ethoxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine;
2-(2-difluoromethyl-4-methylbenzimidazol-l-yl)-4,6-dimorpholino-l,3)5-triazine;
2-(2-difluoromethyl-5-hydroxybenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine;
2-(2-aminobenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine;
2-(6-amino-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-
morpholino-1,3,5-triazine;
54

2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethylpyrrolidin-1 -yl)-6-
morpholino-l,3,5-triazine;
2-(2-methylbenzimidazol-1 -yl)-4,6-dimorpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-l-yl)-4,6-dimorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(piperazin-1 -yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5 -oxo-1,4-diazepan-1 -
yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-morpholino-6-(3-oxopiperazin-l-yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-1-yl)-6-(4-formylpiperazin-1-yl)-4-
morpholinopyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-
morpholinopyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-(3,3-dimethylmorpholino)-6-
morpholinopyrimidine;
2-(2-aminobenzimidazol-1 -yl)-4,6-dimorpholinopyrimidine;
2-(2-difluoromethyl-4-methoxybenzimidazol-l-yl)-4-(2,6-dimethylmorpholino)-6-
morpholinopyrimidine; or
2-(5-ammo-2-difluoromethylbenzimidazol-l-yl)-4,6-di(2,6-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(2-hydroxymethylpyrrolidin-1-yl)-6-
morpholinopyrimidine;
2-(6-amino-4-chrolo-2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-
morpholino-1,3,5-triazine;
2-(6-amino-4-chrolo-2-difluoromethylbenzimidazol-l-yl)-4-[methyl(l-methylpiperidin-4-
yl)amino]-6-morpholino-l,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethylpyrrolidin-1 -yl)-6-
morpholino-1,3,5-triazine;
2-(4-chrolo-2-difluoromethyl-5 -hydroxybenzimidazol-1 -yl)-4,6-dimorpholino-1,3,5-
triazine;
2-(5,6-dimethyl-2-difluoromethylbenzimidazol-l-yl)-4,6-dimorpholino-l,3,5-triazine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5-
triazine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(cz.y-2,3 -
dimethylmorpholino)-l,3,5-triazine;
55

4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(trans-2,3-
dimethylmorpholino)-l,3,5-triazine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2-
dimethylmorpholino)-l,3,5-triazine;
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-6-
morpholino-1,3,5-triazine;
4-(4-acetylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-
1,3,5-triazine;
4-(4-acetylpiperazin-1 -yl)-2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino-1,3,5-
triazine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-
morpholinopyrimidine;
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3-
dimethy lmorpholino)pyrimidine;
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3-
dimethylmorpholino)pyrimidine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2-
dimethylmorpholino)pyrimidine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-6-
morpholinopyrimidine;
4-(4-acetylpiperazin-l-yl)-2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-6-
morpholinopyrimidine;
4-(4-acetylpiperazin-1 -yl)-2-(2-hydroxymethylbenzimidazol-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
morpholino-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
(cis-2,3-dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
(trans-2,3-dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
(2,2-dimethylmorpholino)-1,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(N,N-
dimethylcarbamoylpiperazin)-1 -yl]-6-morpholino-1,3,5-triazine;
56

2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-
l-yl]-6-morpholino-l,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
morpholino-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-1 -yl]-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
(cis-2,3-dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
(trans-2,3 -dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
(2,2-dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(N,N-
dimethylcarbamoylpiperazin)-l-yl]-6-morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-
1 -yl] -6-morpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-morpholino-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cw-2,3-
dimethylmorpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-(trans-2,3 -
dimethylmorpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-(2,2-
dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-[4-(2-furoyl)piperazin-1 -yl]-6-
morpholino-1,3,5 -triazine;
2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-
morpholino-l,3,5-triazine;
4- [4-(2-furoyl)piperazin-1 -yl] -2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-
morpholinopyrimidine;
57

2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cis-2,3-
dimethylmorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(trans-2,3-
dimethylmorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(2,2-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-
morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-
morpholinopyrimidine;
4-[4-(2-furoyl)piperazin-1 -yl]-2-(2-hydroxymethylbenzimidazol-1 -yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5-
triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3-
dimethylmorpholino)-1,3,5-triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3-
dimethylmorpholino)-l,3,5-triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2-
dimethylmorpholino)-1,3,5-triazine;
4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethy-4-hydroxybenzimidazol-1-yl)-6-
morpholino)-l ,3,5-triazine;
4-(4-acetonylpiperazin-1-yl)-2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-6-
morpholino-1,3,5-triazine;
4-(4-acetonylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-morpholino-1,3,5-
triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(cis-2,3 -
dimethylmorpholino)pyrimidine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3-
dimethylmorpholino)pyrimidine;
4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2-
dimethylmorpholino)pyrimidine;
58

4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-l-yl)-2-(2-hydroxymethylbenzimidazol-l-yl)-6-
morpholinopyrimidinne;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)-1,3,5-
triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino)-6-(4-
propionylpiperazin-1 -yl)-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino)-6-(4-
propionylpiperazin-1 -yl)-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-(4-
propionylpiperazin-1 -yl)-1,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin-
l-yl)-l,3,5-triazine;
2-(4-aniino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)-l,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1-yl)-4-morpholino-6-(4-propionylpiperazin-1-yl)-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino-6-(4-
propionylpiperazin-1 -yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(trans-2,3-dimethylmorpholino-6-(4-
propionylpiperazin-1 -yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino-6-(4-
propionylpiperazin-1 -yl)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin-
l-yl)pyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)pyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)pyrimidine;
59

2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazin-1 -yl)-6-morpholino-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazin-l-yl)-6-(cis-2,3-
dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazin-l-yl)-6-(trans-2,3-
dimethylmorpholino)-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazin-1 -yl)-6-(2,2-
dimethylmorpholino)-1,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazin-1 -yl)-6-
morpholino-1,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazin-1 -yl)-6-
morpholino-1,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-morpholino-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(cis-2,3-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(trans-2,3-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(2,2-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholino-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(cis-2,3 -
dimethylmorpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(trans-2,3-
dimethylmorpholino-1,3,5 -triazine;
60

2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(2,2-
dimethylmorpholino-l,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -
6-morpholino-l,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholino-1,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholino-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(cis-2,3-
dimethylmorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(trans-2,3-
dimethylmorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(2,2-
dimethylmorpholinopyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -
6-morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-
morpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-[4-(3-hydroxypropyl)piperazi-1 -yl]-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxycarbonylpiperazin-l-yl)-6-(cis-2,3-
dimetylmorpholino)-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans-
2,3-dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(2,2-
dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-
6-morpholino-l,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxycarbonylpiperazin-l-yl)-6-
morpholino-1,3,5-triazine;
61

2-(2-hydroxymethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-
morpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(cis-2,3 -
dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans-
2,3-dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxycarbonylpiperazin-l-yl)-6-(2,2-
dimethy lmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-
6-morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5-oxo-1,4-diazepan-1 -yl)-1,3,5-
triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(3 -oxopiperazin-1 -yl)-1,3,5 -
triazine; and
2-(2-difluoromethylbenzimidazol-1 -yl)-6-(3,5-dioxopiperazin-1 -yl)-4-morpholino-1,3,5-
triazine.
7. The immunosuppressive agent according to Claim 1, wherein the heterocyclic
compound is selected from the group consisting of:
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(2-hydroxymethylpyrrolidin-1 -yl)-6-
morpholino-1,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-
morpholinopyrimidine; and
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(3,3 -dimethylmorpholino)-6-
morpholinopyrimidine.
8. The immunosuppressive agent according to Claim 1, wherein the heterocyclic
compound is selected from the group consisting of:
62

2-(2-difluoromethylbenzimidazol-1 -yl)-4,6-dimorpholino-1,3,5-triazine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-
morpholinopyrimidine; and
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5-
triazine.
9. The immunosuppressive agent according to any one of Claims 1 to 8, wherein the
disorder of interest is rejection or graft versus host disease; an inflammatory bowel disease
such as ulcerative colitis or Crohn disease; an inflammatory or allergenic skin disease such
as psoriasis or atopic dermatitis; an inflammatory or allergenic respiratory disorder such as
obstructive pulmonary disease or asthma; autoimmune disease such as rheumatoid arthritis,
systemic lupus erythematosus, scleroderma or Sjogren syndrome; malignant lymphoma,
multiple myeloma, leukemia; sepsis, fulminant hepatitis or the like.
10. A heterocyclic compound represented by the general Formula (II):

wherein,
n represents 0-2;
X represents a nitrogen atom or CH;
Y represents -(CH2)n1-, wherein n1 is 1-2;
R1 and R2, both or either, represent a hydrogen atom, a hydroxyl group, a halogen, an
amino group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkyl group, or a
cyano group;
R3 represents a hydrogen atom, a difluoromethyl group, an amino group, a C1-C6
alkylamino group, a methyl or a hydroxymethyl group;
R4 and R5 represent a hydrogen atom, or a C1-C6 alkyl group;
63

R7 represents a hydrogen atom, a C1-C6 alkyl group, a formyl, a C1-C6 hydroxyalkyl, a C1-
C6 alkoxycarbonyl, a C1-C6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, or a
substituted carbamoyl;
or a pharmaceutically acceptable salt thereof.
11. The compound according to Claim 10, wherein the heterocyclic compound is:
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5-
triazine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(cis-2,3-
dimethylmorpholino)-l,3,5-triazine;
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3-
dimethylmorpholino)-l,3,5-triazine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2-
dimethylmorpholino)-l,3,5-triazine;
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-6-
morpholino-1,3,5-triazine;
4-(4-acetylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-
1,3,5-triazine;
4-(4-acetylpiperazin-1 -yl)-2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino-1,3,5-
triazine;
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-
morpholinopyrimidine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(cis-2,3-
dimethylmorpholino)pyrimidine;
4-(4-acetylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3-
dimethylmorpholino)pyrimidine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2-
dimethylmorpholino)pyrimidine;
4-(4-acetylpiperazin-1 -yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-6-
morpholinopyrimidine;
4-(4-acetylpiperazin-l-yl)-2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-6-
morpholinopyrimidine;
4-(4-acetylpiperazin-l-yl)-2-(2-hydroxymethylbenzimidazol-l-yl)-6-
morpholinopyrimidine;
64

2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
morpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
(cis-2,3-dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
(trans-2,3-dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
(2,2-dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(N,N-
dimethylcarbamoylpiperazin)-1 -yl] -6-morpholino-1,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-
l-yl]-6-morpholino-l,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
morpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-1 -yl]-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
(cis-2,3-dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
(trans-2,3-dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-l-yl]-6-
(2,2-dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(N,N-
dimethylcarbamoylpiperazin)-l-yl]-6-morpholinopyrimidine;
2-(4-arnino-2-difluoromethylbenzimidazol-l-yl)-4-[4-(N,N-dimethylcarbamoylpiperazin)-
1 -yl] -6-morpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(N,N-dimethylcarbamoylpiperazin)-1 -yl] -6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(2-furoyl)piperazin-1 -yl]-6-morpholino-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cis-2,3-
dimethylmorpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(2-furoyl)piperazin-1 -yl]-6-(trans-2,3-
dimethylmorpholino-l,3,5-triazine;
65

2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(2,2-
dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-
morpholino-1,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-
morpholino-1,3,5-triazine;
4- [4-(2-furoyl)piperazin-1 -yl] -2-(2-hydroxymethylbenzimidazol-1 -yl)-6-morpholino-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(cis-2,3-
dimethylmorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-(trans-2,3 -
dimethy lmorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-(2,2-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-[4-(2-furoyl)piperazin-l-yl]-6-
morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(2-furoyl)piperazin-1 -yl] -6-
morpholinopyrimidine;
4-[4-(2-furoyl)piperazin-l-yl]-2-(2-hydroxymethylbenzimidazol-l-yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-morpholino-1,3,5 -
triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3-
dimethylmorpholino)-l,3,5-triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3-
dimethylmorpholino)-1,3,5-triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(2,2-
dimethylmorpholino)-1,3,5-triazine;
4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-6-
morpholino-1,3,5-triazine;
4-(4-acetonylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6-
morpholino-1,3,5-triazine;
66

4-(4-acetonylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-morpholino-1,3,5-
triazine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(cis-2,3-
dimethylmorpholino)pyrimidine;
4-(4-acetonylpiperazin-l-yl)-2-(2-difluoromethylbenzimidazol-l-yl)-6-(trans-2,3-
dimethylmorpholino)pyrimidine;
4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethylbenzimidazol-1 -yl)-6-(2,2-
dimethy lmorpholino)pyrimidine;
4-(4-acetonylpiperazin-1 -yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-1 -yl)-2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-6-
morpholinopyrimidine;
4-(4-acetonylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-
morpholinopyrimidinne;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)-1,3,5-
triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(cis-2,3 -dimethylmorpholino)-6-(4-
propionylpiperazin-1 -yl)-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(trans-2,3 -dimethylmorpholino)-6-(4-
propionylpiperazin-1 -yl)-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino)-6-(4-
propionylpiperazin-1 -yl)-1,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin-
l-yl)-l,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)-l,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -yl)-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(cis-2,3-dimethylmorpholino-6-(4-
propionylpiperazin-1 -yl)pyrimidine;
67

2-(2-difluoromethylbenzimidazol-1 -yl)-4-(trans-2,3 -dimethylmorpholino-6-(4-
propionylpiperazin-1 -yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(2,2-dimethylmorpholino-6-(4-
propionylpiperazin-1 -yl)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-l-yl)-4-morpholino-6-(4-propionylpiperazin-
l-yl)pyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)pyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-morpholino-6-(4-propionylpiperazin-1 -
yl)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-morpholino-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(cis-2,3-
dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(trans-2,3-
dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(2,2-
dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(4-methoxyacetylpiperazi-1-yl)-6-
morpholino-1,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholino-1,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-morpholino-
1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazi-1-yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(cis-2,3-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxyacetylpiperazi-l-yl)-6-(trans-2,3-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-(2,2-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxyacetylpiperazi-1 -yl)-6-
morpholinopyrimidine;
68

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazi-1-yl)-6-
morpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazi-1-yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(cis-2,3 -
dimethylmorpholino-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(trans-2,3-
dimethylmorpholino-1,3,5 -triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(2,2-
dimethylmorpholino-1,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -
6-morpholino-l,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholino-1,3,5 -triazine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholino-1,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(cis-2,3-
dimethylmorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-[4-(3 -hydroxypropyl)piperazi-1 -yl] -6-(trans-2,3 -
dimethylmorpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-[4-(3-hydroxypropyl)piperazi-l-yl]-6-(2,2-
dimethy lmorpholinopyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -
6-morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4- [4-(3 -hydroxypropyl)piperazi-1 -yl] -6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholino-1,3,5 -triazine;
69

2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(cis-2,3 -
dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans-
2,3-dimethylmorpholino)-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxycarbonylpiperazin-l-yl)-6-(2,2-
dimethylmorpholino)-1,3,5-triazine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1-yl)-
6-morpholino-l ,3,5-triazine;
2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholino-1,3,5-triazine;
2-(2-hydroxymethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-
morpholino-l,3,5-triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-l-yl)-4-(4-methoxycarbonylpiperazin-l-yl)-6-(cis-2,3-
dimethy lmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(trans-
2,3-dimethylmorpholino)pyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-(2,2-
dimethylmorpholino)pyrimidine;
2-(2-difluoromethyl-4-hydroxybenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-
6-morpholinopyrimidine;
2-(4-amino-2-difluoromethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholinopyrimidine;
2-(2-hydroxymethylbenzimidazol-1 -yl)-4-(4-methoxycarbonylpiperazin-1 -yl)-6-
morpholinopyrimidine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(5-oxo-1,4-diazepan-1-yl)-1,3,5-
triazine;
2-(2-difluoromethylbenzimidazol-1 -yl)-4-morpholino-6-(3 -oxopiperazin-1 -yl)-1,3,5-
triazine; and
2-(2-difluoromethylbenzimidazol-l-yl)-6-(3,5-dioxopiperazin-l-yl)-4-morpholino-l,3,5-
triazine.
70

12. An antitumor agent comprising as an effective ingredient a compound according to
either of Claims 10 or 11.
71

A novel immunosuppressive agent, more specifically an immunosuppressive agent
comprising, as an active ingredient, a heterocyclic compound represented by the general
formula (I) (wherein X or other variables are as defined in the specification) or a
pharmaceutically acceptable salt thereof; a novel heterocyclic compound represented by
the general formula (II) (wherein X or other variables are as defined in the specification)
or a pharmaceutically acceptable salt thereof; and use of the compound or salt as an
antitumor agent.

Documents:

03220-kolnp-2007-abstract.pdf

03220-kolnp-2007-claims.pdf

03220-kolnp-2007-correspondence others.pdf

03220-kolnp-2007-description complete.pdf

03220-kolnp-2007-drawings.pdf

03220-kolnp-2007-form 1.pdf

03220-kolnp-2007-form 3.pdf

03220-kolnp-2007-form 5.pdf

03220-kolnp-2007-international publication.pdf

03220-kolnp-2007-international search report.pdf

03220-kolnp-2007-others pct form.pdf

03220-kolnp-2007-pct priority document notification.pdf

03220-kolnp-2007-priority document.pdf

3220-KOLNP-2007-(02-08-2013)-ANNEXURE TO FORM 3.pdf

3220-KOLNP-2007-(02-08-2013)-CORRESPONDENCE.pdf

3220-KOLNP-2007-(03-09-2013)-CORRESPONDENCE.pdf

3220-KOLNP-2007-(03-09-2013)-OTHERS.pdf

3220-KOLNP-2007-(13-12-2013)-CORRESPONDENCE.pdf

3220-KOLNP-2007-(14-12-2012)-ABSTRACT.pdf

3220-KOLNP-2007-(14-12-2012)-CLAIMS.pdf

3220-KOLNP-2007-(14-12-2012)-CORRESPONDENCE.pdf

3220-KOLNP-2007-(14-12-2012)-DESCRIPTION (COMPLETE).pdf

3220-KOLNP-2007-(14-12-2012)-DRAWINGS.pdf

3220-KOLNP-2007-(14-12-2012)-FORM-1.pdf

3220-KOLNP-2007-(14-12-2012)-FORM-13.pdf

3220-KOLNP-2007-(14-12-2012)-FORM-2.pdf

3220-KOLNP-2007-(14-12-2012)-OTHERS.pdf

3220-KOLNP-2007-(14-12-2012)-PA.pdf

3220-KOLNP-2007-(14-12-2012)-PETITION UNDER RULE 137.pdf

3220-KOLNP-2007-(17-01-2013)-ANNEXURE TO FORM 3.pdf

3220-KOLNP-2007-(17-01-2013)-CORRESPONDENCE.pdf

3220-KOLNP-2007-(19-12-2012)-CORRESPONDENCE.pdf

3220-KOLNP-2007-(19-12-2012)-ENGLISH TRANSLATION OF PRIORITY DOCUMENT.pdf

3220-KOLNP-2007-(19-12-2012)-PETITION UNDER RULE 137.pdf

3220-KOLNP-2007-(31-07-2012)-ANNEXURE TO FORM 3.pdf

3220-KOLNP-2007-(31-07-2012)-EXAMINATION REPORT REPLY RECIEVED.pdf

3220-KOLNP-2007-(31-07-2012)-OTHERS-1.pdf

3220-KOLNP-2007-(31-07-2012)-OTHERS-2.pdf

3220-KOLNP-2007-(31-07-2012)-OTHERS-4.pdf

3220-KOLNP-2007-(31-07-2012)-OTHERS-5.pdf

3220-KOLNP-2007-(31-07-2012)-OTHERS.pdf

3220-KOLNP-2007-ASSIGNMENT.pdf

3220-KOLNP-2007-CORRESPONDENCE OTHERS-1.1.pdf

3220-kolnp-2007-form 18.pdf

3220-KOLNP-2007-PA.pdf

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Patent Number

264538

Indian Patent Application Number

3220/KOLNP/2007

PG Journal Number

02/2015

Publication Date

09-Jan-2015

Grant Date

05-Jan-2015

Date of Filing

31-Aug-2007

Name of Patentee

ZENYAKU KOGYO KABUSHIKIKAISHA

Applicant Address

2-9, NIHONBASHI-MUROMACHI 3-CHOME, CHUO-KU, TOKYO

Inventors:

#	Inventor's Name	Inventor's Address
1	HARUTA KAZUHIKO	C/O LABORATORY OF ZENYAKU KOGYO KABUSHIKIKAISHA, 33-7, OHIZUMI-MACHI 2-CHOME,, NERIMA-KU, TOKYO 1780062
2	MATSUNO TOSHIYUKI	C/O LABORATORY OF ZENYAKU KOGYO KABUSHIKIKAISHA, 33-7, OHIZUMI-MACHI 2-CHOME,, NERIMA-KU, TOKYO 1780062
3	TSUCHIDA YOSHIO	C/O LABORATORY OF ZENYAKU KOGYO KABUSHIKIKAISHA, 33-7, OHIZUMI-MACHI 2-CHOME,, NERIMA-KU, TOKYO 1780062
4	WATANABE TETSUO	C/O LABORATORY OF ZENYAKU KOGYO KABUSHIKIKAISHA, 33-7, OHIZUMI-MACHI 2-CHOME,, NERIMA-KU, TOKYO 1780062
5	YOSHIOKA KIMITOMO	C/O LABORATORY OF ZENYAKU KOGYO KABUSHIKIKAISHA, 33-7, OHIZUMI-MACHI 2-CHOME,, NERIMA-KU, TOKYO 1780062
6	YUI RYUGO	C/O LABORATORY OF ZENYAKU KOGYO KABUSHIKIKAISHA, 33-7, OHIZUMI-MACHI 2-CHOME,, NERIMA-KU, TOKYO 1780062
7	YAGUCHI SHINICHI	C/O LABORATORY OF ZENYAKU KOGYO KABUSHIKIKAISHA, 33-7, OHIZUMI-MACHI 2-CHOME,, NERIMA-KU, TOKYO 1780062

PCT International Classification Number

A61K 31/5377

PCT International Application Number

PCT/JP2006/304937

PCT International Filing date

2006-03-13

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2005-069255	2005-03-11	Japan