Phosphatidylinositol-3-kinase (PI3K) is a lipid signaling kinase, which is present universally throughout species, ranging from plants or yeasts to mammals including humans. PI3K is an enzyme for phosphorylating the hydroxyl group at the 3-position of phosphatidylinositol, phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-diphosphate, which are cell membrane phospholipids, and from each of these substrates, phosphatidylinositol-3-phosphate, phosphatidylinositol-3,4-diphosphate, and phosphatidylinositol-3,4,5-triphosphate (PIP3) are produced. These phosphorylated phosphatidylinositols thus produced act as an intracellular second messenger. Particularly, PIP3 causes migration of various molecules having pleckstrin homology (PH) domains to a position near the cell membrane to induce activation of the molecules, and thus it is considered to be the most important phosphorylated phosphatidylinositol (“The Journal of Biological Chemistry”, 1999, Vol. 274, p. 8347-8350).
PI3K is divided into three classes, Classes I, II, and III, according to various characteristics, and from the viewpoints that the only enzyme producing PIP3 in vivo is Class I PI3K, the Class I PI3K is considered to be the most important class (“Biochimica et Biophysica Acta”, 2008, Vol. 1784, p. 159-185). The Class I PI3K is subdivided into IA and IB. The Class IA PI3K consists of heterodimers including a combination of a 110-kDa catalytic subunit (p110α, β, or δ) and a 50- to 85-kDa regulatory subunit (p85α, p85β, p55α, p55γ, or p50α), and the Class IB PI3K is a heterodimer of a 110-kDa catalytic subunit (p110γ) and a 101-kDa regulatory subunit (p101) (“Nature Immunology”, 2003, No. 4, p. 313-319). Hereinafter, the respective names of PI3K are referred to as PI3Kα, β, δ, and γ, corresponding to catalytic subunits included therein.
PI3Kα and β are widely present in a biological body and deficiency of PI3Kα and β in mice has been reported to be fetally lethal in both cases (“The Journal of Biological Chemistry”, 1999, Vol. 274, p. 10963-10968; and “Mammalian Genome”, 2002, Vol. 13, p. 169-172). As a result of studies using subtype selective compounds, it has been reported that PI3Kα plays an important role in insulin signaling and a PI3Kα inhibitor causes insulin resistance (“Cell”, 2006, Vol. 125, p. 733-747). Further, it has been reported that PI3Kβ is involved in platelet aggregation and a PI3Kβ inhibitor has an antithrombotic effect (“Nature Medicine”, 2005, Vol. 11, p. 507-514). On the other hand, mice deficient in PI3Kβ or γ are all born normally, and no problems concerning growth, life span, reproduction, or the like have been found (“Science”, 2000, Vol. 287, p. 1040-1046; and “Molecular and Cellular Biology”, 2002, Vol. 22, p. 8580-8591). In particular, expression of PI3Kδ is significantly limited to hemocytes and lymphoid tissues, and mice deficient in PI3Kδ have been found to have significant damage in activation of lymphocytes. A close relationship between the activation of lymphocytes and immunity/inflammation is well known, and compounds selectively inhibiting PI3Kδ have a potential to be immunity/inflammatory inhibitors having both a potent inhibitory action on the activation of lymphocytes and safety.
Interleukin-2 (IL-2) is a kind of cytokine which is mainly produced from activated T cells. IL-2 induces proliferation and activation of lymphocytes via an IL-2 receptor which is a receptor for IL-2. IL-2 is a very important molecule in signaling the activation of an immune system, and its production inhibitors (for example, Tacrolimus and Cyclosporin A) have been used clinically as immunosuppressing agents. In addition, anti-IL-2 receptor monoclonal antibodies such as Basiliximab and Daclizumab have been used clinically as immunosuppressing agent.
B cells are one of the main subsets of lymphocytes, along with T cells, and are cells which is a main actor of humoral immunity. It is known that humoral immunity plays an extremely important role in preventing infection from pathogens or the like, but in autoimmune diseases such as rheumatoid arthritis and the like, abnormal activation of humoral immunity occurs, which is deeply involved in the pathogenesis. In fact, an anti-CD20 antibody, Rituximab, has been used clinically as a drug for treating rheumatoid arthritis.
As the compound having a PI3K inhibitory action, for example, the compounds of the formula (A-1) (Patent Document 1), the formula (A-2) (Patent Document 2), the formula (A-3) (Patent Document 3), the formula (B-1) (Patent Document 4), the formula (B-2) (Patent Document 5), the formula (B-3) (Patent Document 6), the formula (C) (Patent Document 7), the formula (D-1) (Patent Document 8), the formula (D-2) (Patent Document 9), the formula (E-1) (Patent Document 10), the formula (E-2) (Patent Document 11), the formula (E-3) (Patent Document 12), the formula (F) (Patent Document 13), the formula (G) (Patent Document 14), the formula (H) (Patent Document 15 and Non-Patent Document 1), the formula (J) (Patent Document 16), and the formula (K) (Patent Document 17) described below have been reported. However, the compound of the formula (I) of the present application as described later is different in the structure of the group R1 of the formula (I) from the compounds of the formulae (A-1) to (E-3), (H), and (K). It is different in structure from the compounds of the formulae (F) and (G), in that it has a benzimidazolyl-1-yl group. As the group R2 of the formula (J), a heteroaryl group has been disclosed, but there is no specific disclosure of the benzimidazolyl-1-yl group, and there is no disclosure of the compound of the formula (I) of the present invention in Patent Document 16. Further, there is no description of a PI3Kδ selective inhibitory action in any documents.

(wherein R2 in the formulae (A-1) to (E-3) represents a difluoromethyl group or the like. R1 and R2 in the formula (F) are combined with each other to form an unsubstituted or substituted morpholino group, together with N to which they are bonded, X represents a bond or the like, and R3 represents an unsubstituted or substituted indolyl group. R2 in the formula (G) represents a substituted indol-4-yl group at the position 5 or 6. R3 in the formula (H) represents a difluoromethyl group or the like, and R6 represents a morpholino group which may be substituted, or the like. In the formula (J), Y1 and Y2 represent N, CH, or the like, X represents NR4CR6R7 or the like, R1 represents a heterocyclic group or the like, and R2 represents a heteroaryl group or the like. In the formula (K), X, Y, and Z represent N or CH, provided that at least two of X, Y, and Z represent N, R1 represents heteroaryl or the like, R2 represents a heterocycle or the like, Q represents a bond, azetidinylen-4-amino, or the like, T represents —C(O)—, —C(═S)—, or —S(O)2—, and R5 represents halogen or —O—S(O)2—R7. For the other symbols, reference may be made to the publication.)
It has been reported that the compounds of the formula (L-1) (Patent Document 18), the formula (L-2) (Patent Document 19), the formula (L-3) (Patent Document 20), the formula (L-4) (Patent Document 21), and the formula (L-5) (Patent Document 22) described below have an anti-tumor activity. Further, in Non-Patent Document 2, it has been suggested that a secondary amine compound of the formula (M) has an Lck inhibitory action and an IL-2 production inhibitory action, and is applied for autoimmune diseases and rejection reaction in organ transplantation. However, the compound of the formula (I) of the present invention essentially has a difluoromethyl group, which is different in the structure from the compounds of the formulae (L-1), (L-2), and (M). It is also different in the structure of the group of R1 of the formula (I) from the compounds of the formulae (L-3) and (L-5). In addition, it is different in the structure of the substituent on a benzimidazole ring from the compound of the formulae (L-4). Further, there is no description of a PI3Kδ selective inhibitory action in any literature.

(in the formula (L-1), both of X and Y represent N, or one of X and Y represents N and the other represents CR7, and R6 represents H or C1-6 alkyl; in the formula (L-2), both of X and Y represent N, or one of X and Y represents N and the other represents CR3, and R1 represents a morpholino group or the like; in the formula (L-3), X represents N or CH, R1 represents CHnF3-n (n is 1 or 2), and R2 represents morpholino which may be substituted, or the like; in the formula (L-4), X represents N or CH, and R1 represents halogen or a hydroxyl group; in the formula (L-5), X represents N or CH, R1 represents a morpholino group which may be substituted with 1 to 4 C1-6 alkyl groups, and Y represents C1-6 alkyl; and in the formula (M), R1 represents a morpholino group or the like. For the other symbols, reference may be made to the publication.)
Furthermore, a quinazolin-4-one derivative (Patent Documents 23 to 25) has been reported as a PI3Kδ selective inhibitor, and its usability in inflammation, immune diseases, or hematologic tumors (leukemia and the like) is indicated. As other PI3Kδ selective inhibitors, a thiazolylurea derivative (Patent Document 26) has been reported together with its usability in inflammation, immune diseases, or the like.
Furthermore, the invention relating to a triazine or pyrimidine derivative having a PI3Kδ selective inhibitory action, which is an invention in the prior art by the present inventors, has been disclosed after the priority date of the present application (Patent Document 27). The compound of the present invention is different in the structure of the group R1 in the formula (I) from the compound disclosed in the prior application.
USPTO Backgrounds
USPTO Backgrounds