Many protein kinases constitute a large family of kinases, which control various signal transduction in cells by catalysis. Many diseases are related to intracellular abnormal responses induced by the regulation of protein kinase, including autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancers and cardiovascular diseases.
Janus kinase (JAK) is a type of tyrosine kinase. There are four members of JAK, including JAK1, JAK2, JAK3 and TYK2. JAKs play an important role in signal transduction of a variety of cytokines. JAK1, JAK2 and TYK2 widely exist in various tissues and cells, while JAK3 is mainly found in lymphocytes. JAK3 can be bound specifically non-covalently to the common γ chain (Fcγ) of cytokine receptor, while JAK1 is bound to a beta chain. Both JAK3 and JAK1 are activated by IL-2, IL-4, IL-7, IL-9, and IL-15 cytokines. JAK2 plays an important role in the erythropoietin (EPO) signaling pathway, including promoting red blood cell differentiation and activating STAT5.
Signal transducer and activator of transcription (STAT) is a group of cytoplasmic proteins which can be bound to DNA in the regulatory region of the target gene. As downstream substrates of JAKs, STATs can be self-activated by tyrosine phosphorylation under the stimulation of an external signal, and then transferred to the nucleus, where they regulates gene transcription.
Cytokine is bound to an associated receptor, resulting in dimerization of the receptor. JAKs coupled with the receptor are in proximity to each other and are activated by the phosphorylation of interactive tyrosine residues. Activated JAKs catalyze the phosphorylation of tyrosine residues of the receptor itself, thereby forming the corresponding “docking sites” for binding of STATs to the receptor complex. SH2 domains of STATs are bound to phosphotyrosine residues of the receptor, and the phosphorylation of C-terminal tyrosine residues is achieved under the role of JAKs. Two phosphorylated STAT molecules interact with each other to form homologous/heterologous dimers, which dissociate from receptor molecules in the cell nucleus, where they bind to promoter regions of a target gene and regulate gene transcription and expression.
Many abnormal immune responses, such as autoimmune diseases including allergies, asthma, (allogeneic) transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, myeloproliferative disorders, and hematologic malignancies including leukemia and lymphoma, and their variations are associated with JAK/STAT signaling pathway.
A JAK3 deficiency is associated with a severe combined immunodeficiency immune (SCID) phenotype in both rodents and humans. The SCID phenotype of JAK3−/− mammals and the lymphoid cell specific expression of JAK3 are two advantageous properties that make JAK3 a target for immunosuppression. T cells of mice having a JAK3 deficiency cannot respond to IL-2, and T cells of mice having a JAK1 deficiency have a weak response to IL-2. IL-2 plays a critical role in T cell modulation. For example, when an antibody is bound to the extracellular part of the IL-2 receptor, the antibody bound IL-2 receptor could effectively prevent transplant rejection.
Further animal studies have indicated that JAK3 not only plays a critical role in B and T lymphocyte maturation, but that it is also essential to maintain T cell function. Modulation of immune activity through this novel mechanism can be useful for the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases.
JAK kinase inhibitors, particularly JAK3 kinase inhibitors, could impede T-cell activation and prevent graft rejection after transplantation, and also could provide a therapeutic benefit for other autoimmune disorders. JAK3 is also involved in many biological processes. For example, the proliferation and survival of murine mast cells induced by IL-4 and IL-9 have been shown to be dependent on JAK3- and gamma chain-signaling (Suzuki et al., 2000, Blood 96: 2172-2180). JAK3 also plays an important role in IgE receptor-mediated mast cell degradation reactions. JAK3 inhibition also leads to immunosuppression in transplant rejection. JAK3 plays a pivotal role in IgE receptor-mediated mast cell degradation responses (Malaviya et al., 1999, Biochem. Biophys. Res. Commun. 257:807-813), and inhibition of JAK3 kinase activity has been demonstrated to prevent type I hypersensitivity, including anaphylaxis (Malaviya et al., 1999, J. Biol. Chem. 274: 27028-27038). JAK3 inhibition has also been shown to result in immune suppression for allograft rejection (Kirken, 2001, Transpl. Proc. 33:3268-3270). JAK3 kinases have also been involved in the mechanism of other diseases, such as early and late stages of rheumatoid arthritis; familial amyotrophic lateral sclerosis; leukemia; mycosis fungoides; and abnormal cell growth. As an important protein kinase, JAK3 can adjust the function of lymphocytes, macrophages, and mast cells. JAK3 inhibitors are expected to be involved in the treatment or prevention of lymphocytes, macrophages, or mast cell function-related diseases.
For JAK2 subtypes, JAK2 kinase-JAK2 V617F (mutation causes JAK2 kinase activity abnormal), a somatic cell gain-of-function mutation, was found in classic Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms, which include primary thrombocytosis, polythemia vera, and primary myelofibrosis. Therefore, people had a strong interest in the development of JAK2-targeted therapies for these diseases. Some studies found that in patients suffering from marrow fibrosis, JAK2 kinase mutation was produced in more than 50% of patients in vivo, and disease-related symptoms such as anemia, splenomegaly, and the risk of transformation to acute myeloid leukemia (AML) were associated with the increased activity of, and hyperactive JAK-STAT signaling pathway resulting from JAK2 gene mutation. Meanwhile, JAK2 activity was increased abnormally in a variety of solid tumors and hematological tumors (glioblastoma, breast cancer, multiple myeloma, prostate cancer, AML, etc.). Therefore, the development of a selective inhibitor of JAK2 for myeloproliferative neoplasms and leukemia therapy has great medical value and market potential (it is estimated to be billions of dollars). Recently, a selective inhibitor of JAK2 named Ruxolitinib (INCB-018424), developed by INCYTE in cooperation with NOVARTIS, has been approved by the FDA, and appeared on the market successfully. (Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis. Srdan Verstovsek, M.D., Ph.D., Hagop Kantarjian, M.D., Ruben A. Mesa, M.D, et al. N Engl J Med 2010; 363:1117-1127).
A series of JAK inhibitors have been disclosed by some patent applications, including WO2001042246, WO2002000661, WO2009054941, and WO2011013785 etc.
Although a series of JAK kinase inhibitors having function in immune diseases have been disclosed, there remains a need to develop new compounds with better efficacy. After continuous efforts, the present invention provides compounds of formula (I), and finds that the compounds having such structure exhibit excellent effects and actions.