Compounds useful as inhibitors of indoleamine 2,3-dioxygenase

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The present invention relates to compounds useful as inhibitors of indoleamine 2,3-dioxygenase (IDO). The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in vitro applications.

tryptophan (Trp) is an essential amino acid protein, niacin and the neurotransmitter serotonin (serotonin) biosynthesis required. Heme - dependent dioxygenase indole amine 2,3-dioxygenase is responsible for the Trp extrahepatic into N- formyl kynurenine, which is the first Trp metabolism rate-limiting step. N- formyl-kynurenine is called kynurenine more precursors of biologically active molecules, the kynurenine having immunomodulatory properties.

IDO initially described as part of a mammalian parasite resistance to infection defense mechanisms. Trp depletion may lead to intracellular pathogens such as Toxoplasma (Toxoplasma gondii) or Chlamydia trachomatis growth arrest. Recently, obviously induce IDO is an enzyme that has a major role in the regulation of immune cells. Reduce Trp content and increase Kynurenine pool through the induction and maintenance of regulatory T cells caused inhibition of effector immune cells and promote adaptive immune suppression.

In many of the immune system have been related to the activation of a large number of disorders observed IDO Trp to increase the conversion of kynurenine (turnover), the conditions such as infection, cancer, autoimmune disease, trauma, and AIDS. Other study based on these indications show that induce IDO results in inhibition of T- cell responses and improve tolerability. In cancer, a lot of evidence that IDO upregulation of tumor cell detachment from the immune surveillance mechanism. IDO expression in a wide range of solid tumors (Uyttenhove et al., Nat Med 2003; 10:. 1269-74) and has been observed in primary and metastatic cancer cells. IDO in tumors induced by pro-inflammatory cytokines, pro-inflammatory cytokines including the type I and type II interferons and TGF-β Some oncogenic mutations in KIT can also lead to increased expression of IDO, such as loss of tumor suppressor Binl or activating mutations. In some tumors, IDO expression related to immune incompetence , and the latest reports indicating increased effector T cells reduce human gastrointestinal tumors IDO expression in tumor invasion is accompanied.

a large number of pre-clinical data has been disclosed further confirms the role of IDO in the anti-tumor immune response. For example, to force cancer cells to induce IDO shown to confer a survival advantage. Other IDO inhibitors in vivo study based show Kynurenine content by reducing tumor growth caused by lymphocyte-dependent decrease. Preclinical research also identified IDO inhibitor traitor and promote tumor antigen of therapeutic agents such as radiation, chemotherapy, or a combination vaccine act in conjunction range.