US20080125470A1 - N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase - Google Patents

N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase Download PDF

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US20080125470A1
US20080125470A1 US11/856,967 US85696707A US2008125470A1 US 20080125470 A1 US20080125470 A1 US 20080125470A1 US 85696707 A US85696707 A US 85696707A US 2008125470 A1 US2008125470 A1 US 2008125470A1
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alkyl
alkynyl
alkenyl
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haloalkyl
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Andrew P. Combs
Brian M. Glass
Richard B. Sparks
Eddy Wai Tsun Yue
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Incyte Corp
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Definitions

  • the present invention is directed to modulators of indoleamine 2,3-dioxygenase (IDO), as well as compositions and pharmaceutical methods thereof.
  • IDO indoleamine 2,3-dioxygenase
  • Trp Tryptophan
  • IDO 5-hydroxytryptamine
  • Trp is an essential amino acid required for the biosynthesis of proteins, niacin and the neurotransmitter 5-hydroxytryptamine (serotonin).
  • the enzyme indoleamine 2,3-dioxygenase also known as INDO or IDO
  • IDO indoleamine 2,3-dioxygenase
  • a depletion of Trp resulting from IDO activity is a prominent gamma interferon (IFN- ⁇ )-inducible antimicrobial effector mechanism.
  • IFN- ⁇ stimulation induces activation of IDO, which leads to a depletion of Trp, thereby arresting the growth of Trp-dependent intracellular pathogens such as Toxoplasma gondii and Chlamydia trachomatis .
  • IDO activity also has an antiproliferative effect on many tumor cells, and IDO induction has been observed in vivo during rejection of allogeneic tumors, indicating a possible role for this enzyme in the tumor rejection process (Daubener, et al., 1999, Adv. Exp. Med. Biol., 467: 517-24; Taylor, et al., 1991, FASEB J., 5: 2516-22).
  • HeLa cells co-cultured with peripheral blood lymphocytes acquire an immuno-inhibitory phenotype through up-regulation of IDO activity.
  • a reduction in PBL proliferation upon treatment with interleukin-2 (IL2) was believed to result from IDO released by the tumor cells in response to IFNG secretion by the PBLs.
  • IL2 interleukin-2
  • This effect was reversed by treatment with 1-methyl-tryptophan (1MT), a specific IDO inhibitor. It was proposed that IDO activity in tumor cells may serve to impair antitumor responses (Logan, et al., 2002, Immunology, 105: 478-87).
  • Trp depletion has received much attention.
  • IDO is involved in induction of immune tolerance.
  • Studies of mammalian pregnancy, tumor resistance, chronic infections and autoimmune diseases have shown that cells expressing IDO can suppress T-cell responses and promote tolerance.
  • Accelerated Trp catabolism has been observed in diseases and disorders associated with cellular immune activation, such as infection, malignancy, autoimmune diseases and AIDS, as well as during pregnancy.
  • increased levels of IFNs and elevated levels of urinary Trp metabolites have been observed in autoimmune diseases; it has been postulated that systemic or local depletion of Trp occurring in autoimmune diseases may relate to the degeneration and wasting symptoms of these diseases.
  • IDO immunodeficiency virus
  • IDO inhibition can enhance the levels of virus-specific T cells and, concomitantly, reduce the number of virally-infected macrophages in a mouse model of HIV (Portula et al., 2005, Blood, 106:2382-90).
  • IDO is believed to play a role in the immunosuppressive processes that prevent fetal rejection in utero. More than 40 years ago, it was observed that, during pregnancy, the genetically disparate mammalian conceptus survives in spite of what would be predicted by tissue transplantation immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7: 320-38). Anatomic separation of mother and fetus and antigenic immaturity of the fetus cannot fully explain fetal allograft survival. Recent attention has focused on immunologic tolerance of the mother.
  • the mammalian conceptus appears to suppresses T-cell activity and defends itself against rejection, and blocking tryptophan catabolism during murine pregnancy allows maternal T cells to provoke fetal allograft rejection (Munn, et al., 1998, Science 281: 1191-3).
  • IDO inhibitor 1-MT
  • chemotherapeutic agents to reduce tumor growth in mice, suggesting that IDO inhibition may also enhance the anti-tumor activity of conventional cytotoxic therapies (Muller et al., 2005, Nature Med., 11:312-9).
  • TDLNs mouse tumor-draining lymph nodes
  • pDCs plasmacytoid dendritic cells
  • IDO degrades the indole moiety of tryptophan, serotonin and melatonin, and initiates the production of neuroactive and immunoregulatory metabolites, collectively known as kynurenines.
  • kynurenines neuroactive and immunoregulatory metabolites
  • IDO expressed by dendritic cells (DCs) can greatly affect T-cell proliferation and survival. IDO induction in DCs could be a common mechanism of deletional tolerance driven by regulatory T cells.
  • tryptophan metabolism and kynurenine production might represent a crucial interface between the immune and nervous systems (Grohmann, et al., 2003, Trends Immunol., 24: 242-8).
  • availability of free serum Trp is diminished and, as a consequence of reduced serotonin production, serotonergic functions may also be affected (Wirleitner, et al., 2003, Curr. Med. Chem., 10: 1581-91).
  • interferon- ⁇ has been observed to induce neuropsychiatric side effects, such as depressive symptoms and changes in cognitive function. Direct influence on serotonergic neurotransmission may contribute to these side effects.
  • IDO activation leads to reduced levels of tryptophan, the precursor of serotonin (5-HT)
  • IDO may play a role in these neuropsychiatric side effects by reducing central 5-HT synthesis.
  • kynurenine metabolites such as 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN) have toxic effects on brain function.
  • 3-OH-KYN is able to produce oxidative stress by increasing the production of reactive oxygen species (ROS), and QUIN may produce overstimulation of hippocampal N-methyl-D-aspartate (NMDA) receptors, which leads to apoptosis and hippocampal atrophy.
  • ROS reactive oxygen species
  • NMDA hippocampal N-methyl-D-aspartate
  • Both ROS overproduction and hippocampal atrophy caused by NMDA overstimulation have been associated with depression (Wichers and Maes, 2004, J. Psychiatry Neurosci., 29: 11-17).
  • IDO activity may play a role in depression.
  • Small molecule inhibitors of IDO are being developed to treat or prevent IDO-related diseases such as those described above.
  • PCT Publication WO 99/29310 reports methods for altering T cell-mediated immunity comprising altering local extracellular concentrations of tryptophan and tryptophan metabolites, using an inhibitor of IDO such as 1-methyl-DL-tryptophan, p-(3-benzofuranyl)-DL-alanine, p-[3-benzo[b]thienyl]-DL-alanine, and 6-nitro-L-tryptophan) (Munn, 1999).
  • IDO in immunosuppression, tumor resistance and/or rejection, chronic infections, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhea), autoimmune diseases or disorders (such as rheumatoid arthritis), and immunologic tolerance and prevention of fetal rejection in utero
  • therapeutic agents aimed at suppression of tryptophan degradation by inhibiting IDO activity are desirable.
  • Inhibitors of IDO can be used to activate T cells and therefore enhance T cell activation when the T cells are suppressed by pregnancy, malignancy or a virus such as HIV. Inhibition of IDO may also be an important treatment strategy for patients with neurological or neuropsychiatric diseases or disorders such as depression.
  • the compounds, compositions and methods herein help meet the current need for IDO modulators.
  • the present invention provides, inter alia, compounds of Formula J:
  • the present invention further provides compositions comprising a compound of Formula I, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention further provides methods of modulating enzyme activity of IDO comprising contacting a compound of Formula I, or pharmaceutically acceptable salt thereof, with the IDO.
  • the present invention further provides methods of treating IDO-associated diseases, including cancer, viral infection and depression, comprising administering to a patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of altering extracellular tryptophan levels in a mammal comprising administering to the mammal an effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present invention further provides methods of inhibiting immunosuppression, such as IDO-mediated immunosuppresion, in a patient comprising administering to the patient an effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • immunosuppression such as IDO-mediated immunosuppresion
  • the present invention provides compounds which are modulators of IDO having Formula J:
  • W is O, S, or NR 1 ;
  • U is CR 3 or N
  • X is CR 4 or N
  • Q is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, pentahalosulfanyl, Cy 4 , —(C 1-4 alkyl)-Cy 4 , CN, NO 2 , OR a4 , —(C 1-4 alkyl)-OR a4 , SR a4 , —(C 1-4 alkyl)-SR
  • R 1 is H, C 1-10 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
  • R 2 is halo, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, pentahalosulfanyl, Cy 3 , CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR c3 C(O)OR a3 , C( ⁇ NR i3 )NR c3 R d3 , NR c3 C( ⁇ NR i3
  • R 3 and R 4 are independently selected from H, halo, C 1-4 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
  • R 5 is H, C(O)R 6 , C(O)OR 7 , or C(O)NR 8 NR 9 ;
  • R 6 and R 7 are independently selected from H, C 1-8 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
  • R 8 and R 9 are independently selected from H, C 1-8 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
  • R 1 and R 2 together with the atoms to which they are attached form a heteroaryl or a 4-20 membered heterocycloalkyl ring, wherein said heteroaryl or 4-20 membered heterocycloalkyl ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR
  • R 2 and R 3 together with the atoms to which they are attached form an aryl, cycloalkyl, heteroaryl, or 4-20 membered heterocycloalkyl ring, wherein said aryl, cycloalkyl, heteroaryl, or 4-20 membered heterocycloalkyl ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 1 , CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c
  • R 1 and R 4 together with the atoms to which they are attached form a heteroaryl or a 4-20 membered heterocycloalkyl ring, wherein said heteroaryl or 4-20 membered heterocycloalkyl ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O) b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR
  • R a3 and R a4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy 5 , and Cy 5 -(C 1-6 alkyl)-, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5
  • R b3 and R b4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy 5 , and Cy 5 -(C 1-6 alkyl)-, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5
  • R c3 and R c4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy 5 , and Cy 5 -(C 1-6 alkyl)-, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5
  • R d3 and R d4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy 5 , and Cy 5 -(C 1-6 alkyl)-, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5
  • R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c
  • R c4 and R d4 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c
  • Cy, Cy 1 , Cy 2 , Cy 3 , Cy 4 , Cy 5 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, pentahalosulfanyl, CN, NO 2 , OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O) b6 , OC(O)NR c6 R d6 , NR c6 R d6 , NR c6 C(O)R b6 , NR c6 C(O)OR a6 , C( ⁇ NR i6 )NR c6 R d6 , NR
  • R a , R a1 , R a2 , R a5 and R a6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl,
  • R b , R b1 , R b2 , R b5 , and R b6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl
  • R c , R c1 , R c2 , R c5 , and R c6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl
  • R d , R d1 , R d2 , R d5 , and R d6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl
  • R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group;
  • R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group;
  • R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group;
  • R c5 and R d5 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group;
  • R c6 and R d6 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group;
  • R e , R e1 , R e2 , R e3 , R e4 , R e5 , and R e6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, hal
  • R f , R f1 , R f2 , R f3 , R f4 , R f5 , and R f6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo
  • R i , R i1 , R i2 , R i3 R i4 , R i5 , and R i6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo,
  • Q is other than substituted or unsubstituted azetidin-2-one or substituted or unsubstituted 5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one.
  • W is O.
  • U is CR 3 .
  • X is N.
  • W is S.
  • U is N.
  • X is CR 4 .
  • W is O and X is N.
  • W is S and U is N.
  • Q is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 4 , —(C 1-4 alkyl)-Cy 4 , CN, NO 2 , OR a4 , —(C 1-4 alkyl)-OR a4 , SR a4 , —(C 1-4 alkyl)-SR a4 , C(O)R b4 , —(C 1-4 alkyl)-C(O)R b4 , C(O)NR c4 R d4 , —(C 1-4 alkyl)-C(O)NR c4 R d4 , C(O)OR a4 , —(C 1-4 alkyl)-
  • Q is aryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 4 , —(C 1-4 alkyl)-Cy 4 , CN, NO 2 , OR a4 , —(C 1-4 alkyl)-OR a4 , SR a4 , —(C 1-4 alkyl)-SR a4 , C(O)R b4 , —(C 1-4 alkyl)-C(O)R b4 , C(O)NR c4 R d4 , —(C 1-4 alkyl)-C(O)NR c4 R d4 , C(O)OR a4 , —(C 1-4 alkyl)-C(O)OR
  • Q is phenyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, CN, NO 2 , OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR d4 , NR c4 C(O)OR a4 , S(O)R b4 , S(O)NR c4 R
  • Q is phenyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl.
  • Q is phenyl optionally substituted by 1, 2, 3, 4, or 5 halo.
  • Q is C 1-6 alkyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, pentahalosulfanyl, Cy 4 , —(C 1-4 alkyl)-Cy 4 , CN, NO 2 , OR a4 , —(C 1-4 alkyl)-OR a4 , SR a4 , —(C 1-4 alkyl)-SR a4 , C(O)R b4 , —(C 1-4 alkyl)-C(O)R b4 , C(O)NR c4 R d4 , —(C 1-4 alkyl)-C(O)NR c4 R d4 , C(O)OR a4 , —(C 1-4 alky
  • Q is C 1-6 alkyl substituted by Cy 4 .
  • Q is C 1-6 alkyl substituted by phenyl, wherein said phenyl is substituted by C 1-4 alkyl.
  • R 2 is halo, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, CY3, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , C(O)R a3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , S(O)R b3 S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , NR
  • R 2 is halo, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, or Cy 3 , wherein said C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-10 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 3 , CN, NO 2 , OR a3 , SR 3 , C(O)R, C(O)OR a6 , C(O)NR 6 R 7 , NR c3 R d3 , SOR b6 , S(O)NR c6 R d6 , and SO 2 R.
  • R 2 is C 1-10 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-10 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R, C(O)OR a6 , C(O)NR 6 R 7 , NR c3 R d3 , SOR b6 , S(O)NR c6 R d6 , and SO 2 R.
  • R 2 is C 1-10 alkyl, aryl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-10 alkyl, C 1-6 haloalkyl, and NR c3 R d3 .
  • R 2 and R 3 together with the atoms to which they are attached form a cycloalkyl or 4-20 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 1 , CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)R
  • R 2 and R 3 together with the atoms to which they are attached form a cycloalkyl or 4-20 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 1 , CN, NO 2 , OR 31 , SR 11 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR d1
  • R 2 and R 3 together with the atoms to which they are attached form a cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR d1 , NR c1 C(O)OR a1 ,
  • R 2 and R 3 together with the atoms to which they are attached form a cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, CN, NO 2 , OR a1 , and SR a1 .
  • R 5 is H.
  • the compounds of the invention have Formula JJ:
  • the compounds of the invention have Formula III:
  • the compounds of the invention have Formula IV:
  • the present invention provides compounds of Formula II:
  • W is O, S, or NR 1 ;
  • U is CR 3 or N
  • X is CR 4 or N
  • Q is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 4 , —(C 1-4 alkyl)-Cy 4 , CN, NO 2 , OR a4 , —(C 1-4 alkyl)-OR a4 , SR a4 , —(C 1-4 alkyl)-SR a4 , C(O)R
  • R 1 is H, C 1-10 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
  • R 2 is halo, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 3 , CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR c3 C(O)OR a3 , C( ⁇ NR i3 )NR c3 R d3 , NR c3 C( ⁇ NR i3 )NR c3 R d3
  • R 3 and R 4 are independently selected from H, halo, C 1-4 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
  • R 6 and R 7 are independently selected from H, C 1-8 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
  • R 8 and R 9 are independently selected from H, C 1-8 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
  • R 1 and R 2 together with the atoms to which they are attached form a heteroaryl or a 4-20 membered heterocycloalkyl ring, wherein said heteroaryl or 4-20 membered heterocycloalkyl ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR
  • R 2 and R 3 together with the atoms to which they are attached form an aryl, cycloalkyl, heteroaryl, or 4-20 membered heterocycloalkyl ring, wherein said aryl, cycloalkyl, heteroaryl, or 4-20 membered heterocycloalkyl ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 1 , CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c
  • R 1 and R 4 together with the atoms to which they are attached form a heteroaryl or a 4-20 membered heterocycloalkyl ring, wherein said heteroaryl or 4-20 membered heterocycloalkyl ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 2 , CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR
  • R a3 and R a4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy 5 , and Cy 5 -(C 1-6 alkyl)-, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR 5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 ,
  • R b3 and R b4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy 5 , and Cy 5 -(C 1-6 alkyl)-, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5
  • R c3 and R c4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy 5 , and Cy 5 -(C 1-6 alkyl)-, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5
  • R d3 and R d4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy 5 , and Cy 5 -(C 1-6 alkyl)-, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5
  • R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c
  • R c4 and R d4 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Cy 5 , CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c
  • Cy, Cy 1 , Cy 2 , Cy 3 , Cy 4 , Cy 5 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, CN, NO 2 , OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , NR c6 R d6 , NR c6 C(O)R b6 , NR c6 C(O)OR a5 , C( ⁇ NR i6 )NR c6 R d6 , NR c6 C( ⁇ NR i
  • R a , R a1 , R a2 , R a5 , and R a6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl
  • R b , R b1 , R b2 , R b5 , and R b6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl
  • R c , R c1 , R c2 , R c5 , and R c6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl
  • R d , R d1 , R d2 , R d5 , and R d6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl
  • R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group;
  • R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group;
  • R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group;
  • R c5 and R d5 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group;
  • R c6 and R d6 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heteroaryl or heterocycloalkyl group;
  • R e , R e1 , R e2 , R e3 , R e4 , R e5 , and R e6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, hal
  • R f , R f1 , R f2 , R f3 , R f4 , R f5 , and R f6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo
  • R 1 , R i1 , R i2 , R i3 , R i4 , R i5 , and R i6 are independently selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo
  • Q is other than substituted or unsubstituted azetidin-2-one or substituted or unsubstituted 5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one.
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • stable refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
  • alkyl is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include ethenyl, propenyl, and the like.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms.
  • cycloalkyl refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles.
  • cycloalkyl groups can have from 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkyl groups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2 triple bonds.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like.
  • a cycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • heteroaryl refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety.
  • heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
  • heterocycloalkyl refers to a non-aromatic heterocycle where one or more of the ring-forming atoms is a heteroatom such as an O, N, or S atom.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles.
  • heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles.
  • a heterocycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • moieties in which any ring-forming C, N, or S atom bears one or two oxo substituents are also included in which any ring-forming C, N, or S atom bears one or two oxo substituents.
  • the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.
  • halo or “halogen” includes fluoro, chloro, bromo, and iodo.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxyl group.
  • cyanoalkyl refers to an alkyl group substituted with a cyano group.
  • alkoxy refers to an —O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • arylalkyl refers to alkyl substituted by aryl and “cycloalkylalkyl” refers to alkyl substituted by cycloalkyl.
  • An example arylalkyl group is benzyl.
  • heteroarylalkyl refers to alkyl substituted by heteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted by heterocycloalkyl.
  • pentahalosulfanyl refers to moieties of formula —SX 5 where each X is independently selected from F, Cl, Br, or I.
  • pentahalosulfanyl is SF 5 .
  • amino refers to NH 2 .
  • alkylamino refers to an amino group substituted by an alkyl group.
  • dialkylamino refers to an amino group substituted by two alkyl groups.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C ⁇ N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone—enol pairs, amide—imidic acid pairs, lactam—lactim pairs, amide—imidic acid pairs, enamine—imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.
  • Compounds of the invention can be present together with other substances, such as with water or solvent in the form of hydrates or solvates, or present in isolated form.
  • the compounds of the invention, and salts thereof are isolated.
  • isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed, or discovered.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 90% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • prodrugs refer to any covalently bonded carriers which release the active parent drug when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design , ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
  • novel compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry
  • chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • Preparation of Compounds can Involve the Protection and Deprotection of Various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein by reference in its entirety.
  • Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art.
  • An example method includes fractional recrystallization using a “chiral resolving acid” which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
  • the compounds of the invention can be prepared, for example, using the reaction pathways and techniques as described below.
  • the amide 1-2 is can then be either A) chlorinated with suitable chlorination reagent (such as PCl 5 , POCl 3 , SO 2 Cl 2 , or alike) followed by addition of NH 2 OH or B) thionated (with a suitable thionating agent such as Lawesson's reagent) and subsequently S-alkylated (with a suitable alkylating agent such as MeI or MeOTf) followed by addition of NH 2 OH to afford the desired products 1-3.
  • suitable chlorination reagent such as PCl 5 , POCl 3 , SO 2 Cl 2 , or alike
  • suitable thionated with a suitable thionating agent such as Lawesson's reagent
  • S-alkylated with a suitable alkylating agent such as MeI or MeOTf
  • Compounds of the invention can modulate activity of the enzyme indoleamine-2,3-dioxygenase (IDO).
  • IDO indoleamine-2,3-dioxygenase
  • modulate is meant to refer to an ability to increase or decrease activity of an enzyme or receptor.
  • compounds of the invention can be used in methods of modulating IDO by contacting the enzyme with any one or more of the compounds or compositions described herein.
  • compounds of the present invention can act as inhibitors of IDO.
  • the compounds of the invention can be used to modulate activity of IDO in cell or in an individual in need of modulation of the enzyme by administering a modulating (e.g., inhibiting) amount of a compound of the invention.
  • the present invention further provides methods of inhibiting the degradation of tryptophan in a system containing cells expressing IDO such as a tissue, living organism, or cell culture.
  • the present invention provides methods of altering (e.g., increasing) extracellular tryptophan levels in a mammal by administering an effective amount of a compound of composition provided herein. Methods of measuring tryptophan levels and tryptophan degradation are routine in the art.
  • the present invention further provides methods of inhibiting immunosuppression such as IDO-mediated immunosuppression in a patient by administering to the patient an effective amount of a compound or composition recited herein.
  • immunosuppression has been associated with, for example, cancers, tumor growth, metastasis, viral infection, viral replication, etc.
  • the present invention further provides methods of treating diseases associated with activity or expression, including abnormal activity and/or overexpression, of IDO in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof.
  • Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the IDO enzyme, such as over expression or abnormal activity.
  • An IDO-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating enzyme activity.
  • IDO-associated diseases include cancer, viral infection such as HIV infection, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g., organ transplant rejection), and autoimmune diseases including asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis and systemic lupus erythematosusor.
  • Example cancers treatable by the methods herein include cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, and the like.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” the IDO enzyme with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having IDO, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the IDO enzyme.
  • the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • the term “treating” refers to (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • One or more additional pharmaceutical agents or treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and/or tyrosine kinase inhibitors can be used in combination with the compounds of the present invention for treatment of IDO-associated diseases, disorders or conditions.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • Suitable antiviral agents contemplated for use in combination with the compounds of the present invention can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs.
  • NRTIs nucleoside and nucleotide reverse transcriptase inhibitors
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • protease inhibitors and other antiviral drugs.
  • Example suitable NRTIs include zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emitricitabine [( ⁇ )-FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD, (( ⁇ )-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).
  • ZT zidovudine
  • ddI didanosine
  • ddC zalcitabine
  • d4T stavudine
  • NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B.
  • Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549.
  • Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan M), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoure
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
  • antimetabolites including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TaxolTM), mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.
  • certain natural products and their derivatives for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins
  • vinblastine vincristine, vindesine
  • bleomycin dactinomycin, daunorubicin,
  • cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.
  • cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis-platin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.
  • anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF- ⁇ , etc.).
  • trastuzumab Herceptin
  • costimulatory molecules such as CTLA-4, 4-1BB and PD-1
  • cytokines IL-10, TGF- ⁇ , etc.
  • anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4.
  • anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
  • Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • the compounds of the invention can be administered in the form of pharmaceutical compositions which is a combination of a compound of the invention and a pharmaceutically acceptable carrier.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • topical including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal,
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
  • Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, for example see International Patent Pub. No. WO 2002/000196.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the compounds of the invention can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like.
  • Another aspect of the present invention relates to fluorescent dye, spin label, heavy metal or radio-labeled compounds of the invention that would be useful not only in imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the IDO enzyme in tissue samples, including human, and for identifying IDO enzyme ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes IDO enzyme assays that contain such labeled compounds.
  • the present invention further includes isotopically-labeled compounds of the invention.
  • An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 C, 82 B, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound.
  • radio-labeled or “labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S and 32 Br.
  • Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art.
  • a radio-labeled compound of the invention can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • kits useful for example, in the treatment or prevention of IDO-associated diseases or disorders, obesity, diabetes and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • the compounds of the Examples were found to be inhibitors of IDO according to one or more of the assays provided herein. In some instances where the compounds of the examples were isolated by preparative HPLC in the presence of trifluoroacetic acid (TFA) or other acid, the compound may have been obtained as the corresponding salt.
  • TFA trifluoroacetic acid
  • Step A Ethyl-3-[2-(methylamino)-1,3-thiazol-4-yl]isoxazole-3-carboxylate
  • Step B 3-[2-(Methylamino)-1,3-thiazol-4-yl]isoxazole-3-carboxylic acid
  • Step C N-(3-Chloro-4-fluorophenyl)-5-[2-(methylamino)-1,3-thiazol-4-yl]isoxazole-3-carboxamide
  • Step D N-(3-Chloro-4-fluorophenyl)-N′-hydroxy-5-[2-(methylamino)-1,3-thiazol-4-yl]isoxazole-3-carboximidamide
  • N-(3-Chloro-4-fluorophenyl)-5-[2-(methylamino)-1,3-thiazol-4-yl]isoxazole-3-carboxamide (22 mg, 0.062 mmol) was suspended in benzene (1.5 mL) and phosphorus pentachloride (33 mg, 0.16 mmol) was added. The mixture was stirred for 3 h at 80° C. and evaporated in vacuo to give a tan solid. Benzene (2.0 mL) was added and the mixture was reevaporated twice.
  • IDO Human idoleamine 2,3-dioxygenase
  • N-terminal His tag Human idoleamine 2,3-dioxygenase (IDO) with an N-terminal His tag was expressed in E. coli and purified to homogeneity. IDO catalyzes the oxidative cleavage of the pyrrole ring of the indole nucleus of tryptophan to yield N′-formylkynurenine.
  • the assays were performed at room temperature as described in the literature using 95 nM IDO and 2 mM D-Trp in the presence of 20 mM ascorbate, 5 ⁇ M methylene blue and 0.2 mg/mL catalase in 50 mM potassium phosphate buffer (pH 6.5).
  • HeLa cells (#CCL-2) were obtained from the American Type Tissue Culture Collection (ATCC, Manassas, Va.) and routinely maintained in minimum essential medium (eagle) with 2 mM L-glutamine and Earle's BSS adjusted to contain 1.5 g/L sodium bicarbonate, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate and 10% fetal bovine serum (all from Invitrogen). Cells were kept at 37° C. in a humidified incubator supplied with 5% CO 2 . The assay was performed as follows: HeLa cells were seeded in a 96 well culture plate at a density of 5 ⁇ 10 3 per well and grown overnight.
  • IFN- ⁇ 50 ng/mL final concentration
  • serial dilutions of compounds in total volume of 200 ⁇ L culture medium
  • 140 ⁇ L of the supernatant per well was transferred to a new 96 well plate.
  • 10 ⁇ L of 6.1 N trichloroacetic acid (#T0699, Sigma) was mixed into each well and incubated at 50° C. for 30 min to hydrolyze N-formylkynurenine produced by indoleamine 2,3-dioxygenase to kynurenine.
  • the reaction mixture was then centrifuged for 10 min at 2500 rpm to remove sediments.
  • Monocytes are collected from human peripheral mononuclear cells by leukophoresis. Monocytes are then seeded at a density of 1 ⁇ 10 6 cells/well in a 96 well plate, using RPMI 1640 medium supplemented with 10% fetal bovine serum and 2 mM L-glutamine (all from Invitrogen). Adherent cells are retained on the plate after overnight culture at 37° C.
  • Adherent monocytes are then stimulated for 5-7 days with 100 ng/ml GM-CSF (# 300-03, PeproTech) and 250 ng/ml IL-4 (#200-04, PeproTech), followed by activation with 5 ⁇ g/mL LPS from Salmonella typhimurium (#437650, Sigma) and 50 ng/mL IFN- ⁇ (# 285-IF, R&D Systems) for additional 2 days to induce dendritic cell maturation.
  • T cell proliferation is measured by BrdU incorporation assay, using a colorimetric Cell Proliferation ELISA kit per manufacturer's instruction (#1647229, Roche Molecular Biochemicals). Cells are continuously cultured for 16-18 hrs in presence of 10 ⁇ M BrdU labeling solution.
  • the labeling medium was removed, and 200 ⁇ L FixDenat per well as added to the cells and incubated for 30 minutes at room temperature.
  • the FixDenat solution as removed and 100 ⁇ L/well anti-BrdU-POD antibody conjugate working solution was added.
  • the reaction as carried out for 90 minutes at room temperature.
  • the antibody conjugate as then removed, and cells are rinsed three times with 200 ⁇ L/well washing solution.
  • 100 ⁇ L/well of substrate solution is added and the results are obtained using a microplate reader (Spectra Max PLUS, Molecular Devices) during color development. Multiple readings at various time points are obtained to ensure the data is within the linear range.
  • the data is routinely obtained from replicated experiments, and appropriate controls are included. See: Terness P, et al.
  • In vivo anti-tumor efficacy can be tested using modified tumor allograft/xenograft protocols. For instance, it has been described in the literature that IDO inhibition can synergize with cytotoxic chemotherapy in immune-competent mice (Muller, A. J., et al). This synergy was shown to be dependent on T-cells by comparison of the synergistic effects of an investigational IDO inhibitor in murine tumor xenograft models (e.g. B16 and related variants, CT-26, LLC) grown in immune competent syngenic mice to that observed in syngenic mice treated with neutralizing anti-CD4 antibodies, or the same tumors grown in immune-compromised mice (e.g. nu/nu).
  • murine tumor xenograft models e.g. B16 and related variants, CT-26, LLC
  • tumor-mediated immune suppressive activity of IDO will likely differ depending on the immunogenic potential of different tumor models, genetic modifications can be made to the tumor cells to increase their immunogenic potential. For instance, expression of GM-CSF in B16.F10 cells increases their immunogenic potential (Dranoff, G., et al). As such, in some tumor models (e.g. B16.F10) one can generate [poly]clones that express immune stimulatory proteins such as GM-CSF and test the growth inhibitory effects of IDO inhibitors against tumors established from these tumor cells in both immune-competent and compromised mice.
  • immune stimulatory proteins such as GM-CSF
  • a third avenue for assessing the efficacy of IDO inhibitors in vivo employs ‘pre-immunization’ murine tumor allograft/xenograft models.
  • immune-competent mice are sensitized to a specific tumor antigen or antigens to mimic a therapeutic anti-tumor vaccination. This primes the mice for an anti-tumor response mediated by the immune system when mice are subsequently challenged with murine tumor cell lines (possessing similar tumor antigens to those used for immunization) in xenograft experiments.
  • Expression of IDO has been shown to blunt the anti-tumor response and allow xenografts to grow more rapidly.
  • IDO inhibitor 1-MT Uyttenhove, C., et al.
  • therapeutic immunization may be used to evaluate the impact of IDO inhibitors in vivo.
  • a well characterized immunogenic peptide e.g. TRP-2; SVYDFFVWL
  • immune system modifiers such as anti-CTL-4 antibody
  • Efficacy is assess by animal survival (time to morbidity) or by the measurement of tumor metastases to the lungs and/or other organs at defined timepoints.
  • any/all of the above mentioned models it may also be possible to directly and/or indirectly measure the number and/or activity of tumor reactive immune cells.
  • Methods for measuring the number and/or activity of tumor reactive immune cells are well established and can be performed using techniques familiar to those schooled in the art (Current Protocols in Immunology, vol 4, Coligan, J. E., et al; Immunotherapy of Cancer, Human Press, 2006, Disis, M. L. and references therein).
  • a reduction in the immune suppressive effects of IDO may result in increased numbers or reactivity of tumor specific immune cells.
  • IDO inhibition may further increase the number or reactivity of tumor reactive immune cells when combined with other therapeutics, for example chemotherapeutics and/or immune modulators (e.g. anti-CTLA4 antibody).
  • All allograft/xenograft experiments can be performed using standard tumor techniques (reviewed by Corbett, et al).
  • the cloning and introduction of genes (e.g. IDO, GM-CSF) into tumor cell lines can be performed using techniques familiar to those schooled in the art (reviewed in Sambrook, J, et al). See: Corbett, T., Polin, L., et al. In vivo methods for screening and preclinical testing. Cancer Drug Discovery and Development: Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, 2 nd Ed. Teicher, B. A. and Andrews, P.
  • Monocytes and PBL can be obtained by countercurrent centrifugal elutriation of leukopheresis packs from HIV-1, 2 and hepatitis B seronegative donors.
  • Monocytes are cultivated in suspension culture using Teflon flasks in Dulbecco's Modified Eagle's Medium (DMEM, Sigma-Aldrich) supplemented with 10% heat-inactivated pooled human serum, 1% glutamine, 50 ⁇ g/mL gentamicin, 10 ⁇ g/mL ciprofloxacin (Sigma), and 1000 U/mL highly purified recombinant human macrophage colony stimulating factor. After seven days in culture, MDM are infected with HIV-1 ADA at multiplicity of infection of 0.01.
  • DMEM Dulbecco's Modified Eagle's Medium
  • mice Four-wk old male NOD/C.B-17 SCID mice can be purchased (Jackson Laboratory). Animals are maintained in sterile microisolator cages under pathogen-free conditions. All animals are injected intraperitoneally with rat anti-CD122 (0.25 mg/mouse) three days before PBL transplantation and twice with rabbit asialo-GM1 antibodies (0.2 mg/mouse) (Wako) one day before and three days after PBL injection (20 ⁇ 10 6 cells/mouse). HIV-1 ADA -infected MDM (3 ⁇ 10 5 cells in 10 ⁇ L) are injected intracranially (i.c.) eight days following PBL reconstitution generating hu-PBL-NOD/SCID HIVE mice. Immediately following i.c.
  • mice injection of HIV-1 infected MDM the hu-PBL-NOD/SCID HIVE mice are subcutaneously (s.c) implanted with control (vehicle) or compound pellets (14 or 28 day slow release, Innovative Research).
  • Initial experiments are designed to confirm the induction of virus-specific CTL in the hu PBL-NOD/SCID HIVE animals treated with IDO compounds. This is confirmed by tetramer staining and neuropathologic analyses of MDM elimination from the brain tissue. Then, the experiment is designed to analyze human lymphocyte reconstitution, humoral immune responses, and neuropathological alterations. In these experiments, animals are bled on day 7 and sacrificed at 14 and 21 days after i.c. injection of human MDM.
  • HIV-1-specific antibodies are detected by Western blot tests according to the manufacturer instructions (Cambridge Biotech HIV-1 Western blot kit, Calypte Biomedical). Similar amount of virus-specific antibodies are detected in control and compound-treated animals. A total of three independent experiments can be performed using three different human leukocyte donors.
  • Two-color FACS analysis can be performed on peripheral blood at wk 1-3 and splenocytes at wk 2 and 3 after i.c. injection of human MDM.
  • Cells are incubated with fluorochrome-conjugated monoclonal Abs (mAbs) to human CD4, CD8, CD56, CD3, IFN- ⁇ (eBioscience) for 30 min at 4° C.
  • mAbs monoclonal Abs
  • eBioscience IFN- ⁇ intracellular staining is performed in combination with anti-human CD8 and FITC-conjugated anti-mouse CD45 to exclude murine cells.
  • Brain tissue is collected at days 14 and 21 after i.c. injection of MDM, fixed in 4% phosphate-buffered paraformaldehyde and embedded in paraffin or frozen at ⁇ 80° C. for later use. Coronal sections from the embedded blocks are cut in order to identify the injection site. For each mouse, 30-100 (5- ⁇ m-thick) serial sections are cut from the human MDM injection site and 3-7 slides (10 sections apart) are analyzed. Brain sections are deparaffinized with xylene and hydrated in gradient alcohols. Immunohistochemical staining follows a basic indirect protocol, using antigen retrieval by heating to 95° C. in 0.01 mol/L citrate buffer for 30 min for antigen retrieval.
  • mAb to vimentin (1:50, clone 3B4, Dako Corporation), which identifies all human leukocytes is used.
  • Human MDM and CD8 + lymphocytes are detected with CD68 (1:50 dilution, clone KP 1) and CD8 (1:50 dilution, clone 144B) antibodies, respectively.
  • Virus-infected cells are labeled with mAb to HIV-1 p24 (1:10, clone Kal-1, all from Dako).
  • Reactive murine microglial cells are detected with Jba-1 antibody (1:500, Wako).
  • IDO human IDO
  • Abs obtained from the Department of Cell Pharmacology, Central Research Institute, graduate School of Medicine, Hokkaido University, Sapporo, Japan.
  • Primary antibodies are detected with the appropriate biotinylated secondary antibodies and visualized with avidin-biotin complexes (Vectastain Elite ABC kit, Vector Laboratories) and horseradish peroxidase (HRP) coupled dextran polymer (EnVision, Dako Corporation). Immunostained sections are counterstained with Mayer's hematoxylin. Sections from which primary antibody is deleted or irrelevant IgG isotype is incorporated served as controls.

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Publication number Priority date Publication date Assignee Title
US20050223587A1 (en) * 2002-01-22 2005-10-13 Biomatera Inc. Method of drying biodegradable polymers
US20060258719A1 (en) * 2005-05-10 2006-11-16 Combs Andrew P Modulators of indoleamine 2,3-dioxygenase and methods of using the same
US20070185165A1 (en) * 2005-12-20 2007-08-09 Combs Andrew P N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
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CN108137597A (zh) 2015-07-28 2018-06-08 百时美施贵宝公司 TGFβ受体拮抗剂
JP2018525415A (ja) 2015-08-25 2018-09-06 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｔｇｆベータ受容体アンタゴニスト
KR20180069903A (ko) 2015-11-02 2018-06-25 파이브 프라임 테라퓨틱스, 인크. Cd80 세포외 도메인 폴리펩타이드 및 이들의 암 치료에서의 용도
CA3005855A1 (en) 2015-11-19 2017-05-26 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
TWI791422B (zh) 2015-11-23 2023-02-11 美商戊瑞治療有限公司 用於癌症治療之單獨fgfr2抑制劑或與免疫刺激劑組合
CN108602829A (zh) 2015-12-15 2018-09-28 百时美施贵宝公司 Cxcr4受体拮抗剂
US11752131B2 (en) 2016-02-19 2023-09-12 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and pharmaceutical compositions for the treatment of obesity
EP3423483A4 (en) 2016-03-02 2019-08-21 Board Of Regents Of the University Of Texas System VARIANTS OF HUMAN ENZYME KYNURENINASE HAVING IMPROVED PHARMACOLOGICAL PROPERTIES
AU2017228470A1 (en) 2016-03-04 2018-08-30 Bristol-Myers Squibb Company Combination therapy with anti-CD73 antibodies
BR112018071307A2 (pt) 2016-04-18 2019-02-26 Celldex Therapeutics, Inc. anticorpos agonistas que ligam cd40 humana e usos dos mesmos
EP3452451A4 (en) 2016-05-04 2019-11-13 Bristol-Myers Squibb Company INDOLEAMINE 2,3-DIOXYGENASE INHIBITORS AND METHODS OF USE
JP2019522627A (ja) 2016-05-04 2019-08-15 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ インドールアミン２，３−ジオキシゲナーゼ阻害剤およびその使用方法
CN109414421A (zh) 2016-05-04 2019-03-01 百时美施贵宝公司 吲哚胺2,3-双加氧酶的抑制剂及其使用方法
JP2019516681A (ja) 2016-05-04 2019-06-20 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ インドールアミン２，３−ジオキシゲナーゼ阻害剤およびその使用方法
KR20190003686A (ko) 2016-05-04 2019-01-09 브리스톨-마이어스 스큅 컴퍼니 인돌아민 2,3-디옥시게나제의 억제제 및 그의 사용 방법
JP7027401B2 (ja) 2016-07-14 2022-03-01 ブリストル－マイヤーズ スクイブ カンパニー Ｔｉｍ３に対する抗体およびその使用
WO2018017633A1 (en) 2016-07-21 2018-01-25 Bristol-Myers Squibb Company TGF Beta RECEPTOR ANTAGONISTS
JP2019528300A (ja) 2016-08-26 2019-10-10 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ インドールアミン２，３−ジオキシゲナーゼの阻害剤およびその使用方法
UY37466A (es) 2016-11-03 2018-01-31 Phenex Discovery Verwaltungs Gmbh N-hidroxiamidinheterociclos sustituidos como moduladores de la indolamina 2,3-dioxigenasa
PT3559009T (pt) 2016-12-22 2021-05-04 Calithera Biosciences Inc Composições e métodos para inibir a atividade da arginase
WO2018132279A1 (en) 2017-01-05 2018-07-19 Bristol-Myers Squibb Company Tgf beta receptor antagonists
JP2020506895A (ja) 2017-01-17 2020-03-05 ボード オブ レジェンツ, ザ ユニバーシティ オブ テキサス システムBoard Of Regents, The University Of Texas System インドールアミン２，３−ジオキシゲナーゼおよび／またはトリプトファンジオキシゲナーゼの阻害剤として有用な化合物
MX2019011558A (es) * 2017-03-29 2019-11-28 Merck Sharp & Dohme Nuevos compuestos sustituidos de n'-hidroxicarbamimidoil-1,2,5-oxa diazol como inhibidores de indolamina 2,3-dioxigenasa (ido).
WO2018183608A1 (en) 2017-03-31 2018-10-04 Five Prime Therapeutics, Inc. Combination therapy for cancer using anti-gitr antibodies
TWI788340B (zh) 2017-04-07 2023-01-01 美商必治妥美雅史谷比公司 抗icos促效劑抗體及其用途
EP3612030A4 (en) 2017-04-21 2021-04-28 Ikena Oncology, Inc. AHR INDOLE INHIBITORS AND THEIR USES
WO2018201014A1 (en) 2017-04-28 2018-11-01 Five Prime Therapeutics, Inc. Methods of treatment with cd80 extracellular domain polypeptides
US11066392B2 (en) 2017-05-12 2021-07-20 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
KR101965348B1 (ko) * 2017-06-26 2019-04-03 한국화학연구원 N'-히드록시인다졸카르복시이미다미드 유도체 화합물, 이의 광학이성질체, 또는 이의 약학적으로 허용가능한 염, 및, 이를 유효성분으로 포함하는 항암용 조성물
MX2019014885A (es) 2017-06-30 2020-02-13 Bristol Myers Squibb Co Formas amorfas y cristalinas de inhibidores de indolamina 2,3-dioxigenasa (ido).
KR20200032180A (ko) 2017-07-28 2020-03-25 브리스톨-마이어스 스큅 컴퍼니 항암제로서의 시클릭 디뉴클레오티드
AU2018319016B2 (en) 2017-08-17 2023-08-31 Ikena Oncology, Inc. AHR inhibitors and uses thereof
US10947263B2 (en) 2017-08-31 2021-03-16 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
US10953032B2 (en) 2017-08-31 2021-03-23 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
KR20200039796A (ko) 2017-08-31 2020-04-16 브리스톨-마이어스 스큅 컴퍼니 항암제로서의 시클릭 디뉴클레오티드
WO2019043103A1 (en) * 2017-09-01 2019-03-07 Netherlands Translational Research Center B.V. 3-HYDROXY-IMIDAZOLIDIN-4-ONE COMPOUNDS AS INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE
US11649212B2 (en) 2017-10-09 2023-05-16 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2019074824A1 (en) 2017-10-09 2019-04-18 Bristol-Myers Squibb Company INDOLEAMINE 2,3-DIOXYGENASE INHIBITORS AND METHODS OF USE
EP3694552A1 (en) 2017-10-10 2020-08-19 Tilos Therapeutics, Inc. Anti-lap antibodies and uses thereof
EP3694867A1 (en) 2017-10-10 2020-08-19 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
US11427610B2 (en) 2017-10-16 2022-08-30 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
JP2021501801A (ja) 2017-11-01 2021-01-21 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 癌の処置に用いるための免疫刺激アゴニスト抗体
JP7167146B2 (ja) 2017-11-06 2022-11-08 ブリストル－マイヤーズ スクイブ カンパニー Ｈｐｋ１阻害剤として有用なイソフラノン化合物
EP3724177A1 (en) 2017-12-12 2020-10-21 Phenex Discovery Verwaltungs-GmbH Oxalamides as modulators of indoleamine 2,3-dioxygenase
CN111788227A (zh) 2017-12-27 2020-10-16 百时美施贵宝公司 抗cd40抗体及其用途
US11447449B2 (en) 2018-01-05 2022-09-20 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
KR20200108870A (ko) 2018-01-12 2020-09-21 브리스톨-마이어스 스큅 컴퍼니 Tim3에 대한 항체 및 그의 용도
US10519187B2 (en) 2018-02-13 2019-12-31 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
EP3762397B1 (en) 2018-03-08 2024-05-01 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
AU2019239747A1 (en) 2018-03-21 2020-10-08 Bristol-Myers Squibb Company Antibodies binding to VISTA at acidic pH
AU2019236865A1 (en) 2018-03-23 2020-10-01 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
WO2019185870A1 (en) 2018-03-29 2019-10-03 Phenex Discovery Verwaltungs-GmbH Spirocyclic compounds as modulators of indoleamine 2,3-dioxygenase
EP3773714A1 (en) 2018-04-12 2021-02-17 Bristol-Myers Squibb Company Anticancer combination therapy with cd73 antagonist antibody and pd-1/pd-l1 axis antagonist antibody
EP3781179A4 (en) 2018-04-16 2022-11-09 Board of Regents, The University of Texas System HUMAN KINURENINASE ENZYMES AND USES THEREOF
US10973834B2 (en) 2018-04-16 2021-04-13 Arrys Therapeutics, Inc. EP4 inhibitors and use thereof
WO2019206800A1 (en) 2018-04-24 2019-10-31 Phenex Discovery Verwaltungs-GmbH Spirocyclic compounds as modulators of indoleamine 2,3-dioxygenase
US20230339891A1 (en) 2018-05-03 2023-10-26 Bristol-Myers Squibb Company Uracil derivatives as mer-axl inhibitors
KR20210024586A (ko) 2018-06-27 2021-03-05 브리스톨-마이어스 스큅 컴퍼니 T 세포 활성화제로서 유용한 치환된 나프티리디논 화합물
PT3814347T (pt) 2018-06-27 2023-07-18 Bristol Myers Squibb Co Compostos de naftiridinona úteis como ativadores de células t
CN113056483A (zh) 2018-07-09 2021-06-29 戊瑞治疗有限公司 结合到ilt4的抗体
CN112638948A (zh) 2018-07-11 2021-04-09 戊瑞治疗有限公司 在酸性pH下结合至VISTA的抗体
US11046649B2 (en) 2018-07-17 2021-06-29 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
US20210299126A1 (en) 2018-07-23 2021-09-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US20210355113A1 (en) 2018-07-23 2021-11-18 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US10959986B2 (en) 2018-08-29 2021-03-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11253525B2 (en) 2018-08-29 2022-02-22 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN113164780A (zh) 2018-10-10 2021-07-23 泰洛斯治疗公司 抗lap抗体变体及其用途
CN113316590A (zh) 2018-11-16 2021-08-27 百时美施贵宝公司 抗nkg2a抗体及其用途
US20230295087A1 (en) 2019-05-13 2023-09-21 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
US20230242478A1 (en) 2019-05-13 2023-08-03 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
US20220306630A1 (en) 2019-08-06 2022-09-29 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
AR119821A1 (es) 2019-08-28 2022-01-12 Bristol Myers Squibb Co Compuestos de piridopirimidinonilo sustituidos útiles como activadores de células t
EP4031575A1 (en) 2019-09-19 2022-07-27 Bristol-Myers Squibb Company Antibodies binding to vista at acidic ph
MX2022005839A (es) 2019-11-19 2022-06-09 Bristol Myers Squibb Co Compuestos utiles como inhibidores de la proteina helios.
MX2022006134A (es) 2019-11-26 2022-06-17 Bristol Myers Squibb Co Sales/cocristales de (r)-n-(4-clorofenil)-2-((1s,4s)-4-(6-fluoroqu inolin-4-il)ciclohexil)propanamida.
CN115279764A (zh) 2019-11-26 2022-11-01 医肯纳肿瘤学公司 多晶型咔唑衍生物及其用途
US20230118629A1 (en) 2019-12-23 2023-04-20 Bristol-Myers Squibb Company Substituted piperazine derivatives useful as t cell activators
CN114846007A (zh) 2019-12-23 2022-08-02 百时美施贵宝公司 可用作t细胞激活剂的经取代的喹唑啉基化合物
IL294269A (en) 2019-12-23 2022-08-01 Bristol Myers Squibb Co Substitute quinolinyl piperazine compounds are useful as t-cell activators
AR120823A1 (es) 2019-12-23 2022-03-23 Bristol Myers Squibb Co Compuestos bicíclicos sustituidos útiles como activadores de células t
IL294273A (en) 2019-12-23 2022-08-01 Bristol Myers Squibb Co Substituted heteroaryl compounds are useful as t-cell activators
JP2023517794A (ja) 2020-01-06 2023-04-27 ハイファイバイオ（ホンコン）リミテッド 抗ｔｎｆｒ２抗体及びその使用
IL294466A (en) 2020-01-07 2022-09-01 Hifibio Hk Ltd Anti-galectin-9 antibody and uses thereof
CN115279771A (zh) 2020-01-15 2022-11-01 缆图药品公司 Map4k1抑制剂
KR20220151189A (ko) 2020-03-09 2022-11-14 브리스톨-마이어스 스큅 컴퍼니 증진된 효능제 활성을 갖는 cd40에 대한 항체
TW202140441A (zh) 2020-03-23 2021-11-01 美商必治妥美雅史谷比公司 經取代之側氧基異吲哚啉化合物
EP4132971A1 (en) 2020-04-09 2023-02-15 Merck Sharp & Dohme LLC Affinity matured anti-lap antibodies and uses thereof
US20230192867A1 (en) 2020-05-15 2023-06-22 Bristol-Myers Squibb Company Antibodies to garp
WO2021258010A1 (en) 2020-06-19 2021-12-23 Gossamer Bio Services, Inc. Oxime compounds useful as t cell activators
AU2021325225A1 (en) 2020-08-10 2023-03-23 Gv20 Therapeutics Llc Compositions and methods for treating autoimmune diseases and cancers by targeting IGSF8
EP4228764A1 (en) 2020-10-14 2023-08-23 Five Prime Therapeutics, Inc. Anti-c-c chemokine receptor 8 (ccr8) antibodies and methods of use thereof
AU2021400725A1 (en) 2020-12-16 2023-08-03 Gossamer Bio Services, Inc. Compounds useful as t cell activators
US20240109899A1 (en) 2021-02-04 2024-04-04 Bristol-Myers Squibb Company Benzofuran compounds as sting agonists
CA3210553A1 (en) 2021-02-12 2022-08-18 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives for the treatment of cancer
EP4305041A1 (en) 2021-03-08 2024-01-17 Blueprint Medicines Corporation Map4k1 inhibitors
WO2022197641A1 (en) 2021-03-15 2022-09-22 Rapt Therapeutics, Inc. 1h-pyrazolo[3,4-d]pyrimidin-6-yl-amine derivatives as hematopoietic progenitor kinase 1 (hpk1) modulators and/or inhibitors for the treatment of cancer and other diseases
EP4314068A1 (en) 2021-04-02 2024-02-07 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
IL307338A (en) 2021-04-05 2023-11-01 Bristol Myers Squibb Co Pyridinyl substituted oxisoisoindoline compounds for cancer therapy
JP2024515243A (ja) 2021-04-06 2024-04-08 ブリストル－マイヤーズ スクイブ カンパニー ピリジニル置換されたオキソイソインドリン化合物
AU2022312496A1 (en) 2021-07-14 2024-02-22 Blueprint Medicines Corporation Heterocyclic compounds as map4k1 inhibitors
CN117940406A (zh) 2021-07-15 2024-04-26 缆图药品公司 Map4k1抑制剂
WO2023122778A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Pyridazinone derivatives useful as t cell activators
WO2023122777A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
WO2023122772A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
WO2023150186A1 (en) 2022-02-01 2023-08-10 Arvinas Operations, Inc. Dgk targeting compounds and uses thereof
WO2024036100A1 (en) 2022-08-08 2024-02-15 Bristol-Myers Squibb Company Substituted tetrazolyl compounds useful as t cell activators
WO2024036101A1 (en) 2022-08-09 2024-02-15 Bristol-Myers Squibb Company Tertiary amine substituted bicyclic compounds useful as t cell activators
WO2024033389A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033388A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033458A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydroazepine derivatives
WO2024033457A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives

Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3553228A (en) * 1967-09-26 1971-01-05 Colgate Palmolive Co 3-substituted-4h(1)benzopyrano(3,4-d) isoxazoles
US3948928A (en) * 1972-03-17 1976-04-06 Dainippon Pharmaceutical Co., Ltd. 3-Substituted-1,2-benzisoxazoles and pharmaceutically acceptable acid addition salts thereof
US4116974A (en) * 1975-09-11 1978-09-26 Philagro Herbicidal and phytohormonal amidoximes
US4323681A (en) * 1980-09-29 1982-04-06 American Home Products Corporation 4-Amino-2-substituted-5-pyrimidinecarboxamidoximes and carbothioamides
US4699916A (en) * 1983-07-22 1987-10-13 Bayer Aktiengesellschaft Substituted furazan pesticides
US5364864A (en) * 1991-05-27 1994-11-15 Pierre Fabre Medicament 1,4-disubstituted piperidines, their preparation and their application in therapy
US5712294A (en) * 1994-05-27 1998-01-27 Adir Et Compagnie N-pyridyl carboxamides and derivatives
US6482822B1 (en) * 1998-09-23 2002-11-19 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) N-(iminomethyl)amines derivatives, their preparation, their use as medicines and compositions containing them
US6780858B2 (en) * 2000-01-13 2004-08-24 Tularik Inc. Antibacterial agents
US20040234623A1 (en) * 2003-04-01 2004-11-25 Medical College Of Georgia Research Institute, Inc. Use of inhibitors of indoleamine-2,3-dioxygenase in combination with other therapeutic modalities
US20060194802A1 (en) * 2005-01-20 2006-08-31 Hassan Abdellaoui Phenylamino isothiazole carboxamidines as MEK inhibitors
US20060258719A1 (en) * 2005-05-10 2006-11-16 Combs Andrew P Modulators of indoleamine 2,3-dioxygenase and methods of using the same
US20070037752A1 (en) * 2003-10-15 2007-02-15 Siegfried Ansorge Novel alanyl-amino peptidase inhibitors for functionally influencing different cells and treating immunological, inflammatory, neuronal, and other diseases
US20070037785A1 (en) * 2003-10-15 2007-02-15 Siegfried Ansorge Novel dipeptidyl peptidase IV inhibitors used for functionally influencing different cells and treating immunological, infammatory, neuronal, and other diseases
US20070185165A1 (en) * 2005-12-20 2007-08-09 Combs Andrew P N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20070203140A1 (en) * 2006-02-09 2007-08-30 Combs Andrew P N-hydroxyguanidines as modulators of indoleamine 2,3-dioxygenase
US20070265257A1 (en) * 2004-09-08 2007-11-15 Mitsubishi Pharma Corporation Morpholine Compound
US20080119491A1 (en) * 2006-09-19 2008-05-22 Incyte Corporation Amidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20080146624A1 (en) * 2006-09-19 2008-06-19 Incyte Corporation Amidines as modulators of indoleamine 2,3-dioxygenase
US20080182882A1 (en) * 2006-11-08 2008-07-31 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20080214549A1 (en) * 2007-01-12 2008-09-04 Shaw Antony N N-Substituted Glycine Derivatives: Hydroxylase Inhibitors
US20080214546A1 (en) * 2006-09-19 2008-09-04 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms

Family Cites Families (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3354174A (en) 1964-02-19 1967-11-21 Sterling Drug Inc 1-and 2-benzimidazolyl-lower-alkylamidoximes, amidines-, and guanidines
US3286855A (en) * 1965-06-01 1966-11-22 Standard Trailer Company Crane extension and resulting crane assembly
DE2040628A1 (de) 1970-08-17 1972-02-24 Fahlberg List Veb Neue herbizide Mittel
JPS5621033B2 (ja) * 1973-09-05 1981-05-16
FR2323683A1 (fr) 1975-09-11 1977-04-08 Philagro Sa Nouveaux derives d'amidoximes, leur preparation et les compositions qui les contiennent
JPS58208275A (ja) 1982-05-20 1983-12-03 Lion Corp ５−アミノ−ピラゾ−ル誘導体及び該化合物を含有する抗腫瘍剤
JPS60193968A (ja) 1984-03-13 1985-10-02 Toyo Jozo Co Ltd シクロペンテン環を有するイミダゾ−ルアミドオキシムおよびその製造法
JPS6259283A (ja) 1985-09-10 1987-03-14 Kaken Pharmaceut Co Ltd セフアロスポリン化合物
JP2696342B2 (ja) 1988-06-27 1998-01-14 日本曹達株式会社 アミジン誘導体、その製造方法及び殺ダニ剤・農園芸用殺菌剤
EP0352832B1 (en) 1988-07-05 1992-05-06 Akzo N.V. Compounds with bronchodilator activity
JPH04297449A (ja) 1991-03-27 1992-10-21 Hokko Chem Ind Co Ltd Ｎ−ヒドロキシベンジルグアニジン誘導体および農園芸用殺菌剤
JPH05186458A (ja) 1991-04-26 1993-07-27 Japan Tobacco Inc 新規なベンゾピラン誘導体
JP2709677B2 (ja) 1992-06-19 1998-02-04 株式会社大塚製薬工場 ホスホン酸ジエステル誘導体
US5731315A (en) 1995-06-07 1998-03-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted sulfonic acid n- (aminoiminomethyl)phenylalkyl!-azaheterocyclamide compounds
PL326353A1 (en) 1995-10-17 1998-09-14 Astra Pharma Prod Pharmaceutically active quinozolinic compounds
WO1997030047A1 (en) 1996-02-17 1997-08-21 Agrevo Uk Limited Fungicidal 1,2,4-oxadiazoles and analogues
US5955495A (en) 1996-05-03 1999-09-21 Hoffmann-La Roche Inc. Method of treating diseases of the CNS
JPH11171702A (ja) 1997-09-24 1999-06-29 Takeda Chem Ind Ltd 害虫防除方法
AU1628599A (en) 1997-12-05 1999-06-28 Medical College Of Georgia Research Institute, Inc. Regulation of t cell-mediated immunity by tryptophan
TR200001686T2 (tr) 1997-12-10 2000-11-21 Dainippon Ink And Chemicals, Inc. Oksim türevleri ve bunları içeren tarım kimyasalları
AR018424A1 (es) 1998-06-02 2001-11-14 Sumitomo Chem Takeda Agro Co Compuesto oxadiazolina, composicion agroquimica que lo comprende y uso del mismo para la preparacion de dicha composicion
KR100396738B1 (ko) 1999-03-03 2003-09-03 삼진제약주식회사 피페라진 유도체 및 그 제조방법
CA2370267A1 (en) 1999-04-09 2000-10-19 Basf Aktiengesellschaft Prodrugs of thrombin inhibitors
CA2716369C (en) 1999-05-24 2013-05-14 Mitsubishi Tanabe Pharma Corporation Phenoxypropylamine compounds
JP2001158786A (ja) 1999-11-30 2001-06-12 Takeda Chem Ind Ltd 哺乳動物の外部寄生虫防除剤
JP2001158785A (ja) 1999-11-30 2001-06-12 Takeda Chem Ind Ltd 農薬組成物
PT1294358E (pt) 2000-06-28 2004-12-31 Smithkline Beecham Plc Processo de moagem por via humida
GB0108102D0 (en) 2001-03-30 2001-05-23 Pfizer Ltd Compounds
RS99503A (en) * 2001-06-18 2006-12-15 Applied Research Systems Ars Holding N.V. Pyrrolidine oxadiazole- and thiadiazole derivatives
GB0208224D0 (en) 2002-04-10 2002-05-22 Celltech R&D Ltd Chemical compounds
AU2002307243B2 (en) 2002-04-12 2008-01-03 Medical College Of Georgia Research Institute, Inc. Antigen-presenting cell populations and their use as reagents for enhancing or reducing immune tolerance
JP2005538953A (ja) 2002-05-28 2005-12-22 ３−ディメンショナル ファーマシューティカルズ， インコーポレイテッド 新規チオフェンアミジン、それらの組成物、および補体媒介疾患および病気を治療する方法
US7157462B2 (en) 2002-09-24 2007-01-02 Euro-Celtique S.A. Therapeutic agents useful for treating pain
US8008281B2 (en) 2003-03-27 2011-08-30 Lankenau Institute For Medical Research Methods for the treatment of cancer
ATE536353T1 (de) 2003-08-20 2011-12-15 Vertex Pharma 2-(4-amino-1,2,5-oxadiazol-4-yl)-imidazol- verbindungen als protein kinase inhibitoren
JP5065908B2 (ja) 2004-12-24 2012-11-07 プロシディオン・リミテッド Ｇタンパク質結合受容体作動薬
WO2006133417A1 (en) 2005-06-07 2006-12-14 Valeant Pharmaceuticals International Phenylamino isothiazole carboxamidines as mek inhibitors
DE102005060466A1 (de) 2005-12-17 2007-06-28 Bayer Cropscience Ag Carboxamide
JP4297449B2 (ja) 2006-05-12 2009-07-15 株式会社サクラクレパス 墨汁
EP2064207B1 (en) 2006-09-19 2013-11-06 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
EP2121621B1 (en) 2006-12-08 2014-05-07 Exelixis Patent Company LLC Lxr and fxr modulators
KR101927291B1 (ko) * 2008-07-08 2018-12-10 인사이트 홀딩스 코포레이션 인돌아민 ２,３-디옥시게나아제의 억제제로서의 １,２,５-옥사디아졸

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3553228A (en) * 1967-09-26 1971-01-05 Colgate Palmolive Co 3-substituted-4h(1)benzopyrano(3,4-d) isoxazoles
US3948928A (en) * 1972-03-17 1976-04-06 Dainippon Pharmaceutical Co., Ltd. 3-Substituted-1,2-benzisoxazoles and pharmaceutically acceptable acid addition salts thereof
US4116974A (en) * 1975-09-11 1978-09-26 Philagro Herbicidal and phytohormonal amidoximes
US4323681A (en) * 1980-09-29 1982-04-06 American Home Products Corporation 4-Amino-2-substituted-5-pyrimidinecarboxamidoximes and carbothioamides
US4699916A (en) * 1983-07-22 1987-10-13 Bayer Aktiengesellschaft Substituted furazan pesticides
US5364864A (en) * 1991-05-27 1994-11-15 Pierre Fabre Medicament 1,4-disubstituted piperidines, their preparation and their application in therapy
US5712294A (en) * 1994-05-27 1998-01-27 Adir Et Compagnie N-pyridyl carboxamides and derivatives
US6482822B1 (en) * 1998-09-23 2002-11-19 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) N-(iminomethyl)amines derivatives, their preparation, their use as medicines and compositions containing them
US6780858B2 (en) * 2000-01-13 2004-08-24 Tularik Inc. Antibacterial agents
US20040234623A1 (en) * 2003-04-01 2004-11-25 Medical College Of Georgia Research Institute, Inc. Use of inhibitors of indoleamine-2,3-dioxygenase in combination with other therapeutic modalities
US20070037785A1 (en) * 2003-10-15 2007-02-15 Siegfried Ansorge Novel dipeptidyl peptidase IV inhibitors used for functionally influencing different cells and treating immunological, infammatory, neuronal, and other diseases
US20070037752A1 (en) * 2003-10-15 2007-02-15 Siegfried Ansorge Novel alanyl-amino peptidase inhibitors for functionally influencing different cells and treating immunological, inflammatory, neuronal, and other diseases
US20070265257A1 (en) * 2004-09-08 2007-11-15 Mitsubishi Pharma Corporation Morpholine Compound
US20060194802A1 (en) * 2005-01-20 2006-08-31 Hassan Abdellaoui Phenylamino isothiazole carboxamidines as MEK inhibitors
US20060258719A1 (en) * 2005-05-10 2006-11-16 Combs Andrew P Modulators of indoleamine 2,3-dioxygenase and methods of using the same
US20070185165A1 (en) * 2005-12-20 2007-08-09 Combs Andrew P N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20070203140A1 (en) * 2006-02-09 2007-08-30 Combs Andrew P N-hydroxyguanidines as modulators of indoleamine 2,3-dioxygenase
US20080119491A1 (en) * 2006-09-19 2008-05-22 Incyte Corporation Amidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20080146624A1 (en) * 2006-09-19 2008-06-19 Incyte Corporation Amidines as modulators of indoleamine 2,3-dioxygenase
US20080214546A1 (en) * 2006-09-19 2008-09-04 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20080182882A1 (en) * 2006-11-08 2008-07-31 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20080214549A1 (en) * 2007-01-12 2008-09-04 Shaw Antony N N-Substituted Glycine Derivatives: Hydroxylase Inhibitors
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050223587A1 (en) * 2002-01-22 2005-10-13 Biomatera Inc. Method of drying biodegradable polymers
US20080262031A1 (en) * 2005-02-04 2008-10-23 Ctg Pharma S.R.L. 4-Aminoquinoline Derivatives as Antimalarials
US8034953B2 (en) 2005-05-10 2011-10-11 Incyte Corporation Modulators of indoleamine 2,3-dioxygenase and methods of using the same
US20060258719A1 (en) * 2005-05-10 2006-11-16 Combs Andrew P Modulators of indoleamine 2,3-dioxygenase and methods of using the same
US11192868B2 (en) 2005-05-10 2021-12-07 Incyte Corporation Modulators of indoleamine 2,3-dioxygenase and methods of using the same
US10208002B2 (en) 2005-05-10 2019-02-19 Incyte Corporation Modulators of indoleamine 2,3-dioxygenase and methods of using the same
US8846726B2 (en) 2005-05-10 2014-09-30 Incyte Corporation Modulators of indoleamine 2,3-dioxygenase and methods of using the same
US8372870B2 (en) 2005-05-10 2013-02-12 Incyte Corporation Modulators of indoleamine 2,3-dioxygenase and methods of using the same for treating cancer
US8951536B2 (en) 2005-12-20 2015-02-10 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20070185165A1 (en) * 2005-12-20 2007-08-09 Combs Andrew P N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US8450351B2 (en) 2005-12-20 2013-05-28 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20080214546A1 (en) * 2006-09-19 2008-09-04 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US8377976B2 (en) 2006-09-19 2013-02-19 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20110172279A1 (en) * 2006-09-19 2011-07-14 Incyte Corporation, A Delaware Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US8507541B2 (en) 2006-09-19 2013-08-13 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US20080146624A1 (en) * 2006-09-19 2008-06-19 Incyte Corporation Amidines as modulators of indoleamine 2,3-dioxygenase
US20080182882A1 (en) * 2006-11-08 2008-07-31 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US8796319B2 (en) 2008-07-08 2014-08-05 Incyte Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
US8822511B2 (en) 2008-07-08 2014-09-02 Incyte Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
US8993605B2 (en) 2008-07-08 2015-03-31 Incyte Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
US11207302B2 (en) 2008-07-08 2021-12-28 Incyte Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
US20100015178A1 (en) * 2008-07-08 2010-01-21 Combs Andrew P 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
US9320732B2 (en) 2008-07-08 2016-04-26 Incyte Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
US8088803B2 (en) 2008-07-08 2012-01-03 Incyte Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
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US10034864B2 (en) 2008-07-08 2018-07-31 Incyte Holdings Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
US10369137B2 (en) 2008-07-08 2019-08-06 Incyte Corporation 1,2,5-Oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
US9499497B2 (en) 2012-11-20 2016-11-22 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US10280157B2 (en) 2013-11-08 2019-05-07 Incyte Corporation Process for the synthesis of an indoleamine 2,3-dioxygenase inhibitor
US9873688B2 (en) 2013-11-08 2018-01-23 Incyte Holdings Corporation Process for the synthesis of an indoleamine 2,3-dioxygenase inhibitor
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