WO2019206800A1 - Composés spirocycliques en tant que modulateurs de l'indoléamine 2,3-dioxygénase - Google Patents

Composés spirocycliques en tant que modulateurs de l'indoléamine 2,3-dioxygénase Download PDF

Info

Publication number
WO2019206800A1
WO2019206800A1 PCT/EP2019/060078 EP2019060078W WO2019206800A1 WO 2019206800 A1 WO2019206800 A1 WO 2019206800A1 EP 2019060078 W EP2019060078 W EP 2019060078W WO 2019206800 A1 WO2019206800 A1 WO 2019206800A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkylene
independently selected
cycloalkyl
membered
Prior art date
Application number
PCT/EP2019/060078
Other languages
English (en)
Inventor
Christoph Steeneck
Olaf Kinzel
Simon ANDERHUB
Martin HORNBERGER
Sheena PINTO
Barbara HERKERT
Thomas Hoffmann
Original Assignee
Phenex Discovery Verwaltungs-GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Phenex Discovery Verwaltungs-GmbH filed Critical Phenex Discovery Verwaltungs-GmbH
Publication of WO2019206800A1 publication Critical patent/WO2019206800A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel compounds which act as modulators of indoleamine 2,3-dioxygenase (ID01 ) and to the use of said compounds in the prophylaxis and/or treatment of diseases or conditions mediated by indoleamine 2,3- dioxygenase.
  • ID01 indoleamine 2,3-dioxygenase
  • the invention further relates to pharmaceutical compositions comprising the novel compounds.
  • Tryptophan is an essential amino acid and naturally serves as a building block for proteins. The majority of adult Tryptophan intake is not utilized for protein synthesis though, but channeled into two conversion pathways. The first pathway leading to the production of Serotonine degrades approximately 1 % of ingested Tryptophan, whereas the majority of -90% of Tryptophan fuels the so called Kynurenine pathway (Le Floc ' h et al.; Amino Acids. 201 1 ; 41 (5): 1 195-205).
  • the Kynurenine pathway of Tryptophan degradation is initialized by a specific set of enzymes, including Indoleamine 2,3-dioxygenase 1 (ID01 ) and Tryptophan 2,3- dioxygenase (TD02).
  • ID01 Indoleamine 2,3-dioxygenase 1
  • TD02 Tryptophan 2,3- dioxygenase
  • N-Formylkynurenine is subsequently converted to Kynurenine, which can be further metabolized to such diverse products as Xanthurenic acid, Anthranilic acid or Nicotinamide to name a few (Stone, Darlington; Nat Rev Drug Discov. 2002; 1 (8):609-20).
  • TDO TDO
  • ID01 in contrast is found in a variety of tissues such as lung, digestive tract, uterus and secondary lymphoid organs (Theate et al.; Cancer Immunol Res. 2015;3(2): 161 -72) and is readily (further) induced by pro inflammatory cytokines (Taylor, Feng; FASEB J. 1991 ;5(1 1 ):2516-22 1991 ).
  • ID01 has been implicated in a protective role in fetal rejection. Mice, treated with the ID01 inhibitor 1 -Methyl-T ryptophan lost their allogeneic concept! in a T cell dependent manner (Munn et al.; Science. 1998;281 (5380): 1 191 -3).
  • ID01 creates an immunosuppressive environment by catabolizing Tryptophan, thereby locally depleting this amino acid and creating immune privilege sites. Tryptophan depletion is most likely sensed through the General Control Nonderepressable Kinase 2 (GCN2) and leads to activation of the integrated stress response of cells (Munn et al.; Immunity. 2005;22(5):633-42) with consecutive inhibition of T cell proliferation (Munn et al.; J Exp Med. 1999; 189(9): 1363-72). Additionally, a low Tryptophan environment also sensitizes activated T cells to apoptosis via Fas (Lee et al.; Immunology. 2002;107(4):452-60).
  • GCN2 General Control Nonderepressable Kinase 2
  • Treg cells are important to maintain immune homeostasis and induce immune tolerance to avoid inappropriate immune response as is the case in autoimmune disease (Sakaguchi et al.; Eur J Immunol. 2007;37 Suppl 1 :S1 16-23).
  • expression of the transcription factor FOXP3 is an important marker for regulatory T cells (Fontenot et al.; Nat Immunol. 2003;4(4):330-6) and co-cultivation of murine naive CD4+ T cells with IDO positive Dendritic cells led to a remarkable increase in FOXP3 expression of the CD4+ population.
  • Kynurenines such as Kynurenine itself, 3-Hydroxykynurenine and Kynurenic acid also serve as ligands for the Aryl Hydrocarbon Receptor (AHR) albeit with differentially reported efficacies (DiNatale et al.; Toxicol Sci. 2010; 1 15(1 ):89-97, Mezrich et al.; J Immunol ⁇ 2010;185(6):3190-8).
  • the AHR has been implicated in the transcriptional regulation of ID01 via a self- sustaining autocrine feed-forward loop with the AHR acting either directly on ID01 transcription (Li et al.; J Immunol ⁇ 2016;197(3):962-70) or with IL-6 as mediator (Litzenburger et al.; Oncotarget. 2014;5(4):1038-51 ).
  • the polarization of naive CD4+ T cells towards Treg cells by Kynurenines is dependent on the AHR (Kimura et al.; Proc Natl Acad Sci U S A.
  • ID01 has been detected in most human tumors, such as prostate, pancreas, lung, ovarian, colorectal cancer, melanoma and leukemia (Uyttenhove et al. ; Nat Med. 2003;9(10): 1 69-74; Hanagiri et al.; J Clin Cell Immunol 2014, 5:5, Okamoto et al.; Clin Cancer Res. 2005; 1 1 (16):6030-9; Francee et al.; Br J Cancer. 2012; 106(1 ): 141 -7, Brody et al.; Cell Cycle.
  • ID01 positive cells were also often found in immune cells in the tumor stroma and adjoining tumor draining lymph nodes (Astigiano et al.; Neoplasia. 2005;7(4):390-6, Chen et al.; Breast Cancer Res. 2014;16(4):410, Polak et al.; Br J Cancer. 2007;96(12): 1879-87, Theate et al.; Cancer Immunol Res. 2015;3(2):161 -72).
  • a negative correlation of ID01 expression either in tumor or in stromal cells with markers of disease progression has been observed in most of these cases.
  • ID01 tumor derived ID01 is a decisive factor for immune escape
  • research also investigated the role of ID01 in immune cells.
  • Munn et al. found a subset of plasmacytoid Dendritic cells in Tumor draining lymph nodes expressing ID01. Although these cells comprised less than 1 % of all lymph node cells they acted as potent and dominant suppressors of T cell proliferation (Munn et al.; J Clin Invest. 2004; 1 14(2): 280-290). The relative contribution of ID01 from immune cells versus tumor derived ID01 is still under debate. Koblish et al.
  • ID01 Apart from its relevance for tumor immune evasion, ID01 is implicated in a plethora of other medical conditions.
  • Favre et al. were able to demonstrate a crucial role for the Kynurenine 3- Hyd roxykyn u ren i ne in this process and it is therefore hypothesized that patients with HIV may benefit from ID01 inhibition together with antiretroviral therapy (Favre et al.; Sci Transl Med. 2010 May 19;2(32):32ra36.).
  • ID01 also seems to be involved in disorders of the central nervous system because its downstream products 3-Hydroxy kynurenine and quinolinic acid act as neurotoxins (Okuda et al.; J Neurochem. 1998;70(1 ):299-307, Schwarcz et al.; Science. 1983;219(4582):316-8). Thereby, ID01 is also implicated in the disease development of Huntington ' s disease, Amyotrophic lateral sclerosis, Alzheimer ' s disease, Parkinson ' s disease and Schizophrenia (Thevandavakkam et al.; CNS Neurol Disord Drug Targets. 2010;9(6):791-800; Chen et al.; Neurotox Res.
  • ID01 inhibitors may therefore be of high potential value for the treatment of HIV and CNS disorders and the reported preclinical data on efficacy against tumors either alone or in combination with other drugs validate the use of ID01 inhibitors as a treatment option for antineoplastic therapies.
  • WO 2006/122150 discloses compounds with a N-hydroxyamidino motif as potential modulators of ID01. The efficacy of compounds having said motif is demonstrated e.g. in WO 2008/036642, WO 2008/036643, WO 2008/036652, WO 2008/036653 and WO 2008/05178.
  • the present invention further relates to the use of the compounds according to formula (1 ) for the preparation of a medicament for the treatment and/or prophylaxis of a disease or condition mediated by indoleamine 2,3-dioxygenase.
  • the present invention also relates to a method for treating or preventing a disease or condition mediated by indoleamine 2,3-dioxygenase, the method comprising administering an effective amount of a compound according to formulae (1 ) and (2) to a patient in need thereof. Accordingly, the present invention provides a compound represented by formulae (1 ) or
  • A represents C3-io-cycloalkyl, which may be optionally fused with a phenyl ring being unsubstituted or substituted with 1 to 3 R a , 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10- membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R x , 0-R x , OC(0)-R x , S-R x , S(0) 2 -R x , S(0) 2 N(R 1 ) 2 , N(R 1 ) 2 , NR 1 C(0)R x , C(0)N(R 1 ) 2 , C(0)0-R x , C(0)-R x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl, wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci- 6 -alkyl, C3-6- cycloalkyl and
  • R a represents halogen, CN, Ci - 6 -alkyl, halo-Ci- 6 -alkyl, hydroxy-Ci- 6 -alkyl, C3-6-cycloalkyl or halo-C3-6-cycloalkyl;
  • R x represents Ci- 6 -alkyl, C3-6-cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci-e-alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • B represents a bond or Ci-2-alkylene
  • alkylene is unsubstituted or substituted with one or two C- M -aikyl
  • D represents 6- to 10-membered mono- or bicyclic aryl or 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R z , 0-R z , OC(0)-R z , S-R z , S(0) 2 -R z , S(0) 2 N(R 1 ) 2 , N(R 1 ) 2 , NR 1 C(0)R z , C(0)N(R 1 ) 2 , C(0)0-R z , C(0)-R z , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, and 6-membered aryl,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci- 6 -alkyl, C3-6- cycloalkyl and halo-Ci-e-alkyl, or
  • heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, CN and oxo;
  • R z represents Ci- 6 -alkyl, C3-e-cycloalkyl or 3- to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • E represents a 6-membered aryl or 6-membered heteroaryl containing 1 to 2 nitrogen atoms
  • R 5 is independently selected from hydrogen, halogen and C-i-e-alkyl
  • T represents hydrogen, CN, C(0)N(R 1 ) 2 , C(0)0-R x , C(C)-R X , COOH, Ci -6 -alkyl, C 2.6 - alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6- membered heterocycloalkyl, 6-membered aryl-Ci- 6 alkyl, 5- to 6-membered heteroaryl- C-i-e-alkyi, 3- to 6-membered heterocycloalkyl-Ci-e-alkyl, or 3- to 6-membered cycloalkyl-Ci- 6 -alkyl,
  • alkyl, alkenyl cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co-e-alkylene-OH, -Co- 6 -alkylene-R x , -Co- 6 -alkylene-0-R x , -Co-e-alkylene- OC(0)-R x , -Co-6-alkylene-S-R x , -Co-6-alkylene-S(0)2-R x , -Co-6-alkylene-S(0)2N(R 1 )2, -Co- 6-alkylene-N(R 1 )2, -Co-6-alkylene-NR 1 C(0)R x , -Co-6-alkylene-C(0)N(R 1 )2, -Co-6-alkylene- C(0)0-R x , -Co- 6 -alkylene-
  • R 10 represents hydrogen, Ci - 6 -alkyl, h a lo-Ci - b -al ky I ; or
  • R 10 and T form together with the carbon atom to which they are attached a 3- to 10- membered mono- or bicyclic ring system which is saturated or partially unsaturated and wherein the ring system may further contain 1 , 2 or 3 heteroatoms independently selected from N, O and S,
  • ring system is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OH, OCi-e-alkyl, oxo, Ci- 6 -alkyl and halo-Ci- 6 -alkyl;
  • W represents O, NOR 4 , NR 1 , NON, or NS(0) 2 Ci- 6 -alkyl
  • X is hydrogen, halogen, Ci- 6 -alkyl, C3-6-cycloalkyl, O-Ci- 6 -alkyl, S-Ci- 6 -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, Ci-e-alkyl, ha!o-C-i-e-alkyl, OR 1 or CN;
  • Z represents -C2-3-alkylene-, -O-Oi-2-alkylene-, -Ci-2-alkylene-O-, -C(0)NR 3 -Co-i- alkylene-, -Ci-alkylene-NR 3 C(0)-, -Co-i-alkylene-C(0)NR 3 -, -S(0) t -Ci- 2 -alkylene-, -C1-2- alkylene-S(0)t-, -NR 9 -Ci-2-alkylene- or -Ci-2-alkylene-NR 9 -,
  • alkylene is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of OR 4 , Ci- 6 -alkyl, halogen and halo-Ci- 6 -alkyl;
  • R 9 is hydrogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, C(0)-Ci- 6 -alkyl, or C(0)-halo-Ci- 6 -alkyl;
  • R 1 is hydrogen or Ci- 6 -alkyl
  • R 2 is halogen, Ci-e-alkyl, C3-6-cycloalkyl, halo-Ci-e-alkyl, OR 4 , S(0) 2 N(R 1 ) 2 , S(0) 2 -Ci-e- alkyl, S(0) 2 -C 3-6 -cycloalkyl, S(0) 2 -halo-Ci- 6 -alkyl, C(0)N(R 1 ) 2 , ON, C(0)0R 4 or oxo, or two R 2 on the same carbon atom form together with the carbon atom to which they are attached a C3-10 cycloalkyl group, or
  • R 3 is hydrogen or Ci- 6 -alkyl
  • R 4 is hydrogen or Ci-e-alky!
  • n 1 or 2;
  • o 0, 1 , 2, 3 or 4;
  • p 0, 1 , 2 or 3;
  • t 0, 1 or 2
  • the compound is represented by formula (1 ) or (2) wherein
  • A represents C3-io-cycloalkyl, which may be optionally fused with a phenyl ring, 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10-membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R x , 0-R x , OC(0)-R x , S-R x , S(0) 2 -R x , S(0) 2 N(R 1 ) 2 , N(R 1 ) 2 , NR 1 C(0)R x , C(0)N(R 1 )2, C(0)0-R x , C(0)-R x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl, wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci- 6 -alkyl, C3-6- cycloalkyl and hal
  • R x represents Ci-6-alkyl, C 3-6 -cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci-e-a!ky!, halo-Ci- 6 -alkyl, OR 1 and CN;
  • B represents a bond or Ci- 2 -alkylene, wherein alkylene is unsubstituted or substituted with one or two Ci-4-alkyl;
  • D represents 6- to 10-membered mono- or bicyclic aryl or 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R z , 0-R z , OC(0)-R z , S-R z , S(0) 2 -R z , S(0) 2 N(R 1 ) 2 , N(R 1 )2, NR 1 C(0)R z , C(0)N(R 1 )2, C(0)0-R z , C(0)-R z , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, and 6-membered aryl,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci-6-alkyl, C3-6- cycloalkyl and halo-Ci-6-alkyl, or
  • heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, CN and oxo;
  • R z represents Ci-6-alkyl, C 3 -e-cycloalkyl or 3- to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, C-i-e-alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • E represents a 6-membered aryl or 6-membered heteroaryl containing 1 to 2 nitrogen atoms
  • R 5 is independently selected from hydrogen, halogen and C-i-e-a!kyl
  • T represents hydrogen, CN, C(0)N(R 1 ) 2 , C(0)0-R x , C(0)-R x , COOH, Ci -6 -alkyl, C 2 -e- alkenyl, C3-6-cycloalkyl, 6-mem bered aryl, 5- to 6-mem bered heteroaryl, 3- to 6- membered heterocycloalkyl, 6-membered aryl-C-i-e alkyl, 5- to 6-mem bered heteroaryl- Ci- 6 -alkyl, 3- to 6-membered heterocycloalkyl-Ci- 6 -alkyl, or 3- to 6-membered cycloalkyl-Ci- 6 -alkyl,
  • alkyl, alkenyl cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co- 6 -alkylene-OH, -Co- 6 -alkylene-R x , -Co- 6 -alkylene-0-R x , -Co- 6 -alkylene- OC(0)-R x , -Co-6-alkylene-S-R x , -Co-e-alkylene-S(0)2-R x , -Co-e-alkylene-S(0)2N(R 1 )2, -Co- 6-alkylene-N(R 1 )2, -Co-6-alkylene-NR 1 C(0)R x , -Co-6-alkylene-C(0)N(R 1 )2, -Co-6-alkylene- C(0)0-R x , -Co- 6 -
  • R 10 represents hydrogen, Ci -b-alkyl, h a lo-Ci -b-al ky I ; or
  • R 10 and T form together with the carbon atom to which they are attached a 3- to 10- membered mono- or bicyclic ring system which is saturated or partially unsaturated and wherein the ring system may further contain 1 , 2 or 3 heteroatoms independently selected from N, O and S,
  • ring system is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OH, OCi- 6 -alkyl, oxo, Ci- 6 -alkyl and halo-Ci- 6 -alkyl;
  • W represents O, NOR 4 , NR 1 , NON, or NS(0) 2 Ci- 6 -alkyl
  • X is hydrogen, halogen, Ci- 6 -alkyl, C3-6-cycloalkyl, O-Ci- 6 -alkyl, S-Ci- 6 -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, Ci-e-alkyl, halo-Ci-e-alkyl, OR 1 and CN;
  • Z represents -C2-3-alkylene-, -O-Ci-2-alkylene-, -Ci-2-alkylene-O-, -C(0)NR 3 -Co-i- alkylene-, -Ci-alkylene-NR 3 C(0)-, -Co-i-alkylene-C(0)NR 3 -, -S(0) t -Ci- 2 -alkylene-, -C1-2- alkylene-S(0) t -, -NR 9 -Ci-2-alkylene- or -Ci-2-alkylene-NR 9 -,
  • alkylene is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of OR 4 , Ci- 6 -alkyl, halogen and halo-Ci- 6 -alkyl;
  • R 9 is hydrogen, Ci-e-alkyi, halo-Ci-e-alkyl, C(0)-Ci- 6 -alkyl, or C(0)-halo-Ci- 6 -alkyl;
  • R 1 is hydrogen or Ci-e-alkyl;
  • R 2 is Ci- 6 -alkyi, C3-6-cycioalkyl, halo-Ci-e-alkyl, OR 4 , S(0) 2 N(R 1 ) 2 , S(0) 2 -Ci- 6 -alkyl, S(0) 2 -C 3-6 -cycloaikyl, S(0) 2 -halo-Ci- 6 -alkyi, C(0)N(R 1 ) 2 , ON, C(0)0R 4 or oxo, or two R 2 on the same carbon atom form together with the carbon atom to which they are attached a C 3-10 cycloalkyl group, or
  • R 3 is hydrogen or Ci-e-alkyl
  • R 4 is hydrogen or Ci- 6 -alkyl
  • n 1 or 2;
  • o 0, 1 , 2, 3 or 4;
  • p 0, 1 , 2 or 3;
  • t 0, 1 or 2
  • the compound is represented by the following formulae (1 -1 ) and (1 -2)
  • A represents C3-10 cycloalkyl, which may be optionally fused with a phenyl ring being unsubstituted or substituted with 1 to 3 R a , 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10- membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R*, 0-R x , OC(0)-R x , S-R x , S(0) 2 -R x , S(0) 2 N(R 1 ) 2 , N(R 1 ) 2 , NR 1 C(0)R x , C(0)N(R 1 ) 2 , C(0)0-R x , C(0)-R x , CN, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl, wherein heteroaryl and aryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci- 6 -alkyl, C3-6- cycloalkyl and hal
  • R a represents halogen, CN, C 1 - 6 -alkyl, halo-Ci- 6 -alkyl, hydroxy-Ci- 6 -alkyl, C 3-6 -cycloalkyl or halo-C 3-6 -cycloalkyl;
  • R x represents Ci- 6 -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • D represents 6- to 10-membered mono- or bicyclic aryl or 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, OH, R z , 0-R z , OC(0)-R z , S-R z , S(0)2-R z , S(0) 2 N(R 1 ) 2 , N(R 1 ) 2 , NR 1 C(0)R z , C(0)N(R 1 ) 2 , C(0)0-R z , C(0)-R z , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci-e-alkyl; C3-6- cycloalkyl, and halo-Ci- 6 -alkyl, or
  • heterocylic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, CN and oxo;
  • R z represents Ci-e-alkyl, C3-e-cycloalkyl or 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, C-i-e-alkyi, halo-Ci- 6 -alkyl, OR 1 and CN;
  • V is O or CR 7 R 8 ;
  • R 2 is C1-6 alkyl, C3-6 cycloalkyl, halo-Ci-e-alkyl, OR 4 , S(0)2N(R 1 )2, S(0)2-Ci-e-alkyl, S(0) 2 -C 3-6 -cycloalkyl, S(0) 2 -halo-Ci- 6 -alkyl, S(0) 2 N(R 1 ) 2 , C(0)N(R 1 ) 2 , CN, C(0)OR 4 or oxo, or
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, halo-Ci-6-alkyl and OR 4 ;
  • T represents hydrogen, CN, C(0)N(R 1 ) 2 , C(0)0-R x , C(0)-R x , COOH, Ci -6 -alky, IC2-6- alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6- membered heterocycloalkyl, 6-membered aryl-C-i-6 alkyl, 5- to 6-membered heteroaryl- Ci- 6 -alkyl, 3- to 6-membered heterocycloalkyl-Ci- 6 -alkyl or 3- to 6-membered cycloalkyl-
  • alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co- 6 -alkylene-OH, -Co- 6 -alkylene-R x , -Co- 6 -al ky len e-O- R x , - Co-6-alkylene-OC(0)-R x , -Co-6-alkylene-S-R x , -Co-6-alkylene-S(0)2-R x , -Co-6-alkylene- S(0) 2 N(R 1 ) 2 , -Co-6-alkylene-N(R 1 ) 2 , -Co-6-alkylene-NR 1 C(0)R x , -Co-e-alkylene- C(0)N(R 1 ) 2 , -Co- 6 -a I ky I e
  • o 0, 1 , 2, 3 or 4;
  • n 1 or 2.
  • the compound is represented by the following formulae (1 -3) and (1 -4) wherein
  • X is hydrogen, halogen, Ci- 6 -alkyl, C3-6-cycloalkyl, O-Ci- 6 -alkyl, S-Ci-e-alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, Ci-e-a!kyl, halo-Ci-e-alkyl, OR 1 or CN;
  • R 5 is independently selected from hydrogen, halogen and Ci- 6 -alkyl
  • R 6 is independently selected from halogen, OH, R z , 0-R z , OC(0)-R z , S-R z , S(0) 2 -R z , S(0) 2 N(R 1 ) 2 , N(R 1 ) 2I NR 1 C(0)R z , C(0)N(R 1 ) 2 , C(0)0-R z , C(0)-R z , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , C-i-e-alkyl; C3-6- cycloalkyl, and halo-Ci- 6 -alkyl,
  • R z represents Ci-e-alkyl, C3-e-cycloalkyl or 3- to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, halo-Ci- 6 -alkyl and OR 4 ;
  • T represents hydrogen, CN, C(0)N(R 1 ) 2 , C(0)0-R x , C(C)-R X , COOH, Ci -6 -alkyl, halo- Ci- 6 -aikyl, C 2-6 -alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-Ci- 6 alkyl, 5- to 6-membered heteroaryl-Ci- 6 -alkyl, 3- to 6-membered heterocyclyl-C-i-e-alkyl or 3- to 6-membered cycloalkyl-Ci- 6 -alkyl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co-e-
  • U is N or CR 5 ;
  • V is O or CR 7 R 8 ;
  • p 0, 1 , 2 or 3;
  • q 0, 1 , 2, 3 or 4.
  • X is hydrogen, halogen, Ci-e-alkyl, C3-6-cycloalkyl, O-Ci- 6 -alkyl, S-Ci- 6 -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, Ci-e-alky!, halo-Ci- 6 -alkyl, OR 1 or CN;
  • R 5 is independently selected from hydrogen, halogen and C-i-e-alkyl
  • R 6 is independently selected from halogen, OH, R z , 0-R z , OC(0)-R z , S-R z , S(0) 2 -R z , S(0) 2 N(R 1 ) 2 , N(R 1 ) 2 , NR 1 C(0)R z , C(0)N(R 1 ) 2I C(0)0-R z , C(0)-R z , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci-e-alkyl; C3-6- cycloalkyl, and halo-Ci- 6 -alkyl,
  • R z represents Ci-e-a!kyl, C3-6-cycloalkyl or 3- to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, C-i-e-alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, halo-Ci-e-alkyl and OR 4 ;
  • T represents hydrogen, CN, C(0)N(R 1 ) 2 , C(0)0-R x , C(C)-R X , COOH, Ci-e-alkyl, halo- Ci- 6 -alkyl, C2-6-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-Ci-6 alkyl, 5- to 6-membered heteroaryl-Ci- 6 -alkyl, 3- to 6-membered heterocyclyl-Ci- 6 -alkyl or 3- to 6-membered cycloalkyl-Ci- 6 -alkyl,
  • alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co- 6 -alkylene-OH, -Co- 6 -alkylene-R x , -Co- 6 -alkylene-0-R x , -Co-e-alkylene- OC(0)-R x , -Co-6-alkylene-S-R x , -Co-6-alkylene-S(0)2-R x , -Co-6-alkylene-S(0)2N(R 1 )2, -Co- 6 -alkylene-N(R 1 ) 2 , -Co- 6 -alkylene-NR 1 C(0)R x , -Co-6-alkylene-C(0)N(R 1 ) 2 , -Co-e-alkylene- C(0)0-R x , -Co-Co
  • U is N or CR 5 ;
  • p 0, 1 , 2 or 3;
  • q 0, 1 , 2, 3 or 4.
  • the compound is represented by the following formula (1 -6)
  • X is hydrogen, halogen, Ci-e-alkyl, C 3 -e-cycioalkyl, O-Ci- 6 -alkyl, S-Ci-e-alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 or CN;
  • R 5 is independently selected from hydrogen, halogen and Ci- 6 -alkyl
  • R 6 is independently selected from halogen, OH, R z , 0-R z , OC(0)-R z , S-R z , S(0) 2 -R z , S(0) 2 N(R 1 ) 2 , N(R 1 )2, NR 1 C(0)R z , C(0)N(R 1 )2, C(0)0-R z , C(0)-R z , CN, COOH, 5 or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci-6-alkyl; C3-6- cycloalkyl, and halo-Ci- 6 -alkyl,
  • R z represents Ci-6-alkyl, C 3-6 -cycloalkyl or 3- to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci-6-alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, haio-Ci-e-alkyl and OR 4 ;
  • T represents hydrogen, CN, C(C)N(R 1 ) 2 , C(0)0-R x , C(0)-R x , COOH, Ci-e-alkyl, halo- Ci-6-alkyl, C 2-6 -alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-C-i- 6 alkyl, 5- to 6-membered heteroaryl-Ci-6-alkyl, 3- to 6-membered heterocyclyl-Ci-6-alkyl or 3- to 6-membered cycloalkyl-Ci-6-alkyl,
  • alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co- 6 -alkylene-OH, -Co- 6 -alkylene-R x , -Co- 6 -alkylene-C-R x , -Co- 6 -alkylene- OC(C)-R x , -Co-6-alkylene-S-R x , -Co-6-alkylene-S(C)2-R x , -Co-6-alkylene-S(0)2N(R 1 )2, -Co- 6-alkylene-N(R 1 )2, -Co-6-alkylene-NR 1 C(C)R x , -Co-6-alkylene-C(C)N(R 1 )2, -Co-e-alkylene- C(0)0-R x , -Co
  • p 0, 1 , 2 or 3;
  • q 0, 1 , 2, 3 or 4.
  • Q is OR 4 or CN
  • X is hydrogen, halogen, Ci- 6 -alkyl, C3-6-cycloalkyl, O-Ci- 6 -alkyl, S-Ci- 6 -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 or CN;
  • R 5 is independently selected from hydrogen, halogen and Ci-e-alkyl
  • R 6 is independently selected from halogen, OH, R z , 0-R z , OC(0)-R z , S-R z , S(0) 2 -R z , S(0) 2 N(R 1 ) 2 , N(R 1 ) 2 , NR 1 C(0)R z , C(0)N(R 1 ) 2 , C(0)0-R z , C(0)-R z , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci- 6 -alkyl; C3-6- cycloalkyl, and halo-Ci- 6 -alkyl,
  • R z represents Ci- 6 -alkyl, C 3-6 -cycloalkyl or 3- to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo-Ci- 6 -alkyl and OR 4 ;
  • T represents hydrogen, CN, C(0)N(R 1 ) 2 , C(0)0-R x , C(0)-R x , COOH, Ci -6 -alkyl, halo- Ci-e-alkyl, C2-6-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-C-i- 6 alkyl, 5- to 6-membered heteroaryl-Ci- 6 -alkyl, 3- to 6-membered heterocyclyl-Ci-e-alkyl or 3- to 6-membered cycloalkyl-Ci- 6 -alkyl,
  • alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co- 6 -alkylene-OH, -Co- 6 -aikylene-R x , -Co- 6 -alkylene-0-R x , -Co-e-alkylene- OC(0)-R x , -Co-6-alkylene-S-R x , -Co-6-alkylene-S(0)2-R x , -Co-6-alkylene-S(0)2N(R 1 )2, -Co- 6-alkylene-N(R 1 )2, -Co-6-alkylene-NR 1 C(0)R x , -Co-6-alkylene-C(0)N(R 1 )2, -Co-e-alkylene- C(0)0-R x , -Co- 6 -alkylene-OH
  • U is N or CR 5 ;
  • p 0, 1 , 2 or 3;
  • q 0, 1 , 2, 3 or 4.
  • the compound is represented by the following formulae (2-1 ) and (2-2)
  • X is hydrogen, halogen, Ci- 6 -alkyl, C3-6-cycloalkyl, O-Ci- 6 -alkyl, S-Ci-e-alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, Ci-e-alkyl, halo-Ci- 6 -alkyl, OR 1 or CN;
  • R 5 is independently selected from hydrogen, halogen and Ci- 6 -alkyl
  • T represents hydrogen, CN, C(0)N(R 1 ) 2 , C(0)0-R x , C(0)-R x , COOH, Ci-6-alkyl, halo- Ci-e-alkyl, C2-6-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-Ci- 6 alkyl, 5- to 6-membered heteroaryl-Ci- 6 -alkyl, 3- to 6-membered heterocyclyl-Ci-e-alkyl or 3- to 6-membered cycloalkyl-Ci- 6 -alkyl,
  • alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co- 6 -alkylene-OH, -Co- 6 -alkylene-R x , -Co- 6 -alkylene-0-R x , -Co- 6 -alkylene- OC(0)-R x , -Co-6-alkylene-S-R x , -Co-6-alkylene-S(0)2-R x , -Co-6-alkylene-S(0)2N(R 1 )2, -Co- 6-alkylene-N(R 1 )2, -Co-6-alkylene-NR 1 C(0)R x , -Co-6-alkylene-C(0)N(R 1 )2, -Co-6-alkylene- C(0)0-R x , -Co- 6 -alkylene-C
  • R x represents Ci-e-alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, C-i-e-alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • D represents 6- to 10-membered mono- or bicyclic aryl or 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, OH, R z , 0-R z , OC(0)-R z , S-R z , S(0) 2 -R z , S(0) 2 N(R 1 ) 2 , N(R 1 )2, NR 1 C(0)R z , C(0)N(R 1 ) 2 , C(0)0-R z , C(0)-R z , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci- 6 -alkyl; C3-6- cycloalkyl, and halo-Ci- 6 -alkyl, or
  • heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, CN and oxo;
  • R z represents Ci-e-alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • V is O or CR 7 R 8 ;
  • R 2 is Ci- 6 alkyl, C 3.6 cycloalkyl, halo-Ci -6 -alkyl, OR 4 , S(0) 2 N(R 1 ) 2 , S(0) 2 -Ci- 6 -alkyl, S(0) 2 -C 3-6 -cycloalkyl, S(0) 2 -halo-Ci -6 -alkyl, S(0) 2 N(R 1 ) 2 , C(0)N(R 1 ) 2 , CN, C(0)0R 4 or oxo, or
  • two R 2 at different carbon atoms form together a -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, CH 2 - CH(CH 3 )-, -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 - group;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, halogen, Ci-6 alkyl, halo-Ci-6-alkyl and OR 4 ;
  • o 0, 1 , 2, 3 or 4;
  • n 1 or 2.
  • X is hydrogen, halogen, Ci-e-alkyl, C 3-6 -cycloalkyl, O-Ci- 6 -alkyl, S-Ci- 6 -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C-i-e-alkyl, halo-Ci- 6 -alkyl, OR 1 or CN;
  • R 5 is independently selected from hydrogen, halogen and Ci- 6 -alkyl
  • R 6 is independently selected from halogen, OH, R z , C-R z , OC(0)-R z , S-R z , S(0) 2 -R z , S(0) 2 N(R 1 ) 2 , N(R 1 ) 2 , NR 1 C(0)R z , C(0)N(R 1 ) 2 , C(0)0-R z , C(0)-R z , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci-e-alkyl; C3-6- cycloalkyl, and halo-Ci- 6 -alkyl,
  • R z represents Ci-e-alkyl, C3-e-cycloalkyl or 3- to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, halo-Ci- 6 -alkyl and OR 4 ;
  • T represents hydrogen, CN, C(0)N(R 1 )2, C(0)0-R x , C(0)-R x , COOH, Ci-6-alkyl, halo- Ci- 6 -alkyi, C2-e-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-C-i-e alkyl, 5- to 6-membered heteroaryl-C-i- 6 -alkyl, 3- to 6-membered heterocyclyl-Ci- 6 -alkyl or 3- to 6-membered cycloalkyl-Ci- 6 -alkyl,
  • alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co-6-alkylene-OH, -Co-6-alkylene-R x , -Co-6-alkylene-0-R x , -Co-e-alkylene- OC(0)-R x , -Co-6-alkylene-S-R x , -Co-6-alkylene-S(0)2-R x , -Co-6-alkylene-S(0)2N(R 1 )2, -Co- 6-alkylene-N(R 1 )2, -Co-6-alkylene-NR 1 C(0)R x , -Co-6-alkylene-C(0)N(R 1 )2, -Co-6-alkylene- C(0)0-R x , -Co- 6 -alkylene-C(0)-R x ,
  • U is N or OR 5 ;
  • V is O or CR 7 R 8 ;
  • p 0, 1 , 2 or 3;
  • q 0, 1 , 2, 3 or 4.
  • X is hydrogen, halogen, Ci-e-alkyl, C3-6-cycloalkyl, O-Ci-e-alkyl, S-Ci- 6 -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 or CN;
  • R 5 is independently selected from hydrogen, halogen and Ci-e-alkyl
  • R 6 is independently selected from halogen, OH, R z , 0-R z , OC(0)-R z , S-R z , S(0)2-R z , S(0) 2 N(R 1 ) 2 , N(R 1 ) 2 , NR 1 C(0)R z , C(0)N(R 1 ) 2 , C(0)0-R z , C(0)-R z , CN, COOH, 5- or 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S and 6-membered aryl,
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 , Ci- 6 -alkyl; C3-6- cycloalkyl, and halo-Ci- 6 -alkyl,
  • R z represents Ci- 6 -alkyl, C3-6-cycloalkyl or 3- to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from O, N and S,
  • alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 and CN;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, ha!o-Ci-e-alkyl and OR 4 ;
  • T represents hydrogen, CN, C(0)N(R 1 ) 2 , C(C)0-R x , C(0)-R x , COOH, Ci-e-alkyl, halo- Ci- 6 -alkyl, C 2 -e-alkenyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6-membered aryl-C-i- 6 alkyl, 5- to 6-membered heteroaryl-Ci- 6 -alkyl, 3- to 6-membered heterocyclyl-C-i-e-alkyl or 3- to 6-membered cycloalkyl-Ci- 6 -alkyl,
  • alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co-e-alkylene-OH, -Co- 6 -alkylene-R x , -Co- 6 -alkylene-0-R x , -Co-e-alkylene- 0C(0)-R x , -Co-6-alkylene-S-R x , -Co-6-alkylene-S(0)2-R x , -Co-6-alkylene-S(0)2N(R 1 )2, -Co- 6-alkylene-N(R 1 )2, -Co-6-alkylene-NR 1 C(0)R x , -Co-6-alkylene-C(0)N(R 1 )2, -Co-6-alkylene- C(0)0-R x , -Co- 6 -alkylene-C(0)
  • U is N or CR 5 ;
  • p 0, 1 , 2 or 3;
  • q 0, 1 , 2, 3 or 4.
  • T represents hydrogen, halogen, CN, Ci - 6 -alkyl, halo-Ci- 6 -alkyl, C3-6-cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, 6- membered aryl-Ci-e alkyl, 5- to 6-membered heteroaryl-Ci-e-alkyl, 3- to 6-membered heterocyclyl-Ci- 6 -alkyl or 3- to 6-membered cycloalkyl-Ci- 6 -alkyl,
  • alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co-e-alkylene-OH, -Co-e-alkylene-CN, -Co- 6 -alkylene-R x and -Co- 6 -alkylene-O- R x .
  • T represents hydrogen, Ci- 6 -alkyl, halo-Ci-e-alkyl, C3-6-cycloalkyl, 3- to 6 membered cycloalkyl-Ci- 6 -alkyl,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of Ci - 6 -alkyl, halo-Ci- 6 -alkyl, C3-6- cycloalkyl, halogen, CN, OH and O-Ci-e-alkyl.
  • T represents Ci- 6 -alkyl, halo-Ci- 6 -alkyl, C3-6-cycloalkyl, 3- to 6 membered cycloalkyl-Ci- 6 -alkyl,
  • alkyl and cycloalkyl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of Ci - 6 -alkyl, halo-Ci- 6 -alkyl, C3-6- cycloalkyl, halogen, CN, OH and O-Ci- 6 -alkyl.
  • the compound 2 3-dihydro-N-(1 -methyl-1 H-pyazol-3-yl)-spiro[1 H-indene-1 ,4’- piperidine]-1’-acetamide is excluded.
  • the compound is represented by formula (1 ).
  • A represents C3-io-cycloalkyl, which may be optionally fused with a phenyl ring, 3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from O, N and S, 6- to 10- membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, R x , 0-R x , OC(0)-R x , S-R x , S(0) 2 -R x , S(0) 2 N(R 1 ) 2 , N(R 1 ) 2 , NR 1 C(0)R x
  • A represents C3-6- cycloalkyl, which may be optionally fused with a phenyl ring, 3- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, N and S, 6- or 10-membered mono or bicyclic aryl or 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, OH, R x , 0-R x , OC(0)-R x , N(R 1 ) 2 , NR 1 C(0)R x , C(0)N(R 1 ) 2 , C(0)0-R x , C(0)-R x , CN
  • A represents phenyl or 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O, N and S, wherein phenyl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, OH, R x , O- R x , C(0)0-R x , C(0)-R x , CN and COOH.
  • A represents phenyl which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, OH, R x , 0-R x , C(0)0-R x , C(0)-R x , CN and COOH.
  • R x represents Ci- 6 -alkyl or C 3-6 -cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, C-i- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 and CN.
  • X is hydrogen, halogen, Ci- 6 -alkyl, C3-6-cycloalkyl, O-Ci- 6 -alkyl, S-Ci- 6 -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 or CN;
  • R 5 is independently selected from hydrogen, halogen and Ci-e-alkyl
  • U is N or CR 5 ;
  • p 0, 1 , 2 or 3;
  • R a represents halogen, CN, C1 - 6 -alkyl, halo-Ci-e-alkyl, hydroxy-Ci-e-alkyl, C3-6-cycloalkyl or halo-C3-6-cycloalkyl.
  • X is hydrogen, halogen, Ci- 6 -alkyl, C3-6-cycloalkyl, O-Ci- 6 -alkyl, S-Ci- 6 -alkyl, CN or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen, C1- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 or CN;
  • R 5 is independently selected from hydrogen, halogen and Ci- 6 -alkyl
  • U is N or CR 5 ; and p is 0, 1 , 2 or 3.
  • X is halogen, Ci- 6 -alkyl, C 3-6 -cycloalkyl, or CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen or Ci-6-alkyl;
  • R 5 is independently selected from hydrogen, halogen and Ci-e-alkyl
  • U is N or CR 5 ;
  • p 0, 1 , 2 or 3.
  • X is halogen, Ci- 6 -alkyl, C 3-6 -cycloalkyl, or CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen or Ci- 6 -alkyl;
  • R 5 is independently selected from hydrogen, halogen and Ci- 6 -alkyl
  • U is N or CR 5 ;
  • p 0, 1 , 2 or 3.
  • U is N.
  • U is CR 5 and R 5 is independently selected from hydrogen, halogen and
  • Ci-e-alkyl Ci-e-alkyl
  • X is halogen, Ci- 6 -alkyl, C 3-6 -cycloalkyl, or CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen or Ci- 6 -alkyl.
  • A represents wherein
  • X is halogen, Ci- 6 -alkyl, C3-6-cycloalkyl or CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with halogen or Ci- 6 -alkyl.
  • B represents a bond
  • W represents O, NCN or NOR 4 , more preferably W represents O.
  • R 6 is independently selected from halogen and R z ; wherein R z represents Ci- 6 -alkyl, C3-6-cycloalkyl, wherein alkyl, and cycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci - 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 and CN.
  • R 6 is halo-Ci- 6 -alkyl.
  • E represents a 6-membered aryl.
  • X represents hydrogen, halogen, C-i-e- alkyl, C 3-6 -cycloalkyl, O-Ci-6-alkyl or CN, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C-i- 6 -alkyl, haio-Ci-6-alkyl, OR 1 or CN.
  • X represents halogen, Ci- 6 -alkyl or CN, wherein alkyl is unsubstituted or substituted with 1 to 4 halogen atoms.
  • X is halogen, most preferably, X is Cl.
  • R 5 represents hydrogen, halogen or Ci- 6 -alkyl, more preferably hydrogen or Ci-e-alkyl, most preferably hydrogen.
  • R 6 is independently selected from halogen and R z ; wherein R z represents Ci-6-alkyl, C 3-6 -cycloalkyl, wherein alkyl, and cycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, Ci - 6 -alkyl, halo-Ci-6-alkyl, OR 1 and CN. More preferably, R 6 is halo-Ci-e-alkyl.
  • D represents phenyl or 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O, N and S, wherein phenyl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, OH, R z , O- R z , OC(0)-R z , N(R 1 ) 2 , NR 1 C(0)R z , C(0)N(R 1 ) 2 , C(0)0-R z , C(0)-R z , ON, COOH, 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S, and 6-membered aryl, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OR 1 ,
  • R z represents Ci- 6 -alkyl or C3-6-cycioalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 or 6 substituents independently selected from the group consisting of halogen, Ci- 6 -alkyl, halo-Ci- 6 -alkyl, OR 1 and CN.
  • T represents CN, C(0)N(R 1 ) 2 , C(0)C-R x , C(C)-R x , COOH, Ci -e-alkyl, C 2.6 -alkenyl, C 3.6 -cycloalkyl, 6- membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, 6- membered aryl-C-i-e alkyl, 5- to 6-membered heteroaryl-Ci- 6 -alkyl, 3- to 6-membered heterocycloalkyl-Ci- 6 -alkyl, or 3- to 6-membered cycloalkyl-Ci- 6 -alkyl, wherein alkyl, alkenyl cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to
  • T represents CN, C(0)N(R 1 ) 2 , C(0)0-R x , C(0)-R x , COOH, Ci- 6 -alkyl, C 3.6 -cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocycloalkyl, wherein alkyl, alkenyl cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co-e- alkylene-OH, -Co- 6 -alkylene-R x , -Co- 6 -alkylene-0-R x , -Co- 6 -alkylene-OC(0)-R x , -Co- 6 - alkylene-S-R
  • T represents CN, C(0)N(R 1 )2, C(0)0-R x , C(0)-R x , COOH, Ci-6-alkyl, or Cs-e-cycloalkyl, wherein alkyl, alkenyl cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, - Co- 6 -alkylene-OH, -Co- 6 -alkylene-R x , -Co- 6 -alkylene-0-R x , -Co- 6 -alkylene-OC(0)-R x , -Co- 6 - alkylene-S-R x , -Co-6-alkylene-S(0)2-R x , -C o-6 -alkylene-S(0)
  • T is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -Co- 6 -alkylene-OH, and -Co- 6 -alkylene-CN.
  • T is Ci-e-alkyl.
  • Z represents -C2-3- alkylene-, -O-Ci- 2 -alkylene-, -Ci-2-alkylene-O-, -C(0)NR 3 -Co-i-aikylene-, -Ci-alkylene- NR 3 C(0)-, -Co-i-alkylene-C(0)NR 3 -, -S(0)t-Ci- 2 -aikylene-, -Ci- 2 -alkyiene-S(0)t-, -NR 9 - Ci-2-alkylene- or -Ci- 2 -alkylene-NR 9 -, wherein alkylene is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of O-C 1-6 - alkyl, Ci- 6 -alkyl, halogen and halo-Ci- 6 -alkyl.
  • Z represents -C2-3- alkylene-, -O-Ci- 2 -alkylene-, -Ci-2-alkylene-O-, -C(0)NR 3 -Co-i-alkyiene-, -Ci-alkylene- NR 3 C(0)-, -Co-i-aikylene-C(0)NR 3 -, -NR 9 -Ci-2-alkylene- or -Ci-2-alkylene-NR 9 -, wherein alkylene is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of O-C-i-e-alkyl, Ci- 6 -alkyl, halogen and halo-Ci- 6 -alkyl.
  • Z represents -C2-3- alkylene-, -O-Ci-2-alkylene-, -Ci-2-alkylene-O-, -NR 9 -Ci-2-alkylene- or -Ci-2-alkylene- NR 9 -, wherein alkylene is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of O-Ci- 6 -alkyl, Ci- 6 -alkyl, halogen and halo-Ci- 6 -alkyl.
  • Z represents -ethylene-, -O-methylene-, or methylene-O-, with methylene-O- being more preferred
  • methylene and ethylene are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of O-Ci- 6 -alkyl, Ci-e-a!kyl, halogen and halo-Ci- 6 -alkyl.
  • Z represents an ethylene group which is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of O-Ci- 6 -alkyl, Ci- 6 -alkyl, halogen and halo-Ci- 6 -alkyl.
  • Z represents -CH2-O-.
  • R 9 is hydrogen
  • m is 1.
  • m is 2.
  • o is 0, 1 or 2, more preferably, o is 0 or 1 and most preferred, o is 0.
  • the compound according to formula (1 ) is selected from
  • the compound according to formula (1 ) is selected from
  • the compound according to formula (1 ) is selected from
  • the invention further relates to a compound according to formulae (1 ) or (2) for use as medicament.
  • the compound according to formulae (1 ) or (2) is further useful in the prophylaxis and/or treatment of a disease or condition mediated by indoleamine 2,3-dioxygenase.
  • the disease or condition is selected from the group consisting of cancer, viral and bacterial infections such as HIV infection, hanta virus infection, tuberculosis, leprae, depression, epilepsy, neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, trauma, age-related cataracts, organ transplantation, cardiovascular disease, endometriosis, type-2 diabetic nephropathy, chronic obstructive pulmonary disease (CORD), osteoporosis, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus.
  • the disease or condition is cancer.
  • the compound according to formulae (1 ) or (2) is administered with one or more therapeutic agents for cancer selected from the group consisting of PD-1 agent, PD-L1 agent, CTLA-4 agent, AhR modulator, chemotherapeutic agent, anticancer vaccine, onolytic viruses, TLR agonists, STING agonists, and cytokine therapy as well as other immuno oncology, or wherein the compound is administered under irradiation therapy.
  • one or more therapeutic agents for cancer selected from the group consisting of PD-1 agent, PD-L1 agent, CTLA-4 agent, AhR modulator, chemotherapeutic agent, anticancer vaccine, onolytic viruses, TLR agonists, STING agonists, and cytokine therapy as well as other immuno oncology, or wherein the compound is administered under irradiation therapy.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to formulae (1 ) or (2) and pharmaceutically acceptable excipients.
  • Ci- 6 -alkyl means a saturated alkyl chain having 1 , 2, 3, 4, 5, or 6 carbon atoms which may be straight chained or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, ferf-butyl, n-pentyl, isopentyl, neopentyl and hexyl.
  • halo-Ci- 6 -alkyi means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen atom which may be the same or different.
  • Preferred example thereof include CHF2, CF3, CH2CH2CI, and CH2CF3.
  • A“Cx-y-alkylene” means that the respective group is divalent and connects the attached residue with the remaining part of the molecule.
  • X is an integer selected from 0, 1
  • y is an integer selected from 0, 1 , 2, and 3.
  • “Co-alkylene” is meant to represent a bond.
  • An alkylene group may be straight chained or branched.
  • a C3-io-cycioalkyl group or C3-io-carbocycle means a saturated or partially unsaturated mono-, bi-, spiro-, or multicyclic ring system comprising 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, adamantyl, spiro[3.3]heptane and pentacyclo[4.2.0.0 2 ' 5 .0 3 ' 8 .0 4 ' 7 ]octyl.
  • a C3-6-cycloalkyl group means a cycloalkyl ring having 3, 4, 5 or 6 carbon atoms.
  • the C3-io-cycloalkyl group can be connected to the remainder of the molecule via a bond or the cycloalkyl group may share a carbon at the attachment point with the remainder of the molecule.
  • Illustrative examples of the attachment possibilities are shown below:
  • a 3- to 10-membered heterocycloalkyl group means a saturated or partially unsaturated mono-, bi-, tri-, spiro or multicyclic ring system having 3, 4, 5, 6, 7, 8, 9 or 10 ring members.
  • a 3- to 6-membered heterocycloalkyl group means a saturated or partially unsaturated mono-, bi-, spiro or multicyclic ring system having 3, 4, 5 or 6 ring members.
  • the heterocycloalkyl comprises up to 5 heteroatoms, such as 1 , 2, 3, 4 or 5 heteroatoms, preferably 1 , 2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms and most preferably 1 heteroatom, wherein the heteroatoms are independently selected from N, O, S, S(O) and S(0) 2 , preferably N, O and S.
  • Examples thereof include epoxidyl, azetidinyl, oxetanyl, pyrrol id iny I, tetrahydrofuranyl, piperidinyl, piperazinyl tetrahydro-pyranyl, 1 ,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1 ,4-dihydropyridinyl, 2- azaspiro [3.3]heptane and 3,6-dihydro-2H-thiopyranyl.
  • the heterocycloalkyl group can be connected to the remainder of the molecule via a carbon atom or nitrogen atom.
  • a 5-14-mem bered mono-, bi- or tricyclic heteroaromatic ring system (within the application also referred to as heteroaryl) containing up to 4 heteroatoms means a monocyclic heteroaromatic ring such as pyrrolyl, imidazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl. It further means a bicyclic ring system wherein the heteroatom (s) may be present in one or both rings including the bridgehead atoms.
  • Examples thereof include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzodioxanyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl, pyrazolo[1 ,5-a]pyrimidinyl and dibenzo[b,d]furanyl.
  • the nitrogen or sulphur atom of the heteroaryl system may also be optionally oxidized to the corresponding A/-oxide, S-oxide or S,S-dioxide. If not stated otherwise, the heteroaryl system can be connected via a carbon or nitrogen atom. Examples for A/-linked heterocycles are
  • a 6-10-mem bered mono- or bicyclic aromatic ring system (within the application also referred to as aryl) means an aromatic carbon cycle such as phenyl or naphthyl.
  • Halogen is selected from fluorine, chlorine, bromine and iodine.
  • the compounds of the present invention are further intended to include all possible geometric isomers. 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 forms. A bond in a structure diagram represented by a wavy line“ww” is intended to indicate that the structure represents the cis or the trans isomer, or a mixture of the cis and trans isomers in any ratio.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 35 S, 36 CI and 125 l.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the disclosure also includes “deuterated analogs” of compounds of Formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • deuterated analogs of compounds of Formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Such compounds may exhibit increased resistance to metabolism and thus be useful for increasing the half-life of any compound of Formula (I) when administered to a mammal, e.g. a human. See, for example, Foster in Trends Pharmacol. Sci. 1984:5;524.
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F labeled compound may be useful for PET or SPECT studies.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as ⁇ ” or“hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the compounds of the present invention can be in the form of a prodrug compound.
  • Prodrug compound means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • prodrug examples include compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated.
  • these compounds can be produced from compounds of the present invention according to well-known methods.
  • prodrug examples are compounds, wherein the carboxylate in a compound of the present invention is, for example, converted into an alkyl-, aryl-, choline-, amino, acyloxymethylester, linolenoylester.
  • Metabolites of compounds of the present invention are also within the scope of the present invention.
  • tautomerism like e.g. keto-enol tautomerism
  • the individual forms like e.g. the keto and enol form, are each within the scope of the invention as well as their mixtures in any ratio. Same applies for stereoisomers, like e.g. enantiomers, cis/trans isomers, conformers and the like.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of the present invention may be obtained from stereoselective synthesis using optically pure starting materials. Another way to obtain pure enantiomers from racemic mixtures would use enantioselective crystallization with chiral counterions.
  • the compounds of the present invention can be in the form of a pharmaceutically acceptable salt or a solvate.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the present invention which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • the compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • inner salts or betaines can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • solvates such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol.
  • the compounds of the present invention are useful as inhibitors of ID01. Hence, they are potential therapeutic agents for the prophylaxis and/or treatment of I D01 -mediated diseases or conditions such as cancer, viral and bacterial infections such as HIV infection, hanta virus infection, tuberculosis, leprae, depression, epilepsy, neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, trauma, age-related cataracts, organ transplantation, cardiovascular disease, endometriosis, type-2 diabetic nephropathy, chronic obstructive pulmonary disease (COPD), osteoporosis, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus.
  • I D01 -mediated diseases or conditions such as cancer, viral and bacterial infections such as HIV infection, hanta virus infection, tuberculosis, leprae, depression, epilepsy, neurodegenerative diseases such
  • the compounds are used in the prophylaxis and/or treatment of cancer.
  • cancer types that may be treated using the compounds and compositions described herein include but are not limited to carcinomas, sarcomas, lymphomas and leukemias, germ cell tumors and blastomas, cancer of adrenal gland, bladder, brain, breast, bone, cervix, colorectum, colon, connective tissue, endometrium, esophagus, head, liver, lung, mesothelial lining, muscle, neck, ovary, pancreas, prostate, skin, stomach, testis, thyroid, white blood cell, or glioblastoma, mesothelioma, melanoma, renal cell carcinoma, gastric carcinoma, choriocarcinoma, cutaneous basocellular carcinoma, testicular seminoma and ovarian dysgerminoma.
  • carcinomas sarcomas, lymphomas and leukemias, germ cell tumors and blastomas
  • compositions comprising at least one compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients like a prodrug compound or other therapeutic agents.
  • Additional therapeutic agents are preferably selected from known cancer therapeutics. Examples thereof include PD-1 agent, PD-L1 agent, AhR modulators, CTLA-4 agent as well as chemotherapeutic agents, anticancer vaccines, onolytic viruses, TLR agonists, STING agonists, cytokine therapy and other immuno oncology.
  • the compounds of the present invention may also be administered to a patient while the patient undergoes irradiation therapy.
  • PD-1 agents include, but are not limited to, Pembrolizumab, Cemiplimab and Nivolumab.
  • PD-L1 agents examples include, but are not limited to, Atezolizumab, Avelumab and Durvalumab.
  • CTLA-4 agents examples include, but are not limited to, Ipilimumab.
  • chemotherapeutic agents include, but are not limited to, Cyclophosphamide, Busulfan, Carmustin, Temozolimide, Procarbazin,Trabectedin, Cisplatin, Carboplatin, Methotrexat, Pemetrexed, 6-Mercatopurine, 6-Thioguanine, Cladibine, Clofarabine, Nelarabine, Pentostatine, 5-Fluorouracil, Cytarabine, Gemcitabine, Azacitidine, Vincristine, Vinblastine, Vindesine, Paclitaxel, Docetaxel, Cabazitaxel, Ixabepilone, Eribulin, Estra mu stine phosphate, Topotecan, Irinotecan, Etoposide, Teniposide, Dactinomycin, Bleomycin, Doxorubicin, Daunorubicin, Epirubicin, Idarubicin, Mitoxantron, all-trans retinoic acid, Be
  • anticancer vaccines include, but are not limited to, Hepa-VAC-101 and Sipuleucel-T.
  • oncolytic viruses include, but are not limited to, H101 , Talimogene laherparepvec.
  • Toll like receptor agonists include, but are not limited to, Imiquimod, Resiquimod, monophosphoryl lipid A, BCG , CpG ODNs, Motolimod, GSK1795091 and Telratolimod.
  • STING agonists include, but are not limited to, ADU-S100 and MK-1454.
  • cytokine therapy examples include, but are not limited to, IL-2, GM-CSF, IL-12 and IL-10.
  • Immune-Oncology therapeutics examples include, but are not limited to Chimeric antigen receptor, or CAR T-cell therapy, such as Tisagenlecleucel, Axicabtagen Ciloleucel, agents targeting T cell co-stimulatory (e.g. 0X40) or co-inhibitory (e.g. LAG 3) molecules and immune response modifying enzymes such as Asparaginase or Kynureninase.
  • CAR T-cell therapy such as Tisagenlecleucel, Axicabtagen Ciloleucel, agents targeting T cell co-stimulatory (e.g. 0X40) or co-inhibitory (e.g. LAG 3) molecules and immune response modifying enzymes such as Asparaginase or Kynureninase.
  • compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, emulsions and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, emulsions and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non- aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • the compounds of the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of the present invention are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams.
  • the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • LiHMDS lithium bis(trimethylsilyl)amide m multiplet
  • the compounds of the present invention can be prepared by a combination of methods known in the art including the procedures described in schemes 1 and 2 below.
  • the following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.
  • Scheme 1 shows the synthesis of intermediates of the present invention of structure A- 6.
  • Treatment of ketone intermediates of structure A-1 with NaBH 4 leads to hydroxy intermediates of structure A-2.
  • Under treatment with pyridinium p-toluenesulfonate intermediate A-2 undergoes elimination reaction to the corresponding double bond intermediate A-3.
  • T reatment with lithium bis(trimethylsilyl)amide followed by ferf-butyl bis(2-chloroethyl)carbamate affords the corresponding spirocyclic intermediate A-4.
  • Double bond reduction with, for example, hydrogen and Pd catalysis affords intermediates A-5 which can be deprotected with TFA to give intermediates of structure A-6.
  • Scheme 2 shows the synthesis of example compounds of the present invention of structure B-5.
  • Treatment of intermediates A-6 with a-chloro ester intermediate B-1 affords intermediates of structure B-2.
  • Saponification with NaOH gives the corresponding carboxylic acid intermediates B-3 which can undergo amide coupling with B-4 and, for example, HATU to afford compounds of structure B-5.
  • B-6 is first amide coupled with B-4 and, for example, EDC/HOBt to give intermediates B-7.
  • /V-Alkylation reaction of intermediates A-6 with B- 7 affords compounds of structure B-5.
  • Step 1 6-Fluoro-2,3-dihydro-1 H-inden-1-ol (Int 1 b)
  • Lithium bis(trimethylsilyl)amide (21 mL, 1 M solution in THF) was added dropwise to a cooled solution of 5-fluoro-1 H-indene (Int 1c) (1.30 g, 9.70 mmol) in THF (20 mL) at 0 °C. The mixture was stirred at 0 °C under N 2 for 1 h.
  • ferf-Butyl bis(2- chloroethyl)carbamate (2.34 g, 9.70 mmol) dissolved in THF (2 mL) was added dropwise at 0 °C and the mixture was stirred at the same temperature for 10 min. The mixture was stirred at rt overnight.
  • Step 4 ferf-Butyl 5-fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-T-carboxylate (Int 1e)
  • Step 5 5-Fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine] trifluoroacetate salt
  • Int 1 To a solution of ferf-butyl 5-fluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-1 '- carboxylate (Int 1e) (1 18 mg, 0.38 mmol) in DCM (6 mL) was added TFA (1 mL) and the mixture was stirred at rt for 1 h. The mixture was concentrated to dryness to give the title compound as a yellow oil, which was used in the next step directly.
  • Steps 1-3 Mixture of regioisomers ferf-butyl 5,7-difluorospiro[indene-1 ,4'-piperidine]-1 carboxylate and ferf-butyl 4,6-difluorospiro[indene-1 ,4'-piperidine]-1 '-carboxylate (Int 2b)
  • Step 4 ferf-Butyl 5,7-difluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-T-carboxylate (Int 2c) and ferf-butyl 4,6-difluoro-2,3-dihydrospiro[indene-1 ,4'-piperidine]-1 '- carboxylate (Int 2d)
  • Step 1 ferf-Butyl 6-(trifluoromethyl)-2/-/-spiro[benzofuran-3,4'-piperidine]-1 '-carboxylate
  • Step 2 ferf-Butyl 2'-oxo-6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidine]-T- carboxylate (Int 6c)
  • Step 3 6-(Trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidine]-2'-one (Int 6)
  • Step 2 2-(1 -Benzyl-1 ,2,3, 6-tetrahydropyridin-4-yl)ethan-1-ol (Int 7d)
  • Step 3 1-Benzyl-4-(2-(2-bromo-5-(trifluoromethyl)phenoxy)ethyl)-1 ,2,3,6-tetrahydro- pyridine (Int 7e)
  • Step 5 7-(Trifluoromethyl)spiro[chromane-4,4'-piperidine] (Int 7)
  • Step 1 4-(((2-Bromo-5-(trifluoromethyl)phenyl)thio)methyl)pyridine (Int 8c)
  • Step 2 4-(((2-Bromo-5-(trifluoromethyl)phenyl)thio)methyl)-1-(4-methoxybenzyl) pyridin-1 -ium chloride (Int 8d)
  • Step 3 4-(((2-Bromo-5-(trifluoromethyl)phenyl)thio)methyl)-1 -(4-methoxybenzyl)-
  • Step 4 1 '-(4-Methoxybenzyl)-6-(trifluoromethyl)-2/-/-spiro[benzo[b]thiophene-3,4'- piperidine] (Int 8f)
  • Step 5 6-(Trifluoromethyl)-2H-spiro[benzo[b]thiophene-3,4'-piperidine] hydrogen chloride (Int 8)
  • Step 2 Methyl 1 ,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate (Int 9c)
  • Step 4 8-((2-Bromo-5-(trifluoromethyl)phenoxy)methyl)-1 ,4-dioxaspiro[4.5]dec-7-ene
  • Step 5 6-(T rifluoromethyl)-2H-dispiro[benzofuran-3, 1 '-cyclohexane-4', 2"-
  • Step 8 6'-(Trifluoromethyl)-2'H-spiro[azepane-4,3'-benzofuran]-7-one (Int 9i)
  • Step 11 6'-(Trifluoromethyl)-2'H-spiro[azepane-4,3'-benzofuran] hydrochloride (Int 9)
  • Step 1 ferf-Butyl 2-(2,3-dihydrospiro[indene-1 ,4'-piperidin]-1 '-yl)acetate (Int 10b)
  • Step 2 2-(2,3-Dihydrospiro[indene-1 ,4'-piperidine]-T-yl)acetic acid (Int 10)
  • Step 2 2-(2,3-Dihydrospiro[indene-1 ,4'-piperidine]-1 '-yl)propanoic acid (Int 11 )
  • Step 1 Methyl 2-(2'-oxo-6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidine]-T-yl) propanoate (Int 12a)
  • Step 1 4-Amino-2-bromo-4-oxobutanoic acid (Int 14b)
  • Step 1 Ethyl 2-(cyclopropylmethyl)-1 ,3-dithiane-2-carboxylate (Int 15b)
  • Step 3 A/-(4-Chlorophenyl)-2-(cyc!opropylmethyl)-1 ,3-dithiane-2-carboxamide (Int 15d)
  • Step 4 N-(4-Chlorophenyl)-2-(cyclopropylmethyl)-1 ,3-dithiane-2-carboxamide (Int 15e)
  • Step 6 1-((4-Chlorophenyl)amino)-3-cyclopropyl-1-oxopropan-2-yl methanesulfonate
  • Step 7 2-Bromo-A/-(4-chlorophenyl)-3-cyclopropylpropanamide (Int 15)
  • Step 1 Methyl 3-(4-fluorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'- piperidin]-T-yl)propanoate (Int 16b)
  • Step 2 3-(4-Fluorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidin]-T- yl)propanoic acid (Int 16)
  • Step 1 1 -Bromocyclobutane-1 -carboxylic acid (Int 17b)
  • PE:EtOAc 10:1
  • Example 1 A mixture of 2-(2,3-dihydrospiro[indene-1 ,4'-piperidin]-T-yl)acetic acid (Int 10) (65 mg, 0.27 mmol), HATU (154 mg, 0.41 mmol) and DIPEA (87 mg, 0.68 mmol) in DMF (5 mL) was stirred at rt for 1 h. 4-Chloroaniline (41 mg, 0.32 mmol) was added and the mixture was stirred overnight at rt. Water (20 ml_) was added and the mixture was extracted with EtOAc (3 x 20 ml_).
  • Example 1 /3a Stereoselective route for (S)-A/-(4-Chlorophenyl)-2-(6-(trifluoromethyl)-
  • Step 1 Methyl (R)-2-((methylsulfonyl)oxy)butanoate (Int 1/3b)
  • Step 2 Methyl (S)-2-(6-(trifluorom ethyl )-2/- -spiro[benzofuran-3,4'-piperidin]-T ⁇ yl)butanoate (Int 1/3c)
  • methyl (R)-2-((methylsulfonyl)oxy)butanoate (Int 1/3b) 141 mg, 0.72 mmol
  • K 2 CO 3 199 mg, 1.44 mmol
  • 6-(trifluoromethyl)- 2H-spiro[benzofuran-3,4'-piperidine] hydrochloride (253 mg, 0.86 mmol). The mixture was stirred at 50 °C overnight.
  • Step 3 (S)-2-(6-(Trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidin]-1 '-yl)butanoic acid (Int 1/3d)
  • Step 4 (S)-/V-(4-Chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'- piperidin]-T-yl)butanamide (1/3a)
  • Example 1/3 b The absolute configuration of Example 1/3 b was assigned by chiral HPLC comparison with Example 1/3a.
  • 1 H NMR 500 MHz, DMSO-de
  • Example was prepared similar as described for Example 3 using the appropriate building blocks.
  • Step 1 N-(4-Chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'- piperidin]-1 '-yl)propanamide, mixture of isomers (10a)
  • Step 2 Separate isomers A/-(4-Chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H- spiro[benzofuran-3,4'-piperidin]-T-yl)propanamide (10b, 10c, 10d, 10e)
  • Fraction A was further separated by preparative chiral-SFC (stationary phase CHIRALCEL OD (Daicel), mobile phase CCte/MeOH) to afford two separate enantiomers of A/-(4-chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H-spiro[benzofuran- 3,4'-piperidin]-T-yl)propanamide (10b and 10c).
  • Fraction B was separated by preparative chiral-SFC (stationary phase CHIRALCEL OD (Daicel), mobile phase C02/MeOH) to afford two separate enantiomers of N-(4- chlorophenyl)-2-(2'-oxo-6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidine]-T- yl)propanamide (10d and 10e).
  • Step 1 3-(6-(T rifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidin]-T-yl)dihydrofuran-
  • Example 21 W-(4-Chlorophenyl)-3-cyclopropyl-2-(6-(irifluoromeihyl)-2/-/-spiro
  • Step 1 Methyl (R)-3-cyclopropyl-2-((methylsulfonyl)oxy)propanoate (21 b)
  • Step 3 (S)-3-Cyclopropyl-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidin]-T- yl)propanoic acid (21 d) To a solution of methyl (S)-3-cyclopropyi-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-
  • Step 4 (S)-A/-(4-chlorophenyl)-3-cyclopropyl-2-(6-(trifluoromethyl)-2 -/-spiro[benzo- furan-3,4'-piperidin]-T-yl)propanamide (21 e)
  • Example 21 f (R)-A/-(4-Chlorophenyl)-3-cyclopropyl-2-(6-(irifluoromethyl)-2H- spiro[benzofuran-3,4'-piperidin]-1 '-yl)propanamide (21 f) prepared by chiral separation
  • Example 21 f (trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidin]-T-yl)propanamide (21 f) as the second eluting enantiomer.
  • the absolute configuration of Example 21 f was assigned by chiral HPLC comparison with Example 21e.
  • Example 24 A/-(4-Chlorophenyl)-2-(1 ,1-dioxido-6-(trifluoromethyl)-2/-/- spiro[benzo[b]thiophene-3,4'-piperidin]-1 '-yl)butanamide (24)
  • Step 1 1 '-(1-((4-Chlorophenyl)amino)-1-oxobutan-2-yl)-6-(trifluoromethyl)-2H- spiro[benzo[b]thiophene-3,4'-piperidine] 1 '-oxide 1 ,1 -dioxide (24a)
  • Step 2 A/-(4-Chlorophenyl)-2-(1 , 1-dioxido-6-(trifluoromethyl)-2H-spiro[benzo[b] thiophene-3, 4'-piperidin]-1 '-yl)butanamide (24)
  • Examples 25b, 25c, 25d, 25e Separate isomers of A/-(4-Chlorophenyl)-2-(6'- (frifluoromethyi)-2'H-spiro[azepane-4,3'-benzofuran]-1 -yl)butanamide (25b, 25c, 25d, 25e)
  • Step 1 A/-(4-Chlorophenyl)-2-(6'-(trifluoromethyl)-2'H-spiro[azepane-4,3'-benzofuran]- 1 -yl)butanamide (25a)
  • Step 2 Separate isomers of A/-(4-Chlorophenyl)-2-(6'-(trifluoromethyl)-2'H- spiro[azepane-4,3'-benzofuran]-1-yl)butanamide (25b, 25c, 25d, 25e)
  • Step 1 A/-(4-Chlorophenyl)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'-piperidin]-1 yl)butanethioamide (30a)
  • Step 2 4-Chloro-A/-(1-(methylthio)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran-3,4'- piperidin]-T-yl)but-1-en-1-yl)aniline (30b)
  • Step 3 A/-(4-Chlorophenyl)-/V-hydroxy-2-(6-(trifluoromethyl)-2/-/-spiro[benzofuran-3,4'- piperidin]-T-yl)butanimidamide
  • To a solution of 4-chloro-A/-(1-(methylthio)-2-(6-(trifluoromethyl)-2H-spiro[benzofuran- 3,4'-piperidin]-T-yl)but-1-en-1-yl)aniline (30b) (1 10 mg, 0.23 mmol) in EtOH (1.5 ml_) was added a 50% solution (w/w) of NH2OH in water (0.5 ml_) at 70 °C and the mixture was stirred at 70 °C overnight.
  • SKOV-3 cells were obtained from the American Type Culture Collection (ATCC® HTB- 77TM) and maintained in McCoy ' s medium (Pan Biotech) supplemented with 10 % fetal bovine serum and 1 % Penicilin/Streptomycin. Cells were kept at 37° C in a humidified incubator with 5 % CO 2 . For assay preparation, cells were seeded at a density of 2 * 10 5 /ml into black clear bottom 96 well plates in 100 pi medium/well supplemented with 50 ng/ml Interferon gamma (eBioscience, Thermo Fisher Scientific).

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés spirocycliques de formules (1) et (2) qui agissent en tant que modulateurs de l'indoléamine 2,3-dioxygénase (IDO1) et l'utilisation desdits composés dans la prophylaxie et/ou le traitement de maladies ou d'états pathologiques à médiation par l'indoléamine 2,3-dioxygénase. L'invention concerne en outre des compositions pharmaceutiques comprenant les nouveaux composés.
PCT/EP2019/060078 2018-04-24 2019-04-18 Composés spirocycliques en tant que modulateurs de l'indoléamine 2,3-dioxygénase WO2019206800A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18169000.9 2018-04-24
EP18169000 2018-04-24

Publications (1)

Publication Number Publication Date
WO2019206800A1 true WO2019206800A1 (fr) 2019-10-31

Family

ID=62062912

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2019/060078 WO2019206800A1 (fr) 2018-04-24 2019-04-18 Composés spirocycliques en tant que modulateurs de l'indoléamine 2,3-dioxygénase

Country Status (1)

Country Link
WO (1) WO2019206800A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020201825A2 (fr) 2019-03-29 2020-10-08 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Signature d'activation de récepteur d'hydrocarbures aryliques (ahr) et procédés de détermination d'état de signalisation d'ahr
WO2020208190A1 (fr) 2019-04-10 2020-10-15 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Gène 1 induit par l'interleukine 4 (il4i1) en tant que biomarqueur et ses utilisations
WO2021116357A1 (fr) 2019-12-10 2021-06-17 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Gène 1 induit par l'interleukine 4 (il4i1) et métabolites respectifs en tant que biomarqueurs pour le cancer

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006122150A1 (fr) 2005-05-10 2006-11-16 Incyte Corporation Modulateurs de l'indolamine 2,3-dioxygenase et leurs procedes d'utilisation
WO2007028638A1 (fr) * 2005-09-09 2007-03-15 Euro-Celtique S.A. Composes fondus et spirocycle ainsi que l'utilisation de ceux-ci
WO2008005178A2 (fr) 2006-06-20 2008-01-10 Lutron Electronics Co., Inc. Ensemble d'actionnement à écran tactile destiné à une commande d'éclairage
WO2008036643A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation Amidinohétérocycles modulateurs de l'indoléamine 2,3-dioxygénase
WO2008036653A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles modulateurs de l'indoléamine 2,3-dioxygénase
WO2008036642A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles en tant que modulateurs d'indoléamine 2,3-dioxygénase
WO2008036652A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation Amidines servant de modulateurs d'indoléamine 2,3-dioxygénase
WO2016078770A1 (fr) * 2014-11-21 2016-05-26 Laboratorios Del Dr. Esteve, S.A. Composés de spiro-isoquinoline-1,4'-pipéridine à activité multimodale contre la douleur
WO2017189386A1 (fr) * 2016-04-29 2017-11-02 Iomet Pharma Ltd. Nouveaux composés d'imidazopyridine substitués en tant qu'inhibiteurs d'indoléamine 2,3-dioxygénase et/ou de tryptophane-2,3-dioxygénase

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006122150A1 (fr) 2005-05-10 2006-11-16 Incyte Corporation Modulateurs de l'indolamine 2,3-dioxygenase et leurs procedes d'utilisation
WO2007028638A1 (fr) * 2005-09-09 2007-03-15 Euro-Celtique S.A. Composes fondus et spirocycle ainsi que l'utilisation de ceux-ci
WO2008005178A2 (fr) 2006-06-20 2008-01-10 Lutron Electronics Co., Inc. Ensemble d'actionnement à écran tactile destiné à une commande d'éclairage
WO2008036643A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation Amidinohétérocycles modulateurs de l'indoléamine 2,3-dioxygénase
WO2008036653A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles modulateurs de l'indoléamine 2,3-dioxygénase
WO2008036642A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles en tant que modulateurs d'indoléamine 2,3-dioxygénase
WO2008036652A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation Amidines servant de modulateurs d'indoléamine 2,3-dioxygénase
WO2016078770A1 (fr) * 2014-11-21 2016-05-26 Laboratorios Del Dr. Esteve, S.A. Composés de spiro-isoquinoline-1,4'-pipéridine à activité multimodale contre la douleur
WO2017189386A1 (fr) * 2016-04-29 2017-11-02 Iomet Pharma Ltd. Nouveaux composés d'imidazopyridine substitués en tant qu'inhibiteurs d'indoléamine 2,3-dioxygénase et/ou de tryptophane-2,3-dioxygénase

Non-Patent Citations (58)

* Cited by examiner, † Cited by third party
Title
ASTIGIANO ET AL., NEOPLASIA, vol. 7, no. 4, 2005, pages 390 - 6
BANERJEE ET AL., ONCOGENE, vol. 27, no. 20, 2008, pages 2851 - 7
BERTAZZO ET AL., BIOCHIM BIOPHYS ACTA, vol. 1527, no. 3, 2001, pages 167 - 75
BRODY ET AL., CELL CYCLE, vol. 8, no. 12, 2009, pages 1930 - 4
CHAMULEAU ET AL., HAEMATOLOGICA, vol. 93, no. 12, 2008, pages 1894 - 8
CHEN ET AL., BREAST CANCER RES., vol. 16, no. 4, 2014, pages 410
CHEN ET AL., NEUROTOX RES., vol. 18, no. 2, 2010, pages 132 - 42
CURTI ET AL., BLOOD, vol. 109, no. 7, 2007, pages 2871 - 7
DARLINGTON, NAT REV DRUG DISCOV., vol. 1, no. 8, 2002, pages 609 - 20
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 13 January 2014 (2014-01-13), XP002782293, Database accession no. 1519051-99-0 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 25 January 2017 (2017-01-25), XP002782291, Database accession no. 2059145-79-6 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 25 January 2017 (2017-01-25), XP002782292, Database accession no. 2059012-05-2 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 26 January 2017 (2017-01-26), XP002782290, Database accession no. 2059525-13-0 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 29 January 2017 (2017-01-29), XP002782288, Database accession no. 2060872-73-1 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 29 January 2017 (2017-01-29), XP002782289, Database accession no. 2060754-11-0 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 29 January 2017 (2017-01-29), XP002782294, Database accession no. 2060687-25-2 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 31 January 2017 (2017-01-31), XP002782287, Database accession no. 2062347-59-3 *
DINATALE ET AL., TOXICOL SCI., vol. 115, no. 1, 2010, pages 89 - 97
FALLARINO ET AL., CELL DEATH DIFFER., vol. 9, no. 10, 2002, pages 1069 - 77
FALLARINO ET AL., TRANSPL IMMUNOL., vol. 17, no. 1, 2006, pages 58 - 60
FAVRE ET AL., SCI TRANSL MED., vol. 2, no. 32, 19 May 2010 (2010-05-19), pages 32ra36
FERDINANDE ET AL., BR J CANCER, vol. 106, no. 1, 2012, pages 141 - 7
FONTENOT ET AL., NAT IMMUNOL., vol. 4, no. 4, 2003, pages 330 - 6
FOSTER, TRENDS PHARMACOL. SCI., vol. 5, 1984, pages 524
GUILLEMIN ET AL., NEUROPATHOL APPL NEUROBIOL., vol. 31, no. 4, 2005, pages 395 - 404
HANAGIRI ET AL., J CLIN CELL IMMUNOL, vol. 5, 2014, pages 5
HORNYAK ET AL., FRONT IMMUNOL., vol. 9, 31 January 2018 (2018-01-31), pages 151
HOU ET AL., CANCER RES., vol. 67, no. 2, 15 January 2007 (2007-01-15), pages 792 - 801
KEGEL ET AL., INT J TRYPTOPHAN RES., vol. 7, 2014, pages 15 - 22
KIMURA ET AL., PROC NATL ACAD SCI USA., vol. 105, no. 28, 15 July 2008 (2008-07-15), pages 9721 - 6
KOBLISH ET AL., MOL CANCER THER., vol. 9, no. 2, 2010, pages 489 - 98
LE FLOC'H ET AL., AMINO ACIDS, vol. 41, no. 5, 2011, pages 1195 - 205
LEE ET AL., IMMUNOLOGY, vol. 107, no. 4, 2002, pages 452 - 60
LI ET AL., J IMMUNOL, vol. 197, no. 3, 2016, pages 962 - 70
LIM ET AL., PROG NEUROBIOL., 2016
LITZENBURGER ET AL., ONCOTARGET, vol. 5, no. 4, 2014, pages 1038 - 51
MELLOR ET AL., J IMMUNOL., vol. 171, no. 4, 2003, pages 1652 - 5
MEZRICH ET AL., J IMMUNOL, vol. 185, no. 6, 2010, pages 3190 - 8
MILLER ET AL., NEUROBIOL DIS., vol. 15, no. 3, 2004, pages 618 - 29
MULLER ET AL., NAT MED., vol. 11, no. 3, 2005, pages 312 - 9
MUNN ET AL., IMMUNITY, vol. 22, no. 5, 2005, pages 633 - 42
MUNN ET AL., J CLIN INVEST., vol. 114, no. 2, 2004, pages 280 - 290
MUNN ET AL., J EXP MED., vol. 189, no. 9, 1999, pages 1363 - 72
MUNN ET AL., SCIENCE, vol. 281, no. 5380, 1998, pages 1191 - 3
OKAMOTO ET AL., CLIN CANCER RES., vol. 11, no. 16, 2005, pages 6030 - 9
OKUDA ET AL., J NEUROCHEM., vol. 70, no. 1, 1998, pages 299 - 307
POLAK ET AL., BR J CANCER, vol. 96, no. 12, 2007, pages 1879 - 87
SAKAGUCHI ET AL., EUR J IMMUNOL., vol. 37, no. 1, 2007, pages 116 - 23
SCHWARCZ ET AL., SCIENCE, vol. 219, no. 4582, 1983, pages 316 - 8
SHARMA ET AL., BLOOD, vol. 113, no. 24, 11 June 2009 (2009-06-11), pages 6102 - 11
SPRANGER ET AL., J IMMUNOTHER CANCER, vol. 2, 2014, pages 3
TAYLOR, FENG, FASEB J. 1991, vol. 5, no. 11, 1991, pages 2516 - 22
TERNESS ET AL., J EXP MED., vol. 196, no. 4, 2002, pages 447 - 57
THEATE ET AL., CANCER IMMUNOL RES., vol. 3, no. 2, 2015, pages 161 - 72
THEVANDAVAKKAM ET AL., CNS NEUROL DISORD DRUG TARGETS, vol. 9, no. 6, 2010, pages 791 - 800
TOMEK ET AL., ANAL BIOANAL CHEM, vol. 405, 2013, pages 2515 - 2524
TOMEK ET AL., BIOCHIM BIOPHYS ACTA, vol. 1850, no. 9, September 2015 (2015-09-01), pages 1772 - 80
UYTTENHOVE ET AL., NAT MED., vol. 9, no. 10, 2003, pages 1269 - 74

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020201825A2 (fr) 2019-03-29 2020-10-08 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Signature d'activation de récepteur d'hydrocarbures aryliques (ahr) et procédés de détermination d'état de signalisation d'ahr
WO2020208190A1 (fr) 2019-04-10 2020-10-15 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Gène 1 induit par l'interleukine 4 (il4i1) en tant que biomarqueur et ses utilisations
WO2021116357A1 (fr) 2019-12-10 2021-06-17 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Gène 1 induit par l'interleukine 4 (il4i1) et métabolites respectifs en tant que biomarqueurs pour le cancer

Similar Documents

Publication Publication Date Title
EP3774755B1 (fr) Composés spirocycliques utilisés comme modulateurs d'indoléamine 2,3-dioxygénase
WO2019115586A1 (fr) Oxalamides utilisés comme modulateurs de l'indoléamine 2,3-dioxygénase
ES2928169T3 (es) Derivados de 4-(3H-indol-5-il)-N-(piridin-2-il)pirimidin-2-amina como inhibidores de proteína cinasa, y método de preparación y uso médico de los mismos
JP5006987B2 (ja) ４環性化合物を含む医薬
KR20220092920A (ko) 헬리오스의 소분자 분해제 및 사용 방법
ES2964534T3 (es) Derivados de ftalazina isoxazol alcoxi, método de preparación de los mismos, composición farmacéutica y uso de la misma
BRPI1011649A2 (pt) compostos tetracíclicos e composição farmacêutica que os compreende
WO2019206800A1 (fr) Composés spirocycliques en tant que modulateurs de l'indoléamine 2,3-dioxygénase
CA2935071A1 (fr) Derives de piperidine-dione
WO2020021024A1 (fr) Composés bicycliques substitués en tant que modulateurs du récepteur d'hydrocarbures aryle (ahr)
UA122746C2 (uk) СПОЛУКИ-МОДУЛЯТОРИ АРИЛГІДРОКАРБОНОВОГО РЕЦЕПТОРА (AhR)
TW201819362A (zh) 作為吲哚胺2,3-二氧酶調節劑的經取代n-羥基甲脒基雜環化合物
CA3202355A1 (fr) Composes pour la degradation de la kinase 2 dependante des cyclines par l'intermediaire d'une voie de l'ubiquitine-proteosome
WO2019158070A1 (fr) Antagoniste du récepteur a2a et/ou a2b
CN111295380B (zh) 一种高活性csf1r抑制剂化合物
TW202144341A (zh) Zeste同源基因增強子2抑制劑及其用途
CA3110474A1 (fr) Compose agoniste de proteine sting a activite elevee
CN118055933A (zh) 选择性parp1抑制剂及其应用
US20220204498A1 (en) Pyrido-pyrimidinyl compounds and methods of use
CA3216489A1 (fr) Composes bicycliques condenses substitues servant d'inhibiteurs de parp et leur utilisation
IL270927A (en) Cyclic compounds and compositions are fused 5,6 to treat parasitic diseases
US20230057166A1 (en) Phenoxy-pyridyl-pyrimidine compounds and methods of use
CN112028891B (zh) 腺苷受体拮抗剂
CA3234693A1 (fr) Nouveaux modulateurs de l'ehmt1 et de l'ehmt2 et leur utilisation therapeutique
WO2021172359A1 (fr) Promédicament inhibiteur de cdk9 et liposome le comprenant

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19720503

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19720503

Country of ref document: EP

Kind code of ref document: A1