WO2015140717A9 - Dérivés substitués par 3-indole, compositions pharmaceutiques et procédés d'utilisation - Google Patents

Dérivés substitués par 3-indole, compositions pharmaceutiques et procédés d'utilisation Download PDF

Info

Publication number
WO2015140717A9
WO2015140717A9 PCT/IB2015/051957 IB2015051957W WO2015140717A9 WO 2015140717 A9 WO2015140717 A9 WO 2015140717A9 IB 2015051957 W IB2015051957 W IB 2015051957W WO 2015140717 A9 WO2015140717 A9 WO 2015140717A9
Authority
WO
WIPO (PCT)
Prior art keywords
fluoro
indol
benzo
alkyl
mmol
Prior art date
Application number
PCT/IB2015/051957
Other languages
English (en)
Other versions
WO2015140717A1 (fr
Inventor
Sandra CAUWENBERGHS
Stefano Crosignani
Gregory DRIESSENS
Frederik Deroose
Original Assignee
Iteos Therapeutics
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
Priority claimed from BE2014/0776A external-priority patent/BE1021253B1/fr
Application filed by Iteos Therapeutics filed Critical Iteos Therapeutics
Priority to EP15714653.1A priority Critical patent/EP3119763A1/fr
Priority to CA2942761A priority patent/CA2942761A1/fr
Priority to JP2016557605A priority patent/JP2017507983A/ja
Publication of WO2015140717A1 publication Critical patent/WO2015140717A1/fr
Priority to AU2016231832A priority patent/AU2016231832B2/en
Priority to CA2979616A priority patent/CA2979616C/fr
Priority to JP2017548261A priority patent/JP6775516B2/ja
Priority to MX2017011951A priority patent/MX2017011951A/es
Priority to BR112017019699-9A priority patent/BR112017019699A2/pt
Priority to RU2017130845A priority patent/RU2672252C1/ru
Priority to US15/072,534 priority patent/US9873690B2/en
Priority to PCT/IB2016/051509 priority patent/WO2016147144A1/fr
Priority to EP16711022.0A priority patent/EP3271354A1/fr
Priority to SG11201706992TA priority patent/SG11201706992TA/en
Priority to CN201680028408.7A priority patent/CN107635990A/zh
Priority to KR1020177029203A priority patent/KR102013512B1/ko
Publication of WO2015140717A9 publication Critical patent/WO2015140717A9/fr
Priority to IL254124A priority patent/IL254124A0/en
Priority to HK18103418.8A priority patent/HK1243999A1/zh

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/10Drugs for disorders of the urinary system of the bladder
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D407/00Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel 3-(indol-3-yl)-pyridine derivatives, including pharmaceutically acceptable enantiomers, salts and solvates thereof.
  • Compounds of the invention are inhibitors of TDO2 (tryptophan 2,3-dioxygenase) and are useful as therapeutic compounds, particularly in the treatment and/or prevention of cancers.
  • TDO2 tryptophan 2,3-dioxygenase
  • tryptophan an essential amino acid
  • tryptophan is catabolized in the local microenvironment of tumors, immune- privileged sites, or sites of inflammation (Mellor AL and Munn DH., Nat Rev Immunol, 2008, 8, 74–80).
  • cancer cells In these tissues, cancer cells, immune cells, or specialized epithelial cells (e.g., syncytiotrophoblasts in the placenta) create an immunosuppressive environment in tumors that shuts down antitumor immune responses in tumors and in tumor-draining lymph nodes by inducing T-cell anergy and apoptosis through depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites (Munn DH et al., J Exp Med., 1999, 189, 1363–1372; Fallarino F et al., Cell Death Differ., 2002, 9, 1069–1077).
  • epithelial cells e.g., syncytiotrophoblasts in the placenta
  • tryptophan 2,3-dioxygenase which is considered responsible for regulating systemic tryptophan levels in the liver
  • TDO2 tryptophan 2,3-dioxygenase
  • bladder carcinoma hepatocarcinoma, melanoma, mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head and neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myeloma, and pancreatic carcinoma
  • pancreatic carcinoma Pancreatic carcinoma
  • TDO2 expression in tumor cells prevents tumor surveillance by the immune system and thus prevents tumor rejection by locally degrading tryptophan (Opitz CA et al., Nature, 2011, 478(7368), 197-203).
  • the first evidence for this was provided through inhibition of TDO2 by a small molecule which inhibited tumor growth in a P815 mastocytoma tumor model with a prophylactic vaccination approach (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497- 502).
  • P815mTDO2 expressing tumors were rejected less in comparison to P815 tumors transfected with an empty vector, clearly demonstrating a growth benefit for TDO2 expressing tumors.
  • TDO2 Inhibition with a TDO2 inhibitor strongly decreased tumor growth in P815mTDO2 implanted tumors. Anti-tumor activity with the TDO2 inhibitor was equally observed in the P815 control implanted tumors negative for TDO2, thus providing evidence for an effect of TDO2 expressed in the immune system of the animal.
  • HCC hepatocellular carcinoma
  • RNA expression is a good indication for therapeutic evaluation of TDO2 inhibitors (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502).
  • TDO2 is expressed in neurons, microglia and
  • astrocytes and the potential benefit of TDO2 inhibition in the context of glioma was shown in another animal model.
  • Platten and collaborators demonstrated that the tryptophan catabolite kynurenine produced by TDO expressed in the tumor cells suppresses antitumour immune responses and promotes tumor-cell survival and motility through the AHR in an autocrine/paracrine fashion (Opitz CA et al., Nature, 2011, 478(7368), 197-203).
  • the TDO-AHR pathway is active in human brain tumors and is associated with malignant progression and poor survival.
  • TDO2 mRNA tumor types in which TDO2 mRNA was found are breast carcinoma, bladder, renal cell, pancreatic, colorectal, head & neck carcinoma and lung carcinoma as well as melanoma thus broadening the scope of TDO2 targeting beyond HCC and glioma (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502).
  • the enhanced Tryptophan degradation observed in patients with gynecological cancers ovarian carcinoma, cervical cancer, endometrial cancer provides additional rationale for TDO2 targeting in those cancers (Sperner-Schweger B et al, Immunology, 2011, 216 (3); 296-301).
  • tryptophan catabolism in some cancers might be also increased by the expression of indoleamine 2,3-dioxygenase (IDO1) by tumor cells (Uyttenhove, C. et al., Nat. Med., 2003, 9, 1269-1274). Because tryptophan catabolism is induced by inflammatory mediators, notably IFN- gamma, it is thought to represent an endogenous mechanism that restricts excessive immune responses, thereby preventing immunopathology.
  • IDO1 indoleamine 2,3-dioxygenase
  • TDO2 expression has been demonstrated in neurons, brain vasculature and additionally in the case of schizophrenia in astroglial cells (Miller C et al., 2004, Neurobiology Dis, 15(3):618-29).
  • the kynurenine pathway is now considered as a therapeutic target in cognitive diseases like bipolar disorder or Tourette syndrome and neurodegenerative disorders like Alzheimer, motor neuron disease like Amyotrophic lateral sclerosis, Multiple sclerosis, Huntington or Parkinson's disease (Stone TW, 2013, Br J of Pharmacol, 169(6): 1211-27; Wu et al, 2013, Plos One, 8(4):e59749; Füvesi et al, 2012, J Neural Transm, 119(2):225-34; Widner et al, 2002, J Neural Transm, 109(2):181-9; Comings et al, 1996, Pharmacogenetics,
  • TDO2 inhibitors were proposed in WO2010/008427 and by Dolusic, E. et al.
  • the present invention provides new TDO2 inhibitors which may be administered to a mammalian subject having a condition or disease where it is desirable to modulate, and in particular decrease, activity of TDO2, including, without limitation, patients diagnosed with cancer, or any subject being at risk of developing a cancer. Also provided are compositions containing these compounds and uses thereof.
  • a compound of Formula I is provided or a pharmaceutically acceptable salt, solvent or solvate thereof, where A1, A2, A3, Y1, Y2, Y4, R1, R2, R3, X1 and X3 are as defined herein.
  • a first one of A 1 , A 2 and A 3 is N, a second one of A 1 , A 2 and A 3 is C and the third one of A 1 , A 2 and A 3 is N or O.
  • a 2 is N and one of A 1 and A 3 is N or S and the other is C.
  • a 1 or A 3 is S, A 1 -Y 1 or A 3 -Y 3 is SO 2 .
  • a 2 is C and one of A 1 and A 3 is N and the other is N or O.
  • a 1 or A 3 is O, and C is substituted with CR 6 R 7 R 8 as defined herein and one of R 6 , R 7 , R 8 is a 1.
  • A1 or A3 is O, and C is substituted with CR 6 R 7 R 8 and R 6 , R 7 or R 8 is heterocyclyl or C1-heterocycyl, the heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or 2,6-diazaspiro[3.3]heptane, any of which may be optionally substituted with one or more of C1-C3 alkyl, amino, hydroxyl, halogen, COCH 3 , COOH, or SO 2 CH 3 .
  • one of A 1 , A 2 or A 3 is S or A 1 -Y 1 , A 2 -Y 2 , or A 3 -Y 3 is SO 2 ; one of A 1 , A 2 or A 3 is N or C and one of A 1 , A 2 and A 3 is C.
  • X 1 and X 2 are independently H or F.
  • R 1 , R 2 and R 3 represent each independently H, halogen or methyl, or may each be H.
  • a pharmaceutical composition which comprises a compound according to Formula I is provided, or a pharmaceutically acceptable enantiomer, salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
  • a medicament which comprises a compound according to Formula I, or a pharmaceutically acceptable enantiomer, salt or solvate thereof.
  • a compound of Formula I, or a pharmaceutically acceptable enantiomer, salt or solvate thereof is provided, for use in the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, chronic viral infections such as HCV and HIV, depression, and obesity, or for use as TDO2 inhibitor.
  • a method of treating and/or preventing of cancer is provided, for use in the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, chronic viral infections such as HCV and HIV, depression, and obesity, or for use as TDO2 inhibitor.
  • the method comprises administering a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • a process for manufacturing a compound of Formula I or a pharmaceutically acceptable enantiomer, salt or solvate thereof is provide. The process comprises:
  • X 1 and X 2 represent each independently H, halogen, alkyl, haloalkyl
  • Z 1 represents H or an amino protecting group
  • Y represents an halogen, an alkylsulfonyloxy having 1-6 carbon atoms or arylsulfonyloxy having 6-10 carbon atoms; with a compound of Formula (ii)
  • R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , Y 1 , Y 2 and Y 3 are as defined herein; and Z 2 and Z 3 represent H or alkyl groups, with the possibility for Z 2 and Z 3 to form a ring;
  • X 1 and X 2 represent each independently H, halogen, alkyl, or haloalkyl
  • R 1 , R 2 and R 3 represent each independently H, halogen, C1-C6 alkyl, alkoxy, or haloalkyl, optionally substituted by one or more substituents selected from halogen, hydroxyl, OR 4 , COOR 4 , CONR 4 R 5 , NR 4 COR 5 , NR 4 R 5 , SO 2 R 4 , SO 2 NR 4 R 5 , NR 4 SO 2 R 5 , SO 2 R 4 , aryl, CO-alkyl, or C1-C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 4 and R 5 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino; A 1 , A 2 and A 3 represent each independently C
  • each of Y 1 , Y 2 and Y 3 is either absent or represent independently
  • R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, or SO 2 R 11 , wherein R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, hydroxyl, or amino; v) C1-C10 alkyl, linear or branched; optionally substituted with up to three substituents selected from halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 ,
  • heterocyclyl substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino; vi) heterocyclyl or C1-C2 alkyl - heterocyclyl; wherein the heterocyclyl is optionally substituted with up to three substituents halogen, hydroxyl, oxo, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO-alkyl, or alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6
  • heterocyclyl optionally substituted with up to three
  • a 1 , A 2 and A 3 are not all C;
  • compound of Formula I is not 3-(benzofuran-5-yl)-6-chloro-1H-indole or 3- (benzo[d][1,3]dioxol-5-yl)-1H-indole.
  • compound of Formula I is not 3-(benzofuran-5-yl)-6-chloro-1H-indole or 3- (benzo[d][1,3]dioxol-5-yl)-1H-indole.
  • X 1 and X 2 represent each independently H, halogen, alkyl, haloalkyl, preferably H or F;
  • R 1 , R 2 and R 3 represent each independently H, halogen, C1-C6 alkyl, alkoxy, haloalkyl, optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, OR 4 , COOR 4 , CONR 4 R 5 , NR 4 COR 5 , NR 4 R 5 , SO 2 R 4 , SO 2 NR 4 R 5 , NR 4 SO 2 R 5 , SO 2 R 4 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 4 and R 5 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • R 1 , R 2 and R 3 represent each independently H, halogen or alkyl, preferably R 1 , R 2 and R 3 represent each independently H, halogen or methyl, preferably R 1 , R 2 and R 3 represent each H;
  • a 1 , A 2 and A 3 represent each independently C, N or O;
  • each of Y 1 , Y 2 and Y 3 is either absent or represent independently
  • R 6 , R 7 and R 8 represent each independently:
  • R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, SO 2 R 11 , wherein R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • C1-C10 alkyl linear or branched, preferably methyl, ethyl or propyl
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO- alkyl
  • R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl,
  • R 11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl,
  • cycloalkyl optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • heterocyclyl preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • NR 6 R 7 , R 6 , R 7 and the nitrogen atom to which they are attached form together a ring, said ring being preferably an heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 11 , SO 2 R 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, al
  • a 1 , A 2 and A 3 are not all C;
  • compound of Formula I is not 3-(benzofuran-5-yl)-6-chloro-1H-indole or 3- (benzo[d][1,3]dioxol-5-yl)-1H-indole.
  • the fused heterocycle which substitutes the indole ring in Formula I is aromatic.
  • the fused heterocycle which substituted the indole ring in Formula I is partially aromatic.
  • the heterocycle which substituted the indole ring in Formula I is non-aromatic.
  • X 1 and X 2 represent each independently H or halogen, preferably H or F.
  • X 1 represents H and X 2 represents F.
  • R 1 , R 2 and R 3 represent each H.
  • X 1 and X 2 represent each independently H or halogen and R 1 , R 2 and R 3 represent each H; preferably X 1 represents H and X 2 represents F and R 1 , R 2 and R 3 represent each H
  • a first one of A 1 , A 2 and A 3 is N
  • a second one of A 1 , A 2 and A 3 is C
  • the third one of A 1 , A 2 and A 3 is N or O.
  • a 2 is N and one of A 1 and A 3 is N or S r and the other is C. According to one embodiment, in Formula I, A 2 is C and one of A 1 and A 3 is N and the other is N or O.
  • a 1 or A 3 is O, and C is substituted with CR 6 R 7 R 8 and R 6 , R 7 or R 8 is heterocyclyl or C1-heterocycyl
  • the heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or2,6-diazaspiro[3.3]heptane, any of which may be optionally substituted with one or more of C1-C3 alkyl, amino, hydroxyl, halogen, COCH 3 , COOH, or SO 2 CH 3 .
  • a 1 or A 3 is S
  • a 1 -Y 1 or A 3 -Y 3 is SO 2 .
  • one of A 1 , A 2 or A 3 is S or A 1 -Y 1 , A 2 -Y 2 , or A 3 -Y 3 is SO 2 ; one of A 1 , A 2 or A 3 is N or C and one of A 1 , A 2 and A 3 is C.
  • preferred compounds of Formula I are those of Formula II-1
  • a 1 and A 3 are not both C.
  • one of A 1 and A 1 is S and the other is C, A 1 -Y 1 or A 3 -Y 3 is optionally SO 2 , and the C is optionally substituted with oxo.
  • preferred compounds of Formula I are those of Formula II-2
  • ⁇ A 1 , A 3 ⁇ are not ⁇ C, N ⁇ , ⁇ N, C ⁇ or ⁇ C, C ⁇ .
  • preferred compounds of Formula I are those of Formula II-1a
  • Y 1 represents H and Y 3 is as defined in Formula I, preferably, Y 3 represents:
  • R 6 , R 7 and R 8 represent each independently:
  • C1-C10 alkyl linear or branched, preferably methyl, ethyl or propyl
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • -CO-R 11 wherein R 11 represents a group selected from amine, alkyl
  • R 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • R 6 , R 7 and R 8 represent each independently:
  • C1-C10 alkyl linear or branched, preferably methyl, ethyl or propyl
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • amine alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 ,
  • NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH;
  • R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • R 6 , R 7 and the carbon atom to which they are attached form together a ring, said ring being preferably an heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 ,
  • Y 3 represents H and Y 1 is as defined in Formula I, preferably, Y 1 represents:
  • R 6 , R 7 and R 8 represent each independently:
  • C1-C10 alkyl linear or branched, preferably methyl, ethyl or propyl
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • amine alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 ,
  • R 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • Y 3 represents H and Y 2 is as defined in Formula I, preferably, Y 2 represents:
  • R 6 , R 7 and R 8 represent each independently:
  • C1-C10 alkyl linear or branched, preferably methyl, ethyl or propyl
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • -CO-R 11 or–SO 2 R 11 wherein R 11 represents a group selected from
  • R 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, SO 2 R 11 , wherein R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • C1-C10 alkyl, linear or branched, preferably methyl, ethyl or propyl;
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • amine, alkyl, heterocyclyl preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide
  • Y 2 represents:
  • amine alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 ,
  • NR 9 SO 2 R 10 SOR 9 , aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
  • preferred compounds of Formula I are those of Formula II-2b1
  • R 6 , R 7 and R 8 represent each independently:
  • R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, SO 2 R 11 , wherein R 11 represents a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; • C1-C10 alkyl, linear or branched, preferably methyl, ethyl or propyl;
  • NR 9 COR 10 NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SOR 9 , aryl, CO-alkyl, wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
  • heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
  • preferred compounds of Formula I are those of Formula II-2b2
  • R 6 , R 7 and R 8 represent each independently:
  • heterocyclyl or C1-heterocycl preferably selected from piperidine, pyrrolidine, piperazine, morpholine or 2,6-diazaspiro[3.3]heptane; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , aryl, CO- alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl,
  • R 11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR 9 , COOR 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 R 10 , SO 2 R 9 , SO 9
  • R 9 and R 10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
  • one ore more of the heterocycles is substituted with at least one of H or a group selected from SO 2 CH 3 , C1-C3 lower akyl, preferably CH 3 , or COOH.
  • preferred compounds of Formula I are those of Formula II-2b3
  • R 1 , R 2 or R 3 are each independently H, halogen, or C1-C6 alkyl, preferably, C1 alkyl.
  • X 1 and X 2 are independently H or halogen.
  • Particularly preferred compounds of Formula I of the invention are those listed in Table 1 hereafter. TABLE 1
  • the term“Cpd” means compound.
  • the compounds of Table 1 were named using ChemBioDraw ® Ultra version 12.0 (PerkinElmer).
  • the compounds of Formula I and subformulae thereof may contain an asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non-racemic mixtures as well.
  • a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art.
  • the compounds of the invention may be in the form of“pharmaceutically acceptable salts”.
  • Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, lactobionate, benzenesulfonate, laurate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate,
  • methylnitrate calcium edetate, mucate, napsylate, chloride, clavulanate, N oleate, edetate, estolate, pantothenate, polygalacuronate, salicylate, glutamate,
  • naphthylate 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, ornithine, N,N-dibenzyethelenediamine, piperazine, tri(hydroxymethyl_aminomethane, tetramethylammonium hydroxide, - methylgucamine, ammonium salt, potassium, sodium, tromethamine, 2- (diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. Preferred, pharmaceutically acceptable salts include
  • hydrochloride/chloride hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.
  • the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention.
  • the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH)
  • the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
  • Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of these methods:
  • salts which are as defined above. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e.
  • esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • references to compounds of Formula I throughout this specification includes all of ts subformulae, Formula II (including II-1, II-1a, II-1a1, II-1a2, II-1b, II-1b1, II-1b2, II-2, II- 2a, II-2a1, II-2a2, II-2b, II-2b1, II-2b2, II-2b3) include references to enantiomers, salts, solvates, polymorphs, multi - component complexes and liquid crystals thereof.
  • the compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of Formula I.
  • salts of the compounds of the invention are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention.
  • non-pharmaceutically acceptable salts which may for example be used in the isolation and/or purification of the compounds of the invention.
  • salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.
  • the invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I. Process for manufacturing The compounds of Formula I can be prepared by different ways with reactions known to a person skilled in the art.
  • the invention further relates to a first process for manufacturing of compounds of Formula I
  • X 1 and X 2 are as defined in Formula I;
  • Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art
  • Y represents an halogen (preferably iodine, bromine or chlorine), an alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any leaving group known to those skilled in the art
  • R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , Y 1 , Y 2 and Y 3 are as defined in Formula I;
  • Z 2 and Z 3 represent H or alkyl groups, with the possibility for Z 2 and Z 3 to form a ring; so as to obtain a compound of Formula (iii),
  • step (b1) of the process of the invention may be performed with or without a catalyst such as but not limited to Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(II) or 1,1'-bis(diphenylphosphino)ferrocene- dichloro palladium(II), Pd(OAc) 2 , or Pd/C in the presence or absence of an additional ligand, such as but not limited to X-Phos, S-Phos, P(oTol) 3 , PPh 3 , BINAP, P(tBu) 3 or any other suitable phosphine ligand known to those skilled in the art.
  • a catalyst such as but not limited to Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(II) or 1,1'-bis(diphenylphos
  • step (a1) of the process of the invention may be performed in the presence of bases such as but not limited to K 3 PO 4 , K 2 CO 3 , Na 2 CO 3 .
  • step (a1) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to dioxane, THF, DMF, water or mixtures thereof, preferably in a mixture of dioxane or THF and water.
  • step (a1) of the process of the invention may be performed at a temperature ranging from 20 °C to about 180 °C, with or without microwave irradiation, for a period ranging from 10 minutes to a few hours, e.g.10 minutes to 24 h.
  • the deprotection (b1) may be performed, depending on the nature of the group Z 1 , by treatment with bases, such as but not limited to sodium hydroxide, potassium hydroxide, potassium carbonate.
  • bases such as but not limited to sodium hydroxide, potassium hydroxide, potassium carbonate.
  • the deprotection may be performed in the presence or absence of a suitable solvent such as but not limited to methanol, ethanol, isopropanol, tert-butanol, THF, DMF, Dioxane, water or a mixture thereof.
  • the deprotection may be performed at a temperature ranging from 20 °C to 100 °C, preferably at about 85 °C, for a few hours, e.g. one hour to 24 h.
  • the deprotection (b1) may be performed, depending on the nature of the group Z 1 in the presence of strong acids, such as but not limited to HCl, TFA, HF, HBr.
  • the deprotection may be performed in the presence or absence of a suitable solvent such as methanol, ethanol, isopropanol, tert-butanol, THF, DMF, Dioxane, water or a mixture thereof.
  • the deprotection may be performed at a temperature between about 20 °C to about 100 °C, for a period comprised between 10 minutes and a few hours, e.g. 10 minutes to 24 h.
  • the invention further relates to a second process of manufacturing of compounds of Formula I
  • X 1 , X 2 , R 1 , R 2 , R 3 , A 1 , A 2 , A 3 are as defined in Formula I, Y 1’ , Y 2’ and Y 3’ represent respectively Y 1 , Y 2 and Y 3 as defined in Formula I with the condition that at least one of Y 1’ , Y 2’ and Y 3’ is H;
  • Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art; so as to obtain a compound of Formula (v)
  • alkylation step (a2) is performed in presence of a compound of Formula (vi) Y4 X
  • Y 4 represent Y 1 , Y 2 or Y 3 , as defined in Formula I, with the condition that Y 4 is not H or absent;
  • X represents an halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoro- methylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art.
  • halogen preferably iodine, bromine or chlorine
  • alkylsulfonyloxy having 1-6 carbon atoms preferably methylsulfonyloxy or trifluoro- methylsulfonyloxy
  • arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art.
  • step (a2) of the process of the invention may be performed in the presence of bases such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium diisopropyl amide, buthyl lithium.
  • step (a2) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to DMF, methanol, ethanol, isopropanol, tert-butanol, THF, dioxane, dichloromethane, water.
  • step (a2) of the process of the invention may be performed in the presence or absence of catalytic amounts of appropriate iodide salts, such as but not limited to tetrabutylammonium iodide.
  • step (a2) of the process of the invention may be performed at a temperature ranging from 20 °C to about 180 °C, with or without microwave irradiation.
  • step (a2) of the process of the invention may be performed for a period ranging from 10 minutes and a few hours, e.g.10 minutes to 24 h.
  • the deprotection step (b2) may be performed in conditions described above for deprotection (b1).
  • the invention further relates to a third process of manufacturing of compounds of Formula II-2a1 wherein Y 1 is H:
  • Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art; with a compound of Formula (viii)
  • Y represents an hydroxyl, halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art; so as to obtain a compound of Formula (ix)
  • step (a3) of the process of the invention may be performed in the presence of a suitable amide coupling reagent, such as but not limited to HATU, DCC, DIC, BOP, PyBOP, in the presence or absence of additional additives such as but not limited to HOBt.
  • step (a3) of the process of the invention may be performed in the presence of bases such as but not limited to triethylamine,
  • step (a3) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to
  • step (a3) further comprises adding a suitable acid, such as but not limited to acetic acid, wherever necessary to complete cyclization.
  • step (a3) of the process of the invention may be performed at a temperature ranging from 20 °C to about 180 °C, with or without microwave irradiation.
  • step (a3) of the process of the invention may be performed for a period ranging from 10 minutes and a few hours, e.g.10 minutes to 24 h.
  • the deprotection step (b3) may be performed in conditions described above for deprotection (b1).
  • the invention further relates to a fourth process for manufacturing of compounds of Formula I
  • Z 1 represents H or an amino protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art
  • Z 2 and Z 3 represent H or alkyl groups, with the possibility for Z 2 and Z 3 to form a ring; with a compound of Formula (xi)
  • R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , Y 1 , Y 2 and Y 3 are as defined in Formula I;
  • Y represents an halogen (preferably iodine, bromine or chlorine), an alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any leaving group known to those skilled in the art so as to obtain a compound of Formula (xii),
  • step (b4) of the process of the invention may be performed with or without a catalyst such as but not limited to Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(II) or 1,1'-bis(diphenylphosphino)ferrocene- dichloro palladium(II), Pd(OAc) 2 , or Pd/C in the presence or absence of an additional ligand, such as but not limited to X-Phos, S-Phos, P(oTol) 3 , PPh 3 , BINAP, P(tBu) 3 or any other suitable phosphine ligand known to those skilled in the art.
  • a catalyst such as but not limited to Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , dichlorobis(triphenylphosphine)palladium(II) or 1,1'-bis(diphenylphos
  • step (a4) of the process of the invention may be performed in the presence of bases such as but not limited to K 3 PO 4 , K 2 CO 3 , Na 2 CO 3 .
  • step (a4) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to dioxane, THF, DMF, water or mixtures thereof, preferably in a mixture of dioxane or THF and water.
  • step (a4) of the process of the invention may be performed at a temperature ranging from 20 °C to about 180 °C, with or without microwave irradiation, for a period ranging from 10 minutes to a few hours, e.g.10 minutes to 24 h.
  • the deprotection step (b4) may be performed in conditions described above for deprotection (b1).
  • the synthesis pathways for any individual compound of Formula (I) will depend on the specific substituents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art.
  • compounds of Formula I can be converted to alternative compounds of Formula I, employing suitable interconversion techniques well known by a person skilled in the art.
  • Compounds of the Formula I and related formulae can furthermore be obtained by liberating compounds of the Formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
  • Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the Formula I and related formulae, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, in particular those which carry an R*-N group, in which R* denotes an amino- protecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the Formula I, but carry a–COOR** group, in which R** denotes a hydroxyl-protecting group, instead of a -COOH group.
  • amino-protecting group is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups.
  • acyl group is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxy ⁇ carbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxy ⁇ carbonyl, ethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr.
  • alkanoyl such as acetyl, propionyl and butyryl
  • aralkanoyl such as phenylacetyl
  • aroyl such as benzoyl and tolyl
  • Preferred amino-protecting groups are BOC and Mtr, further ⁇ more CBZ, Fmoc, benzyl and acetyl.
  • the term“hydroxyl-protecting group” is likewise known in general terms and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.
  • the nature and size of the hydroxyl-protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, in particular 1-10, carbon atoms.
  • hydroxyl- protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p- toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.
  • the compounds of the Formula I and related formulae are liberated from their functional derivatives– depending on the protecting group used– for example strong inorganic acids, such as hydrochloric acid, perchloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
  • Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50°C, preferably between 15 and 30°C (room temperature).
  • the BOC, OtBu and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCl in dioxane at 15-30°C, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°C.
  • Protecting groups which can be removed hydrogenolytically can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon).
  • a catalyst for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon.
  • Suitable solvents are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100°C and pressures between about 1 and 200 bar, preferably at 20-30°C and 1-10 bar.
  • Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
  • suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2- dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or
  • amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethyl ⁇ formamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.
  • NMP N-methylpyrrolidone
  • DMF dimethyl ⁇ formamide
  • nitriles such as acetonitrile
  • sulfoxides such as dimethyl sulfoxide (DMSO)
  • carbon disulfide such as carboxylic acids, such as formic acid or acetic acid
  • nitro compounds such as nitromethane or nitrobenzene
  • esters such as ethyl acetate, or mixtures of the said
  • Esters can be hydrolysed, for example, using HCl, H 2 SO 4 , or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 and 100°C.
  • Free amino groups can furthermore be acylated in a conventional manner using an acyl chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloromethane or THF and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60°C and +30°C.
  • a base such as triethylamine or pyridine
  • the invention relates to the use of compounds of Formula I and subformulae in particular those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates thereof, as TDO2 inhibitors. Accordingly, in another aspect, the invention relates to the use of these compounds or enantiomers, salts and solvates thereof for the synthesis of pharmaceutical active ingredients, such as TDO2 inhibitors. In one embodiment, the invention relates to the use of compounds of Formula I and subformulae in particular those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates thereof, for increasing immune recognition and destruction of the cancer cells. The compounds of the invention are therefore useful as medicaments, in particular in the prevention and/or treatment of cancer.
  • compounds of the invention or pharmaceutically acceptable enantiomers, salts or solvates thereof are for use in the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, chronic viral infections such as HCV and HIV, depression, and obesity.
  • the invention further relates to a method for treatment or prevention of cancer, neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, chronic viral infections such as HCV and HIV, depression, and obesity, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable enantiomers, salts or solvates thereof.
  • Various cancers are known in the art.
  • the cancer may be metastatic or non-metastatic.
  • the cancer may be may be familial or sporadic.
  • the cancer is selected from the group consisting of: leukemia and multiple myeloma. Additional cancers that can be treated using the methods of the invention include, for example, benign and malignant solid tumours and benign and malignant non-solid tumours.
  • solid tumours include, but are not limited to: biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, intraepithelial neoplasms (including Bowen’s disease and Paget’s disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, renal cancer (including adenocarcinoma and Wilms tumour), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi’s sarcoma, basocellular
  • non-solid tumours include but are not limited to hematological neoplasms.
  • a hematologic neoplasm is a term of art which includes lymphoid disorders, myeloid disorders, and AIDS associated leukemias.
  • Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias).
  • Lymphomas include, for example, Hodgkin’s disease, non- Hodgkin’s lymphoma lymphomas, and lymphocytic lymphomas).
  • Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.
  • the invention also provides for a method for delaying in patient the onset of cancer comprising the administration of a pharmaceutically effective amount of a compound of Formula I or pharmaceutically acceptable enantiomer, salt and solvate thereof to a patient in need thereof.
  • the patient is a warm-blooded animal, more preferably a human.
  • the compounds of the invention are especially useful in the treatment and/or prevention of cancer. In a specific embodiment, the compounds of the invention are especially useful in the treatment and/or prevention of cancer.
  • the invention further provides the use of a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof for the manufacture of a medicament for treating and/or preventing cancer.
  • a method for modulating TDO2 activity in a patient, preferably a warm blooded animal, and even more preferably a human, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a
  • compositions comprising a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
  • the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable enantiomer, salt and solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.
  • Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof, as active ingredient.
  • a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof for the manufacture of a medicament for modulating TDO2 activity in a patient, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof.
  • the compounds of the invention may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • suitable administration forms which may be solid, semi-solid or liquid, depending on the manner of administration– as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person;
  • Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous
  • compositions which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof.
  • carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrol
  • the formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc..
  • the compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
  • the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • the active compound of the invention may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
  • the number of carbon atoms present in a given group is designated “Cx to Cy", where x and y are the lower and upper limits, respectively.
  • the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are determined by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. As used herein, "optionally substituted” means that at least 1 hydrogen atom of the optionally substituted group has been replaced.
  • alkyl by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C n H 2n+1 wherein n is a number greater than or equal to 1.
  • Alkyl groups may contain 1 to 10 carbons (inclusive), i.e., C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10, i.e., C1-C10 alkyl.
  • alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms.
  • Alkyl groups may be linear or branched and may be substituted as indicated herein.
  • Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl).
  • haloalkyl alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
  • Non-limiting examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoro methyl and the like.
  • the haloalkyl is a C1 to C6 alkyl group substituted with at least one halogen.
  • the haloalkyl is a C1 to C4 alkyl group substituted with at least one halogen.
  • Each halogen substitution may be independently selected.
  • the term "cycloalkyl” as used herein is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups.
  • Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms.
  • Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.
  • the term“heteroatom” referns to a sulfur, nitrogen or oxygen atom. Where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocyclyl".
  • heterocyclyl or“heterocycle” as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom- containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen
  • heteroatoms may optionally be quaternized.
  • the heterocycle may contain 3 to 7 carbon atoms (inclusive), or an integer therebetween. Any of the carbon atoms of the
  • heterocyclic group may be substituted by oxo (for example piperidone,
  • heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
  • Non limiting exemplary heterocyclic groups include piperidinyl, azetidinyl, tetrahydropyranyl, piperazinyl, imidazolinyl, morpholinyl, oxetanyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, indolyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, thiomorpholinyl, thiomorpholinylsulfoxide, thiomorpholinylsulfone, pyrrolizinyl.
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic.
  • the aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic (carbon-containing ring) systems enumerated herein.
  • Non- limiting examples of aryl comprise phenyl, biphenylyl, biphenylenylnaphthalenyl, indenyl.
  • heteroaryl as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
  • heteroaryl include: pyridazinyl, pyridinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benz
  • arylalkyl refers to any group -alkyl-aryl.
  • alkylaryl refers to any group -aryl-alkyl.
  • heteroarylalkyl refers to any group -alkyl-heteroaryl.
  • alkylheteroaryl refers to any group -heteroaryl-alkyl.
  • alkoxy refers to any group O-alkyl.
  • haloalkoxy refers to any group O-haloalkyl.
  • amino refers to a -NH2 group or any group derived thereof by substitution of one nor two hydrogen atom by an organic aliphatic or aromatic group.
  • groups derived from -NH2 are“alkylamino” groups, i.e. N-alkyl groups, comprising monoalkylamino and dialkylamino.
  • amino include NH2, NHMe or NMe2.
  • amino-protecting group refers to a protecting group for an amine function. According to a preferred embodiment, the amino-protecting group is selected in the groups comprising: arylsulphonyl, tert-butoxy carbonyl, methoxymethyl, para-methoxy benzyl or benzyl.
  • leaving group refers to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
  • the leaving group is selected in the groups comprising: halogen, preferably iodine, bromine or chlorine; alkylsulfonyloxy having 1-6 carbon atoms, preferably methylsulfonyloxy or trifluoromethylsulfonyloxy; or arylsulfonyloxy having 6-10 carbon atoms, preferably phenyl- or p-tolylsulfonyloxy.
  • solvate is used herein to describe a compound in this invention that contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule, e.g., ethanol.
  • a solvate does not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents to non-solvate compounds of Formula I and its subformula as defined herein.
  • the term "solvate” as used herein is a combination, physical association and/or solvation of a compound of the present invention with a solvent molecule. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • solvate encompasses both solution-phase and isolatable solvates.
  • “Solvate” may encompass solvates of salts of the compounds of Formula I.
  • the term "hydrate” refers to when the solvent molecule is water and may be an inorganic salt containing nH 2 O, wherein n is the number of water molecules per formula unit of the salt. N may be 1 ⁇ 2, 11 ⁇ 2 , or an integer from 1 to 10. A hydrate which has lost water
  • the compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and prodrugs thereof and isotopically- labeled compounds of Formula I.
  • the invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.
  • prodrug as used herein means the pharmacologically acceptable derivatives of compounds of Formula I, such as for example esters, whose in vivo biotransformation product generates the biologically active drug. Prodrugs are generally characterized by increased bio-availability and are readily metabolized into biologically active compounds in vivo.
  • predrug means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the predrug reaches the area of the body where administration of the drug is indicated.
  • patient refers to a warm-blooded animal, more preferably a human, who/which is awaiting the receipt of, or is receiving medical care or is/will be the object of a medical procedure.
  • human refers to a subject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).
  • the terms “treat”, “treating” and “treatment”, as used herein, are meant to include alleviating, attenuating or abrogating a condition or disease and/or its attendant symptoms.
  • prevent refers to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient’s risk of acquiring a condition or disease.
  • therapeutically effective amount means the amount of active agent or active ingredient that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which/whom it is administered.
  • administration or a variant thereof (e.g.
  • administering means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.
  • pharmaceutically acceptable is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.
  • pharmaceutical vehicle as used herein means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered.
  • Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.
  • the words “comprise”, “comprises”, and “comprising” are to be interpreted inclusively rather than exclusively.
  • HPLC Preparative High Performance Liquid Chromatography
  • triphenylphosphine psi is pound per square inch; PPM is parts per million; qd po means daily by mouth; rt is room temperature; RT is retention time; TLC is thin layer chromatography; TFA is trifluoroacetic acid; TEA is triethylamine.
  • reaction mixture was stirred for 1 hour and quenched with saturated aqueous NaHCO 3 (30 mL).
  • the aqueous layer was extracted with DCM (70 mL ⁇ 2).
  • the combined organic layers were washed with brine (20 mL), dried over anhydrous
  • Step 2 To a solution of 3-(5-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-benzo[d]imidazol-2- yl)propanamide (Step 1; 480 mg crude; 0.92 mmol) in EtOH (10 mL) was added KOH (116 mg; 2.07 mmol).

Abstract

La présente invention concerne des composés de formule (I) ou des énantiomères, sels ou solvates pharmaceutiquement acceptables de ceux-ci. L'invention concerne en outre l'utilisation des composés de formule I en tant qu'inhibiteurs de la TDO2. L'invention concerne également l'utilisation des composés de formule I pour le traitement du VIH, de la dépression et de l'obésité. L'invention se rapporte en outre à un procédé destiné à fabriquer les composés de formule (I).
PCT/IB2015/051957 2014-03-18 2015-03-17 Dérivés substitués par 3-indole, compositions pharmaceutiques et procédés d'utilisation WO2015140717A1 (fr)

Priority Applications (17)

Application Number Priority Date Filing Date Title
EP15714653.1A EP3119763A1 (fr) 2014-03-18 2015-03-17 Dérivés substitués par 3-indole, compositions pharmaceutiques et procédés d'utilisation
CA2942761A CA2942761A1 (fr) 2014-03-18 2015-03-17 Derives substitues par 3-indole, compositions pharmaceutiques et procedes d'utilisation
JP2016557605A JP2017507983A (ja) 2014-03-18 2015-03-17 新規な3−インドール置換誘導体、医薬組成物、および使用方法
CN201680028408.7A CN107635990A (zh) 2015-03-17 2016-03-17 新型3‑吲哚取代的衍生物、药物组合物及使用方法
KR1020177029203A KR102013512B1 (ko) 2015-03-17 2016-03-17 신규 3-인돌 치환 유도체, 제약 조성물 및 사용 방법
BR112017019699-9A BR112017019699A2 (pt) 2015-03-17 2016-03-17 derivados substituídos por 3-indol, composições farmacêuticas e métodos para uso
PCT/IB2016/051509 WO2016147144A1 (fr) 2015-03-17 2016-03-17 Nouveaux dérivés substitués par un 2-indole, compositions pharmaceutiques et leurs procédés d'utilisation
JP2017548261A JP6775516B2 (ja) 2015-03-17 2016-03-17 新奇な3−インドール置換誘導体、医薬組成物、および使用方法
MX2017011951A MX2017011951A (es) 2015-03-17 2016-03-17 Derivados sustituidos de indol 3 novedosos, composiciones farmaceuticas y metodos para uso.
AU2016231832A AU2016231832B2 (en) 2015-03-17 2016-03-17 Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use
RU2017130845A RU2672252C1 (ru) 2015-03-17 2016-03-17 Новые 3-индол замещенные производные, фармацевтические композиции и способы применения
US15/072,534 US9873690B2 (en) 2015-03-17 2016-03-17 3-indol substituted derivatives, pharmaceutical compositions and methods for use
CA2979616A CA2979616C (fr) 2015-03-17 2016-03-17 Nouveaux derives substitues par un 2-indole, compositions pharmaceutiques et leurs procedes d'utilisation
EP16711022.0A EP3271354A1 (fr) 2015-03-17 2016-03-17 Nouveaux dérivés substitués par un 2-indole, compositions pharmaceutiques et leurs procédés d'utilisation
SG11201706992TA SG11201706992TA (en) 2015-03-17 2016-03-17 Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use
IL254124A IL254124A0 (en) 2015-03-17 2017-08-23 New 3-indole-transformed histories, medicinal preparations and methods of use
HK18103418.8A HK1243999A1 (zh) 2015-03-17 2018-03-12 新型3-吲哚取代的衍生物、藥物組合物及使用方法

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US201461996975P 2014-03-18 2014-03-18
US61/996,975 2014-03-18
EP14160578.2 2014-03-18
EP14160578 2014-03-18
BE2014/0776A BE1021253B1 (fr) 2014-03-18 2014-11-06 Nouveaux derives substitues de 3-indol, compositions pharmaceutiques et methode d'utilisation
BEBE2014/0776 2014-11-06

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/072,534 Continuation-In-Part US9873690B2 (en) 2015-03-17 2016-03-17 3-indol substituted derivatives, pharmaceutical compositions and methods for use

Publications (2)

Publication Number Publication Date
WO2015140717A1 WO2015140717A1 (fr) 2015-09-24
WO2015140717A9 true WO2015140717A9 (fr) 2016-03-24

Family

ID=54143823

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2015/051957 WO2015140717A1 (fr) 2014-03-18 2015-03-17 Dérivés substitués par 3-indole, compositions pharmaceutiques et procédés d'utilisation

Country Status (4)

Country Link
EP (1) EP3119763A1 (fr)
JP (1) JP2017507983A (fr)
CA (1) CA2942761A1 (fr)
WO (1) WO2015140717A1 (fr)

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3148531A1 (fr) 2014-05-15 2017-04-05 iTeos Therapeutics Dérivés de pyrrolidine -2,5-dione, compositions pharmaceutiques et procédés pour une utilisation en tant qu'inhibiteursde de ido1
HUE042390T2 (hu) 2014-06-19 2019-06-28 Ariad Pharma Inc Heteroaril vegyületek kinázgátlásra
JP2018052817A (ja) * 2015-01-21 2018-04-05 大日本住友製薬株式会社 新規ベンズイミダゾール誘導体およびその医薬用途
US9873690B2 (en) * 2015-03-17 2018-01-23 Pfizer Inc 3-indol substituted derivatives, pharmaceutical compositions and methods for use
CA2994917A1 (fr) 2015-08-10 2017-02-16 Pfizer Inc. Derives substitues par un 3-indole, compositions pharmaceutiques et leurs procedes d'utilisation
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
EP3269714A1 (fr) 2016-07-13 2018-01-17 Netherlands Translational Research Center B.V. Inhibiteurs de tryptophane 2,3-dioxygénase
CN109952300B (zh) 2016-09-24 2022-01-18 百济神州有限公司 5或8-取代的咪唑并[1,5-a]吡啶
SG10202107880XA (en) 2017-05-12 2021-09-29 Harpoon Therapeutics Inc Mesothelin binding proteins
EP4245375A3 (fr) 2017-05-30 2023-12-06 Bristol-Myers Squibb Company Compositions comprenant une combinaison d'un anticorps anti-lag-3, d'un inhibiteur de voie pd-1 et d'un agent immunothérapeutique
JP7062792B2 (ja) 2018-02-13 2022-05-06 ギリアード サイエンシーズ, インコーポレイテッド Pd-1/pd-l1阻害剤
AU2019255750B2 (en) 2018-04-19 2021-10-21 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
CN108586432B (zh) * 2018-05-31 2020-08-25 温州医科大学 一种3-(吲哚-5-基)-吲唑衍生物及其应用
CR20210013A (es) 2018-07-13 2021-02-26 Gilead Sciences Inc Inhibidores de pd-1/pd-l1
BR112021005769A2 (pt) 2018-09-25 2021-07-06 Harpoon Therapeutics Inc proteínas de ligação a dll3 e métodos de uso
AU2019366355B2 (en) 2018-10-24 2022-10-13 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
WO2021024020A1 (fr) 2019-08-06 2021-02-11 Astellas Pharma Inc. Polythérapie impliquant des anticorps dirigés contre la claudine 18.2 et inhibiteurs de point de contrôle immunitaire pour le traitement du cancer
WO2021218912A1 (fr) * 2020-04-30 2021-11-04 南京明德新药研发有限公司 Composés contenant du benzosultame
IL298993A (en) 2020-07-07 2023-02-01 BioNTech SE Therapeutic RNA for HPV positive cancer
WO2022135666A1 (fr) 2020-12-21 2022-06-30 BioNTech SE Programme de traitement faisant intervenir des protéines cytokines
TW202245808A (zh) 2020-12-21 2022-12-01 德商拜恩迪克公司 用於治療癌症之治療性rna
WO2022135667A1 (fr) 2020-12-21 2022-06-30 BioNTech SE Arn thérapeutique pour le traitement du cancer
CA3225254A1 (fr) 2021-07-13 2023-01-19 BioNTech SE Agents de liaison multispecifiques contre cd40 et cd137 en polytherapie du cancer
TW202333802A (zh) 2021-10-11 2023-09-01 德商拜恩迪克公司 用於肺癌之治療性rna(二)
WO2023097007A1 (fr) * 2021-11-24 2023-06-01 Remix Therapeutics Inc. Composés et procédés de modulation de l'épissage
WO2023170606A1 (fr) 2022-03-08 2023-09-14 Alentis Therapeutics Ag Utilisation d'anticorps anti-claudine-1 pour augmenter la disponibilité des lymphocytes t
WO2023225244A1 (fr) * 2022-05-20 2023-11-23 Biogen Ma Inc. Composés hétérocycliques pour le traitement de la maladie de huntington

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1794986B (zh) * 2003-03-27 2012-09-05 兰肯瑙医学研究所 治疗癌症的新药物
JP2007520558A (ja) 2004-02-04 2007-07-26 スミスクライン・ビーチャム・コーポレイション キナーゼ阻害剤として有用なピリミジノン化合物
EP1940787A4 (fr) * 2005-10-27 2009-07-01 Lankenau Inst Medical Res Nouveaux inhibiteurs de l'ido et leurs procedes d'utilisation
EP2137168B1 (fr) * 2007-03-16 2016-09-14 Lankenau Institute for Medical Research Nouveaux inhibiteurs ido et leurs procédés d'utilisation
US20110159017A1 (en) 2008-04-11 2011-06-30 Ludwig Institute For Cancer Research Ltd. Trytophan catabolism in cancer treatment and diagnosis
CA2772371A1 (fr) 2009-05-27 2010-12-02 F. Hoffmann-La Roche Ag Composes bicycliques indole-pyrimidine inhibiteurs de pi3k selectifs pour p110 delta et leurs procedes d'utilisation
JP6401773B2 (ja) 2013-03-11 2018-10-10 ザ リージェンツ オブ ザ ユニヴァシティ オブ ミシガン Betブロモドメイン阻害剤およびこれを用いる治療方法
AU2014230814B2 (en) 2013-03-14 2017-12-21 Boehringer Ingelheim International Gmbh Substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of Cathepsin C

Also Published As

Publication number Publication date
JP2017507983A (ja) 2017-03-23
CA2942761A1 (fr) 2015-09-24
WO2015140717A1 (fr) 2015-09-24
EP3119763A1 (fr) 2017-01-25

Similar Documents

Publication Publication Date Title
WO2015140717A9 (fr) Dérivés substitués par 3-indole, compositions pharmaceutiques et procédés d'utilisation
AU2016231832B2 (en) Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use
US9758505B2 (en) 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
US9126984B2 (en) 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use
AU2015260826B2 (en) Pyrrolidine-2,5-dione derivatives, pharmaceutical compositions and methods for use as IDO1 inhibitors
US10544095B2 (en) 3-indol substituted derivatives, pharmaceutical compositions and methods for use
US20150266857A1 (en) Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use
WO2018178338A1 (fr) Dérivés de 2-oxo-thiazole en tant qu'inhibiteurs de a2a et composés destinés à être utilisés dans le traitement de cancers
US20160263087A1 (en) Novel 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use
EP3066090A1 (fr) Dérivés de 4-(indol-3-yl)pyrazole, compositions pharmaceutiques et procédés d'utilisation
BE1021253B1 (fr) Nouveaux derives substitues de 3-indol, compositions pharmaceutiques et methode d'utilisation
OA18111A (en) Pyrrolidine-2,5-dione derivatives, pharmaceutical compositions and methods for use as IDO1 inhibitors

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: 15714653

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase in:

Ref document number: 2942761

Country of ref document: CA

ENP Entry into the national phase in:

Ref document number: 2016557605

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase in:

Ref country code: DE

REEP Request for entry into the european phase

Ref document number: 2015714653

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2015714653

Country of ref document: EP