WO2022029063A1 - Pyrido[1,2,4]triazolo[1,5-c]pyrimidin-5-amines - Google Patents

Pyrido[1,2,4]triazolo[1,5-c]pyrimidin-5-amines Download PDF

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WO2022029063A1
WO2022029063A1 PCT/EP2021/071543 EP2021071543W WO2022029063A1 WO 2022029063 A1 WO2022029063 A1 WO 2022029063A1 EP 2021071543 W EP2021071543 W EP 2021071543W WO 2022029063 A1 WO2022029063 A1 WO 2022029063A1
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alkyl
alkoxy
triazolo
cycloalkyl
pyrido
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PCT/EP2021/071543
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French (fr)
Inventor
Julien LEFRANC
Ludwig Zorn
Ilona GUTCHER
Lars RÖSE
Benjamin Bader
Detlef STÖCKIGT
Matyas GORJANACZ
Christina KOBER
Bernd Buchmann
Michael Platten
Daniel Baumann
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Bayer Aktiengesellschaft
Bayer Pharma Aktiengesellschaft
Deutsches Krebsforschungszentrum
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Publication of WO2022029063A1 publication Critical patent/WO2022029063A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention covers pyrido[1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-amine compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses, as a sole agent or in combination with other active ingredients.
  • the AHR (Aryl Hydrocarbon Receptor) is a ligand-activated transcription factor, belonging to the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family, and is located in the cytosol. Upon ligand binding, the AHR translocates to the nucleus where it heterodimerises with ARNT (AHR Nuclear Translocator) upon which it interacts with DREs (Dioxin Response Elements) of AHR-responsive genes to regulate their transcription.
  • ARNT AHR Nuclear Translocator
  • DREs Dioxin Response Elements
  • the AHR is best known for binding to environmental toxins and inducing the metabolic machinery, such as cytochrome P 450 enzymes (eg.
  • CYP1A1 , CYP1A2 and CYP1 B1 required for their elimination (Reyes et al., Science, 1992, 256(5060): 1193-5).
  • Activation of AHR by xenobiotics has demonstrated its role in numerous cellular processes such as embryogenesis, tumourigenesis and inflammation.
  • AHR is expressed in many cells of the immune system, including dendritic cells (DCs), macrophages, T cells and NK cells, and plays an important role in immunoregulation (Nguyen et al., Front Immunol, 2014, 5:551).
  • the classic exogenous AHR ligands TCDD and 3- methylcholanthrene, for example, are known to induce profound immunosuppression, promote carcinogenesis and induce tumour growth (Gramatzki et al., Oncogene, 2009, 28(28) :2593-605; Bui et al., Oncogene, 2009, 28(41 ):3642-51 ; Esser et al., Trends Immunol, 2009, 30:447-454).
  • AHR activation promotes regulatory T cell generation, inhibits Th1 and Th 17 differentiation, directly and indirectly, and decreases the activation and maturation of DCs (Wang et al., Clin Exp Immunol, 2014, 177(2):521-30; Mezrich et al., J Immunol, 2010, 185(6): 3190-8; Wei et al., Lab Invest, 2014, 94(5):528-35; Nguyen et al., PNAS, 2010, 107(46): 19961-6).
  • AHR activation modulates the innate immune response and constitutive AHR expression has been shown to negatively regulate the type-l interferon response to viral infection (Yamada et al., Nat Immunol, 2016). Additionally, mice with a constitutively active AHR spontaneously develop tumours (Andersson et al., PNAS, 2002, 99(15): 9990-5).
  • the AHR can also bind metabolic products of tryptophan degradation.
  • Tryptophan metabolites such as kynurenine and kynurenic acid
  • Tryptophan metabolites are endogenous AHR ligands that activate the AHR under physiological conditions (DiNatale et al., Toxicol Sci, 2010, 115(1):89-97; Mezrich et al., J Immunol, 2010, 185(6):3190-8; Opitz et al., Nature, 2011 , 478(7368): 197-203).
  • Other endogenous ligands are known to bind the AHR although their physiological roles are currently unknown (Nguyen & Bradfield, Chem Res Toxicol, 2008, 21 (1):102-116).
  • immunosuppressive properties of kynurenine and tryptophan degradation are well described and are implicated in cancer-associated immunosuppression.
  • the enzymes indoleamine-2,3-dioxygenases 1 and 2 (IDO1/IDO2) as well as tryptophan-2,3-dioxygenase 2 (TDO2) are responsible for catalysing the first and rate-limiting step of tryptophan metabolism.
  • IDO1/2-mediated degradation of tryptophan in tumours and tumour-draining lymph nodes reduces anti-tumour immune responses and inhibition of IDO can suppress tumour formation in animal models (Uyttenhove et al., Nat Med, 2003, 9(10):1269-74 ; Liu et al., Blood, 2005, 115(17): 3520-30; Muller et al., Nat Med, 11 (3):312-9; Metz, Cancer Res, 2007, 67(15):7082-7).
  • TDO2 is also strongly expressed in cancer and can lead to the production of immunosuppressive kynurenine.
  • tumour growth In glioma, activation of the AHR by kynurenine, downstream of TDO-mediated tryptophan degradation, enhances tumour growth as a consequence of inhibiting anti-tumour immune responses as well as directly promoting tumour cell survival and motility (Opitz et al., Nature, 2011 , 478(7368): 197-203).
  • AHR ligands generated by tumour cells therefore act in both an autocrine and paracrine fashion on tumour cells and lymphocytes, respectively, to promote tumour growth.
  • the present invention covers pyrido[1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-amine compounds of general formula (I) which inhibit the AHR.
  • WO 2010/059401 relates to compounds and compositions for expanding the number of CD34+ cells for transplantation.
  • WO 2010/059401 relates inter alia to heterocyclic compounds capable of down-regulating the activity and/or expression of AHR.
  • WO 2012/015914 relates to compositions and methods for modulating AHR activity.
  • WO 2012/015914 relates inter alia to heterocyclic compounds that modulate AHR activity for use in therapeutic compositions.
  • WO 2007040565 relates to the use of [1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-amine derivatives as adenosine receptor antagonists.
  • WO 2006/132275 (EP 1902716 A1) relates to an agent for preventing and/or treating movement disorder.
  • WO 1995/003806 relates to a remedy for Parkinson’s disease.
  • WO 1988/002370 relates to e-fused-[1 ,2,4]triazolo[1 ,5-c]pyrimidines.
  • the compounds of the present invention have surprisingly been found to effectively inhibit AHR for which data are given in biological experimental section and may therefore be used for the treatment or prophylaxis of cancer or other conditions where exogenous and endogenous AHR ligands induce dysregulated immune responses, uncontrolled cell growth, proliferation and/or survival of tumour cells, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival of tumour cells, immunosuppression in the context of cancer inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival of tumour cells, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by AHR, such as, for example, liquid and solid tumours, and/or metastases thereof, e.g.
  • AHR such as, for example, liquid and solid tumours, and/or metastases thereof, e.g.
  • tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours including colon, colorectal and pancreatic tumours, liver tumours, endocrine tumours, mammary and other gynecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • the present invention covers compounds of general formula (I): in which
  • a 1 represents CR 5 or N
  • a 2 represents CR 6 or N
  • a 3 represents CR 7 or N
  • a 4 represents CR 8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
  • R 1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, C1-C4- hydroxyalkyl, Ci-C4-alkoxy-Ci-C4-alkyl-, Cs-Ce-cycloalkyl, C 3 -C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl,
  • R 9 R 10 N-Ci-C 4 -alkyl-, Ci-C 3 -alkyl-S(O) m - or Ci-C 3 -alkyl-SO(NH)-;
  • R 2 represents hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl or Cs-Ce-cycloalkyl;
  • R 3 represents hydrogen, Ci-Ce-alkyl, phenyl or phenyl-Ci-C 3 -alkyl, wherein said Ci-Ce-alkyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, Ci-C4-alkoxy, -S(O) n -Ci-C4-alkyl, phenyl-Ci-C 3 -alkoxy or -NR 9 R 10 and said phenyl groups are optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy or Ci-C 3 -haloalkoxy, or
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one heteroatom selected from O, S, NH, NR a in which R a represents a Ci-C4-alkyl group;
  • R 4 represents hydroxy, Ci-C4-alkoxy or -NR 11 R 12 , or
  • R 2 and R 4 together represent *-C2-Cs-alkanediyl-X 1 -**, *-Ci-C2-alkanediyl-X 2 -Ci-C 3 - alkanediyl-** or *-Ci-C2-alkanediyl-X 2 -C2-C 3 -alkanediyl-X 1 -** to form a 5- to 9-membered ring, wherein * indicates the point of attachment of said group for R 2 and ** indicates the point of attachment of said group for R 4 ;
  • R 5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, C 3 -C6-cycloalkyl or -NR 9 R 10 ;
  • R 6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, C 3 -C6-cycloalkyl or -NR 9 R 10 ;
  • R 7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, C 3 -C6-cycloalkyl or -NR 9 R 10 ;
  • R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR a in which R a represents Ci-C 4 -alkyl or Ci-C 4 - alkoxycarbonyl;
  • R 11 and R 12 are the same or different and represent, independently from each other, hydrogen, Ci-C 4 -alkyl, C 2 -C 4 -hydroxyalkyl, Ci-C 4 -alkoxy-C 2 -C 4 -alkyl-, R 9 R 10 N-C 2 -C 4 -alkyl-, Cs-Ce- cycloalkyl, 4- to 7-membered heterocycloalkyl, said 4- to 7-membered heterocycloalkyl group is optionally substituted, one or two times, independently from each other, with hydroxy, oxo, halogen, Ci-C 4 -alkyl, Ci-C 4 -alkoxy, or -NR 9 R 10 , or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR a in which R a represents Ci-C 4 -alkyl
  • R 13 represents hydrogen, Ci-C 4 -alkyl, benzyl, 4-methoxybenzyl or tert-butoxycarbonyl;
  • R 14 represents hydrogen, Ci-C 4 -alkyl, benzyl or 4-methoxybenzyl
  • R 15 represents Ci-Cs-alkyl or Ci-Cs-haloalkyl
  • R 16 represents C 2 -Ce-hydroxyalkyl, Ci-C 4 -alkoxy-C 2 -Ce-alkyl-, or Cs-Ce-cycloalkyl;
  • R’ and R represent, independently from each other, Ci-Ce-alkyl, Ci-Ce-haloalkyl, or Cs-Ce- cycloalkyl;
  • X 1 represents O, S(O) m , or NR 13 ;
  • X 2 represents O, S(O) m , or NR 14 ; m represents 0, 1 or 2; n represents 0, 1 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon atom. Commonly, it is possible for the number of optional substituents, when present, to be 1 , 2 or 3.
  • halogen means a fluorine, chlorine, bromine or iodine, particularly a fluorine, chlorine or bromine atom.
  • Ci-Ce-alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1 -ethyl propyl,
  • said group has 1 , 2, 3 or 4 carbon atoms (“Ci-C4-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-Cs-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
  • Ci-Ce-haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “Ci-Ce-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
  • Ci-Ce-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1 ,3-difluoropropan-2-yl.
  • Ci-C4-hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “Ci-C4-alkyl” is defined supra, and in which 1 or 2 hydrogen atoms are replaced with a hydroxy group, e.g.
  • a hydroxymethyl 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-di- hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 -hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3-hydroxy-2- methyl-propyl, 2-hydroxy-2-methyl-propyl or 1-hydroxy-2-methyl-propyl group.
  • Ci-C4-alkoxy means a linear or branched, saturated, monovalent group of formula (Ci-C4-alkyl)-O-, which means methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or terf-butoxy.
  • Ci-C4-haloalkoxy means a linear or branched, saturated, monovalent Ci-C4-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • Said Ci-C4-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
  • Ci-Cs-alkanediyl means a bivalent saturated aliphatic radical regarded as derived from an Ci-Cs-alkane by removal of a hydrogen atom from each of the two terminal carbon atoms of the chain, e.g. a methylene, ethylene, propylene, trimethylene, tetramethylene or pentamethylene.
  • Cs-Ce-cycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms (“Cs-Ce-cycloalkyl”).
  • Said Cs-Ce-cycloalkyl group is a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • Said heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1 ,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 , 1 -dioxidothiolanyl,
  • heterospirocycloalkyl means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common ring carbon atom, which “heterospirocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
  • Said heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-,
  • bridged heterocycloalkyl means a bicyclic, saturated heterocycle with 7, 8, 9 or 10 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent, which “bridged heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo- [2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabi- cyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicy
  • heteroaryl means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11 , 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
  • Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl,
  • monocyclic heteroaryl means a monovalent, aromatic ring having 5 or 6 ring atoms (a “5- or 6-membered heteroaryl” group), which contains at least one ring heteroatom and optionally one or two further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
  • Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.
  • a 5-membered heteroaryl group such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl
  • heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g:. tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • any compound which contains a pyrido[1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one moiety for example can exist as a keto tautomer, or an enol tautomer, or even a mixture in any amount of the two tautomers, namely: keto tautomer enol tautomer pyrido[2 ,3-e][1 ,2,4]triazolo[1 , 5-c] pyrido[2 , 3-e][1 ,2 ,4]triazolo[1 ,5-c] pyrimidin-5(6H)-one pyrimidin-5-ol
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • Preferred isomers are those which produce the more desirable biological activity.
  • These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non- stoichiometric ratio.
  • polar solvents in particular water
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nico
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
  • the invention further includes all possible crystallized and polymorphic forms of the inventive compounds, whereby the polymorphs are existing either as a single polymorph form or are existing as a mixture of several polymorphs in all concentrations.
  • the compounds are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the Experimental Section.
  • a 1 represents CR 5 or N
  • a 2 represents CR 6 or N
  • a 3 represents CR 7 or N
  • a 4 represents CR 8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
  • R 1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce- cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl, -NR 9 R 10 or R 9 R 10 N-Ci-C4-alkyl;
  • R 2 represents hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl or Cs-Ce-cycloalkyl;
  • R 3 represents hydrogen, Ci-Ce-alkyl, phenyl or phenyl-Ci-Cs-alkyl, wherein said Ci-Ce-alkyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, Ci-C4-alkoxy, -S(O) n -Ci-C4-alkyl, phenyl- Ci-Cs-alkoxy or -NR 9 R 10 and said phenyl groups are optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-Cs-alkoxy or Ci-Cs-haloalkoxy, or R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one heteroatom selected from O, S, NH, NR a in which R a represents a
  • R 4 represents hydroxy, Ci-C4-alkoxy or -NR 11 R 12 , or
  • R 2 and R 4 together represent *-C2-Cs-alkanediyl-X 1 -**, *-Ci-C2-alkanediyl-X 2 -Ci-Cs- alkanediyl-** or *-Ci-C2-alkanediyl-X 2 -C2-C3-alkanediyl-X 1 -** to form a 5- to 9-membered ring, wherein * indicates the point of attachment of said group for R 2 and ** indicates the point of attachment of said group for R 4 ;
  • R 5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ;
  • R 6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ;
  • R 7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ;
  • R 8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ;
  • R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR a in which R a represents a Ci-C4-alkyl group;
  • R 11 and R 12 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl or Cs-Ce-cycloalkyl, wherein said Ci-C4-alkyl group is optionally substituted with hydroxy;
  • R 13 represents hydrogen, Ci-C4-alkyl, benzyl, 4-methoxybenzyl or tert-butoxycarbonyl;
  • R 14 represents hydrogen, Ci-C4-alkyl, benzyl or 4-methoxybenzyl
  • X 1 represents O or NR 13 ;
  • the present invention covers compounds of general formula (I), supra, in which:
  • a 1 represents CR 5 or N
  • a 2 represents CR 6 or N
  • a 3 represents CR 7 or N
  • a 4 represents CR 8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
  • R 1 represents phenyl or monocyclic heteroaryl, optionally substituted one to two times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce- cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl or -NR 9 R 10 ;
  • R 2 represents hydrogen or Ci-C4-alkyl
  • R 3 represents hydrogen, Ci-C4-alkyl, phenyl or phenyl-methyl, wherein said Ci-C4-alkyl group is optionally substituted once with hydroxy, methoxy, -S(O) n -methyl, phenyl-methoxy or -NR 9 R 10 and said phenyl groups are optionally substituted once with hydroxy, or
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one oxygen atom;
  • R 4 represents hydroxy, methoxy or -NR 11 R 12 , or
  • R 2 and R 4 together represent a group selected from: wherein * indicates the point of attachment of said group with the NH group in formula (I);
  • R 5 represents hydrogen, halogen, methyl or methoxy
  • R 6 represents hydrogen, halogen, methyl or methoxy
  • R 7 represents hydrogen, halogen, methyl or methoxy
  • R 8 represents hydrogen, halogen, methyl or methoxy
  • R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, methyl or tert-butoxycarbonyl
  • R 11 and R 12 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or C3-C4-cycloalkyl, wherein said Ci-Cs-alkyl group is optionally substituted with hydroxy;
  • R 13 represents hydrogen or methyl
  • X 3 represents CH2 or NH; n represents 0 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of general formula (la): in which:
  • a 1 represents CR 5 or N
  • a 2 represents CR 6 or N
  • a 3 represents CR 7 or N
  • a 4 represents CR 8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
  • R 1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce- cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl, -NR 9 R 10 or R 9 R 10 N-Ci-C4-alkyl;
  • R 5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ;
  • R 6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ;
  • R 7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ;
  • R 8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ;
  • R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR a in which R a represents a Ci-C4-alkyl group;
  • R 14 represents hydrogen, Ci-C4-alkyl, benzyl or 4-methoxybenzyl
  • X 3 represents CH 2 or NR 14 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of general formula (lb): in which:
  • a 1 represents CR 5 or N
  • a 2 represents CR 6 or N
  • a 3 represents CR 7 or N
  • a 4 represents CR 8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
  • R 1 represents phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, pyrazolyl or oxadiazolyl, optionally substituted once or twice, independently from each other, with fluoro, chloro, cyano, Ci-C4-alkyl, methoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, oxanyl or -N(CH 3 )2;
  • R 5 , R 6 , R 7 , and R 8 represent, independently from each other, hydrogen, fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl or cyclopropyl; their polymorphs, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of general formula (I): in which
  • a 1 represents CR 5 or N
  • a 2 represents CR 6 or N
  • a 3 represents CR 7 or N
  • a 4 represents CR 8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
  • R 1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, C1-C4- hydroxyalkyl, Ci-C4-alkoxy-Ci-C4-alkyl-, Cs-Ce-cycloalkyl, C 3 -C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl,
  • R 9 R 10 N-Ci-C 4 -alkyl-, Ci-C 3 -alkyl-S(O) m - or Ci-C 3 -alkyl-SO(NH)-;
  • R 2 represents hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl or Cs-Ce-cycloalkyl;
  • R 3 represents hydrogen, Ci-Ce-alkyl, phenyl or phenyl-Ci-C 3 -alkyl, wherein said Ci-Ce-alkyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, Ci-C4-alkoxy, -S(O) n -Ci-C4-alkyl, phenyl-Ci-Cs-alkoxy or -NR 9 R 10 and said phenyl groups are optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-Cs-alkoxy or Ci-Cs-haloalkoxy, or
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one heteroatom selected from O, S, NH, NR a in which R a represents a Ci-C4-alkyl group;
  • R 4 represents hydroxy, Ci-C4-alkoxy or -NR 11 R 12 , or
  • R 2 and R 4 together represent *-C2-Cs-alkanediyl-X 1 -**, *-Ci-C2-alkanediyl-X 2 -Ci-C3- alkanediyl-** or *-Ci-C2-alkanediyl-X 2 -C2-C3-alkanediyl-X 1 -** to form a 5- to 9-membered ring, wherein * indicates the point of attachment of said group for R 2 and ** indicates the point of attachment of said group for R 4 ;
  • R 5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ;
  • R 6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ;
  • R 7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ;
  • R 8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl, 1-R 15 -C3-C6-cycloalkyl, -CC>2-Ci-C4-alkyl, -CO-NR 9 R 10 or -NR 9 R 10 ;
  • R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR a in which R a represents a Ci-C4-alkyl group;
  • R 11 and R 12 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl or Cs-Ce-cycloalkyl, wherein said Ci-C4-alkyl group is optionally substituted with hydroxy;
  • R 13 represents hydrogen, Ci-C4-alkyl, benzyl, 4-methoxybenzyl or tert-butoxycarbonyl;
  • R 14 represents hydrogen, Ci-C4-alkyl, benzyl or 4-methoxybenzyl;
  • R 15 represents Ci-Cs-alkyl or Ci-Cs-haloalkyl;
  • X 1 represents O or NR 13 ;
  • the present invention covers methods of preparing compounds of general formula (I) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula (V):
  • the present invention covers methods of preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental Section herein.
  • the present invention covers intermediate compounds which are useful for the preparation of the compounds of general formula (I), supra.
  • the present invention covers the use of said intermediate compounds for the preparation of a compound of general formula (I) as defined supra.
  • the present invention covers the intermediate compounds which are disclosed in the Example Section of this text, infra.
  • a 1 represents CR 5 or N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • a 1 represents CR 5 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • a 1 represents N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • a 2 represents CR 6 or N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • a 2 represents CR 6 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • a 2 represents N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • a 3 represents CR 7 or N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • a 3 represents CR 7 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • a 3 represents N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • a 4 represents CR 8 or N, their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I), supra, in which:
  • a 4 represents CR 8 , their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • a 4 represents N, their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, C1-C4- haloalkoxy, Ci-C4-hydroxyalkyl, Ci-C4-alkoxy-Ci-C4-alkyl-, Cs-Ce-cycloalkyl, C 3 -Ce- cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl, -NR 9 R 10 , R 9 R 10 N-Ci-C 4 -alkyl-, Ci-C 3 -alkyl-S(O) m - or Ci-C 3 -alkyl-SO(NH)-; their polymorphs, enantiomeres, diastereomeres
  • R 1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, C 3 -Ce- cycloalkyl, C 3 -C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl, -NR 9 R 10 or R 9 R 10 N-Ci-C4-alkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I
  • R 1 represents phenyl or monocyclic heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce- cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl, -NR 9 R 10 or R 9 R 10 N-Ci-C4-alkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 1 represents phenyl or monocyclic heteroaryl, optionally substituted one to two times, independently from each other, with halogen, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl or -NR 9 R 10 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 1 represents phenyl or monocyclic heteroaryl, optionally substituted one to two times, independently from each other, with halogen, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 5- to 6-membered heterocycloalkyl or -NR 9 R 10 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 1 represents phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thiophenyl, pyrolyl, 1 ,2-thiazolyl, oxazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, oxadiazolyl, or imidazpyridinyl, optionally substituted once or twice, independently from each other, with fluoro, chloro, bromo, cyano, Ci-C4-alkyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopropyl methyl, oxanyl or -N(CH 3 ) 2 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates
  • R 1 represents phenyl, pyridinyl, pyridazinyl, furanyl, oxazolyl, pyrazolyl or oxadiazolyl, optionally substituted once or twice, independently from each other, with fluoro, chloro, Ci-C4-alkyl, methoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, oxanyl or -N(CH 3 ) 2 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 2 represents hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl or C 3 -C6-cycloalkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 2 represents hydrogen or Ci-C4-alkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 3 represents hydrogen, Ci-Ce-alkyl, phenyl or phenyl-Ci-C 3 -alkyl, wherein said Ci-Ce-alkyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, Ci-C4-alkoxy, -S(O) n -Ci-C4-alkyl, phenyl-Ci-C 3 -alkoxy or -NR 9 R 10 and said phenyl groups are optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-Cs-alkoxy or Ci-Cs-haloalkoxy; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these
  • R 3 represents hydrogen, Ci-C4-alkyl, phenyl or phenyl-methyl, wherein said Ci-C4-alkyl group is optionally substituted once with hydroxy, methoxy, -S(O) n -methyl, phenyl-methoxy or -NR 9 R 10 and said phenyl groups are optionally substituted once with hydroxy; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one heteroatom selected from O, S, NH, NR a in which R a represents a Ci-C4-alkyl group; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one oxygen atom; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 4 represents hydroxy, Ci-C4-alkoxy or -NR 11 R 12 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 4 represents hydroxy, methoxy or -NR 11 R 12 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 2 and R 4 together represent *-C2-Cs-alkanediyl-X 1 -**, *-Ci-C2-alkanediyl-X 2 -Ci-C3- alkanediyl-** or *-Ci-C2-alkanediyl-X 2 -C2-C3-alkanediyl-X 1 -** to form a 5- to 9-membered ring, wherein * indicates the point of attachment of said group for R 2 and ** indicates the point of attachment of said group for R 4 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 2 and R 4 together represent a group selected from: wherein * indicates the point of attachment of said group with the NH group in formula (I); their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I), supra, in which: R 5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy,
  • R 5 represents hydrogen, halogen or methyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 5 represents hydrogen; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 6 represents hydrogen, halogen or methyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 6 represents hydrogen; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 7 represents hydrogen, halogen, methyl or methoxy; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 7 represents hydrogen; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I), supra, in which: R 8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl, 1-R 15 -C3-C6-cycloalkyl, -CC>2-Ci-C4-alkyl, -CO-NR 9 R 10 or -NR 9 R 10 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR 9 R 10 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 8 represents hydrogen, halogen or methyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 8 represents hydrogen; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 5 , R 6 , R 7 , and R 8 represent, independently from each other, hydrogen, fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl or cyclopropyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I), supra, in which: R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR a in which R a represents Ci-C4-alkyl or C1-C4- alkoxycarbonyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR a in which R a represents a Ci-C4-alkyl group; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, methyl or tert-butoxycarbonyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 11 and R 12 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C2-C4-hydroxyalkyl, Ci-C4-alkoxy-C2-C4-alkyl-, R 9 R 10 N-C2-C4-alkyl-, Cs-Ce- cycloalkyl, 4- to 7-membered heterocycloalkyl, said 4- to 7-membered heterocycloalkyl group is optionally substituted, one or two times, independently from each other, with hydroxy, oxo, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR 9 R 10 , or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR a in which R a represents Ci-C4-alkyl or C1-C4- alkoxycarbonyl and
  • R 11 and R 12 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl or Cs-Ce-cycloalkyl, wherein said Ci-C4-alkyl group is optionally substituted with hydroxy; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 11 and R 12 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or C3-C4-cycloalkyl, wherein said Ci-Cs-alkyl group is optionally substituted with hydroxy; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 13 represents hydrogen, Ci-C4-alkyl, benzyl, 4-methoxybenzyl or tert-butoxycarbonyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • formula (I) in which:
  • R 13 represents hydrogen or methyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 14 represents hydrogen, Ci-C4-alkyl, benzyl or 4-methoxybenzyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 15 represents Ci-Cs-alkyl or Ci-Cs-haloalkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 15 represents methyl or trifluoromethyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • R 16 represents C2-Ce-hydroxyalkyl, Ci-C4-alkoxy-C2-Ce-alkyl-, or Cs-Ce-cycloalkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I), supra, in which: R’ and R” represent, independently from each other, Ci-Ce-alkyl, Ci-Ce-haloalkyl, or Cs-Ce- cycloalkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • X 1 represents O, S(O) m , or NR 13 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • X 1 represents O or NR 13 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • X 2 represents O, S(O) m , or NR 14 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • X 2 represents O or NR 14 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • X 3 represents CH2 or NR 14 ; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • X 3 represents CH2 or NH; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I), supra, in which: m represents 0, 1 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I), supra, in which: m represents 0 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I), supra, in which: m represents 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I), supra, in which: n represents 0, 1 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I), supra, in which: n represents 0 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers compounds of formula (I), supra, in which: n represents 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
  • the present invention covers combinations of two or more of the above mentioned embodiments under the heading “further embodiments of the first aspect of the present invention”.
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula (V), supra.
  • the compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • the compounds according to the invention of general formula (I) can be prepared according to the following scheme 1 .
  • the scheme and procedures described below illustrate synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in scheme 1 can be modified in various ways. The order of transformations exemplified in this scheme is therefore not intended to be limiting.
  • interconversion of any of the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , or R 8 can be achieved before and/or after the exemplified transformations.
  • Ci-Ce-alkyl or Cs-Ce-alkenyl and R b represents hydrogen or-C(O)O-R a .
  • Scheme 3 Route for the preparation of compounds of general formula (IV) in which R 1 , A 1 , A 2 , A 3 , and A 4 have the meaning as given for general formula (I), supra.
  • Scheme 4 describes another route for the preparation of compounds of formula (I).
  • Scheme 5 describes another route for the preparation of compounds of formula (I).
  • Scheme 5 Route for the preparation of compounds of general formula (I) in which R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , A 3 , and A 4 have the meaning as given for general formula (I), supra, R 4 represents -NR 11 R 12 as given for general formula (I), supra, and R represents hydrogen, Ci-Ce- alkyl or Cs-Ce-alkenyl.
  • Scheme 6 describes an alternative route to prepare intermediates (IV) and (IX) respectively.
  • x o
  • Scheme 6 Route for the preparation of compounds of general formula (IV) in which R 1 , A 1 , A 2 , A 3 , and A 4 have the meaning as given for general formula (I), supra and X represents oxygen or sulfur.
  • Scheme 7 describes an alternative route to prepare intermediates (IV) and (IX) respectively.
  • Scheme 8 describes an alternative route to prepare intermediates (IV).
  • Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted.
  • Compounds of the present invention have surprisingly been found to effectively inhibit AHR and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, in humans and animals.
  • disorders and conditions particularly suitable for treatment with an AHR inhibitor of the present invention are liquid and solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
  • breast cancers include, but are not limited to, triple negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to, small-cell and non- small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
  • Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
  • Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • ovarian cancer examples include, but are not limited to serous tumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa cell tumour, Sertoli-Leydig cell tumour and arrhenoblastoma.
  • cervical cancer examples include, but are not limited to squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumour, glassy cell carcinoma and villoglandular adenocarcinoma.
  • Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • esophageal cancer examples include, but are not limited to esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma,.
  • gastric cancer examples include, but are not limited to intestinal type and diffuse type gastric adenocarcinoma.
  • pancreatic cancer examples include, but are not limited to ductal adenocarcinoma, adenosquamous carcinomas and pancreatic endocrine tumours.
  • Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • kidney cancer include, but are not limited to renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms' tumour.
  • bladder cancer examples include, but are not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma and small cell carcinoma.
  • Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to, squamous cell cancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • treating or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
  • the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
  • chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to: yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, provide for the administration of lesser amounts of the administered chemotherapeutic agents, provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, provide for treating a broader spectrum of different cancer types in mammals, especially humans, provide for a higher response rate among treated patients, provide for a longer survival time among treated patients compared to standard chemotherapy treatments, provide a longer time for tumour progression, and/or yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
  • the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervention.
  • the compounds of general formula (I) of the present invention may be used to sensitize a cell to radiation, i.e. treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention.
  • the cell is treated with at least one compound of general formula (I) of the present invention.
  • the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy.
  • the present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death.
  • the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
  • a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of general formula (I) of the present invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell.
  • DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. cis platin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.
  • a cell is killed by treating the cell with at least one method to cause or induce DNA damage.
  • methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage.
  • a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
  • a compound of general formula (I) of the present invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell.
  • a compound of general formula (I) of the present invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell.
  • a compound of general formula (I) of the present invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.
  • the cell is in vitro. In another embodiment, the cell is in vivo.
  • the compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects.
  • the present invention also covers such pharmaceutical combinations.
  • the compounds of the present invention can be combined with: 1311-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, anti
  • compositions comprising a PD-1/-L1 axis antagonist and an AHR antagonist and methods of using the same are provided herein.
  • Data presented herein demonstrate that a combination of AHR inhibition and blockade of the PD-1/-L1 axis reduces the growth of tumor cells in more than an additive manner.
  • PD-1 along with its ligands PD-L1 and PD-L2, function as negative regulators of T cell activation.
  • AHR suppresses immune cell function while increasing cancer cell proliferation and motility.
  • PD-L1 is overexpressed in many cancers and overexpression of PD-1 often occurs concomitantly in tumor infiltrating T cells.
  • compositions comprising a PD-1/-L1 axis antagonist and an AHR antagonist are surprisingly effective in enhancing an immune response and in the treatment of cancer.
  • inventive compounds can also be used as a therapeutic in a variety of other disorders wherein AHR is involved such as, cardiovascular and lung diseases.
  • the compounds according to the invention are suitable for the treatment and/or prophylaxis in particular of cardiovascular, inflammatory and fibrotic disorders and of renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure.
  • the compounds according to the invention can be used in medicaments for the treatment and/or prophylaxis of cardiovascular, inflammatory and fibrotic disorders, renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure.
  • renal insufficiency comprises both acute and chronic manifestations of renal insufficiency, and also underlying or related renal disorders such as diabetic and non-diabetic nephropathies, hypertensive nephropathies, ischaemic renal disorders, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, renal stenoses, glomerulopathies, glomerulonephritis (such as, for example, primary glomerulonephritides; minimal change glomerulonephritis (lipoidnephrosis); membranous glomerulonephritis; focal segmental glomerulosclerosis (FSGS); membrane-proliferative glomerulonephritis; crescentic glomerulonephritis; mesangioproliferative glomerulonephritis (IgA nephritis, Berger's disease); post-infectious glomerulonephritis; secondary
  • the present invention also comprises the use of the compounds according to the invention for the treatment and/or prophylaxis of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uremia, anemia, electrolyte disturbances (for example hypercalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency for example pulmonary oedema, heart failure, uremia, anemia, electrolyte disturbances (for example hypercalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.
  • the present invention also comprises the use of the compounds according to the invention for the treatment and/or prevention of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency for example pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism.
  • the compounds according to the invention are further suitable for the treatment and/or prevention of polycystic kidney disease (PCKD) and of the syndrome of inappropriate ADH secretion (SI ADH).
  • PCKD polycystic kidney disease
  • SI ADH syndrome of inappropriate ADH secretion
  • the compounds according to the invention are also suitable for the treatment and/or prophylaxis of metabolic syndrome, hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, atrial and ventricular arrhythmias and impaired conduction, for example atrioventricular blocks degrees l-lll (AB block l-lll), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV-nodal re-entry tachycardia, Wolff- Parkinson- White syndrome, of acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis,
  • the compounds according to the invention are also suitable for treatment and/or prophylaxis of asthmatic disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH) including left-heart disease, HIV, sickle cell anaemia, thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonary fibrosis-associated pulmonary hypertension, chronic-obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1 -antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysema induced by cigarette smoke) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic-obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • AATD alpha-1 -antitrypsin deficiency
  • the compounds described in the present invention are also active compounds for control of central nervous system disorders characterized by disturbances of the NO/cGMP system. They are suitable in particular for improving perception, concentration, learning or memory after cognitive impairments like those occurring in particular in association with situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post stroke dementia), post-traumatic craniocerebral trauma, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer’s disease, Lewy body dementia, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson’s disease, progressive dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff’s psychosis.
  • the compounds according to the invention are also suitable for treatment and/or prophylaxis of central nervous system disorders such as states of anxiety, tension and depression, CNS-related sexual dysfunctions and sleep disturbances, and for controlling pathological disturbances of the intake of food, stimulants and addictive substances.
  • the compounds according to the invention are furthermore also suitable for controlling cerebral blood flow and thus represent effective agents for controlling migraines. They are also suitable for the prophylaxis and control of sequelae of cerebral infarction (cerebral apoplexy) such as stroke, cerebral ischaemia and craniocerebral trauma.
  • the compounds according to the invention can likewise be used for controlling states of pain and tinnitus.
  • the compounds according to the invention are also suitable for treatment and/or prophylaxis of fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders.
  • fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis).
  • the compounds according to the invention are also suitable for controlling postoperative scarring, for example as a result of glaucoma operations.
  • the compounds according to the invention can also be used cosmetically for ageing and keratinized skin.
  • the compounds according to the invention are suitable for treatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis, glaucoma and gastroparesis.
  • the present invention further provides for the use of the compounds according to the invention for treatment and/or prophylaxis of disorders, especially the disorders mentioned above.
  • the present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld-Jakob.
  • the present invention further provides a method for treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention.
  • the present invention further provides a method for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropathies, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld- Jakob.
  • the inventive compounds can also be used to treat or to prevent uterine fibroids (uterine leiomyoma or uterine myoma) in women.
  • Uterine fibroids are benign tumors of the myometrium, the smooth muscle layer of the uterus. Uterine fibroids grow slowly during a women's life, and their growth is dependent on the female sexual hormones estradiol and progesterone [Kawaguchi K et al. Immunohistochemical analysis of oestrogen receptors, progesterone receptors and Ki-67 in leiomyoma and myometrium during the menstrual cycle and pregnancy Virchows Arch A Pathol Anat Histopathol. 1991 ;419(4):309- 15.], therefore the highest prevalence of uterine fibroids with approx.
  • TDO2 Tryptophan 2,3- dioxygenase, being highly upregulated [Tsibris JC et al. Insights from gene arrays on the development and growth regulation of uterine leiomyomata. Fertil Steril. 2002 Jul;78(1): 114-21.]. TDO2 metabolizes the substrate L-Tryptophan to L-Kynurenine, which can be further metabolized to kynurenic acid.
  • L-Kynurenine and Kynurenic acid are physiological ligands and activators for the arylhydrocarbon receptor AHR [Opitz CA et al. An endogenous tumourpromoting ligand of the human aryl hydrocarbon receptor Nature. 2011 Oct 5;478(7368):197- 203], L-Kynurenine controls at least two physiological processes which are dysregulated in uterine fibroids.
  • L-Kynurenine synthesized by an upregulation of IDO (lndoleamine-2,3-dyoxygenase) or TDO2, and acting via the AHR receptor, suppresses the immune system and thus prevents immune cells from recognizing and clearing the tumor cells [Munn DH Blocking IDO activity to enhance anti-tumor immunity. Front Biosci (Elite Ed). 2012 Jan 1 ;4:734-45], Furthermore, an upregulation of L-Kynurenine leads to a vasodilation of vessels, and thus can directly increase blood loss and bleeding [Wang Y et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation Nature Medicine 16, 279-285 (2010)].
  • Compounds of the present invention can be utilized to inhibit, block, reduce or decrease AHR activation by exogenous and/or endogenous ligands for the reduction of tumour growth and the modulation of dysregulated immune responses e.g. to block immunosuppression and increase immune cell activation and infiltration in the context of cancer and cancer immunotherapy;
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.
  • the present invention also provides methods of treating a variety of other disorders wherein AHR is involved such as, but not limited to, inflammation, vaccination for infection & cancer, viral infections, obesity and diet-induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids.
  • treating or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as liquid and solid tumours.
  • the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling.
  • the pharmaceutical activity of the compounds according to the invention can be explained by their activity as AHR inhibitors.
  • the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, particularly liquid and solid tumours.
  • the present invention covers the use of a compound of formula (I), described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, particularly liquid and solid tumours.
  • the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, particularly liquid and solid tumours.
  • the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, particularly liquid and solid tumours.
  • a pharmaceutical composition preferably a medicament
  • the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, particularly liquid and solid tumours, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
  • a compound of general formula (I) as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
  • the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • a compound of general formula (I) as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • excipients in particular one or more pharmaceutically acceptable excipient(s).
  • Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.
  • the present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at
  • the compounds according to the invention can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • the compounds according to the invention for oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal
  • compositions according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia, fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)), ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chainlength triglycerides fatty oils, liquid polyethylene glycols, paraffins), surfactants, emulsifier
  • the present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signalinggeneric name disorders, particularly liquid and solid tumours.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity.
  • a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit.
  • a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of- parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • drug holidays in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
  • the multiplicities are stated according to the signal form which appears in the spectrum, NMR-spectroscopic effects of a higher order were not taken into consideration.
  • Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.
  • Table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.
  • HATU (7-aza-1H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
  • XPhos Pd G1 [2-(2-aminoethyl)phenyl](chloro)palladium-dicyclohexyl(2',4',6'- triisopropyl[biphenyl]-2-yl)phosphine (1 :1)
  • XPhos Pd G4 methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-iso-propy-
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g.
  • Methyl 5-chlorothiophene-3-carboxylate (800 mg, 4.53 mmol, CAS [36157-43-4], commercially available at e.g. ABCR) was solubilised in ethanol (20 mL), hydrazine hydrate (1.1 mL, 23 mmol) was added and the mixture was stirred at reflux temperature for 20h. After cooling to room temperature the mixture was poured into icewater, stirred, and the formed solid was obtained via filtration. After drying 410 mg (100 % purity, 51 % yield) of the target compound was obtained, which was used without further purification.
  • the mixture was treated with water and ethyl acetate and extracted three times with ethyl acetate.
  • the organic phase was dried by filtering through a silicone filter and concentrated.
  • the crudematerial was purified by flash chromatography to afford 2.71 g (100 % purity) in a quantitative yield of the target compound.
  • Ethyl (2-cyanopyridin-3-yl)carbamate (436 mg, 2.28 mmol; CAS [54-85-3], commercially available, e.g. ABCR) and 4-cyanobenzohydrazide (441 mg, 2.74 mmol) were stirred in DMF (7.4 mL) at 120°C for 6h. Then acetic acid (7.4 mL) was added at 100°C and the reaction mixture was stirred for 24h at this temperature. The reaction mixture was cooled to room temperature and added to water. After stirring for 10 minutes filtered, washed with water and the solid was dried under reduced pressure at 60°C to give 599 mg (92 % purity, 84 % yield) of the target compound, which was used without further purification.
  • Step 1
  • the suspension was diluted with ethyl acetate, filtered and the solid was stirred in methanol/ dichloromethane, basified with triethylamine and evaporated. The resulting solid was washed, filtered with ethyl acetate and acetonitril/water (95:5) and dried under reduced pressure at 60°C to give 19.2 mg (90 % purity, 39 % yield) of the target compound.
  • the suspension was diluted with ethyl acetate, filtered and the solid was stirred in methanol/ dichloromethane, basified with triethylamine and evaporated to give 49.5 mg (96 % purity, 55 % yield) of the target compound.
  • the average value also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested.
  • the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
  • Transactivation assays in human cell line (in vitro assays 1 and 2) Transactivation assays were carried out in U87 MG glioblastoma cells (ATCC #HTB-14) endogenously expressing AHR. In addition the cells were stably transfected with an AHR inducible firefly luciferase reporter gene construct that carried AHR-binding sites (DRE) in its promoter and a renilla reporter gene construct with constitutively active promoter. Kynurenic acid is an endogenous AHR activating ligand and was used to prestimulate test cells prior to testing the antagonistic properties of compounds.
  • DRE AHR-binding sites
  • Firefly luciferase and Renilla activity was determined by the DualGlo Luciferase Assay System (Promega, #2920). Renilla activity was used to assess toxic effects of compounds.
  • Cells in medium were grown for 20 hours in absence (negative control) or presence of increasing concentrations of test compounds (typical dilutions: 72 pmol/L, 0.25 nmol/L, 0.89 nmol/L; 3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470 nmol/L, 1.6 pmol/L, 5.7 pmol/L and 20 pmol/L in duplicates).
  • test compounds typically dilutions: 72 pmol/L, 0.25 nmol/L, 0.89 nmol/L; 3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470 nmol/L, 1.6 pmol/L, 5.7 pmol/L and 20 pmol/L in duplicates.
  • test compounds typically dilutions: 72 pmol/L, 0.25 nmol/L, 0.89 nmol/L; 3.1 nmol
  • Firefly luciferase activity was determined by the SteadyGlo Luciferase Assay System (Promega, #E2520).
  • Transactivation assays were carried out in Hepa 1c1c7 cells (ATCC #CRL-2026) endogenously expressing AHR.
  • the cells were stably transfected with an AHR inducible firefly luciferase reporter gene construct that carried AHR-binding sites (DRE) in its promoter.
  • DRE AHR-binding sites
  • Kynurenic acid is an endogenous AHR activating ligand and was used to prestimulate test cells prior to testing the antagonistic properties of compounds.
  • In vitro assay 3 Antagonism in mouse cell line Cells in medium (tryptophan free RPMI (PAN-Biotech #P04-17598), 1 % FCS (Biochrome Superior #S0615), 1 x Penicillin/Streptomycin (Sigma P0781)) supplemented with 200 pM kynurenic acid (Sigma #K3375) were grown for 20 hours in absence (negative control) or presence of increasing concentrations of test compounds (typical dilutions: 72 pmol/L, 0.25 nmol/L, 0.89 nmol/L; 3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470 nmol/L, 1.6 pmol/L, 5.7 pmol/L and 20 pmol/L in duplicates). As positive inhibition control cells without addition of kynurenic acid were incubated. Normalization was done by positive and negative controls.
  • Firefly luciferase activity was determined by the SteadyGlo Luciferase Assay System (Promega, #E2550).
  • Cells in medium were grown for 20 hours in absence (negative control) or presence of increasing concentrations of test compounds (typical dilutions: 72 pmol/L, 0.25 nmol/L, 0.89 nmol/L; 3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470 nmol/L, 1.6 pmol/L, 5.7 pmol/L and 20 pmol/L in duplicates).
  • test compounds typically dilutions: 72 pmol/L, 0.25 nmol/L, 0.89 nmol/L; 3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470 nmol/L, 1.6 pmol/L, 5.7 pmol/L and 20 pmol/L in duplicates.
  • positive activation control cells were incubated with 400 pM kynurenic acid. Normalization was done by positive and negative controls.
  • Firefly luciferase activity was determined by the SteadyGlo Luciferase Assay System (Promega, #2520).

Abstract

The present invention covers pyrido[1,2,4]triazolo[1,5-c]pyrimidin-5- amine compounds of general formula (I): in which R1, R2, R3, R4, A1, A2, A3 and A4 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant aryl hydrocarbon receptor (AHR) signaling as a sole agent or in combination with other active ingredients.

Description

PYRIDO[1,2,4]TRIAZOLO[1,5-C]PYRIMIDIN-5-AMINES
The present invention covers pyrido[1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-amine compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses, as a sole agent or in combination with other active ingredients.
BACKGROUND
The AHR (Aryl Hydrocarbon Receptor) is a ligand-activated transcription factor, belonging to the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family, and is located in the cytosol. Upon ligand binding, the AHR translocates to the nucleus where it heterodimerises with ARNT (AHR Nuclear Translocator) upon which it interacts with DREs (Dioxin Response Elements) of AHR-responsive genes to regulate their transcription. The AHR is best known for binding to environmental toxins and inducing the metabolic machinery, such as cytochrome P 450 enzymes (eg. CYP1A1 , CYP1A2 and CYP1 B1), required for their elimination (Reyes et al., Science, 1992, 256(5060): 1193-5). Activation of AHR by xenobiotics has demonstrated its role in numerous cellular processes such as embryogenesis, tumourigenesis and inflammation.
AHR is expressed in many cells of the immune system, including dendritic cells (DCs), macrophages, T cells and NK cells, and plays an important role in immunoregulation (Nguyen et al., Front Immunol, 2014, 5:551). The classic exogenous AHR ligands TCDD and 3- methylcholanthrene, for example, are known to induce profound immunosuppression, promote carcinogenesis and induce tumour growth (Gramatzki et al., Oncogene, 2009, 28(28) :2593-605; Bui et al., Oncogene, 2009, 28(41 ):3642-51 ; Esser et al., Trends Immunol, 2009, 30:447-454). In the context of immunosuppression, AHR activation promotes regulatory T cell generation, inhibits Th1 and Th 17 differentiation, directly and indirectly, and decreases the activation and maturation of DCs (Wang et al., Clin Exp Immunol, 2014, 177(2):521-30; Mezrich et al., J Immunol, 2010, 185(6): 3190-8; Wei et al., Lab Invest, 2014, 94(5):528-35; Nguyen et al., PNAS, 2010, 107(46): 19961-6). AHR activation modulates the innate immune response and constitutive AHR expression has been shown to negatively regulate the type-l interferon response to viral infection (Yamada et al., Nat Immunol, 2016). Additionally, mice with a constitutively active AHR spontaneously develop tumours (Andersson et al., PNAS, 2002, 99(15): 9990-5).
In addition to xenobiotics, the AHR can also bind metabolic products of tryptophan degradation. Tryptophan metabolites, such as kynurenine and kynurenic acid, are endogenous AHR ligands that activate the AHR under physiological conditions (DiNatale et al., Toxicol Sci, 2010, 115(1):89-97; Mezrich et al., J Immunol, 2010, 185(6):3190-8; Opitz et al., Nature, 2011 , 478(7368): 197-203). Other endogenous ligands are known to bind the AHR although their physiological roles are currently unknown (Nguyen & Bradfield, Chem Res Toxicol, 2008, 21 (1):102-116).
The immunosuppressive properties of kynurenine and tryptophan degradation are well described and are implicated in cancer-associated immunosuppression. The enzymes indoleamine-2,3-dioxygenases 1 and 2 (IDO1/IDO2) as well as tryptophan-2,3-dioxygenase 2 (TDO2) are responsible for catalysing the first and rate-limiting step of tryptophan metabolism. IDO1/2-mediated degradation of tryptophan in tumours and tumour-draining lymph nodes reduces anti-tumour immune responses and inhibition of IDO can suppress tumour formation in animal models (Uyttenhove et al., Nat Med, 2003, 9(10):1269-74 ; Liu et al., Blood, 2005, 115(17): 3520-30; Muller et al., Nat Med, 11 (3):312-9; Metz, Cancer Res, 2007, 67(15):7082-7). TDO2 is also strongly expressed in cancer and can lead to the production of immunosuppressive kynurenine. In glioma, activation of the AHR by kynurenine, downstream of TDO-mediated tryptophan degradation, enhances tumour growth as a consequence of inhibiting anti-tumour immune responses as well as directly promoting tumour cell survival and motility (Opitz et al., Nature, 2011 , 478(7368): 197-203). AHR ligands generated by tumour cells therefore act in both an autocrine and paracrine fashion on tumour cells and lymphocytes, respectively, to promote tumour growth.
The present invention covers pyrido[1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-amine compounds of general formula (I) which inhibit the AHR.
State of the Art
WO 2010/059401 relates to compounds and compositions for expanding the number of CD34+ cells for transplantation. In particular, WO 2010/059401 relates inter alia to heterocyclic compounds capable of down-regulating the activity and/or expression of AHR.
WO 2012/015914 relates to compositions and methods for modulating AHR activity. In particular, WO 2012/015914 relates inter alia to heterocyclic compounds that modulate AHR activity for use in therapeutic compositions.
WO 2007040565 relates to the use of [1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-amine derivatives as adenosine receptor antagonists.
WO 2006/132275 (EP 1902716 A1) relates to an agent for preventing and/or treating movement disorder.
WO 1995/003806 relates to a remedy for Parkinson’s disease.
WO 1988/002370 relates to e-fused-[1 ,2,4]triazolo[1 ,5-c]pyrimidines.
However, the state of the art does not describe the pyrido[1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-amine compounds of general formula (I) of the present invention as described and defined herein. It has now been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.
In particular, the compounds of the present invention have surprisingly been found to effectively inhibit AHR for which data are given in biological experimental section and may therefore be used for the treatment or prophylaxis of cancer or other conditions where exogenous and endogenous AHR ligands induce dysregulated immune responses, uncontrolled cell growth, proliferation and/or survival of tumour cells, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival of tumour cells, immunosuppression in the context of cancer inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival of tumour cells, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by AHR, such as, for example, liquid and solid tumours, and/or metastases thereof, e.g. head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours including colon, colorectal and pancreatic tumours, liver tumours, endocrine tumours, mammary and other gynecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
DESCRIPTION of the INVENTION
In accordance with a first aspect, the present invention covers compounds of general formula (I):
Figure imgf000004_0001
in which
A1 represents CR5 or N;
A2 represents CR6 or N;
A3 represents CR7 or N; A4 represents CR8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
R1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, C1-C4- hydroxyalkyl, Ci-C4-alkoxy-Ci-C4-alkyl-, Cs-Ce-cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl,
-NR9R10, R9R10N-Ci-C4-alkyl-, Ci-C3-alkyl-S(O)m- or Ci-C3-alkyl-SO(NH)-;
R2 represents hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl or Cs-Ce-cycloalkyl;
R3 represents hydrogen, Ci-Ce-alkyl, phenyl or phenyl-Ci-C3-alkyl, wherein said Ci-Ce-alkyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, Ci-C4-alkoxy, -S(O)n-Ci-C4-alkyl, phenyl-Ci-C3-alkoxy or -NR9R10 and said phenyl groups are optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy or Ci-C3-haloalkoxy, or
R2 and R3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C4-alkyl group;
R4 represents hydroxy, Ci-C4-alkoxy or -NR11R12, or
R2 and R4 together represent *-C2-Cs-alkanediyl-X1-**, *-Ci-C2-alkanediyl-X2-Ci-C3- alkanediyl-** or *-Ci-C2-alkanediyl-X2-C2-C3-alkanediyl-X1-** to form a 5- to 9-membered ring, wherein * indicates the point of attachment of said group for R2 and ** indicates the point of attachment of said group for R4;
R5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, C3-C6-cycloalkyl or -NR9R10;
R6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, C3-C6-cycloalkyl or -NR9R10;
R7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, C3-C6-cycloalkyl or -NR9R10;
R8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Qj-Ce-cycloalkyl, 1-R15-C3-C6-cycloalkyl, -CC>2-Ci-C4-alkyl, -CO-NR9R10, -NR9R10, Ci-C4-hydroxyalkyl, Ci-C4-alkoxy-Ci-C4-alkyl-, Ci-C4-alkyl-S-, Ci-C4-alkyl-S-Ci-C4-alkyl-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, -S(=O)(=NH)R’, 4- to 6-membered heterocycloalkyl, or -OR16;
R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents Ci-C4-alkyl or Ci-C4- alkoxycarbonyl;
R11 and R12 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C2-C4-hydroxyalkyl, Ci-C4-alkoxy-C2-C4-alkyl-, R9R10N-C2-C4-alkyl-, Cs-Ce- cycloalkyl, 4- to 7-membered heterocycloalkyl, said 4- to 7-membered heterocycloalkyl group is optionally substituted, one or two times, independently from each other, with hydroxy, oxo, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents Ci-C4-alkyl or Ci-C4- alkoxycarbonyl and is optionally substituted, one or two times, independently from each other, with hydroxy, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10, or together with the nitrogen atom to which they are attached form a heterospirocycloalkyl group, which is optionally substituted, one or two times, independently from each other, with hydroxy, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10, or together with the nitrogen atom to which they are attached form a bridged heterocycloalkyl group, which is optionally substituted, one or two times, independently from each other, with hydroxy, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10;
R13 represents hydrogen, Ci-C4-alkyl, benzyl, 4-methoxybenzyl or tert-butoxycarbonyl;
R14 represents hydrogen, Ci-C4-alkyl, benzyl or 4-methoxybenzyl;
R15 represents Ci-Cs-alkyl or Ci-Cs-haloalkyl;
R16 represents C2-Ce-hydroxyalkyl, Ci-C4-alkoxy-C2-Ce-alkyl-, or Cs-Ce-cycloalkyl;
R’ and R” represent, independently from each other, Ci-Ce-alkyl, Ci-Ce-haloalkyl, or Cs-Ce- cycloalkyl;
X1 represents O, S(O)m, or NR13;
X2 represents O, S(O)m, or NR14; m represents 0, 1 or 2; n represents 0, 1 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
Further, it covers their use in combination with other anti cancer medications such as immunotherapeutics, targeted anti cancer agents or chemotherapy.
DEFINITIONS
The term “substituted” means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
The term “optionally substituted” means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon atom. Commonly, it is possible for the number of optional substituents, when present, to be 1 , 2 or 3.
The term “comprising” when used in the specification includes “consisting of”.
If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text.
The terms as mentioned in the present text have the following meanings:
The term “halogen” means a fluorine, chlorine, bromine or iodine, particularly a fluorine, chlorine or bromine atom.
The term “Ci-Ce-alkyl” means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1 -ethyl propyl,
1.2-dimethylpropyl, neo-pentyl, 1 , 1-dimethylpropyl, hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1 , 1-dimethylbutyl, 2,2-dimethylbutyl,
3.3-dimethylbutyl, 2,3-dimethylbutyl, 1 ,2-dimethylbutyl or 1 ,3-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1 , 2, 3 or 4 carbon atoms (“Ci-C4-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-Cs-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
The term “Ci-Ce-haloalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term “Ci-Ce-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said Ci-Ce-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1 ,3-difluoropropan-2-yl.
The term “Ci-C4-hydroxyalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term “Ci-C4-alkyl” is defined supra, and in which 1 or 2 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-di- hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 -hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3-hydroxy-2- methyl-propyl, 2-hydroxy-2-methyl-propyl or 1-hydroxy-2-methyl-propyl group.
The term “Ci-C4-alkoxy” means a linear or branched, saturated, monovalent group of formula (Ci-C4-alkyl)-O-, which means methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or terf-butoxy.
The term “Ci-C4-haloalkoxy” means a linear or branched, saturated, monovalent Ci-C4-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said Ci-C4-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
2.2.2-trifluoroethoxy or pentafluoroethoxy.
The term “Ci-Cs-alkanediyl” means a bivalent saturated aliphatic radical regarded as derived from an Ci-Cs-alkane by removal of a hydrogen atom from each of the two terminal carbon atoms of the chain, e.g. a methylene, ethylene, propylene, trimethylene, tetramethylene or pentamethylene.
The term “Cs-Ce-cycloalkyl” means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms (“Cs-Ce-cycloalkyl”). Said Cs-Ce-cycloalkyl group is a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term “4- to 7-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 4, 5, 6 or 7 ring atoms in total, which contains one or two identical or different heteroatomcontaining groups selected from the group consisting of -NRb-, -O-, -S-, -SO-, -SO2-, -SO2-NR13-, -SO(=NRb)-, wherein Rb means a hydrogen atom or a Ci-Cs-alkyl group. It being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
Said heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1 ,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 , 1 -dioxidothiolanyl,
1.2-oxazolidinyl, 1 ,3-oxazolidinyl or 1 ,3-thiazolidinyl, tetrahydrothiophene 1-oxide, 1 ,2- thiazolidine 1-oxide, 1 ,3-thiazolidine 1-oxide, tetrahydrothiophene 1 ,1-dioxide, 1 ,2-thiazolidine 1 ,1-dioxide, 1 ,3-thiazolidine 1 ,1-dioxide, 1 ,2,5-thiadiazolidine 1 ,1-dioxide, 1 ,2,4-thiadiazolidine 1 ,1-dioxide, 1 ,2,3-thiadiazolidine 1 ,1-dioxide, tetrahydro-1 H-1A4-thiophen-1 -imine 1-oxide, 1 A4,2-thiazolidin-1-imine 1-oxide or 1 A4,3-thiazolidin-1 -imine 1-oxide, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl or 1 ,2-oxazinanyl, tetrahydro- 2H-thiopyran 1-oxide, 1 ,2-thiazinane 1-oxide, 1 ,3-thiazinane 1-oxide, thiomorpholine 1-oxide, tetrahydro-2 H-thiopyran 1 ,1-dioxide, 1 ,2-thiazinane 1 ,1-dioxide, 1 ,3-thiazinane 1 ,1-dioxide, thiomorpholine 1 ,1-dioxide, 1 ,2,6-thiadiazinane 1 ,1-dioxide, 1 ,2,5-thiadiazinane 1 ,1-dioxide, 1 ,2,4-thiadiazinane 1 ,1-dioxide, 1 ,2,3-thiadiazinane 1 ,1-dioxide, hexahydro-1 A4-thiopyran-1- imine 1-oxide, 1A4,2-thiazinan-1-imine 1-oxide, 1A4,3-thiazinan-1-imine 1-oxide or 1A4- thiomorpholin-1-imine 1-oxide, or a 7-membered ring, such as azepanyl, 1 ,4-diazepanyl, 1 ,4- oxazepanyl, 1 ,4-thiazepanyl, or 1-imino-1A6,4-thiazepane-1-oxid, for example.
The term “heterospirocycloalkyl” means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common ring carbon atom, which “heterospirocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
Said heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[2.6]-, spiro[3.5]-, spiro[3.6]-, spiro[4.5]- and spiro[4.6]-.
The term “bridged heterocycloalkyl” means a bicyclic, saturated heterocycle with 7, 8, 9 or 10 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent, which “bridged heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo- [2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabi- cyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo[3.3.1]- nonyl, azabicyclo[4.2.1]nonyl, diazabicyclo[4.2.1]nonyl, oxazabicyclo[4.2.1]nonyl, thiaza- bicyclo[4.2.1]nonyl, azabicyclo[3.3.2]decyl, diazabicyclo[3.3.2]decyl, oxazabicyclo[3.3.2]decyl, thiazabicyclo[3.3.2]decyl or azabicyclo[4.2.2]decyl.
The term “heteroaryl” means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11 , 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10- membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl.
The term “monocyclic heteroaryl” means a monovalent, aromatic ring having 5 or 6 ring atoms (a “5- or 6-membered heteroaryl” group), which contains at least one ring heteroatom and optionally one or two further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.
In general, and unless otherwise mentioned, the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g:. tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
Further, it is possible for compounds of the present invention to exist as tautomers. For example, any compound which contains a pyrido[1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one moiety for example can exist as a keto tautomer, or an enol tautomer, or even a mixture in any amount of the two tautomers, namely:
Figure imgf000011_0001
keto tautomer enol tautomer pyrido[2 ,3-e][1 ,2,4]triazolo[1 , 5-c] pyrido[2 , 3-e][1 ,2 ,4]triazolo[1 ,5-c] pyrimidin-5(6H)-one pyrimidin-5-ol
The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
Preferred isomers are those which produce the more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non- stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.
Further, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
The term “pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, 3- phenylpropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example.
Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, /V-methylmorpholine, arginine, lysine, 1 ,2-ethylenediamine, /V-methylpiperidine, /V-methyl-glucamine, A/,A/-dimethyl-glucamine, /V-ethyl-glucamine, 1 ,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1 ,3- propanediol, 3-amino-1 ,2-propanediol, 4-amino-1 ,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, A/-benzyl-A/,A/,A/- trimethylammonium, choline or benzalkonium.
Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods. The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown. Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCI", "x CF3COOH", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified.
This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term “prodrugs” here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
The invention further includes all possible crystallized and polymorphic forms of the inventive compounds, whereby the polymorphs are existing either as a single polymorph form or are existing as a mixture of several polymorphs in all concentrations.
The compounds are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the Experimental Section.
In accordance with a second embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
A1 represents CR5 or N;
A2 represents CR6 or N;
A3 represents CR7 or N;
A4 represents CR8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
R1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce- cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl, -NR9R10 or R9R10N-Ci-C4-alkyl;
R2 represents hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl or Cs-Ce-cycloalkyl;
R3 represents hydrogen, Ci-Ce-alkyl, phenyl or phenyl-Ci-Cs-alkyl, wherein said Ci-Ce-alkyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, Ci-C4-alkoxy, -S(O)n-Ci-C4-alkyl, phenyl- Ci-Cs-alkoxy or -NR9R10 and said phenyl groups are optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-Cs-alkoxy or Ci-Cs-haloalkoxy, or R2 and R3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C4-alkyl group;
R4 represents hydroxy, Ci-C4-alkoxy or -NR11R12, or
R2 and R4 together represent *-C2-Cs-alkanediyl-X1-**, *-Ci-C2-alkanediyl-X2-Ci-Cs- alkanediyl-** or *-Ci-C2-alkanediyl-X2-C2-C3-alkanediyl-X1-** to form a 5- to 9-membered ring, wherein * indicates the point of attachment of said group for R2 and ** indicates the point of attachment of said group for R4;
R5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C4-alkyl group;
R11 and R12 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl or Cs-Ce-cycloalkyl, wherein said Ci-C4-alkyl group is optionally substituted with hydroxy;
R13 represents hydrogen, Ci-C4-alkyl, benzyl, 4-methoxybenzyl or tert-butoxycarbonyl;
R14 represents hydrogen, Ci-C4-alkyl, benzyl or 4-methoxybenzyl;
X1 represents O or NR13;
X2 represents O or NR14; n represents 0, 1 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same. In accordance with a third embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
A1 represents CR5 or N;
A2 represents CR6 or N;
A3 represents CR7 or N;
A4 represents CR8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
R1 represents phenyl or monocyclic heteroaryl, optionally substituted one to two times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce- cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl or -NR9R10;
R2 represents hydrogen or Ci-C4-alkyl;
R3 represents hydrogen, Ci-C4-alkyl, phenyl or phenyl-methyl, wherein said Ci-C4-alkyl group is optionally substituted once with hydroxy, methoxy, -S(O)n-methyl, phenyl-methoxy or -NR9R10and said phenyl groups are optionally substituted once with hydroxy, or
R2 and R3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one oxygen atom;
R4 represents hydroxy, methoxy or -NR11R12, or
R2 and R4 together represent a group selected from:
Figure imgf000016_0001
wherein * indicates the point of attachment of said group with the NH group in formula (I);
R5 represents hydrogen, halogen, methyl or methoxy;
R6 represents hydrogen, halogen, methyl or methoxy;
R7 represents hydrogen, halogen, methyl or methoxy;
R8 represents hydrogen, halogen, methyl or methoxy; R9 and R10 are the same or different and represent, independently from each other, hydrogen, methyl or tert-butoxycarbonyl;
R11 and R12 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or C3-C4-cycloalkyl, wherein said Ci-Cs-alkyl group is optionally substituted with hydroxy;
R13 represents hydrogen or methyl;
X3 represents CH2 or NH; n represents 0 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In accordance with a forth embodiment of the first aspect, the present invention covers compounds of general formula (la):
Figure imgf000017_0001
in which:
A1 represents CR5 or N;
A2 represents CR6 or N;
A3 represents CR7 or N;
A4 represents CR8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
R1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce- cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl, -NR9R10 or R9R10N-Ci-C4-alkyl; R5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C4-alkyl group;
R14 represents hydrogen, Ci-C4-alkyl, benzyl or 4-methoxybenzyl;
X3 represents CH2 or NR14; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In accordance with a fifth embodiment of the first aspect, the present invention covers compounds of general formula (lb):
Figure imgf000018_0001
in which:
A1 represents CR5 or N;
A2 represents CR6 or N;
A3 represents CR7 or N;
A4 represents CR8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
R1 represents phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, pyrazolyl or oxadiazolyl, optionally substituted once or twice, independently from each other, with fluoro, chloro, cyano, Ci-C4-alkyl, methoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, oxanyl or -N(CH3)2;
R5, R6, R7, and R8 represent, independently from each other, hydrogen, fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl or cyclopropyl; their polymorphs, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In accordance with a sixth embodiment of the first aspect, the present invention covers compounds of general formula (I):
Figure imgf000019_0001
in which
A1 represents CR5 or N;
A2 represents CR6 or N;
A3 represents CR7 or N;
A4 represents CR8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
R1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, C1-C4- hydroxyalkyl, Ci-C4-alkoxy-Ci-C4-alkyl-, Cs-Ce-cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl,
-NR9R10, R9R10N-Ci-C4-alkyl-, Ci-C3-alkyl-S(O)m- or Ci-C3-alkyl-SO(NH)-;
R2 represents hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl or Cs-Ce-cycloalkyl;
R3 represents hydrogen, Ci-Ce-alkyl, phenyl or phenyl-Ci-C3-alkyl, wherein said Ci-Ce-alkyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, Ci-C4-alkoxy, -S(O)n-Ci-C4-alkyl, phenyl-Ci-Cs-alkoxy or -NR9R10 and said phenyl groups are optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-Cs-alkoxy or Ci-Cs-haloalkoxy, or
R2 and R3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C4-alkyl group;
R4 represents hydroxy, Ci-C4-alkoxy or -NR11R12, or
R2 and R4 together represent *-C2-Cs-alkanediyl-X1-**, *-Ci-C2-alkanediyl-X2-Ci-C3- alkanediyl-** or *-Ci-C2-alkanediyl-X2-C2-C3-alkanediyl-X1-** to form a 5- to 9-membered ring, wherein * indicates the point of attachment of said group for R2 and ** indicates the point of attachment of said group for R4;
R5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl, 1-R15-C3-C6-cycloalkyl, -CC>2-Ci-C4-alkyl, -CO-NR9R10 or -NR9R10;
R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C4-alkyl group;
R11 and R12 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl or Cs-Ce-cycloalkyl, wherein said Ci-C4-alkyl group is optionally substituted with hydroxy;
R13 represents hydrogen, Ci-C4-alkyl, benzyl, 4-methoxybenzyl or tert-butoxycarbonyl;
R14 represents hydrogen, Ci-C4-alkyl, benzyl or 4-methoxybenzyl; R15 represents Ci-Cs-alkyl or Ci-Cs-haloalkyl;
X1 represents O or NR13;
X2 represents O or NR14; m represents 0, 1 or 2; n represents 0, 1 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In accordance with a second aspect, the present invention covers methods of preparing compounds of general formula (I) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula (V):
Figure imgf000021_0001
(V), in which R1, A1, A2, A3 and A4 are as defined supra to react with a compound of general formula (VII):
Figure imgf000021_0002
(VII), in which R2, R3 and R4 are as defined supra thereby giving a compound of general formula (I):
Figure imgf000022_0001
(I), in which R1, R2, R3, R4, A1, A2, A3 and A4 are as defined supra.
The present invention covers methods of preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental Section herein.
In accordance with a third aspect, the present invention covers intermediate compounds which are useful for the preparation of the compounds of general formula (I), supra.
Particularly, the inventions covers the intermediate compounds of general formula (V):
Figure imgf000022_0002
(V), in which R1, A1, A2, A3 and A4 are as defined supra.
In accordance with a forth aspect, the present invention covers the use of said intermediate compounds for the preparation of a compound of general formula (I) as defined supra.
Particularly, the inventions covers the use of intermediate compounds of general formula (V):
Figure imgf000022_0003
(V), in which R1, A1, A2, A3 and A4 are as defined supra for the preparation of a compound of general formula (I) as defined supra.
The present invention covers the intermediate compounds which are disclosed in the Example Section of this text, infra.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A1 represents CR5 or N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A1 represents CR5; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A1 represents N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A2 represents CR6 or N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A2 represents CR6; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A2 represents N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A3 represents CR7 or N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A3 represents CR7; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A3 represents N; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A4 represents CR8 or N, their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A4 represents CR8, their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
A4 represents N, their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, C1-C4- haloalkoxy, Ci-C4-hydroxyalkyl, Ci-C4-alkoxy-Ci-C4-alkyl-, Cs-Ce-cycloalkyl, C3-Ce- cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl, -NR9R10, R9R10N-Ci-C4-alkyl-, Ci-C3-alkyl-S(O)m- or Ci-C3-alkyl-SO(NH)-; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, C3-Ce- cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl, -NR9R10 or R9R10N-Ci-C4-alkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents phenyl or monocyclic heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce- cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl, -NR9R10 or R9R10N-Ci-C4-alkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents phenyl or monocyclic heteroaryl, optionally substituted one to two times, independently from each other, with halogen, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl or -NR9R10; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents phenyl or monocyclic heteroaryl, optionally substituted one to two times, independently from each other, with halogen, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 5- to 6-membered heterocycloalkyl or -NR9R10; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thiophenyl, pyrolyl, 1 ,2-thiazolyl, oxazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, oxadiazolyl, or imidazpyridinyl, optionally substituted once or twice, independently from each other, with fluoro, chloro, bromo, cyano, Ci-C4-alkyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopropyl methyl, oxanyl or -N(CH3)2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R1 represents phenyl, pyridinyl, pyridazinyl, furanyl, oxazolyl, pyrazolyl or oxadiazolyl, optionally substituted once or twice, independently from each other, with fluoro, chloro, Ci-C4-alkyl, methoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, oxanyl or -N(CH3)2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl or C3-C6-cycloalkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 represents hydrogen or Ci-C4-alkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R3 represents hydrogen, Ci-Ce-alkyl, phenyl or phenyl-Ci-C3-alkyl, wherein said Ci-Ce-alkyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, Ci-C4-alkoxy, -S(O)n-Ci-C4-alkyl, phenyl-Ci-C3-alkoxy or -NR9R10and said phenyl groups are optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-Cs-alkoxy or Ci-Cs-haloalkoxy; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R3 represents hydrogen, Ci-C4-alkyl, phenyl or phenyl-methyl, wherein said Ci-C4-alkyl group is optionally substituted once with hydroxy, methoxy, -S(O)n-methyl, phenyl-methoxy or -NR9R10and said phenyl groups are optionally substituted once with hydroxy; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 and R3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C4-alkyl group; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 and R3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one oxygen atom; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R4 represents hydroxy, Ci-C4-alkoxy or -NR11R12; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R4 represents hydroxy, methoxy or -NR11R12; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 and R4 together represent *-C2-Cs-alkanediyl-X1-**, *-Ci-C2-alkanediyl-X2-Ci-C3- alkanediyl-** or *-Ci-C2-alkanediyl-X2-C2-C3-alkanediyl-X1-** to form a 5- to 9-membered ring, wherein * indicates the point of attachment of said group for R2 and ** indicates the point of attachment of said group for R4; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R2 and R4 together represent a group selected from:
Figure imgf000029_0001
wherein * indicates the point of attachment of said group with the NH group in formula (I); their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: R5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy,
Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R5 represents hydrogen, halogen or methyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R5 represents hydrogen; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents hydrogen, halogen or methyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R6 represents hydrogen; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents hydrogen, halogen, methyl or methoxy; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R7 represents hydrogen; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl, 1-R15-C3-C6-cycloalkyl, -CO2-Ci-C4-alkyl, -CO-NR9R10, -NR9R10, Ci-C4-hydroxyalkyl, Ci-C4-alkoxy-Ci-C4-alkyl-, Ci-C4-alkyl-S-, Ci-C4-alkyl-S-Ci-C4-alkyl-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, -S(=O)(=NH)R’, 4- to 6-membered heterocycloalkyl, or -OR16; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: R8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl, 1-R15-C3-C6-cycloalkyl, -CC>2-Ci-C4-alkyl, -CO-NR9R10 or -NR9R10; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R8 represents hydrogen, halogen or methyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R8 represents hydrogen; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R5, R6, R7, and R8 represent, independently from each other, hydrogen, fluoro, chloro, bromo, methyl, methoxy, trifluoromethyl or cyclopropyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents Ci-C4-alkyl or C1-C4- alkoxycarbonyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C4-alkyl group; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R9 and R10 are the same or different and represent, independently from each other, hydrogen, methyl or tert-butoxycarbonyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R12 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C2-C4-hydroxyalkyl, Ci-C4-alkoxy-C2-C4-alkyl-, R9R10N-C2-C4-alkyl-, Cs-Ce- cycloalkyl, 4- to 7-membered heterocycloalkyl, said 4- to 7-membered heterocycloalkyl group is optionally substituted, one or two times, independently from each other, with hydroxy, oxo, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents Ci-C4-alkyl or C1-C4- alkoxycarbonyl and is optionally substituted, one or two times, independently from each other, with hydroxy, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10, or together with the nitrogen atom to which they are attached form a heterospirocycloalkyl group, which is optionally substituted, one or two times, independently from each other, with hydroxy, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10, or together with the nitrogen atom to which they are attached form a bridged heterocycloalkyl group, which is optionally substituted, one or two times, independently from each other, with hydroxy, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R12 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl or Cs-Ce-cycloalkyl, wherein said Ci-C4-alkyl group is optionally substituted with hydroxy; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R11 and R12 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or C3-C4-cycloalkyl, wherein said Ci-Cs-alkyl group is optionally substituted with hydroxy; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R13 represents hydrogen, Ci-C4-alkyl, benzyl, 4-methoxybenzyl or tert-butoxycarbonyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R13 represents hydrogen or methyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R14 represents hydrogen, Ci-C4-alkyl, benzyl or 4-methoxybenzyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R15 represents Ci-Cs-alkyl or Ci-Cs-haloalkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R15 represents methyl or trifluoromethyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
R16 represents C2-Ce-hydroxyalkyl, Ci-C4-alkoxy-C2-Ce-alkyl-, or Cs-Ce-cycloalkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: R’ and R” represent, independently from each other, Ci-Ce-alkyl, Ci-Ce-haloalkyl, or Cs-Ce- cycloalkyl; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
X1 represents O, S(O)m, or NR13; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
X1 represents O or NR13; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
X2 represents O, S(O)m, or NR14; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
X2 represents O or NR14; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
X3 represents CH2 or NR14; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:
X3 represents CH2 or NH; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: m represents 0, 1 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: m represents 0 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: m represents 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: n represents 0, 1 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: n represents 0 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which: n represents 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
In a particular further embodiment of the first aspect, the present invention covers combinations of two or more of the above mentioned embodiments under the heading “further embodiments of the first aspect of the present invention”.
The present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula (V), supra.
The compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
The compounds according to the invention of general formula (I) can be prepared according to the following scheme 1 . The scheme and procedures described below illustrate synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in scheme 1 can be modified in various ways. The order of transformations exemplified in this scheme is therefore not intended to be limiting. In addition, interconversion of any of the substituents R1, R2, R3, R4, R5, R6, R7, or R8 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, metal-catalysed coupling reactions, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art. Specific examples are described in the subsequent paragraphs. Scheme 1 shows a route for the preparation of compounds of general formula (I).
Figure imgf000039_0001
(I) (V)
Scheme 1 : Route for the preparation of compounds of general formula (I) in which R1, R2, R3, R4, A1, A2, A3, and A4 have the meaning as given for general formula (I), supra and Ra represents
Ci-Ce-alkyl or Cs-Ce-alkenyl and Rb represents hydrogen or-C(O)O-Ra.
Scheme 2 describes another route for the preparation of compounds of formula (I).
Figure imgf000040_0001
(I) (X)
Scheme 2: Route for the preparation of compounds of general formula (I) in which R1, R2, R3, R4, A1, A2, A3, A4, and n have the meaning as given for general formula (I), supra.
Scheme 3 describes an alternative route to prepare intermediates (IV).
Figure imgf000040_0002
(II) (XI) (IV)
Scheme 3: Route for the preparation of compounds of general formula (IV) in which R1, A1, A2, A3, and A4 have the meaning as given for general formula (I), supra. Scheme 4 describes another route for the preparation of compounds of formula (I).
Figure imgf000041_0001
(V) (XII) (I)
Scheme 4: Route for the preparation of compounds of general formula (I) in which R1, R2, R3, R4, A1, A2, A3, and A4 have the meaning as given for general formula (I), supra.
Scheme 5 describes another route for the preparation of compounds of formula (I).
Figure imgf000041_0002
Scheme 5: Route for the preparation of compounds of general formula (I) in which R1, R2, R3, R4, A1, A2, A3, and A4 have the meaning as given for general formula (I), supra, R4 represents -NR11R12 as given for general formula (I), supra, and R represents hydrogen, Ci-Ce- alkyl or Cs-Ce-alkenyl.
Scheme 6 describes an alternative route to prepare intermediates (IV) and (IX) respectively.
Figure imgf000041_0003
x = o, s Scheme 6: Route for the preparation of compounds of general formula (IV) in which R1, A1, A2, A3, and A4 have the meaning as given for general formula (I), supra and X represents oxygen or sulfur. Scheme 7 describes an alternative route to prepare intermediates (IV) and (IX) respectively.
Figure imgf000042_0001
X = 0, S
Scheme 7: Route for the preparation of compounds of general formula (IV) in which R1, A1, A2, A3, and A4 have the meaning as given for general formula (I), supra and X represents oxygen or sulfur and Y represents chloro or bromo.
Scheme 8 describes an alternative route to prepare intermediates (IV).
Figure imgf000043_0001
(XIX) (IV)
Scheme 8: Route for the preparation of compounds of general formula (IV) in which R1, A1, A2, A3, and A4 have the meaning as given for general formula (I), supra.
Scheme 9 describes another route for the preparation of compounds of formula (I).
Figure imgf000043_0002
Scheme 9: Route for the preparation of compounds of general formula (I) in which R1, R2, R3, R4, A1, A2, A3, and A4 have the meaning as given for general formula (I), supra and R represents Ci-Ce-alkyl.
Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively inhibit AHR and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, in humans and animals.
Disorders and conditions particularly suitable for treatment with an AHR inhibitor of the present invention are liquid and solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
Examples of breast cancers include, but are not limited to, triple negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non- small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Examples of ovarian cancer include, but are not limited to serous tumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa cell tumour, Sertoli-Leydig cell tumour and arrhenoblastoma.
Examples of cervical cancer include, but are not limited to squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumour, glassy cell carcinoma and villoglandular adenocarcinoma.
Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Examples of esophageal cancer include, but are not limited to esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma,.
Examples of gastric cancer include, but are not limited to intestinal type and diffuse type gastric adenocarcinoma.
Examples of pancreatic cancer include, but are not limited to ductal adenocarcinoma, adenosquamous carcinomas and pancreatic endocrine tumours.
Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers. Examples of kidney cancer include, but are not limited to renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms' tumour.
Examples of bladder cancer include, but are not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma and small cell carcinoma.
Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to, squamous cell cancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer and squamous cell.
Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
The term “treating” or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
Generally, the use of chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to: yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, provide for the administration of lesser amounts of the administered chemotherapeutic agents, provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, provide for treating a broader spectrum of different cancer types in mammals, especially humans, provide for a higher response rate among treated patients, provide for a longer survival time among treated patients compared to standard chemotherapy treatments, provide a longer time for tumour progression, and/or yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
In addition, the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervention.
In a further embodiment of the present invention, the compounds of general formula (I) of the present invention may be used to sensitize a cell to radiation, i.e. treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention. In one aspect, the cell is treated with at least one compound of general formula (I) of the present invention.
Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy.
The present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of general formula (I) of the present invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
In other embodiments of the present invention, a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of general formula (I) of the present invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. cis platin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.
In other embodiments, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of a non-limiting example, a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell. In one aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.
In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.
The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with: 1311-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, apalutamide, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, bosutinib, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, durvalumab, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, Enasidenib, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, inotuzumab ozogamicin, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, lutetium Lu 177 dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, midostaurin, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, mvasi, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymethoIone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG- epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, ribociclib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium (153Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tisagenlecleucel, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.
The compounds of the invention can further be combined with other reagents targeting the immune system, such as immune checkpoint inhibitors. Compositions comprising a PD-1/-L1 axis antagonist and an AHR antagonist and methods of using the same are provided herein. Data presented herein demonstrate that a combination of AHR inhibition and blockade of the PD-1/-L1 axis reduces the growth of tumor cells in more than an additive manner. PD-1 , along with its ligands PD-L1 and PD-L2, function as negative regulators of T cell activation. AHR suppresses immune cell function while increasing cancer cell proliferation and motility. PD-L1 is overexpressed in many cancers and overexpression of PD-1 often occurs concomitantly in tumor infiltrating T cells. Thus results in attenuation of T cell activation and evasion of immune surveillance, which contributes to impaired antitumor immune responses. (Keir M E et al. (2008) Annu. Rev. Immunol. 26:677). Simultaneously targeting both the PD-1/-L1 axis and AHR enhances antitumor immune responses in more than an additive manner, leading to reduction of tumor growth that is unexpected. In some experiments, the resulting effect is greater than the expected or calculated additive effect of the individual components given separately. Thus, compositions comprising a PD-1/-L1 axis antagonist and an AHR antagonist are surprisingly effective in enhancing an immune response and in the treatment of cancer.
In addition, the inventive compounds can also be used as a therapeutic in a variety of other disorders wherein AHR is involved such as, cardiovascular and lung diseases.
Accordingly, the compounds according to the invention are suitable for the treatment and/or prophylaxis in particular of cardiovascular, inflammatory and fibrotic disorders and of renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure.
Accordingly, the compounds according to the invention can be used in medicaments for the treatment and/or prophylaxis of cardiovascular, inflammatory and fibrotic disorders, renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure.
For the purpose of the present invention the term renal insufficiency comprises both acute and chronic manifestations of renal insufficiency, and also underlying or related renal disorders such as diabetic and non-diabetic nephropathies, hypertensive nephropathies, ischaemic renal disorders, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, renal stenoses, glomerulopathies, glomerulonephritis (such as, for example, primary glomerulonephritides; minimal change glomerulonephritis (lipoidnephrosis); membranous glomerulonephritis; focal segmental glomerulosclerosis (FSGS); membrane-proliferative glomerulonephritis; crescentic glomerulonephritis; mesangioproliferative glomerulonephritis (IgA nephritis, Berger's disease); post-infectious glomerulonephritis; secondary glomerulonephritides: diabetes mellitus, lupus erythematosus, amyloidosis, Goodpasture syndrome, Wegener granulomatosis, Henoch- Schbnlein purpura, microscopic polyangiitis, acute glomerulonephritis, pyelonephritis (for example as a result of: urolithiasis, benign prostate hyperplasia, diabetes, malformations, abuse of analgesics, Crohn's disease), glomerulosclerosis, arteriolonecrose of the kidney, tubulointerstitial diseases, nephropathic disorders such as primary and congenital or aquired renal disorder, Alport syndrome, nephritis, immunological kidney disorders such as kidney transplant rejection and immunocomplex-induced renal disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome which can be characterized diagnostically, for example by abnormally reduced creatinine and/or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and/or creatinine, altered activity of renal enzymes, for example glutamyl synthetase, altered urine osmolarity or urine volume, elevated microalbuminuria, macroalbuminuria, lesions on glomerulae and arterioles, tubular dilatation, hyperphosphataemia and/or the need for dialysis. The present invention also comprises the use of the compounds according to the invention for the treatment and/or prophylaxis of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uremia, anemia, electrolyte disturbances (for example hypercalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.
The present invention also comprises the use of the compounds according to the invention for the treatment and/or prevention of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism.
The compounds according to the invention are further suitable for the treatment and/or prevention of polycystic kidney disease (PCKD) and of the syndrome of inappropriate ADH secretion (SI ADH).
Furthermore, the compounds according to the invention are also suitable for the treatment and/or prophylaxis of metabolic syndrome, hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, atrial and ventricular arrhythmias and impaired conduction, for example atrioventricular blocks degrees l-lll (AB block l-lll), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV-nodal re-entry tachycardia, Wolff- Parkinson- White syndrome, of acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), shock such as cardiogenic shock, septic shock and anaphylactic shock, aneurysms, boxer cardiomyopathy (premature ventricular contraction (PVC)), for treatment and/or prophylaxis of thromboembolic disorders and ischaemias such as myocardial ischaemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischaemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, oedema formation, for example pulmonary oedema, cerebral oedema, renal oedema or oedema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, myocardial insufficiency, endothelial dysfunction, to prevent restenoses, for example after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasties (PTCA), heart transplants and bypass operations, and also micro- and macrovascular damage (vasculitis), increased levels of fibrinogen and of low-density lipoprotein (LDL) and increased concentrations of plasminogen activator inhibitor 1 (PAI-1), and also for treatment and/or prophylaxis of erectile dysfunction and female sexual dysfunction.
In addition, the compounds according to the invention are also suitable for treatment and/or prophylaxis of asthmatic disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH) including left-heart disease, HIV, sickle cell anaemia, thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonary fibrosis-associated pulmonary hypertension, chronic-obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1 -antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysema induced by cigarette smoke) and cystic fibrosis (CF).
The compounds described in the present invention are also active compounds for control of central nervous system disorders characterized by disturbances of the NO/cGMP system. They are suitable in particular for improving perception, concentration, learning or memory after cognitive impairments like those occurring in particular in association with situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post stroke dementia), post-traumatic craniocerebral trauma, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer’s disease, Lewy body dementia, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson’s disease, progressive dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff’s psychosis. They are also suitable for treatment and/or prophylaxis of central nervous system disorders such as states of anxiety, tension and depression, CNS-related sexual dysfunctions and sleep disturbances, and for controlling pathological disturbances of the intake of food, stimulants and addictive substances. The compounds according to the invention are furthermore also suitable for controlling cerebral blood flow and thus represent effective agents for controlling migraines. They are also suitable for the prophylaxis and control of sequelae of cerebral infarction (cerebral apoplexy) such as stroke, cerebral ischaemia and craniocerebral trauma. The compounds according to the invention can likewise be used for controlling states of pain and tinnitus.
The compounds according to the invention are also suitable for treatment and/or prophylaxis of fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders. In the context of the present invention, the term fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis).
The compounds according to the invention are also suitable for controlling postoperative scarring, for example as a result of glaucoma operations.
The compounds according to the invention can also be used cosmetically for ageing and keratinized skin.
Moreover, the compounds according to the invention are suitable for treatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis, glaucoma and gastroparesis.
The present invention further provides for the use of the compounds according to the invention for treatment and/or prophylaxis of disorders, especially the disorders mentioned above.
The present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld-Jakob.
The present invention further provides a method for treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention.
The present invention further provides a method for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropathies, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld- Jakob.
In another embodiment, the inventive compounds can also be used to treat or to prevent uterine fibroids (uterine leiomyoma or uterine myoma) in women.
Uterine fibroids are benign tumors of the myometrium, the smooth muscle layer of the uterus. Uterine fibroids grow slowly during a women's life, and their growth is dependent on the female sexual hormones estradiol and progesterone [Kawaguchi K et al. Immunohistochemical analysis of oestrogen receptors, progesterone receptors and Ki-67 in leiomyoma and myometrium during the menstrual cycle and pregnancy Virchows Arch A Pathol Anat Histopathol. 1991 ;419(4):309- 15.], therefore the highest prevalence of uterine fibroids with approx. 70% and >80% in white and afro-american women, respectively, is found from 35 years of age onwards to menopause, when they shrink due to reduced hormone levels [Baird DD et al. High cumulative incidence of uterine leiomyoma in black and white women: Ultrasound evidence Am J Obstet Gynecol. 2003 Jan;188(1):100-7.]. Approx 30% and 45% of white and afro-american women, respectively, do show clinically relevant symptoms due to their fibroids, which are heavy menstrual bleeding and pain, which is related to the menstrual cycle [David M et al. Myoma-associated pain frequency and intensity: a retrospective evaluation of 1548 myoma patients. Eur J Obstet Gynecol Reprod Biol. 2016 Apr; 199: 137-40], Heavy menstrual bleeding in this respect is defined by a blood loss of more than 80 mL in a menstrual bleeding period [Fraser IS et al. The FIGO Recommendations on Terminologies and Definitions for Normal and Abnormal Uterine Bleeding, Semin Reprod Med 2011 ; 29(5): 383-390], Submucosal position of the uterine fibroids, e.g. those located directly below the endometrium, seems to have an even more severe effect on uterine bleeding, which may result in anemia in affected women [Yang JH et al. Impact of submucous myoma on the severity of anemia. Fertil Steril. 2011 Apr;95(5):1769-72], Furthermore, uterine fibroids, due to their symptoms, do severly affect the quality of life of affected women [Downes E et al. The burden of uterine fibroids in five European countries. Eur J Obstet Gynecol Reprod Biol. 2010 Sep;152(1):96-102],
So far, it is not understood how uterine fibroids do cause heavy menstrual bleeding. Disregulated genes in uterine fibroids, in comparison to normal myometrium, can give a hint to understand the underlying mechanisms. In published and internal studies, we found TDO2, Tryptophan 2,3- dioxygenase, being highly upregulated [Tsibris JC et al. Insights from gene arrays on the development and growth regulation of uterine leiomyomata. Fertil Steril. 2002 Jul;78(1): 114-21.]. TDO2 metabolizes the substrate L-Tryptophan to L-Kynurenine, which can be further metabolized to kynurenic acid. Both, L-Kynurenine and Kynurenic acid are physiological ligands and activators for the arylhydrocarbon receptor AHR [Opitz CA et al. An endogenous tumourpromoting ligand of the human aryl hydrocarbon receptor Nature. 2011 Oct 5;478(7368):197- 203], L-Kynurenine controls at least two physiological processes which are dysregulated in uterine fibroids. L-Kynurenine, synthesized by an upregulation of IDO (lndoleamine-2,3-dyoxygenase) or TDO2, and acting via the AHR receptor, suppresses the immune system and thus prevents immune cells from recognizing and clearing the tumor cells [Munn DH Blocking IDO activity to enhance anti-tumor immunity. Front Biosci (Elite Ed). 2012 Jan 1 ;4:734-45], Furthermore, an upregulation of L-Kynurenine leads to a vasodilation of vessels, and thus can directly increase blood loss and bleeding [Wang Y et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation Nature Medicine 16, 279-285 (2010)].
In summary, the upregulation of L-Kynurenine through activation of its physiological receptor AHR seems to support uterine fibroid growth by local suppression of the immune system, and might cause heavy menstrual bleeding by vasodilation of endometrial vessels in proximity to the tumor.
Therefore, a systemic or local application of compounds from the present invention inhibiting activation of the AHR and thus blocking the effect of uterine fibroid derived L-Kynurenine presents a new and valid treatment option for uterine fibroids.
Compounds of the present invention can be utilized to inhibit, block, reduce or decrease AHR activation by exogenous and/or endogenous ligands for the reduction of tumour growth and the modulation of dysregulated immune responses e.g. to block immunosuppression and increase immune cell activation and infiltration in the context of cancer and cancer immunotherapy; This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.
The present invention also provides methods of treating a variety of other disorders wherein AHR is involved such as, but not limited to, inflammation, vaccination for infection & cancer, viral infections, obesity and diet-induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids.
These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
The term “treating” or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as liquid and solid tumours.
In accordance with a further aspect, the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling. The pharmaceutical activity of the compounds according to the invention can be explained by their activity as AHR inhibitors.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, particularly liquid and solid tumours.
In accordance with a further aspect, the present invention covers the use of a compound of formula (I), described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, particularly liquid and solid tumours.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, particularly liquid and solid tumours.
In accordance with a further aspect, the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, particularly liquid and solid tumours. In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, particularly liquid and solid tumours, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s). Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized. The present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes.
It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.
For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)), ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chainlength triglycerides fatty oils, liquid polyethylene glycols, paraffins), surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®), buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), isotonicity agents (for example glucose, sodium chloride), adsorbents (for example highly-disperse silicas), viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine), disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose- sodium (such as, for example, AcDiSol®)), flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)), coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)), capsule materials (for example gelatine, hydroxypropylmethylcellulose), synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), penetration enhancers, stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide), flavourings, sweeteners, flavour- and/or odour-masking agents.
The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signalinggeneric name disorders, particularly liquid and solid tumours.
The term “combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit- of-parts.
A “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
A non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of- parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
EXPERIMENTAL SECTION
NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. The multiplicities are stated according to the signal form which appears in the spectrum, NMR-spectroscopic effects of a higher order were not taken into consideration. Multiplicity of the NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qi, quin = quintet, b, br = broad signal, m = multiplet. NMR signals: shift in ppm. Combinations of multiplicity could be e.g. dd = doublet from doublet. Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.
Table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.
Table 1 : Abbreviations
ACN acetonitrile
AcOH acetic acid
BPR Back Pressure Regulator
CDCh deuterochloroform
DAD diode array detector
DCM dichloromethane
DEA diethylamine
DIPEA N,N-diisopropylethylamine
DMA N,N-dimethylacetamide
DME 1,2-dimethoxyethane
DMF N,N-dimethylformamide
DMSO-de deuterated dimethyl sulfoxide
DMSO dimethyl sulfoxide
EtOAc ethyl acetate
EtOH ethanol
Eq equivalent
ESI electrospray ionisation
Expl. example
HATU (7-aza-1H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
HBTU O-benzotriazole-N,N,N’,N’-tetramethyluronium hexafluorophosphate
HPLC high-pressure liquid chromatography
KA kynurenic acid
LCMS liquid chromatography coupled with mass spectrometry
LPS lipopolysaccharide mL milliliter L microliter min. minute(s) M molar mCPBA meta chloro perbenzoic acid
MeLi methyl lithium
MS mass spectrometry
MTBE methyl tert-butyl ether
MTP microtiter plate n-BuLi n-butyl lithium
NMP N-methyl-2-pyrrolidone p pressure
PBMC peripheral blood mononuclear cells
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
Pd/C Palladium on activated charcoal (10% with 50% water)
PLC pressure liquid chromatography
PyBOB (benzotriazol-l-yl)oxytripyrrolidinophosphonium hexafluorophosphate
RP-HPLC reverse-phase high-pressure liquid chromatography
Rt retention time rt, r.t. room temperature sat. saturated
T3P 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide tBuBrettPhos Pd G3 [(2-Di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1 ,T- biphenyl)-2-(2'-amino-1 ,T-biphenyl)]palladium(ll) methanesulfonate tBuBrettPhos 2-(Di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-
1 , 1 '-biphenyl
TEA triethylamine
THE tetra hydrofuran
TEA trifluoroacetic acid
TLC thin layer chromatography
TNFa tumour necrosis factor alpha M micromolar
UPLC Ultra high performance chromatography
UPLCMS Ultra high performance chromatography mass spectrometry
Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
Xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
XPhos Pd G1 [2-(2-aminoethyl)phenyl](chloro)palladium-dicyclohexyl(2',4',6'- triisopropyl[biphenyl]-2-yl)phosphine (1 :1) XPhos Pd G4 methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-iso-propy-
1 ,1'-biphenyl)(2'-methylamino-1 ,T-biphenyl-2-yl)palladium(ll)
The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.
The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
EXPERIMENTAL SECTION - GENERAL PART
All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.
The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil® or KP- NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity. Analytical LC-MS methods from UPLCMS:
Method 1 :
Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 m, 50x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.
Method 2:
Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 pm, 50x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210- 400 nm.
EXPERIMENTAL SECTION - INTERMEDIATES
Intermediate 1 ethyl 4-chloro-2-(trifluoromethoxy)benzoate
Figure imgf000063_0001
Under argon to 4-chloro-2-(trifluoromethoxy)benzoic acid (5.00 g, 20.8 mmol) was added carefully thionyl dichloride (8.7 mL), 120 mmol) and stirred 15 minutes at rt. Then ethanol (50 mL) was added dropwise carefully under ice cooling to the mixture and stirred at 0°C for 30 minutes, then heated at reflux for 1h and stirred over night at rt and then heated to reflux for additional 4h. After cooling to rt the mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (150 mL) and extracted three times with ethyl acetate. The combined organic layer were washed with brine, filtered using a hydrophobic phase separation filter paper and then concentrated under reduced pressure to give 6.50 g of the target compound which was used without any further purification.
LC-MS (Method 1): Rt = 1.43 min; MS (ESIpos): m/z = 269 [M+ H]+
1H-NMR (400MHz, DMSO-de): 0 [ppm]= 1.30 (t, 3H), 4.33 (q, 2H), 7.67 (dd, 1 H), 7.72 (dq, 1 H), 7.97 (d, 1 H). Intermediate 2
4-chloro-2-(trifluoromethoxy)benzohydrazide
Figure imgf000064_0001
Ethyl 4-chloro-2-(trifluoromethoxy)benzoate (1.00 g, 3.72 mmol) was solubilised in ethanol (18 mL), hydrazine hydrate (1.8 mL, 37 mmol) was added and the mixture was stirred at 80°C over night. After cooling to room temperature aqueous saturated ammonium chloride solution was added and this mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered over a hydrophobic phase separation filter paper and concentrated in vacuo. After drying we obtained 820 mg (85 % purity, 74 % yield) of the target compound, which was used without further purification.
LC-MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 255 [M+H]+
1H-NMR (400MHz, DMSO-de): 0 [ppm]= 4.55 (br s, 2H), 7.54 - 7.62 (m, 3H), 9.66 (s, 1 H).
Intermediate 3
5-chlorothiophene-3-carbohydrazide
Figure imgf000064_0002
Methyl 5-chlorothiophene-3-carboxylate (800 mg, 4.53 mmol, CAS [36157-43-4], commercially available at e.g. ABCR) was solubilised in ethanol (20 mL), hydrazine hydrate (1.1 mL, 23 mmol) was added and the mixture was stirred at reflux temperature for 20h. After cooling to room temperature the mixture was poured into icewater, stirred, and the formed solid was obtained via filtration. After drying 410 mg (100 % purity, 51 % yield) of the target compound was obtained, which was used without further purification.
LC-MS (Method 1): Rt = 0.64 min; MS (ESIpos): m/z = 177 [M+H]+
1H-NMR (400MHz, DMSO-de): 0 [ppm]= 4.49 (br s, 2H), 7.47 (d, 1 H), 7.98 (d, 1 H), 9.63 (br s, 1 H). Intermediate 4 ethyl (2-cyanopyridin-3-yl)carbamate
Figure imgf000065_0001
A mixture of 3-aminopyridine-2-carbonitrile (2.00 g, 16.8 mmol; CAS [42242-11-5], commercially available, e.g. ABCR) and ethyl carbonochloridate (29 mL), 310 mmol; CAS [541-41-3]) was stirred at 110°C for 20h. After cooling to rt the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography to give 2.60 g (88 % purity, 71 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.73 min; MS (ESIpos): m/z = 192 [M+H]
1H-NMR (400MHz, DMSO-de): 0 [ppm]= 1.26 (t, 3H), 4.17 (q, 2H), 7.72 (dd, 1 H), 8.01 (dd, 1 H), 8.51 (dd, 1 H), 10.01 (br s, 1 H).
Intermediate 5 methyl (2-cyanopyridin-3-yl)carbamate
Figure imgf000065_0002
3-Aminopyridine-2-carbonitrile (500 mg, 4.20 mmol) and potassium carbonate (1.74 g, 12.6 mmol) were solubilised in THF and methyl carbonochloridate (650 L, 8.4 mmol) was added. The mixture was stirred at 80°C overnight. The mixture was filtered, washed with THF and concentrated under reduced pressure to give 732 mg (50 % purity, 49 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.58 min; MS (ESIpos): m/z = 178 [M+H]+
1H-NMR (400MHz, DMSO-de): 6 [ppm]= 3.72 (s, 3H), 7.73 (dd, 1 H), 8.03 (dd, 1 H), 8.51 (dd, 1 H), 10.05 (s, 1 H).
Intermediate 6 ethyl (4-cyanopyridin-3-yl)carbamate
Figure imgf000066_0001
3-Aminopyridine-4-carbonitrile (500 mg, 4.20 mmol) was stirred in ethyl carbonochloridate (7.0 mL, 73 mmol; CAS-RN: 541-41-3) for4h at 100°C. The mixture was concentrated under reduced pressure to give 800 mg (100 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.66 min; MS (ESIpos): m/z = 192 [M+H]+
1H NMR (DMSO-de) 0: 10.08 (s, 1 H), 8.78 (s, 1 H), 8.55 (d, J=4.8 Hz, 1 H), 7.85 (dd, J=5.1 , 0.8 Hz, 1 H), 4.17 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H).
Intermediate 7 di-tert-butyl (2-cyanopyridin-3-yl)-2-imidodicarbonate
Figure imgf000066_0002
3-Aminopyridine-2-carbonitrile (900 mg, 7.55 mmol), di-tert-butyl dicarbonate (4.3 mL, 19 mmol; CAS-RN: [24424-99-5]) and 4-(Dimethylamino)pyridine (461 mg, 3.78 mmol; CAS-RN:[1122-58- 3]) were dissolved in 1 ,4-dioxane (13 mL) and treated with N,N-diisopropylethylamine (3.3 mL, 19 mmol; CAS-RN: [7087-68-5]). The mixture was stirred over night at rt. The mixture was treated with water and ethyl acetate and extracted three times. The organic phase was dried by filtering through a silicone filter and concentrated. The crude material was purified by flash chromatography to give 2.55 g (95 % purity, 100 % yield) of the target compound.
LC-MS (Method 2): Rt = 1.27 min; MS (ESIpos): m/z = 320 [M+H]+
1H-NMR (400MHz, DMSO-d6): 5 [ppm]= 1.37 (s, 18H), 7.85 (dd, 1 H), 8.19 (dd, 1 H), 8.74 (dd, 1 H).
Intermediate 8 di-tert-butyl (4-cyanopyridin-3-yl)-2-imidodicarbonate
Figure imgf000067_0001
3-Aminopyridine-4-carbonitrile (200 mg, 1.68 mmol), di-tert-butyl dicarbonate (916 mg, 4.20 mmol) and 4-(Dimethylamino)pyridine (103 mg, 839 pmol; CAS-RN: [1122-58-3]) were dissoved in 1 ,4-dioxane (3 mL) and treated with N,N-diisopropylethylamine (730 pL, 4.2 mmol; CAS- RN:[7087-68-5]). The mixture was stirred over night at rt. The mixture was diluted with ethyl acetate, washed with water and extracted three times with ethyl acetate. The residue was purified by flash chromatography to afford 315 mg (95 % purity, 56 % yield) of the target compound.
LC-MS (Method 2): Rt = 1.24 min; MS (ESIpos): m/z = 320 [M+H]+
1H NMR (400 MHz, DMSO-d6) 6 ppm 1.37 (s, 18 H) 7.99 - 8.05 (m, 1 H) 8.82 (d, 1 H) 8.89 (s, 1 H).
Intermediate 9 di-tert-butyl (3-cyanopyridin-2-yl)-2-imidodicarbonate
Figure imgf000067_0002
2-Aminopyridine-3-carbonitrile (1.00 g, 8.39 mmol), di-tert-butyl dicarbonate (4.8 mL, 21 mmol; CAS-RN: [24424-99-5]) and 4-(Dimethylamino)pyridine (513 mg, 4.20 mmol; CAS-RN:[1122-58- 3]) were dissolved in 1 ,4-dioxane (15 mL) and treated with N,N-diisopropylethylamine (3.7 mL, 21 mmol; CAS-RN: [7087-68-5]). The mixture was stirred over night at rt. The mixture was treated with water and ethyl acetate and extracted three times with ethyl acetate. The organic phase was dried by filtering through a silicone filter and concentrated. The crudematerial was purified by flash chromatography to afford 2.71 g (100 % purity) in a quantitative yield of the target compound.
1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.37 (s, 18H), 7.67 (dd, 1 H), 8.52 (dd, 1 H), 8.81 (dd, 1 H). Intermediate 10
2-(3-fluorophenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one
Figure imgf000068_0001
Ethyl (2-cyanopyridin-3-yl)carbamate (207 mg, 1.08 mmol) and 3-fluorobenzohydrazide (200 mg, 1.30 mmol) were stirred in DMF (4.0 mL) overnight at 120°C. Water was added to the mixture, filtered, washed with water and dried under reduced pressure at 60°C to give 249 mg (82 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.48 min; MS (ESIpos): m/z = 282 [M+H]+
Intermediate 11 2-(4-methoxyphenyl)pyrido[2,3-e][1 , 2 , 4]triazol o[1 ,5-c]pyrimidin-5(6H)-one
Figure imgf000068_0002
Ethyl (2-cyanopyridin-3-yl)carbamate (414 mg, 2.16 mmol) and 4-methoxybenzohydrazide (431 mg, 2.60 mmol) were stirred in DMF (7.0 mL) overnight at 120°C. Water was added to the mixture, filtered, washed with water and dried under reduced pressure at 60°C to give 524 mg (83 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.48 min; MS (ESIpos): m/z = 294 [M+H]+
Intermediate 12
2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one
Figure imgf000069_0001
Methyl (2-cyanopyridin-3-yl)carbamate (720 mg, 4.06 mmol) and 3-methoxybenzohydrazide (810 mg, 4.88 mmol) were stirred in DMF (14 mL) overnight at 120°C. Water was added to the mixture, filtered, washed with water and dried under reduced pressure at 60°C to give 892 mg (75% yield) of the target compound.
LC-MS (Method 2): Rt = 0.50 min; MS (ESIpos): m/z = 294 [M+H]+
Intermediate 13
2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one
Figure imgf000069_0002
Methyl (2-cyanopyridin-3-yl)carbamate (732 mg, 4.13 mmol) and 1-methyl-1 H-pyrazole-4- carbohydrazide (695 mg, 4.96 mmol) were stirred in DMF (5.0 mL) at 120°C overnight. Water was added to the mixture, filtered, washed with water. The solid was dried under reduced pressure at 60°C to give 101 mg (9 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.49 min; MS (ESIpos): m/z = 268 [M+H]+ 1H NMR (DMSO-de) 0: 12.29-12.48 (m, 1 H), 8.64 (dd, J=4.4, 1.4 Hz, 1H), 8.44 (s, 1H), 8.04 (d, J=0.8 Hz, 1 H), 7.82 (dd, J=8.4, 1.3 Hz, 1H), 7.67-7.72 (m, 1 H), 3.95 (s, 3H)
Intermediate 14
2-(4-methoxyphenyl)pyrido[4,3-e][1,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one
Figure imgf000070_0001
Ethyl (4-cyanopyridin-3-yl)carbamate (200 mg, 1.05 mmol) and 4-methoxybenzohydrazide (209 mg, 1.26 mmol) were stirred in DMF (2.0 mL) overnight at 120°C. Water was added to the mixture, filtered, washed with water and dried under reduced pressure at 60°C to give 180 mg (59 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.54 min; MS (ESIneg): m/z = 292 [M-H]-
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.518 (3.00), 2.523 (2.04), 2.539 (2.42), 2.544 (0.51), 2.727 (7.39), 2.887 (8.86), 3.069 (0.38), 3.300 (0.45), 3.308 (0.89), 3.314 (0.45), 3.325 (1.47),
3.379 (2.04), 3.391 (1.47), 3.396 (1.15), 3.403 (0.45), 3.791 (0.83), 3.808 (0.89), 3.813 (0.57),
3.818 (1.53), 3.823 (1.08), 3.833 (8.22), 3.843 (2.36), 3.852 (16.00), 3.881 (0.70), 7.035 (1.66), 7.052 (0.64), 7.057 (1.72), 7.064 (0.45), 7.117 (0.45), 7.124 (3.63), 7.129 (1.15), 7.142 (1.15),
7.147 (3.57), 7.154 (0.38), 7.891 (1.40), 7.913 (1.34), 7.948 (1.21), 8.103 (1.91), 8.105 (1.91),
8.110 (0.51), 8.116 (1.85), 8.118 (1.85), 8.154 (0.45), 8.161 (4.02), 8.166 (1.21), 8.177 (1.08),
8.183 (3.70), 8.189 (0.38), 8.264 (0.51), 8.277 (0.51), 8.357 (0.89), 8.549 (2.87), 8.562 (2.68),
8.791 (3.25), 10.500 (0.51), 10.807 (0.45).
Intermediate 15
2-(4-fluorophenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one
Figure imgf000070_0002
Ethyl (2-cyanopyridin-3-yl)carbamate (207 mg, 1.08 mmol) and 4-fluorobenzohydrazide (200 mg, 1.30 mmol) were stirred in DMF (4.0 mL) overnight at 120°C. Water was added to the mixture, filtered, washed with water and dried under reduced pressure at 60°C to give 237 mg (78 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.49 min; MS (ESIpos): m/z = 282 [M+H]+
Intermediate 16 4-(5-oxo-5,6-dihydropyrido[2,3-e][1 ,2 ,4]triazolo[1 ,5-c]pyrimidin-2-yl)benzonitrile
Figure imgf000071_0001
Ethyl (2-cyanopyridin-3-yl)carbamate (436 mg, 2.28 mmol; CAS [54-85-3], commercially available, e.g. ABCR) and 4-cyanobenzohydrazide (441 mg, 2.74 mmol) were stirred in DMF (7.4 mL) at 120°C for 6h. Then acetic acid (7.4 mL) was added at 100°C and the reaction mixture was stirred for 24h at this temperature. The reaction mixture was cooled to room temperature and added to water. After stirring for 10 minutes filtered, washed with water and the solid was dried under reduced pressure at 60°C to give 599 mg (92 % purity, 84 % yield) of the target compound, which was used without further purification.
LC-MS (Method 1): Rt = 0.80 min; MS (ESIpos): m/z = 289 [M+H]+ 1H-NMR (400MHz, DMSO-de): 0 [ppm]= 7.74 (dd, 1 H), 7.85 (dd, 1 H), 8.04 - 8.09 (m, 2H), 8.38 - 8.43 (m, 2H), 8.68 (dd, 1 H), 12.56 (br s, 1 H).
The following intermediates were prepared analogue to the previous one.
Figure imgf000072_0001
Intermediate 19
2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one
Figure imgf000073_0001
Di-tert-butyl (2-cyanopyridin-3-yl)-2-imidodicarbonate (812 mg, 2.54 mmol) and 1-methyl-1 H- pyrazole-4-carbohydrazide (428 mg, 3.05 mmol) were dissolved in DMF (12 mL) and the mixture was stirred over night at 120°C. Acetic acid (2 mL) were added and the mixture was stirred over night at 100°C. The mixture was pourred into water, stirred 1 h, filtrered and dried under reduced pressure at 60°C. The crudematerial was stirred in dichloromethane and trifluoroacetic acid (5.9 mL, 76 mmol) were added. The mixture was concentrated under reduced pressure to afford 100 mg (70 % purity, 10 % yield) of the target compound.
1 H-NMR (400MHz, DMSO-d6): 6 [ppm]= 3.95 (s, 3H), 7.70 (dd, 1 H), 7.85 (br d, 1 H), 8.04 (s, 1 H), 8.44 (s, 1 H), 8.64 (dd, 1 H), 12.44 (br d, 1 H).
Intermediate 20
2-[1-(propan-2-yl)-1 H-pyrazol-4-yl]pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one
Figure imgf000073_0002
Di-tert-butyl (2-cyanopyridin-3-yl)-2-imidodicarbonate (660 mg, 2.07 mmol) and 1-(propan-2-yl)- 1 H-pyrazole-4-carbohydrazide (417 mg, 2.48 mmol) were dissolved in DMF (5.0 mL) and the mixture was stirred over night at 120°C. Trifluoroacetic acid (1.5 mL) was added to the mixture and stirred 16h at 80°C. Water was added to the mixture, the precipitate was filtered, washed with water and dried under reduced pressure at 60°C.
1 H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.49 (d, 6H), 4.63 (quin, 1 H), 7.70 (dd, 1 H), 7.83 (dd, 1 H), 8.05 (d, 1 H), 8.50 (s, 1 H), 8.64 (dd, 1 H), 12.39 (br s, 1 H).
Intermediate 21
2-(1-methyl-1 H-pyrazol-4-yl)pyrido[4,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one
Figure imgf000074_0001
Di-tert-butyl (4-cyanopyridin-3-yl)-2-imidodicarbonate (600 mg, 1.88 mmol) and 1-methyl-1 H- pyrazole-4-carbohydrazide (316 mg, 2.25 mmol) were dissolved in DMF and the mixture was stirred over night at 120°C. Acetic acid (2.0 mL) were added and the mixture was stirred over night at 100°C. The mixture was poured into water, stirred for 1h, filtered and dried under reduced pressure at 60°C. The crudematerial was stirred in dichloromethane and trifluoroacetic acid (5.9 mL, 76 mmol) were added. The mixture was concentrated under reduced pressure to afford 1.02 g of the target compound in quantitative yield.
1H-NMR (400MHz, DMSO-de): 6 [ppm]= 3.94 (s, 3H), 8.04 (d, 1 H), 8.08 (dd, 1 H), 8.45 (s, 1 H), 8.56 (d, 1 H), 8.80 (d, 1 H), 12.52 - 12.65 (m, 1 H).
Intermediate 22
2-(1 ,3-dimethyl-1 H-pyrazol-4-yl)pyrido[3,2-e][1 ,2 ,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one
Figure imgf000074_0002
Di-tert-butyl (3-cyanopyridin-2-yl)-2-imidodicarbonate (678 mg, 2.12 mmol) and 1 ,3-dimethyl- 1 H-pyrazole-4-carbohydrazide - hydrochloride (485 mg, 2.55 mmol) were dissolved in DMF and stirred over night at 120°C. Trifluoroacetic acid (1.6 mL, 21 mmol; CAS-RN:[76-05-1]) was added and the mixture was stirred 16h at 80°C. The precipitate was filtered and dried under reduced pressure to afford 37.9 mg (100 % purity, 6 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.47 min; MS (ESIneg): m/z = 280 [M-H]-
1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 2.52 (s, 3H), 3.85 (s, 3H), 7.45 (dd, 1 H), 8.31 (s, 1 H), 8.53 (dd, 1 H), 8.69 (dd, 1 H), 12.74 (s, 1 H).
Intermediate 23
5-chloro-2-(3-fluorophenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine
Figure imgf000075_0001
2-(3-Fluorophenyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (249 mg, 885 pmol) was solubilised in phosphoric trichloride (2.6 mL, 28 mmol), N,N-diisopropylethylamine (1.5 mL, 8.9 mmol) was added dropwise and the mixture was stirred for 2h at 80°C. The mixture was poured into ice, stirred for 1 h, filtered, washed with water and dried at 60°C under reduced pressure to give 164 mg (66 % purity, 41 % yield) of the target compound.
LC-MS (Method 2): Rt = 1.16 min; MS (ESIpos): m/z = 300 [M+H]+
Intermediate 24
5-chloro-2-(4-methoxyphenyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine
Figure imgf000075_0002
2-(4-Methoxyphenyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (524 mg, 1.79 mmol) was solubilised in phosphoric trichloride (5.2 mL, 56 mmol), N,N-diisopropylethylamine (3.1 mL, 18 mmol) was added dropwise and the mixture was stirred for 2h at 80°C. The mixture was poured into ice, stirred for 1 h, filtered, washed with water and dried at 60°C under reduced pressure to give 273 mg (71 % purity, 35 % yield) of the target compound.
LC-MS (Method 2): Rt = 1.12 min; MS (ESIpos): m/z = 312 [M+H]+
1H-NMR (400MHz, DMSO-de): 0 [ppm]= 3.87 (s, 3H), 7.16 - 7.19 (m, 2H), 7.98 (dd, 1H), 8.25 - 8.28 (m, 2H), 8.46 (dd, 1H), 9.09 (dd, 1 H).
Intermediate 25
5-chloro-2-(3-methoxyphenyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine
Figure imgf000076_0001
2-(3-Methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one (892 mg, 3.04 mmol) was solubilised in phosphoric trichloride (8.9 mL, 96 mmol), N,N-diisopropylethylamine (5.3 mL, 30 mmol) was added dropwise and the mixture was stirred overnight at 110°C. The mixture was poured into ice, stirred for 1 h, evaporated the organic solvent, filtered, washed with water and dried at 60°C under reduced pressure to give 731 mg (77% yield) of the target compound.
LC-MS (Method 2): Rt = 1.14 min; MS (ESIpos): m/z = 312 [M+H]+
1H-NMR (400MHz, DMSO-d6): 5 [ppm]= 3.90 (s, 3H), 7.18 (ddd, 1 H), 7.54 (t, 1 H), 7.82 (dd, 1 H), 7.92 (dt, 1 H), 7.99 (dd, 1 H), 8.48 (dd, 1 H), 9.10 (dd, 1 H).
Intermediate 26
5-chloro-2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine
Figure imgf000076_0002
2-(1-Methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one (101 mg, 378 pmol) was solubilised in phosphoric trichloride (480 pL, 5.2 mmol), N,N-diisopropylethylamine (660 pL, 3.8 mmol) was added dropwise and the mixture was stirred overnight at 110°C. The mixture was poured into ice (transferred with DCM), stirred for 1 h, the aqueous phase was extracted and the organic phase was dried and evaporated under reduced pressure to give 111 mg (95 % purity, 98 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.78 min; MS (ESIpos): m/z = 286 [M+H]+
1 H-NMR (400MHz, DMSO-d6): 5 [ppm]= 3.97 (s, 3H), 7.96 (dd, 1 H), 8.12 (s, 1 H), 8.45 (dd, 1 H), 8.56 (s, 1 H), 9.07 (dd, 1 H).
Intermediate 27
5-chloro-2-(4-methoxyphenyl)pyrido[4,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine
Figure imgf000077_0001
2-(4-Methoxyphenyl)pyrido[4,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one (100 mg, 341 pmol) was solubilised in phosphoric trichloride (1.1 mL, 12 mmol), N,N-diisopropylethylamine (590 pL, 3.4 mmol) was added carefully and the mixture was stirred overnight at 110°C. The mixture was poured into ice, stirred for 1 h, filtered, washed with water and dried at 60°C under reduced pressure to give 95.0 mg (89 % yield) of the target compound.
LC-MS (Method 2): Rt = 1.12 min; MS (ES+): m/z = 312 [M+H]+
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 0.851 (0.46), 1.171 (0.51), 1.189 (0.85), 1.196 (2.11),
1.206 (0.92), 1.212 (2.16), 1.232 (1.24), 1.241 (1.21), 1.259 (1.12), 1.276 (0.83), 1.353 (0.49),
2.318 (0.44), 2.323 (1.02), 2.327 (1.51), 2.331 (1.09), 2.337 (0.53), 2.518 (16.00), 2.523 (13.04), 2.540 (6.58), 2.660 (0.70), 2.665 (1.26), 2.669 (1.70), 2.673 (1.26), 2.678 (0.68), 2.686 (0.63),
2.729 (0.68), 2.889 (0.80), 2.994 (0.75), 3.514 (1.41), 3.821 (1.21), 3.825 (1.00), 3.839 (1.38),
3.852 (1.58), 3.870 (4.81), 7.122 (0.41), 7.158 (1.21), 7.181 (1.17), 8.087 (0.56), 8.241 (1.12),
8.263 (1.04), 8.385 (0.53), 8.396 (0.53), 8.911 (0.70), 8.924 (0.68), 9.369 (0.78).
Intermediate 28
5-chloro-2-(4-fluorophenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine
Figure imgf000077_0002
2-(4-Fluorophenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one (237 mg, 841 pmol) was solubilised in phosphoric trichloride (2.5 mL, 26 mmol), N,N-diisopropylethylamine (1.5 mL, 8.4 mmol) was added dropwise and the mixture was stirred for 2h at 80°C. The mixture was poured into ice, stirred for 1 h, filtered, washed with water and dried at 60°C under reduced pressure to give 154 mg (77 % purity, 47 % yield) of the target compound. LC-MS (Method 2): Rt = 1.15 min; MS (ESIpos): m/z = 300 [M+H]+
Intermediate 29
4-(5-chloropyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-2-yl)benzonitrile
Figure imgf000078_0001
4-(5-Oxo-5,6-dihydropyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-2-yl)benzonitrile (493 mg, 1.71 mmol) was solubilised in phosphorus(V) oxychloride (4.8 mL, 51 mmol), N,N- diisopropylethylamine (8.9 mL, 51 mmol) was added carefully and the mixture was stirred for 2h at 120 °C. The mixture was poured carefully to icewater and stirred for 1h. Precipitated product was filtered off and dried to give 576 mg (110 % yield) of the title compound. LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 307 [M+H]+
1H-NMR (400MHz, DMSO-de): 6 [ppm]= 8.02 (dd, 1 H), 8.10 (d, 2H), 8.46 - 8.53 (m, 3H), 9.12 (dd, 1 H).
The following intermediates were prepared analogue to the previous one.
Figure imgf000078_0002
Figure imgf000079_0002
Intermediate 32
5-chloro-2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine
Figure imgf000079_0001
2-(1-Methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one (100 mg, 374 pmol) was dissolved in N,N-diisopropylethylamine (2.0 mL, 11 mmol; CAS-RN: [7087-68-5]) and phosphorus oxychloride (1.0 mL, 11 mmol; CAS-RN: [10025-87-3]) was added carefully. The mixture was stirred over night at 110°C. The mixture was pourred into ice water, the precipitate was filtered, washed with water and dried under reduced pressure to get 50.0 mg (95 % purity, 44 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.81 min; MS (ESIpos): m/z = 286 [M+H]+ 1H-NMR (400MHz, DMSO-de): 0 [ppm]= 3.97 (s, 3H), 7.96 (dd, 1 H), 8.12 (d, 1 H), 8.45 (dd, 1 H), 8.56 (s, 1 H), 9.07 (dd, 1 H).
Intermediate 33
5-chloro-2-[1-(propan-2-yl)-1 H-pyrazol-4-yl]pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine
Figure imgf000080_0001
2-[1-(Propan-2-yl)-1 H-pyrazol-4-yl]pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one (200 mg, 677 pmol) was treated witch phosphorus oxychloride (950 pL, 10 mmol; CAS-RN : [10025- 87-3]) and stirred 10 min. at rt. Then N,N-diisopropylethylamine (590 pL, 3.4 mmol; CAS- RN: [7087-68-5]) was added to the mixture and stirred 16h at 90°C. Water was added to the mixture and the precipitate was filtered, washed with water and dried under reduced pressure to get 35.0 mg (62 % purity, 10 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.96 min; MS (ESIpos): m/z = 314 [M+H]+
1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.50 (d, 6H), 4.62 - 4.67 (m, 1 H), 7.97 (dd, 1 H), 8.14 (s, 1 H), 8.45 (dd, 1 H), 8.61 (s, 1 H), 9.07 (dd, 1 H).
Intermediate 34
5-chloro-2-(1-methyl-1 H-pyrazol-4-yl)pyrido[4,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine
Figure imgf000080_0002
2-(1-Methyl-1 H-pyrazol-4-yl)pyrido[4,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one (40.0 mg, 150 pmol) were dissolved in N,N-diisopropylethylamine (130 pL, 750 pmol; CAS-RN:[7087-68-5]) and phosphorus oxychloride (210 pL, 2.2 mmol; CAS-RN: [10025-87-3]) was added carefully. The mixture was stirred 4h at 100°C. Water was added to the mixture and the precipitate was filtered and washed 5 times with water and dried under under reduced pressure at 60°C to afford 30.0 mg (95 % purity, 67 % yield) of the target compound. LC-MS (Method 2): Rt = 0.81 min; MS (ESIpos): m/z = 286 [M+H]+
1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 9.36 (d, 1 H), 8.90 (d, 1 H), 8.58 (s, 1 H), 8.33 (dd, 1 H),
8.12 (d, 1 H), 3.96 (s, 3H).
Intermediate 35 benzyl (6R)-6-{[2-(3-fluorophenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}-5-oxo-
1 , 4-di azepane- 1 -carboxyl ate
Figure imgf000081_0001
5-Chloro-2-(3-fluorophenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine (45.0 mg, 150 pmol), benzyl (6R)-6-amino-5-oxo-1 ,4-diazepane-1 -carboxylate — hydrogen chloride (1/1) (67.5 mg, 225 pmol) and N,N-diisopropylethylamine (52 L, 300 pmol) were stirred in DMSO (1.5 mL) at 60°C for 3h. Water was added to the reaction mixture. The resulting suspension was stirred strongly for 5 min, filtered and washed with water. The solid was dried under reduced pressure at 60°C to give 62.2 mg (82 % purity, 65 % yield) of the target compound.
LC-MS (Method 2): Rt = 1.21 min; MS (ES+): m/z = 527 [M+H]+
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 0.851 (0.54), 1.231 (2.09), 1.352 (0.39), 1.907 (1.70), 2.331 (3.25), 2.336 (1.39), 2.518 (15.07), 2.523 (9.35), 2.539 (16.00), 2.673 (3.32), 2.678 (1.47), 2.994 (0.54), 3.140 (0.39), 3.496 (0.85), 3.519 (1.78), 4.220 (0.46), 4.639 (0.62), 4.969 (0.70),
5.111 (0.39), 5.201 (3.79), 7.189 (1.47), 7.343 (2.09), 7.370 (4.02), 7.383 (2.40), 7.426 (2.01),
7.435 (1.93), 7.450 (2.09), 7.456 (2.16), 7.471 (1.31), 7.476 (1.39), 7.647 (0.93), 7.660 (1.62),
7.674 (1.62), 7.679 (2.16), 7.695 (2.24), 7.700 (1.78), 7.715 (1.86), 7.816 (0.62), 7.840 (0.46),
8.012 (1.24), 8.038 (1.39), 8.089 (1.08), 8.152 (1.39), 8.171 (1.31), 8.531 (0.54), 8.719 (0.93).
Intermediate 36 benzyl (6R)-6-{[2-(4-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}-5- oxo-1 ,4-diazepane-1 -carboxylate
Figure imgf000082_0001
5-Chloro-2-(4-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine (90.0 mg, 289 pmol), benzyl (6R)-6-amino-5-oxo-1 ,4-diazepane-1-carboxylate — hydrogen chloride (1/1) (130 mg, 433 pmol) and N,N-diisopropylethylamine (100 pL, 580 pmol) were stirred in DMSO (2.8 mL) at 60°C for 3h. Water was added to the reaction mixture. The resulting suspension was stirred strongly for 5 min, filtered and washed with water. The solid was dried under reduced pressure at 60°C to give 118 mg (81 % purity, 62 % yield) of the target compound.
LC-MS (Method 2): Rt = 1.18 min; MS (ES+): m/z = 539 [M+H]+
1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.231 (0.75), 1.907 (0.62), 2.331 (1.09), 2.336 (0.47), 2.518 (5.26), 2.522 (3.36), 2.539 (1.51), 2.673 (1.09), 2.678 (0.47), 3.492 (0.42), 3.509 (0.73),
3.819 (0.75), 3.839 (1.22), 3.854 (2.32), 3.867 (16.00), 3.890 (0.65), 3.898 (0.60), 5.200 (1.93),
7.127 (0.60), 7.150 (1.12), 7.157 (3.98), 7.162 (1.67), 7.174 (1.93), 7.180 (4.37), 7.186 (1.35),
7.341 (1.09), 7.369 (2.06), 7.381 (1.17), 7.706 (0.42), 8.003 (0.78), 8.236 (1.46), 8.257 (1.38),
8.700 (0.49).
Intermediate 37 benzyl (6R)-6-({2-[4-chloro-2-(trifluoromethoxy)phenyl]pyrido[2,3-e][1 ,2,4]triazolo[1 ,5- c]pyrimidin-5-yl}amino)-5-oxo-1 ,4-diazepane-1-carboxylate
Figure imgf000082_0002
5-Chloro-2-[4-chloro-2-(trifluoromethoxy)phenyl]pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine
(100 mg, 250 pmol), benzyl (6R)-6-amino-5-oxo-1 ,4-diazepane-1-carboxylate — hydrogen chloride (1/1) (112 mg, 375 pmol) and N,N-diisopropylethylamine (130 pL, 750 pmol) were stirred in DMSO (1 .9 mL) for 2 h at 60 °C. Water was added to the mixture, filtered, washed with water and dried under reduced pressure at 60 °C. to give 90.1 mg (90 % purity, 52 % yield) of the target compound.
LC-MS (Method 1): Rt = 1.38 min; MS (ESIpos): m/z = 627 [M+ H]+
The following intermediate was prepared analogue to the previous one.
Figure imgf000083_0002
Intermediate 39 benzyl (6R)-6-{[2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl]amino}-5-oxo-1 ,4-diazepane-1-carboxylate
Figure imgf000083_0001
5-Chloro-2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine (30.0 mg, 105 pmol), benzyl (6R)-6-amino-5-oxo-1 ,4-diazepane-1-carboxylate (33.2 mg, 126 pmol) and N,N- diisopropylethylamine (55 pL, 320 pmol; CAS-RN: [7087-68-5]) were dissolved in DMSO (1.5 mL) and stirred over night at 60°. The mixture was poured into water, filtered, washed with water, and dried under reduced pressure to get 50.00 mg (90 % purity, 83 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.95 min; MS (ESIpos): m/z = 513 [M+H]+
1H-NMR (400MHz, DMSO-d6): Shift [ppm]= 2.87 - 3.14 (m, 1 H), 3.21 - 3.31 (m, 2H), 3.41 - 3.57 (m, 1 H), 3.97 (s, 3H), 4.11 - 4.30 (m, 1 H), 4.53 - 4.71 (m, 1 H), 4.94 (br dd, 1 H), 5.20 (s, 2H), 7.04 - 7.27 (m, 2H), 7.28 - 7.47 (m, 3H), 7.54 - 7.71 (m, 1 H), 7.70 - 7.80 (m, 1 H), 7.88 (br d, 1 H), 7.93 - 8.03 (m, 1 H), 8.09 (s, 1 H), 8.39 - 8.57 (m, 2H), 8.63 - 8.76 (m, 1 H).
EXPERIMENTAL SECTION - EXAMPLES
Example 1
(3R)-3-{[2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}azepan-2- one
Figure imgf000084_0001
5-Chloro-2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine (75.0 mg, 241 pmol), (3R)-3-aminoazepan-2-one (46.3 mg, 361 pmol) and N,N-diisopropylethylamine (84 pL, 480 pmol) were stirred in DMSO (1000 pL) for 2h at 60°C. The mixture was diluted in DMF and purified by preparative HPLC to give 1.00 mg (90 % purity, 1 % yield) of the target compound.
LC-MS (§HTpost3_basic): Rt = 1.07 min; MS (ESIpos): m/z = 404 [M+H]+
1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.20 - 1.40 (m, 3H), 1.54 - 1.66 (m, 1 H), 1.80 - 2.07 (m, 2H), 2.28 - 2.36 (m, 1 H), 3.12 - 3.23 (m, 1 H), 3.90 (s, 3H), 4.83 - 4.90 (m, 1 H), 7.16 (ddd, 1 H), 7.53 (t, 1 H), 7.75 (dd, 1 H), 7.82 (dd, 1 H), 7.88 - 7.94 (m, 2H), 8.06 (dd, 1 H), 8.23 (dd, 1 H), 8.72 (dd, 1 H).
Example 2
(3R)-3-{[2-(4-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}azepan-2- one
Figure imgf000085_0001
5-Chloro-2-(4-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine (75.0 mg, 241 pmol), (3R)-3-aminoazepan-2-one (46.3 mg, 361 pmol) and N,N-diisopropylethylamine (84 pL, 480 pmol were stirred in DMSO (51 pL) for 2h at 60°C. The mixture was diluted in DMF and purified by preparative HPLC to give 3.00 mg (90 % purity, 3 % yield) of the target compound.
LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 404 [M+ H]+
1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.25 - 1.39 (m, 2H), 1.51 - 1.65 (m, 1 H), 1.81 - 1.90 (m, 2H), 1.97 - 2.06 (m, 1 H), 2.28 - 2.33 (m, 1 H), 3.12 - 3.22 (m, 1 H), 3.87 (s, 3H), 4.85 (dd, 1 H), 7.16 (d, 2H), 7.73 (dd, 1 H), 7.87 (d, 1 H), 8.05 (dd, 1 H), 8.21 - 8.27 (m, 3H), 8.71 (dd, 1 H). Example 3
(3S)-3-{[2-(4-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}azepan-2- one
Figure imgf000085_0002
5-Chloro-2-(4-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine (25.0 mg, 80.2 pmol), (3S)-3-aminoazepan-2-one — hydrogen chloride (1/1) (19.8 mg, 120 pmol) and N,N- diisopropylethylamine (42 pL, 240 pmol) were stirred in DMSO (330 pL) for 2h at 60°C. The mixture was diluted with DMF and purified by preparative HPLC to give 2.00 mg (90 % purity, 6 % yield) of the target compound.
LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 404 [M+ H]+ 1H-NMR (400MHz, DMSO-d6): 5 [ppm]= 1.21 - 1.36 (m, 3H), 1.51 - 1.64 (m, 1 H), 1.80 - 1.93 (m, 2H), 1.97 - 2.07 (m, 1 H), 2.27 - 2.32 (m, 1H), 3.87 (s, 3H), 4.81 - 4.89 (m, 1 H), 7.14 - 7.19 (m, 2H), 7.71 - 7.75 (m, 1H), 7.87 (d, 1 H), 8.05 (dd, 1 H), 8.21 - 8.27 (m, 3H), 8.71 (dd, 1 H).
Example 4
(3R)-3-{[2-(3-methoxyphenyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]amino}pyrrolidin-2- one
Figure imgf000086_0001
5-Chloro-2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine (75.0 mg, 241 pmol), (3R)-3-aminopyrrolidin-2-one (36.1 mg, 361 pmol) and N,N-diisopropylethylamine (84 pL, 480 pmol) were stirred in DMSO (1000 pL) for 2h at 60°C. The mixture was diluted with D F and purified by preparative HPLC to give 21.0 mg (95 % purity, 22 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.93 min; MS (ESIneg): m/z = 374 [M-H]-
1H-NMR (400MHz, DMSO-d6): 5 [ppm]= 2.26 - 2.40 (m, 1 H), 3.90 (s, 3H), 4.93 - 5.05 (m, 1H), 7.15 (ddd, 1 H), 7.53 (t, 1 H), 7.73 (dd, 1H), 7.86 (dd, 1H), 7.92 (dt, 1H), 7.99 - 8.05 (m, 2H), 8.56 (d, 1 H), 8.70 (dd, 1H).
Example 5
(3S)-3-{[2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1,5-c]pyrimidin-5-yl]amino}pyrrolidin-2- one
Figure imgf000086_0002
5-Chloro-2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine (25.0 mg, 80.2 pmol), (3S)-3-aminopyrrolidin-2-one (12.0 mg, 120 pmol) and N,N-diisopropylethylamine (28 pL, 160 pmol) were stirred in DMSO (330 pL) for 2h at 60°C. The mixture was diluted with DMF and purified by preparative HPLC to give 6.00 mg (95 % purity, 19 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.92 min; MS (ESIneg): m/z = 374 [M-H]-
1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 2.27 - 2.38 (m, 1 H), 3.90 (s, 3H), 4.94 - 5.04 (m, 1 H), 7.15 (ddd, 1 H), 7.53 (t, 1 H), 7.73 (dd, 1 H), 7.86 (dd, 1 H), 7.93 (dd, 1 H), 7.99 - 8.05 (m, 2H), 8.56 (d, 1 H), 8.70 (dd, 1 H).
Example 6
(3S)-3-{[2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}piperidin-2- one
Figure imgf000087_0001
5-Chloro-2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine (25.0 mg, 80.2 pmol), (3S)-3-aminopiperidin-2-one — hydrogen chloride (1/1) (18.1 mg, 120 pmol) and N,N- diisopropylethylamine (42 pL, 240 pmol) were stirred in DMSO (500 pL) for 2h at 60°C. The mixture was diluted with DMF and purified by preparative HPLC to give 5.00 mg (95 % purity, 15 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.99 min; MS (ESIneg): m/z = 388 [M-H]-
1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.86 - 1.97 (m, 2H), 2.05 - 2.18 (m, 1 H), 2.23 - 2.31 (m, 1 H), 3.22 - 3.29 (m, 2H), 3.90 (s, 3H), 4.70 - 4.79 (m, 1 H), 7.15 (ddd, 1 H), 7.53 (t, 1 H), 7.70 - 7.75 (m, 1 H), 7.83 (br s, 1 H), 7.85 (dd, 1 H), 7.92 (dt, 1 H), 8.03 (dd, 1 H), 8.43 (d, 1 H), 8.70 (dd, 1 H).
Example 7
(3R)-3-{[2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl]amino}azepan-2-one
Figure imgf000088_0001
5-Chloro-2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine (111 mg, 389 pmol), (3R)-3-aminoazepan-2-one (74.7 mg, 583 pmol) and N,N-diisopropylethylamine (200 pL, 1.2 mmol) were stirred in DMSO for 2h at 60°C (UPLC - 1 PC1 : ok). The mixture was diluted with water, filtered, washed with water and dried under reduced pressure at 60°C to give 54.3 mg (100 % purity, 37 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.84 min; MS (ESIpos): m/z = 378 [M+H]+
1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.19 - 1.38 (m, 1 H), 1.46 - 1.63 (m, 1 H), 1.86 (td, 2H), 1.96 - 2.07 (m, 1 H), 2.25 - 2.36 (m, 1 H), 3.08 - 3.22 (m, 1 H), 3.34 - 3.44 (m, 1 H), 3.96 (s, 3H), 4.83 (dd, 1 H), 7.67 - 7.79 (m, 2H), 8.04 (dd, 1 H), 8.09 (d, 1 H), 8.24 (dd, 1 H), 8.51 (s, 1 H), 8.69 (dd, 1 H).
Example 8
(3R)-3-{[2-(4-methoxyphenyl)pyrido[4,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}azepan-2- one
Figure imgf000088_0002
5-Chloro-2-(4-methoxyphenyl)pyrido[4,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidine (85.0 mg, 273 pmol), (3R)-3-aminoazepan-2-one (69.9 mg, 545 pmol) and N,N-diisopropylethylamine (140 pL, 820 pmol) were stirred in DMSO (1000 pL) for 2h at 60°C. Water was added, the mixture was lyophilised, the residue was dissolved in DMSO and purified by HPLC to give 10.0 mg (95 % purity, 9 % yield) of target compound.
LC-MS (Method 2): Rt = 1.10 min; MS (ESIpos): m/z = 404 [M+H]+ 1H-NMR (400MHz, DMS0-d6): 6 [ppm]= 1.30- 1.36 (m, 1H), 1.53- 1.65 (m, 1H), 1.82-1.91 (m, 2H), 2.00 - 2.08 (m, 1H), 2.33 - 2.37 (m, 1H), 3.13 - 3.22 (m, 1H), 3.36 - 3.42 (m, 1H), 3.86 (s, 3H), 4.82 - 4.89 (m, 1H), 7.13 - 7.19 (m, 2H), 7.93 (d, 1H), 8.15 (dd, 1H), 8.22 - 8.27 (m, 3H), 8.54 (d, 1H), 9.01 (d, 1H). Example 9
(3R)-3-{[2-(4-fluorophenyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]amino}azepan-2-one
Figure imgf000089_0001
5-Chloro-2-(4-fluorophenyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (75.0 mg, 250 pmol), (3R)-3-aminoazepan-2-one (35.3 mg, 275 pmol) and N,N-diisopropylethylamine (130 pL, 750 pmol) were stirred in DMSO (1.7 mL) for 2h at 60°C. The mixture was diluted with water and extracted three times with ethyl acetate. The aqueous phase was dried at the lyo and purified by HPLC to give 7.00 mg (100 % purity, 7 % yield) of target compound.
LC-MS (Method 2): Rt = 1.09 min; MS (ESIpos): m/z = 392 [M+H]+
1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 1.27- 1.39 (m, 1H), 1.52- 1.64 (m, 1H), 1.80- 1.94 (m, 2H), 1.98 - 2.07 (m, 1H), 2.28- 2.36 (m, 1H), 3.11 - 3.22 (m, 1H), 4.85 (br dd, 1H), 7.41 - 7.49
(m, 2H), 7.74 (dd, 1H), 7.90 (d, 1H), 8.06 (dd, 1H), 8.24 (dd, 1H), 8.32 - 8.38 (m, 2H), 8.72 (dd, 1H).
Example 10
4-(5-{[(3R)-2-oxoazepan-3-yl]amino}pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-2-yl)benzonitrile
Figure imgf000090_0001
4-(5-Chloropyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-2-yl)benzonitrile (100 mg, 326 pmol), (3R)-3-aminoazepan-2-one — hydrogen chloride (1/1) (80.5 mg, 489 pmol) and N,N- diisopropylethylamine (170 L, 980 pmol) were stirred in DMSO (3.0 mL) for 2 h at 60°C. The reaction mixture was then cooled to rt and diluted with water. The solid was filtered, washed with water and dried under reduced pressure at 60°C to give 102 mg (95 % purity, 75 % yield) of the title product.
LC-MS (Method 1): Rt = 1.08 min; MS (ESIpos): m/z = 399 [M+ H]+
1H-NMR (400MHz, DMSO-de): 6 [ppm]= 1.25 - 1.39 (m, 1 H), 1.54 - 1.65 (m, 1 H), 1.77 - 1.97 (m, 2H), 1.97 - 2.07 (m, 1 H), 2.29 - 2.36 (m, 1 H, partial in DMSO signal), 3.12 - 3.22 (m, 1H), 3.28 -
3.43 (m, 1 H, partial in water signal), 4.86 (br dd, 1H), 7.76 (dd, 1H), 7.96 (d, 1 H), 8.04 - 8.13 (m, 3H), 8.25 (dd, 1H), 8.44 - 8.50 (m, 2H), 8.73 (dd, 1 H).
The following example was prepared analogue to the previous one.
Figure imgf000091_0002
Example 12
(3R)-3-({2-[1-(propan-2-yl)-1H-pyrazol-4-yl]pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5- yl}amino)azepan-2-one
Figure imgf000091_0001
5-Chloro-2-[1-(propan-2-yl)-1 H-pyrazol-4-yl]pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (35.0 mg, 112 pmol) and (3R)-3-aminoazepan-2-one hydrochloride (20.2 mg, 123 pmol) were dissolved in DMSO (1.0 mL) and N,N-diisopropylethylamine (39 pL, 220 pmol; CAS-RN:[7087- 68-5]) was added. The mixture was stirred 2h at 60°C. The mixture was filtered and purified by preparative HPLC to get 3.00 mg (90 % purity, 6 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.96 min; MS (ESIneg): m/z = 404 [M-H]-
1H-NMR (400MHz, CHLOROFORM-d): 6 [ppm]= 1.39 - 1.46 (m, 1 H), 1.59 (d, 6H), 1.67 - 1.79 (m, 1 H), 1.93 - 2.06 (m, 2H), 2.12 - 2.23 (m, 1 H), 2.44 (br d, 1 H), 3.31 - 3.42 (m, 1 H), 3.42 - 3.54 (m, 1 H), 4.59 (quin, 1 H), 4.91 - 5.00 (m, 1 H), 6.06 (br t, 1 H), 7.57 (dd, 1 H), 7.67 (br d, 1 H), 8.00 (dd, 1 H), 8.30 (d, 2H), 8.74 (dd, 1 H).
Example 13
(3R)-3-{[2-(1-methyl-1 H-pyrazol-4-yl)pyrido[4,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl]amino}azepan-2-one
Figure imgf000092_0001
5-Chloro-2-(1-methyl-1 H-pyrazol-4-yl)pyrido[4,3-e][1 ,2 ,4]triazolo[1 ,5-c]pyrimidine (20.0 mg, 70.0 pmol), (3R)-3-aminoazepan-2-one (10.8 mg, 84.0 pmol) and N,N-diisopropylethylamine (37 pL, 210 pmol; CAS-RN: [7087-68-5]) were dissolved in DMSO (1.5 mL) and stirred over night at 60°C. The mixture was poured into water (15 mL) and extracted three times with ethyl acetate, the organic phase was dried over a hydrophobic sillicone filter and concentrated. The residue was purified using a preparative TLC, (eluent: 10% ethanol in dichloromethane) to get 8.00 mg (95 % purity, 29 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.86 min; MS (ESIpos): m/z = 378 [M+H]+
1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 9.00 (d, 1 H), 8.55-8.51 (m, 2H), 8.31-8.21 (m, 1 H), 8.11-8.08 (m, 2H), 7.82 (d, 1 H), 4.85 (br dd, 1 H), 3.96 (s, 3H), 2.30 (br s, 1 H), 2.01 (br s, 1 H), 1.92-1.80 (m, 2H), 1.62-1.51 (m, 2H)
Example 14
(3R)-3-{[2-(1 ,3-dimethyl-1 H-pyrazol-4-yl)pyrido[3,2-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl]amino}azepan-2-one
Figure imgf000093_0001
Step 1 :
2-(1 ,3-Dimethyl-1 H-pyrazol-4-yl)pyrido[3,2-e][1 ,2 ,4]triazolo[1 ,5-c]pyrimidin-5(6H)-one (37.9 mg, 135 pmol) was treated with phosphorus oxychloride (190 pL, 2.0 mmol; CAS-RN: [10025-87-3]), stirred 10 min. at rt, then N,N-diisopropylethylamine (120 pL, 670 pmol; CAS-RN: [7087-68-5]) was added and the mixture was stirred two days at 90°C.
Step 2:
The mixture was poured into ice water (2.5 mL), dissolved directly with DMSO (2.5 mL) and basified to pH 8 using N,N-diisopropylethylamine (1.0 mL, 6.0 mmol; CAS-RN:[7087-68-5]). In a separate flask, (3R)-3-aminoazepan-2-one hydrochloride (16.5 mg, 100 pmol) was dissolved in DMSO and treated with N,N-diisopropylethylamine (0.5 mL, 3.0 mmol; CAS-RN: [7087-68-5]). Both mixtures were combined and stirred 2h at 60°C. Water was added to the mixture and extracted three times with DCM, the combined organic phases were dried over a hydrophobic silicone filter and concentrated. The residue was purified by flash chromatography to get 3.70 mg (90 % purity, 17 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.86 min; MS (ESIpos): m/z = 392 [M+H]+
1H-NMR (400MHz, CHLOROFORM-d): 6 [ppm]= 1.25 (s, 1 H), 1.42 - 1.59 (m, 2H), 1.70 - 1.80 (m, 1 H), 1 .86 - 2.04 (m, 1 H), 2.49 (br dd, 1 H), 2.69 - 2.72 (m, 3H), 3.27 - 3.40 (m, 1 H), 3.44 (br dd, 1 H), 3.90 - 3.95 (m, 3H), 5.10 (ddd, 1 H), 6.13 (br t, 1 H), 7.34 (dd, 1 H), 7.84 (br d, 1 H), 8.08 (s, 1 H), 8.63 - 8.76 (m, 1 H), 8.89 (dd, 1 H).
Example 15
(6R)-6-{[2-(3-fluorophenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}-1 ,4-diazepan- 5-one
Figure imgf000094_0001
Benzyl (6R)-6-{[2-(3-fluorophenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}-5-oxo- 1 ,4-diazepane-1 -carboxylate (60.0 mg, 114 pmol) was solubilised in dichloromethane (1.8 mL), hydrobromic acid (200 pL, 33 % purity in acetic acid, 1.1 mmol) was added and the mixture was stirred for 2h at rt. The suspension was diluted with ethyl acetate, filtered and the solid was stirred in methanol/ dichloromethane, basified with triethylamine and evaporated. The resulting solid was washed, filtered with ethyl acetate and acetonitril/water (95:5) and dried under reduced pressure at 60°C to give 19.2 mg (90 % purity, 39 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.81 min; MS (ES+): m/z = 393 [M+H]+
Example 16
(6R)-6-{[2-(4-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}-1 ,4- diazepan-5-one
Figure imgf000094_0002
Benzyl (6R)-6-{[2-(4-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}-5- oxo-1 , 4-diazepane-1 -carboxylate (115 mg, 214 pmol) was solubilised in dichloromethane (3.6 mL), hydrobromic acid (380 pL, 33 % purity in acetic acid, 2.1 mmol) was added and the mixture was stirred for 2h at rt. The suspension was diluted with ethyl acetate, filtered and the solid was stirred in methanol/ dichloromethane, basified with triethylamine and evaporated to give 49.5 mg (96 % purity, 55 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.86 min; MS (ES+): m/z = 405 [M+H]+ 1 H-NMR (400MHz, DMS0-d6): 6 [ppm]= 2.57 - 2.66 (m, 1 H), 2.84 (br t, 1 H), 3.08 - 3.21 (m, 2H), 3.48 (br d, 2H), 3.85 (br d, 1 H), 3.87 (s, 3H), 4.97 (br s, 1 H), 7.14 - 7.19 (m, 2H), 7.75 (dd, 1 H), 7.88 (br d, 1 H), 8.06 (dd, 1 H), 8.22 - 8.27 (m, 2H), 8.37 (br d, 1 H), 8.72 (dd, 1 H).
Example 17
(6R)-6-{[2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}-1 ,4- diazepan-5-one
Figure imgf000095_0001
Benzyl (6R)-6-{[2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl]amino}-5-oxo-1 ,4-diazepane-1 -carboxylate (50.0 mg, 90 % purity, 87.8 pmol) was suspended in ethyl acetate (2.5 mL) and hydrobromic acid (20 pL, 32 % in acetic acid, 640 pmol; CAS- RN:[10035-10-6]) was added and the suspension was stirred over night at 40°C. The solid was filtered, washed twice with sodium hydroxide solution (3 M) and three times with water. The solid was dried under reduced pressure at 60°C to get 15.0 mg (93 % purity, 42 % yield) of the target compound.
LC-MS (Method 2): Rt = 0.62 min; MS (ESIpos): m/z = 379 [M+H]+
1H-NMR (400MHz, DMSO-de): 6 [ppm]= 2.60 - 2.66 (m, 1 H), 2.84 - 2.98 (m, 1 H), 2.98 - 3.05 (m, 1 H), 3.05 - 3.18 (m, 1 H), 3.38 - 3.51 (m, 2H), 3.96 (s, 3H), 4.74 - 5.03 (m, 1 H), 7.62 - 7.83 (m, 2H), 7.99 - 8.13 (m, 2H), 8.32 (br dd, 1 H), 8.50 (s, 1 H), 8.70 (br d, 1 H).
Example 18
(6R)-6-({2-[4-chloro-2-(trifluoromethoxy)phenyl]pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl}amino)-1 ,4-diazepan-5-one
Figure imgf000096_0001
Benzyl (6R)-6-({2-[4-chloro-2-(trifluoromethoxy)phenyl]pyrido[2,3-e][1 ,2 ,4]triazolo[1 ,5- c]pyrimidin-5-yl}amino)-5-oxo-1 ,4-diazepane-1 -carboxylate (81.5 mg, 130 pmol) was solubilised in dichloromethane (3.4 mL), hydrobromic acid in acetic acid (210 pL, 33 %, 1.3 mmol) was added and the mixture was stirred for 2 h at rt. The formed solid was obtain by filtration. The solid was stirred in methanol and basified with triethylamine. The resulting suspension was filtered, washed with methanol and dried under reduced pressure at 40 °C to give 25.5 mg (95 % purity, 38 % yield) of the title compound.
LC-MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z = 493 [M+H]+ 1H-NMR (400MHz, DMSO-de): 0 [ppm]= 2.50 - 2.54 (m, 1 H, partial in DMSO signal), 2.64 (dd, 1 H), 2.84 - 3.06 (m, 1 H), 3.07 - 3.17 (m, 1 H), 3.35 - 3.48 (m, 1 H), 4.83 - 4.89 (m, 1 H), 7.76 - 7.82 (m, 1 H), 7.86 (d, 1 H), 8.09 (dd, 1 H), 8.30 (dd, 1 H), 8.45 (d, 1 H), 8.74 (dd, 1 H).
The following example was prepared analogue to the previous one.
Figure imgf000097_0001
EXPERI MENTAL SECTION - BIOLOGICAL ASSAYS
Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein
® the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and
® the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch. The in vitro activity of the compounds of the present invention can be demonstrated in the following assays:
Transactivation Assay in human cell line (in vitro assays 1 and 2) Transactivation assays were carried out in U87 MG glioblastoma cells (ATCC #HTB-14) endogenously expressing AHR. In addition the cells were stably transfected with an AHR inducible firefly luciferase reporter gene construct that carried AHR-binding sites (DRE) in its promoter and a renilla reporter gene construct with constitutively active promoter. Kynurenic acid is an endogenous AHR activating ligand and was used to prestimulate test cells prior to testing the antagonistic properties of compounds.
In vitro assay 1 : Antagonism in human cell line
Cells in medium (tryptophan free RPMI (PAN-Biotech #P04-17598), 1 % FCS (Biochrome Superior #S0615), 1 x Penicillin/Streptomycin (Sigma P0781)) supplemented with 150 pM kynurenic acid were grown for 20 hours in absence (negative control) or presence of increasing concentrations of test compounds (typical dilutions: 72 pmol/L, 0.25 nmol/L, 0.89 nmol/L; 3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470 nmol/L, 1.6 pmol/L, 5.7 pmol/L and 20 pmol/L in duplicates). As positive inhibition control cells supplemented with 150 pM kynurenic acid were incubated in presence of 5 pM Staurosporin. Normalization was done by positive and negative controls.
Firefly luciferase and Renilla activity was determined by the DualGlo Luciferase Assay System (Promega, #2920). Renilla activity was used to assess toxic effects of compounds.
In vitro assay 2: Agonism in human cell line
Cells in medium (tryptophan free RPMI (PAN-Biotech #P04-17598), 1 % FCS (Biochrome Superior #S0615), 1 x Penicillin/Streptomycin (Sigma P0781)) were grown for 20 hours in absence (negative control) or presence of increasing concentrations of test compounds (typical dilutions: 72 pmol/L, 0.25 nmol/L, 0.89 nmol/L; 3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470 nmol/L, 1.6 pmol/L, 5.7 pmol/L and 20 pmol/L in duplicates). As positive activation control cells were incubated with 300 pM kynurenic acid. Normalization was done by positive and negative controls.
Firefly luciferase activity was determined by the SteadyGlo Luciferase Assay System (Promega, #E2520).
Transactivation Assay in mouse cell line (in vitro assays 3 and 4)
Transactivation assays were carried out in Hepa 1c1c7 cells (ATCC #CRL-2026) endogenously expressing AHR. In addition the cells were stably transfected with an AHR inducible firefly luciferase reporter gene construct that carried AHR-binding sites (DRE) in its promoter. Kynurenic acid is an endogenous AHR activating ligand and was used to prestimulate test cells prior to testing the antagonistic properties of compounds.
In vitro assay 3: Antagonism in mouse cell line Cells in medium (tryptophan free RPMI (PAN-Biotech #P04-17598), 1 % FCS (Biochrome Superior #S0615), 1 x Penicillin/Streptomycin (Sigma P0781)) supplemented with 200 pM kynurenic acid (Sigma #K3375) were grown for 20 hours in absence (negative control) or presence of increasing concentrations of test compounds (typical dilutions: 72 pmol/L, 0.25 nmol/L, 0.89 nmol/L; 3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470 nmol/L, 1.6 pmol/L, 5.7 pmol/L and 20 pmol/L in duplicates). As positive inhibition control cells without addition of kynurenic acid were incubated. Normalization was done by positive and negative controls.
Firefly luciferase activity was determined by the SteadyGlo Luciferase Assay System (Promega, #E2550).
In vitro assay 4: Agonism in mouse cell line
Cells in medium (tryptophan free RPMI (PAN-Biotech #P04-17598), 1 % FCS (Biochrome Superior #S0615), 1 x Penicillin/Streptomycin (Sigma P0781)) were grown for 20 hours in absence (negative control) or presence of increasing concentrations of test compounds (typical dilutions: 72 pmol/L, 0.25 nmol/L, 0.89 nmol/L; 3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470 nmol/L, 1.6 pmol/L, 5.7 pmol/L and 20 pmol/L in duplicates). As positive activation control cells were incubated with 400 pM kynurenic acid. Normalization was done by positive and negative controls.
Firefly luciferase activity was determined by the SteadyGlo Luciferase Assay System (Promega, #2520).
Table 2: IC50 values of examples in in vitro assays 1 and 3
Figure imgf000100_0001

Claims

1. A compound of general formula (I):
Figure imgf000101_0001
in which
A1 represents CR5 or N;
A2 represents CR6 or N;
A3 represents CR7 or N;
A4 represents CR8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
R1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, C1-C4- hydroxyalkyl, Ci-C4-alkoxy-Ci-C4-alkyl-, Cs-Ce-cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl,
-NR9R10, R9R10N-Ci-C4-alkyl-, Ci-C3-alkyl-S(O)m- or Ci-C3-alkyl-SO(NH)-;
R2 represents hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl or C3-C6-cycloalkyl;
R3 represents hydrogen, Ci-Ce-alkyl, phenyl or phenyl-Ci-C3-alkyl, wherein said Ci-Ce-alkyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, Ci-C4-alkoxy, -S(O)n-Ci-C4-alkyl, phenyl-Ci-C3-alkoxy or -NR9R10 and said phenyl groups are optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl,
Ci-C3-alkoxy or Ci-C3-haloalkoxy, or
R2 and R3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C4-alkyl group;
R4 represents hydroxy, Ci-C4-alkoxy or -NR11R12, or R2 and R4 together represent *-C2-Cs-alkanediyl-X1-**, *-Ci-C2-alkanediyl-X2-Ci-Cs- alkanediyl-** or *-Ci-C2-alkanediyl-X2-C2-C3-alkanediyl-X1-** to form a 5- to 9-membered ring, wherein * indicates the point of attachment of said group for R2 and ** indicates the point of attachment of said group for R4;
R5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl, 1-R15-C3-C6-cycloalkyl, -CC>2-Ci-C4-alkyl, -CO-NR9R10, -NR9R10, Ci-C4-hydroxyalkyl, Ci-C4-alkoxy-Ci-C4-alkyl-, Ci-C4-alkyl-S-, Ci-C4-alkyl-S-Ci-C4-alkyl-, -S(=O)R’, -S(=O)2R’, -S(=O)2NH2, -S(=O)2NHR’, -S(=O)2N(R’)R”, -S(=O)(=NH)R’, 4- to 6-membered heterocycloalkyl, or -OR16;
R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents Ci-C4-alkyl or C1-C4- alkoxycarbonyl;
R11 and R12 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C2-C4-hydroxyalkyl, Ci-C4-alkoxy-C2-C4-alkyl-, R9R10N-C2-C4-alkyl-, Cs-Ce- cycloalkyl, 4- to 7-membered heterocycloalkyl, said 4- to 7-membered heterocycloalkyl group is optionally substituted, one or two times, independently from each other, with hydroxy, oxo, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents Ci-C4-alkyl or C1-C4- alkoxycarbonyl and is optionally substituted, one or two times, independently from each other, with hydroxy, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10, or together with the nitrogen atom to which they are attached form a heterospirocycloalkyl group, which is optionally substituted, one or two times, independently from each other, with hydroxy, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10, or together with the nitrogen atom to which they are attached form a bridged heterocycloalkyl group, which is optionally substituted, one or two times, independently from each other, with hydroxy, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, or -NR9R10;
R13 represents hydrogen, Ci-C4-alkyl, benzyl, 4-methoxybenzyl or tert-butoxycarbonyl;
R14 represents hydrogen, Ci-C4-alkyl, benzyl or 4-methoxybenzyl;
R15 represents Ci-Cs-alkyl or Ci-Cs-haloalkyl;
R16 represents C2-Ce-hydroxyalkyl, Ci-C4-alkoxy-C2-Ce-alkyl-, or Cs-Ce-cycloalkyl;
R’ and R” represent, independently from each other, Ci-Ce-alkyl, Ci-Ce-haloalkyl, or Cs-Ce- cycloalkyl;
X1 represents O, S(O)m, or NR13;
X2 represents O, S(O)m, or NR14; m represents 0, 1 or 2; n represents 0, 1 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
2. The compound according to claim 1 , wherein:
A1 represents CR5 or N;
A2 represents CR6 or N;
A3 represents CR7 or N;
A4 represents CR8 or N, wherein the total number of N is 1 or 2 and no two N are at neighbouring positions;
R1 represents phenyl or heteroaryl, optionally substituted one to three times, independently from each other, with halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-haloalkyl, Ci-C4-haloalkoxy, Cs-Ce- cycloalkyl, C3-C6-cycloalkyl-Ci-C4-alkyl-, Cs-Ce-cycloalkyl-O-, 4- to 6-membered heterocycloalkyl, -NR9R10 or R9R10N-Ci-C4-alkyl;
R2 represents hydrogen, Ci-C4-alkyl, Ci-C4-haloalkyl or Cs-Ce-cycloalkyl;
R3 represents hydrogen, Ci-Ce-alkyl, phenyl or phenyl-Ci-Cs-alkyl, wherein said Ci-Ce-alkyl group is optionally substituted, one or more times, independently from each other, with hydroxy, halogen, Ci-C4-alkoxy, -S(O)n-Ci-C4-alkyl, phenyl- Ci-Cs-alkoxy or -NR9R10 and said phenyl groups are optionally substituted, one or more times, independently from each other, with hydroxy, halogen, cyano, Ci-Cs-alkyl, Ci-Cs-haloalkyl,
Ci-Cs-alkoxy or Ci-Cs-haloalkoxy, or
R2 and R3 together with the carbon atom to which they are attached form a 3- to 6-membered ring, said ring optionally containing one heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C4-alkyl group;
R4 represents hydroxy, Ci-C4-alkoxy or -NR11R12, or
R2 and R4 together represent *-C2-Cs-alkanediyl-X1-**, *-Ci-C2-alkanediyl-X2-Ci-Cs- alkanediyl-** or *-Ci-C2-alkanediyl-X2-C2-C3-alkanediyl-X1-** to form a 5- to 9-membered ring, wherein * indicates the point of attachment of said group for R2 and ** indicates the point of attachment of said group for R4;
R5 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R6 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R7 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R8 represents hydrogen, halogen, cyano, hydroxy, Ci-C4-alkyl, Ci-C4-alkoxy, C1-C4- haloalkyl, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyl or -NR9R10;
R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-Cs-alkyl or tert-butoxycarbonyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C4-alkyl group;
R11 and R12 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl or Cs-Ce-cycloalkyl, wherein said Ci-C4-alkyl group is optionally substituted with hydroxy;
R13 represents hydrogen, Ci-C4-alkyl, benzyl, 4-methoxybenzyl or tert-butoxycarbonyl;
R14 represents hydrogen, Ci-C4-alkyl, benzyl or 4-methoxybenzyl;
X1 represents O or NR13;
X2 represents O or NR14; n represents 0, 1 or 2; their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same.
3. The compound according to claim 1or 2, which is selected from the group consisting of:
(3R)-3-{[2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}azepan- 2-one
(3R)-3-{[2-(4-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}azepan-
2-one
(3S)-3-{[2-(4-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}azepan- 2-one
(3R)-3-{[2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl]amino}pyrrolidin-2-one
(3S)-3-{[2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl]amino}pyrrolidin-2-one
(3S)-3-{[2-(3-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}piperidin- 2-one
(3R)-3-{[2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl]amino}azepan-2-one
(3R)-3-{[2-(4-methoxyphenyl)pyrido[4,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}azepan- 2-one
(3R)-3-{[2-(4-fluorophenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}azepan-2- one
4-(5-{[(3R)-2-oxoazepan-3-yl]amino}pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-2- yl)benzonitrile
(3R)-3-({2-[4-chloro-2-(trifluoromethoxy)phenyl]pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl}amino)azepan-2-one
(3R)-3-({2-[1-(propan-2-yl)-1 H-pyrazol-4-yl]pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl}amino)azepan-2-one
(3R)-3-{[2-(1-methyl-1 H-pyrazol-4-yl)pyrido[4,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl]amino}azepan-2-one
(3R)-3-{[2-(1 ,3-dimethyl-1 H-pyrazol-4-yl)pyrido[3,2-e][1 ,2 ,4]triazolo[1 ,5-c]pyrimidin-5- yl]amino}azepan-2-one (6R)-6-{[2-(3-fluorophenyl)pyrido[2,3-e][1 ,2 ,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}-1 ,4- diazepan-5-one
(6R)-6-{[2-(4-methoxyphenyl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}-1 ,4- diazepan-5-one
(6R)-6-{[2-(1-methyl-1 H-pyrazol-4-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}- 1 ,4-diazepan-5-one
(6R)-6-({2-[4-chloro-2-(trifluoromethoxy)phenyl]pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5- yl}amino)-1 ,4-diazepan-5-one
(6R)-6-{[2-(5-chlorothiophen-3-yl)pyrido[2,3-e][1 ,2,4]triazolo[1 ,5-c]pyrimidin-5-yl]amino}-1 ,4- diazepan-5-one their polymorphs, enantiomeres, diastereomeres, racemates, tautomeres, N-oxides, hydrates and solvates, as well as their physiological acceptable salts and solvates of these salts, as well as mixtures of the same. method of preparing a compound of general formula (I) according to any one of claims 1 to
3, said method comprising the step of allowing an intermediate compound of general formula (V):
Figure imgf000106_0001
(V), in which R1 , A1 , A2, A3 and A4 are as defined for the compound of general formula (I) according to any one of claims 1 to 2, to react with a compound of general formula (VII):
Figure imgf000106_0002
(VII), in which R2, R3 and R4 are as defined for the compound of general formula (I) according to any one of claims 1 to 2, thereby giving a compound of general formula (I):
Figure imgf000107_0001
(I), in which R1, R2, R3, R4, A1, A2, A3 and A4 are as defined for the compound of general formula
(I) according to any one of claims 1 to 2. A compound of general formula (I) according to any one of claims 1 to 3 for use in the treatment or prophylaxis of a disease. pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 3 and one or more pharmaceutically acceptable excipients. pharmaceutical combination comprising:
® one or more first active ingredients, in particular compounds of general formula (I) according to any one of claims 1 to 3, and
® one or more pharmaceutical active anti cancer compounds or
® one or more pharmaceutical active immune checkpoint inhibitors. Use of a compound of general formula (I) according to any one of claims 1 to 3 for the treatment or prophylaxis of a disease. Use of a compound of general formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for the treatment or prophylaxis of a disease. Use according to claim 8 or 9, wherein the disease is cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, such as liquid and solid tumours, for example. A compound of general formula (V):
Figure imgf000108_0001
(V), in which R1 , A1 , A2, A3 and A4 are as defined for the compound of general formula (I) according to any one of claims 1 to 2. Use of a compound of general formula (V)
Figure imgf000108_0002
(V), in which R1 , A1 , A2, A3 and A4 are as defined for the compound of general formula (I) according to any one of claims 1 to 2, for the preparation of a compound of general formula (I) according to any one of claims 1 to 3.
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