Compounds used cgas inhibitors for the treatment of inflammatory and / or autoimmune diseases

Abstract

The present invention relates to novel compounds, to said compounds for use as a medicine, more in particular for the prevention or treatment of diseases mediated by activity of cGAS, yet more in particular for the prevention or treatment of inflammation conditions or cancer. The present invention also relates to a method for the prevention or treatment of said diseases comprising the use of the novel compounds. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the novel compounds as well as to said compositions or preparations for use as a medicine, more preferably for the prevention or treatment of diseases mediated by activity of cGAS, yet more in particular for the prevention or treatment of inflammation conditions or cancer. The present invention also relates to processes for the preparation of said compounds.

Description

[0001] NOVEL COMPOUNDS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel compounds. The present invention also relates to said compounds for use as a medicine, more in particular for the prevention or treatment of diseases mediated by activity of cyclic GMP-AMP synthase (cGAS), yet more in particular for the prevention or treatment of inflammatory and / or autoimmune diseases. The present invention also relates to a method for the prevention or treatment of said diseases comprising the use of the novel compounds.

[0004] The present invention furthermore relates to pharmaceutical compositions or combination preparations of the novel compounds as well as to said compositions or preparations for use as a medicine, more preferably for the prevention or treatment of diseases mediated by activity of cGAS, yet more in particular for the prevention or treatment of inflammatory and / or autoimmune diseases. The present invention also relates to processes for the preparation of said compounds. The invention also relates to combinations of the novel compounds with other therapeutic agents.

[0005] BACKGROUND OF THE INVENTION

[0006] Innate immunity is considered a first line cellular stress response defending the host cell against invading pathogens and initiating signaling to the adaptive immune system. These processes are triggered by conserved pathogen-associated molecular patterns (PAMPs) through sensing by diverse pattern recognition receptors (PRRs) and subsequent activation of cytokine and type I interferon gene expression. The major antigen-presenting cells, such as monocytes, macrophages, and dendritic cells, produce type I interferons and are critical for eliciting adaptive T- and B-cell immune system responses. The major PRRs detect aberrant, i.e. mislocalized, immature or unmodified nucleic acids on either the cell surface, the inside of lysosomal membranes or within other cellular compartments (Barbalat et al., Annu. Rev. Immunol. 29, 185-214 (2011)).

[0007] Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a key sensor of cytosolic double-strand DNA, serving as ubiquitous danger-associated molecules when originating from microbial source or host sources that can be mitochondrial, extracellular (engulfment tissue damage DNA by myeloid cells) or nuclear (retroelements reverse transcription, nuclear damage). Upon dsDNA binding, cGAS catalyses synthesis of cyclic nucleotide (and 2nd messenger) cGAMP from one ATP and one GTP. cGAMP binds the ER-resident dimeric transmembrane receptor stimulator of interferon genes (STING) causing its activation and exit from ER. STING translocates to the Golgi apparatus where it recruits and activates TANK-binding kinase 1 (TBK1) causing phosphorylation and activation of interferon regulatory transcription factor 3 (IRF3). Next, IRF3 dimerizes and translocates to the nucleus where it promotes expression of type I interferons(IFN-I). In addition, STING also activates the canonical NFKP pathway through the kinase IKKp leading to the production of pro-inflammatory cytokines.

[0008] The cGAS-STING signaling pathway has emerged as a key mediator of inflammation in the settings of infection, cellular stress and tissue damage which are important in different disease indications. Rare genetic diseases like Type I interferonopathies, driven by loss-of-function mutations in cytosolic nucleases (TREX1, SAMHD1, DNASE2), cause accumulation of cytosolic dsDNA which amplifies cGAS-STING signaling and Type I IFN responses. These are the most obvious auto-immune diseases that would benefit from cGAS inhibition (e.g. Aicardi Goutieres Syndrome (AGS), TREX1 subsets of lupus, heterozygous TR EX1 mutation in Familial Chilblain Lupus). Mitochondrial leakage or defects causing accumulation of mtDNA in the cytosol is increasingly recognized as an underlying pathologic inflammatory response in neurodegenerative diseases like Parkinson’s disease subsets (TDP43, PINK1-Perkin), Amyotrophic lateral sclerosis subsets (alpha-synuclein, SOD1) and Frontotemporal dementia (FTD). Several other inflammatory diseases are linked to mtDNA accumulation in the cytosol (nonalcoholic steatohepatitis (NASH), chronic obstructive pulmonary disease (COPD), Inflammatory bowel disease (IBD), anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) and autoimmune diseases (several subsets of SLE). Also reverse transcription of Alu repeat elements into cytosolic Alu cDNA is shown to activate cGAS and is causally linked to an advanced stage of dry age-related macular degeneration (AMD) - Geographic atrophy (GA). Additionally, chromosomal instability also causes increased cytosolic DNA. Recently, it is suggested that some subsets of diverse cancer types show TREX deficiency linked with increased type I interferon responses and worse disease progression suggesting pro-tumorigenic traits of cGAS-STING pathways. Therefore, small molecule inhibitors of cGAS are useful for the treatment or prevention of different disease with an inappropriate cGAS-STING activity.

[0009] In 2017, Pfizer published compound PF-06928215 as an inhibitor of cGAS (Hall et al, PLoS ONE 12(9): e0184843). Nitropyrazole and pyridoindole compounds have been published as cGAS inhibitors in Lama et al, Nat Com 10, 2261 (2019). The patent applications WO / 2022066851 , WO / 2023081441, WO / 2022238327, WO / 2022238335, WO / 2022051634, and WO / 2022137082 also describe cGAS inhibitors.

[0010] However, there is still a great need for novel, alternative or better therapeutics for the prevention or treatment of inflammatory and / or auto-immune diseases and disease indications mediated by cGAS activation. Therapeutics with better target engagement, (cellular) potency, less sideeffects, a higher activity, a lower toxicity, better pharmacokinetic or -dynamic properties, a better (oral) bioavailability, higher (hepatocyte) metabolic stability, varied volume of distribution, effective dosage or combinations thereof would be very welcome.

[0011] The present invention provides a class of novel compounds which can be used as inhibitors ofcGAS or as modulators of cGAS activity in disease indications mediated by cGAS.

[0012] SUMMARY OF THE INVENTION

[0013] The present invention is based on the unexpected finding that at least one of the above-mentioned problems can be solved by the below described compounds.

[0014] The present invention provides new compounds, especially compound of formula (I) as defined by the claims and / or embodiments described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and / or prodrug thereof

[0015]

[0016] In particular, the present invention provides a compound of formula (I), a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, hydrate, polymorph and / or prodrug thereof, wherein:

[0017] each dashed line (

[0018]

[0019] ) represents an optional double bond and whereby two adjacent dashed line cannot form a double bond at the same time;

[0020] the dotted lines

[0021]

[0022] represent the possible points of attachment of -Q-L-X; each E1, E2and E3is independently C, CH, NH or N;

[0023] - T1is CH, C, O or N; T2is C, CH, CH2, N or a bond; T3is C, CH, CH2, N or a bond; and, T4is CH, C or N; wherein T2and T3are not both a bond, and, wherein one and only one of T1, T2, T3and T4is N;

[0024] R1is selected from the group comprising hydrogen, halogen, =0, alkyl, -C(O)O-alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0025] wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynylis unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, - OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, -C(O)OH, -C(O)O-alkyl, -NH2, -NHalkyl, and - N(alkyl)2;

[0026] R2is selected from the group comprising hydrogen, halogen, =0, hydroxyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylaminoalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, -CONR2aR2band -CChR20;

[0027] wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylamino- alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -SCF3, -SF5, -N3, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl (such as -CF3, -CHF2), alkoxy, haloalkoxy (such as -OCF3, -OCHF2), hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -C(O)OR2c, -COR2d, -NR2aR2b(such as -NH2, -NHalkyl, and -N(alkyl)2), -NR2aCOR2d, -CONR2aR2b, and - 0R2c;

[0028] R2ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0029] R2bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0030] R2Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0031] R2dis selected from the group comprising heteroalkyl (e.g. hydroxyalkyl, alkyloxyalkyl), hydroxy, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; or R1and R2together with the carbon atoms to which they are attached can form a heterocyclyl (e.g. pyrrolidinyl),

[0032] wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, - CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;or R2and X together with the atoms to which they are attached can form a heterocyclyl wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;

[0033] R3is selected from the group comprising hydrogen, halogen, nitro, -CN, -NR3aR3b, -(CR3fR3g)q-NR3aR3b, -NR3a-(CR3fR3g)q-NR3aR3b, -O-(CR3fR3g)q-NR3aR3b, -C(O)NR3aR3b, -(CR3fR3g)q-C(O)NR3aR3b, -NR3a-(CR3fR3g)q-C(O)NR3aR3b, -O-(CR3fR3g)q-C(O)NR3aR3b, -CO23C, -(CR3fR3g)q-CO2R3c, -NR3a-(CR3fR3g)q-CO2R3c, -O-(CR3fR3g)q-CO2R3c, -0R3c, -(CR3fR3g)q-OR3c, -NR3a-(CR3fR3g)q-OR3c, -O-(CR3fR3g)q-OR3c, -(CR3fR3g)q-C(O)R3c, -O-(CR3fR3g)q-C(O)R3c, -NR3a-(CR3fR3g)q-C(O)R3c, -O-(CR3fR3g)q-PO(OR3i)2, -NR3a-(CR3fR3g)q-PO(OR3i)2, -NR3aC(O)R3d, -(CR3fR3g)q-NR3aC(O)R3d, -NR3a-(CR3fR3g)q-NR3aC(O)R3d, -N(C(O)R3d)2, -SR3c, -S(O)R3c, -S(O)2R3c, -S(O)2-NR3aR3b, -NR3aS(O)2R3d, -(CR3fR3g)q-NR3aS(O)2R3d, -(CR3fR3g)q-S(O)2NR3a, -NR3a-(CR3fR3g)q-NR3aS(O)2R3d, -S(O)(NR3a)R3c, -S(O)(NR3a)NR3aR3b, -NR3aS(O)(NR3a)R3d, -(CR3fR3g)q-NR3aS(O)(NR3a)R3d, -(CR3fR3g)q-

[0034] S(O)(NR3a)NR3a, -NR3a-(CR3fR3g)q-NR3aS(O)(NR3a)R3d,

[0035]

[0036] R '

[0037]

[0038] , oxo, hydroxyl, sulfhydryl, alkyl, alkenyl, alkynyl, heteroalkyl (e.g., alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl and alkoxyalkylamino), heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylheteroalkyl, heterocyclylheteroalkenyl and heterocyclylheteroalkynyl,

[0039] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl (e.g. alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl and alkoxyalkylamino), heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylheteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, - OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl (e.g. hydroxyalkyl, alkoxy, alkylthio), heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -C(O)OH, -C(O)R3i, -C(0)-0-CH2- O-CO-R3', -PO-(OR3i)2, -SO2F, -NR3aR3b(-NH2, -NHalkyl, and -N(alkyl)2);

[0040] cycle A is selected from the group comprising aryl (such as phenyl), cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl and heteroaryl;

[0041] - Y is NR3hor O;

[0042] each R6is independently selected from the group comprising hydrogen, halogen, -OH, - NR3aR3b, -SH, =S, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl (e.g. alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- or di-)alkyl-amino-alkyl), heteroalkenyl, heteroalkynyl, -(CR3fR3g)q-O- (CR3fR3g)v-CO2R3c, hydroxyalkyl, -(CR3fR3g)q-NR3aSO2R3d, -CO2R3c, -(CR3fR3g)q-O- (CR3fR3g)v-aryl, -(CR3fR3g)q-O-(CR3fR3g)v-heteroaryl, -CONR3aS(O)2R3d, -S(O)2R3d, - (CR3fR3g)q-O-(CR3fR3g)v-CN, -C(O)R3d, aryl, heteroaryl, heterocyclyl, -C(O)NR3aR3b, oxo, - S(O)2NR3aR3b, -0R3cand -(CR3fR3g)q-O-(CR3fR3g)v-O-aryl,

[0043] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl (e.g. alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- or di-)alkyl-amino-alkyl), heteroalkenyl, heteroalkynyl, aryl, heteroaryl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, - CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, heteroalkyl (e.g. alkoxy, hydroxyalkyl, -NH2, -NHalkyl, and -N(alkyl)2), heteroalkenyl and heteroalkynyl;

[0044] R3ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di- )alkyl-amino, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, - SCh-alkyl, aryl, heteroaryl and heterocyclyl;

[0045] R3bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0046] R3Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl,alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, alkyl-COOH, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;

[0047] R3dis selected from the group comprising alkyl, alkenyl, al kynyl , heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, alkoxy, (mono- or di-)alkyl-amino, (mono- or di-)alkyl-amino-alkyl, alkylthio, alkylthioalkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;

[0048] each R3fand R3gare each independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, -NH2, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;

[0049] R3his selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0050] R3' is selected from hydrogen, alkyl, cycloalkyl and aryl wherein each alkyl, cycloalkyl, and aryl is optionally further substituted with one or more halogen;

[0051] m is an integer selected from 0, 1 , 2, 3, 4 or 5

[0052] p is an integer selected from 0, 1, 2, 3, 4 or 5;

[0053] q is an integer selected from 0, 1, 2, 3, 4 or 5;

[0054] v is an integer selected from 0, 1 , 2, 3, 4 or 5;

[0055] Q is selected from -CO-, -SO2-, -SO(=NH)-;

[0056] L is selected from -CRLgRLh-, -NRLb-, or a single bond;

[0057] RLgis selected from the group comprising hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyalkyl, hydroxylalkenyl, hydroxyalkynyl, -NRLaRLb, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, -C(O)NRLaRLb, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, deuterium, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0058] RLhis selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, deuterium, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0059] RLais selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0060] RLbis selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0061] or RLgand RLhtogether with the carbon atoms to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl and heterocyclyl;

[0062] X is selected from the group comprising -ORXc, -NRXaRXb, aryl, heteroaryl, heterocyclyl,heterocyclylalkyl, -SRXc, aminoalkyl, aminoalkenyl, aminoalkynyl, -S(O)2RXd, -NRXbS(O)2RXd, -NRXbC(O)RXc, -NRXbC(O)ORXc, -OC(O)RXd, -C(O)NRXaRXb, -C(O)ORXc, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, alkyl, alkenyl, alkynyl, (mono- or di-)alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl and -N3,

[0063] wherein each of said heteroaryl, heterocyclyl, heterocyclylalkyl, aryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising hydroxyalkyl, -C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -P(O)H2I-S(O)2RXa, -S(O)RXa, cyano, nitro, -C(O)ORXc, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, (mono- or di-)alkyl-aminoalkoxy, -NRXaRXb(such as -NH2, -NHalkyl, and -N(alkyl)2);

[0064] RXais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,

[0065] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2;

[0066] RXbis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyalkynyl is unsubstituted or is substituted withone or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, - NH2, -NHalkyl, and -N(alkyl)2;

[0067] each RXcis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,

[0068] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2;

[0069] RXdis selected from the group comprising alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,

[0070] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy;

[0071] each RXeand RXfare independently selected from alkyl, alkenyl, alkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl,heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,

[0072] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy;

[0073] n is an integer selected from 1, 2, 3, or 4;

[0074] each R4is independently selected from the group comprising halogen, oxo, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, -B(OH)2, -O-SO2-F, -SO2-F, cyano, nitro, -OR4c, -NR4aR4b, - NR4aS(O)2R4d, -NR4aSO2NR4aR4b, -NR4aC(O)R4c, -NR4aC(O)OR4c, -NR4aC(O)NR4aR4b, SR4c, -S(O)R4d, -S(O)2R4C, -S(O)2NR4aR4b, -S(O)(NR4a)R4c, -S(NR4a)(NR4a) R4c, -C(O)OR4c, -C(O)R4c, -C(O)NR3aR3b, -P(O)R4aR4b, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl haloalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -B(OH)2, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)OH, - C(O)Oalkyl, -C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, -NHalkyl, and -N(alkyl)2; or two R4together with the atom(s) to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl,

[0075] wherein each of said cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, is unsubstituted or is substituted with one or more substituents each independently selected from R4e;

[0076] - R4ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl and aminoalkynyl;

[0077] - R4bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;- R4Cis selected from the group comprising hydrogen, alkyl, alkyl substituted with deuterium, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxyalkyl and (mono- or di-)alkyl-aminoalkyl; - R4dis selected from the group comprising alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0078] - R4eis independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxyalkoxyalkyl, -C(O)H, -C(O)OH, -C(O)Oalkyl, -NHC(O)alkyl, - C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, -NHalkyl, and -N(alkyl)2;

[0079] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl, alkoxy, alkoxyalkyl, -C(O)Oalkyl, -NHC(O)alkyl, -C(O)NHalkyl, -C(O)N(alkyl)2, -NHalkyl, and -N(alkyl)2 are optionally substituted with one of more substituents selected from - OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, azido, alkoxy, -NH2, -NHalkyl, and -N(alkyl)2;

[0080] R5is absent or is selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl-amino- alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl; wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl-amino-alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, - CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)OH, C(O)Oalkyl, - C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, - NHalkyl, and - N(alkyl)2;

[0081] or R3and R5together with the atoms to which they are attached form a heteroaryl or heterocyclyl wherein said heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, - OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, phenyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and - N(alkyl)2; and,

[0082] when E1is C, E2is C or CH and E3is C, and, T1is C or CH, T2is N, T3is a bond and T4is C or CH, then E1and E3are both substituted with R4, wherein said two R4groups together form an aryl or heteroaryl, wherein said aryl and heteroaryl is unsubstituted or is substituted with one or more substituents each independently selected from R4e.

[0083] The present invention provides new compounds which have been shown to possess modulatory, more in particular inhibitory activity on cGAS. The present invention furthermore demonstrates that these compounds efficiently inhibit the activity of cGAS. Therefore, these compounds constitute a useful class of new potent compounds that can be used in the treatment and / or prevention of cGAS mediated disorders in animals, mammals and humans, more specifically for the treatment and / or prevention of inflammation conditions, more in particular diseases with cGAS activity or activation, yet more in particular inflammatory diseases, auto-immune diseases, allergic diseases, fibrotic diseases and cancer.

[0084] The present invention furthermore relates to the compounds of the invention for use as a medicine, to the use of such compounds as medicines and to their use for the manufacture of medicaments, more in particular for treating and / or preventing cGAS mediated diseases, in particular inflammation conditions such as in (i) inflammatory diseases, (ii) auto-immune diseases, (iii) allergic diseases, (iv) fibrotic diseases and also for cancer in animals or mammals, more in particular in humans.

[0085] The invention also relates to pharmaceutical compositions comprising the compounds of the invention in an effective amount, to said pharmaceutical compositions for use as a medicine, more in particular for use as a medicine for the prevention or treatment of cGAS mediated disorders and to the method of preparation of manufacturing of said pharmaceutical compositions.

[0086] The present invention also relates to a method of treatment or prevention of cGAS mediated disorders in humans by the administration of one or more such compounds, optionally in combination with one or more other medicines, to a patient in need thereof. Also disclosed herein is a method of treating inflammation conditions (inflammatory diseases, auto-immune diseases, allergic diseases, fibrotic diseases) and cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein in combination with an additional therapeutic agent. In some embodiments, the additional medicine or therapeutic agent is an anti- inflammatory agent, anti-fibrotic agent or anti-allergic agent.

[0087] When reference is made to the treatment or prevention of a cGAS mediated diseases in animals or mammals, more in particular in humans, this in a particular embodiment refers to(i) inflammation conditions, more in particular to inflammatory diseases, auto-immune diseases, allergic diseases, inflammatory conditions of any tissue or organ, diseases with an inflammatory component or any other inflammatory conditions, more in particular which are responsive to cGAS inhibitor or modulator treatment, yet more in particular for which cGAS activity or activation drives, contributes, sustains, enables or the like such disease and (ii) cancer. In a particular embodiment, the cGAS mediated diseases are selected from inflammatory, allergic or autoimmune diseases such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (OLE), Lupus Nephritis (LN), interferonopathies, psoriasis, insulin-dependent diabetes mellitus (IDDM), vasculitis, scleroderma, Aicardi Goutieres syndrome, dermatomyositis, sepsis, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome (SS), age related macular degeneration (AMD), Amyotrophic Lateral sclerosis (ALS), Fronto-temporal dementia (FTD), Alzheimer’s disease, Huntington’s disease and Parkinson’s disease.

[0088] More in particular in relation to the treatment or prevention of inflammation conditions, the invention comprises administering to the patient an effective amount of a compound disclosed herein, also in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an anti- inflammatory agent, anti-fibrotic agent or anti-allergic agent. In particular related to the treatment or prevention of inflammation conditions comprises the treatment or prevention of SLE, interferonopathies or Aicardi Goutieres syndrome in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or comprises treating and / or controlling neuroinflammation in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein. The present invention also relates to a method of preparation of the compounds of the invention comprising the steps for synthesis of the compounds as described herein.

[0089] DETAILED DESCRIPTION OF THE INVENTION

[0090] The present invention will be further described and in some instances with respect to particular embodiments, but the invention is not limited thereto.

[0091] The term “cGAS mediated diseases” or “cGAS mediated disorders” refers to diseases, disorders or conditions in which cGAS signaling is active or activated and whereby cGAS activity or activation is contributing, driving, sustaining, enabling or the like such disease. cGAS mediated diseases includes inflammatory diseases, autoimmune diseases, allergic disorders, but also cancer, fibrotic disorders and neurodegenerative diseases and any other disease with an inflammatory component or any other disease, disorder or ailment favourably responsive to cGAS inhibitor or modulator treatment. In a particular embodiment, the term “cGAS mediated diseases” or “cGAS mediated disorders” refers to diseases, disorders or conditions wherebycGAS is active or activated, more in particular as a consequence of, or cGAS activity is believed to be linked to (i) a genetic abnormality or in a genetic disease like Type I interferonopathies, driven by loss-of-function mutations in cytosolic nucleases (TREX1, SAMHD1, DNASE2), such as in e.g. Aicardi Goutieres Syndrome (AGS), TREX1 subsets of lupus, heterozygous TREX1 mutation in Familial Chilblain Lupus, and / or (ii) (accumulation of) mtDNA in the cytosol such as via mitochondrial leakage or defects thereby underlying pathologic inflammatory response such as in in neurodegenerative diseases like Parkinson’s disease subsets (TDP43, PINK1-Perkin), Amyotrophic lateral sclerosis subsets (alpha-synuclein, SOD1) and Frontotemporal dementia (FTD) or in several other diseases with an inflammatory component such as nonalcoholic steatohepatitis (NASH), chronic obstructive pulmonary disease (COPD), Inflammatory bowel disease (IBD), anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) and subsets of Systemic Lupus Erythematosus (SLE), and / or (iii) cytosolic Alu cDNA, such as through reverse transcription of Alu repeat elements, can form the basis for inflammation via activation of cGAS such as in (advanced stage of) dry age-related macular degeneration (AMD) or Geographic atrophy (GA).

[0092] The term “auto-immune disease(s)” or “auto-immune disorder(s)” refers to diseases that result from an aberrant immune response against its own cells and / or tissues due to a failure of an organism to recognise its own constituent parts (down to the sub-molecular level) as “self’. Auto-immune disorders are divided into “systemic auto-immune diseases” (such as lupus erythematosus, psoriasis, vasculitis, polymyositis, scleroderma, multiple sclerosis, ankylosing spondylitis, rheumatoid arthritis and Sjogren’s syndrome), “auto-immune endocrine disorders” (such as thyroiditis) and “organ-specific auto-immune diseases” (such as Addison disease, haemolytic or pernicious anaemia, Goodpasture syndrome, Graves disease, idiopathic thrombocytopenic purpura, insulin-dependent diabetes mellitus, juvenile diabetes, uveitis, Crohn's disease, ulcerative colitis, pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, auto-immune carditis, myasthenia gravis, glomerulonephritis and spontaneous infertility). The autoimmune disorders are thus directed to own cells or tissues and include a reaction to “auto-antigens”, meaning antigens (e.g. of proteins) that are own constituent parts of the specific mammalian organism. In this mechanism, auto-antigens are recognised by B -and / or T-cells which will install an immune reaction against said auto-antigen.

[0093] A non-limitative list of diseases encompassed by the term “auto-immune diseases” or “autoimmune disorders” comprises therefore Acute disseminated encephalomyelitis (ADEM), Addison's disease, Alopecia areata, Antiphospholipid antibody syndrome (APS), Autoimmune haemolytic anaemia, Autoimmune hepatitis, Bullous pemphigoid, Behget's disease, Coeliac disease, inflammatory bowel disease (IBD) (such as Crohn’s Disease and Ulcerative Colitis), Dermatomyositis, Diabetes mellitus type 1, Goodpasture's syndrome, Graves' disease,Guillain-Barre syndrome (GBS), Hashimoto's disease, Idiopathic thrombocytopenic purpura, Lupus erythematosus, Mixed Connective Tissue Disease, Multiple sclerosis (MS), Myasthenia gravis, Narcolepsy, Pemphigus vulgaris, Pernicious anaemia, Psoriasis, Psoriatic Arthritis, Polymyositis, Primary biliary cirrhosis, Rheumatoid arthritis (RA), Sjogren's syndrome, Temporal arteritis, Vasculitis, Wegener's granulomatosis and atopic dermatitis. Also the following disorders are suspected to be auto-immune diseases: Ankylosing spondylitis, Autoimmune inner ear disease, Chagas disease, Chronic obstructive pulmonary disease (COPD), Endometriosis, Hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, Interstitial cystitis, Morphea, Neuromyotonia, Schizophrenia, Scleroderma, Stiff person syndrome and Vitiligo. Auto-immune disorders are divided into “systemic auto-immune diseases” (such as lupus erythematosus, psoriasis, vasculitis, polymyositis, scleroderma, multiple sclerosis, ankylosing spondylitis, rheumatoid arthritis and Sjogren’s syndrome), “autoimmune endocrine disorders” (such as thyroiditis) and “organ-specific auto-immune diseases” (such as Addison disease, haemolytic or pernicious anaemia, Goodpasture syndrome, Graves disease, idiopathic thrombocytopenic purpura, insulin-dependent diabetes mellitus, juvenile diabetes, uveitis, Crohn's disease, ulcerative colitis, pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, auto-immune carditis, myasthenia gravis, glomerulonephritis and spontaneous infertility).

[0094] The term “inflammatory diseases” or “inflammatory disorders” refers to, but is not limited to disease selected from the group of rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, bronchitis, tuberculosis, chronic cholecystitis, inflammatory bowel disease, acute pancreatitis, sepsis, asthma, chronic obstructive pulmonary disease, dermal inflammatory disorders such as psoriasis and atopic dermatitis, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), cancer-associated inflammation, reduction of tumour-associated angiogenesis, diabetes, treatment of graft v. host disease and associated tissue rejection inflammatory responses, Crohn's disease, delayed-type hypersensitivity, immune-mediated and inflammatory elements of CNS disease; e.g., Alzheimer's, Parkinson's, multiple sclerosis, etc.

[0095] The term “allergic diseases” or “allergic disorders” refers to, but is not limited to diseases selected from the group of asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis, insect bite skin inflammation and blood sucking parasitic infestation.

[0096] The term “fibrotic diseases” as used herein refers to lung fibrosis or pulmonary fibrosis (such as Asbestosis, COVID-19-related pulmonary fibrosis, drug-induced pulmonary fibrosis, hypersensitivity Pneumonitis (HP), idiopathic pulmonary fibrosis (IPF), idiopathic NSIP, pneumoconiosis, rheumatoid arthritis interstitial lung disease (RA-ILD)), liver fibrosis, heartfibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis including kidney fibrosis, bone marrow fibrosis, skin fibrosis, scleroderma or systemic sclerosis and other types of pathological fibrosis.

[0097] The term "cancer" as used herein refers to all types of animal, more specifically human cancers, neoplasm or (malignant) tumours including carcinomas, sarcomas, lymphomas, leukaemias, germ cell tumours and blastomas and thus includes solid and lymphoid cancers. Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumour, cervical cancer, colon cancer, oesophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukaemia, prostate cancer, breast cancer (e.g., ER positive, ER negative, chemotherapy resistant, herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, or melanoma. Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non- small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumours, cancer, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, oesophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget' s Disease of the Nipple, Phyllodes Tumours, Lobular Carcinoma, Ductal Carcinoma, cancer of the pancreatic stellate cells, cancer of the hepatic stellate cells, or prostate cancer.

[0098] In some embodiments, the term cancer refers to bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, oesophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer or prostate cancer. In a particular embodiment, the term “inflammation condition(s)” as used herein refers to inflammatory diseases, auto-immune diseases, allergic diseases, inflammatory conditions of any tissue or organ, diseases with an inflammatory component or any other inflammatoryconditions, more in particular which are responsive to cGAS inhibitor or modulator treatment, yet more in particular for which cGAS activity or activation drives, contributes, sustains, enables or the like such disease.

[0099] The term “inflammation condition(s)” as used herein comprises therefore inflammatory, allergic or autoimmune diseases or diseases with an inflammation component such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (OLE), lupus nephritis (LN), interferonopathies, psoriasis, insulin-dependent diabetes mellitus (IDDM), vasculitis, scleroderma, Aicardi Goutieres syndrome, dermatomyositis, sepsis, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome (SS), age related macular degeneration (AMD), Amyotrophic Lateral sclerosis (ALS), Fronto-temporal dementia (FTD), Alzheimer’s disease, Huntington’s disease and Parkinson’s disease.

[0100] The term “inflammation condition(s)” also comprises disorders with inflammation of any tissue and organs of the body, including musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation such as of the cardiovascular system. Musculoskeletal inflammation refers to any inflammatory condition of the musculoskeletal system, particularly those conditions affecting skeletal joints, including joints of the hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knew, ankle, and foot, and conditions affecting tissues connecting muscles to bones such as tendons. Examples of musculoskeletal inflammation include arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis fibrosa cystic). Neural inflammation or inflammation of the nervous system comprises encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis, schizophrenia and inflammation in the CNS, incl. in neurodegenerative disorders such as Parkinson’s disease, Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease. Ocular inflammation refers to inflammation of any structure of the eye, including the eye lids. Examples of ocular inflammation which may be treated with the compounds of the disclosure include blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis. Inflammation of the vasculature or lymphatic system includes atherosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis. Inflammatory conditions of the digestive system comprises cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory' bowel disease (such as Crohn's disease and ulcerative colitis), ileitis, and proctitis. Inflammatory conditions of the reproductive system include cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tribo - ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.

[0101] Autoimmune conditions having an inflammatory component are also comprised in the term“inflammation condition(s)” and such conditions include systemic lupus erythematosus, cutaneous lupus erythematosus, acute disseminated alopecia universalis, Behcet’s disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anaemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, diabetes mellites type 1 , giant cell arteritis, Goodpasture's syndrome. Grave's disease, Guillain- Barre syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, Ord’s thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, Aicardi-Goutieres syndrome, temporal arteritis, Wegener’s granulomatosis, warm autoimmune haemolytic anaemia, interstitial cystitis, Lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

[0102] The term “inflammation condition(s)” also refers to allergic diseases or T-cell mediated hypersensitivity diseases having an inflammatory component such as contact hypersensitivity, contact dermatitis, urticaria, skin allergies, respiratory allergies (e.g. hay fever, allergic rhinitis) and gluten-sensitive enteropathy (Coeliac disease).

[0103] In general, the term “inflammation condition(s)” comprises any disease with an inflammatory component and thus also comprises appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, pneumonitis, prostatitis, pyelonephritis, and stomatisi, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xenografts, serum sickness, and graft vs host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome. Sezary’s syndrome, congenital adrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemia associated with cancer, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonary' tuberculosis, chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary' thrombocytopenia in adults, acquired (autoimmune) haemolytic anaemia, leukaemia and lymphomas in adults, acute leukaemia of childhood, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis.

[0104] Also fibrotic diseases are part of the cGAS mediated disorders or diseases. Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissueremodelling and the formation of permanent scar tissue. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Fibrotic diseases, more in particular with an active inflammatory component, are also comprised in the term “inflammation condition(s)” and includes systemic sclerosis (SSc), interferonopathies, non-alcoholic steatohepatitis (NASH), interstitial lung disease (I LD), more in particular progressive fibrosing interstitial lung disease (PF- ILD), in particular idiopathic pulmonary fibrosis (IPF).

[0105] The term “treat” or “treating” as used herein is intended to refer to administration of a compound or composition of the invention to a subject for the purpose of effecting a therapeutic benefit or prophylactic benefit, here in particular through inhibition of cGAS. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms, complications or biochemical indications of such disease, disorder or condition, here in particular mediated through cGAS. By "therapeutic benefit" is meant eradication, amelioration, reversing, alleviating, inhibiting the progress of or lessening the severity of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments. For prophylactic benefit, in some embodiments, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. For example certain methods herein treat cancer by decreasing or reducing or preventing the occurrence, growth, metastasis, or progression of cancer or decreasing a symptom of cancer.

[0106] The term “prevent” or “preventing” as used herein is intended to refer to administration of a compound or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit, in particular through inhibition of cGAS whereby appearance or progression of disease, disorder or condition, or, onset or progression of one or more symptoms, complications or biochemical indications or such disease, disorder or condition is at least delayed.

[0107] The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, a patient, who has been the object of treatment, observation or experiment or who is in need of such treatment.

[0108] The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation or partial alleviation of the symptoms of the disease or disorder being treated.

[0109] The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

[0110] The term “antagonist” or “inhibitor” as used herein in reference to inhibitors of the cGAS activity or activation, refers to a compound capable of producing, depending on the circumstance, a functional antagonism or inhibition of cGAS activity or activation.

[0111] It is to be noticed that the term "comprising", used in the claims, should not be interpreted as being restricted to the means listed thereafter; it does not exclude other elements or steps. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments. Where an indefinite or definite article is used when referring to a singular noun e.g. "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated.

[0112] Similarly it should be appreciated that in the description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects.

[0113] The term “leaving group” or “LG” as used herein means a chemical group which is susceptible to be displaced by a nucleophile or cleaved off or hydrolysed in basic or acidic conditions. In a particular embodiment, a leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate, tosylate, triflate).

[0114] The term “protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of a protecting group varies widely. One function of a protecting group is to serve as intermediates in the synthesis of the parental drug substance. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See: “Protective Groups in Organic Chemistry”, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g. making and breaking chemical bonds in anordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

[0115] Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.

[0116] As used herein for terms such as alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl as defined herein, the notion or pre-fix Cx-yor Cx-Cymeans that said alkyl, cycloalkyl, heteroalkyl, alkenyl, alkynyl, heterocyclyl, aryl or heteroaryl consists of x to y carbon or heteroatoms composing the alkyl, cycloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl. This does not include the carbon and / or heteroatoms of (optional) substituents, nor the carbon and / or heteroatoms of the group / molecule on which it is substituted.

[0117] The term “alkyl” or “Ci-isalkyl” as used herein means C1-C18 normal (primary), secondary or tertiary, linear, branched or straight hydrocarbon with no site of unsaturation. Examples are methyl, ethyl, 1 -propyl (n-propyl), 2-propyl (iPr), 1 -butyl, 2-methyl-1 -propyl (i-Bu), 2-butyl (s-Bu), 2-dimethyl-2-propyl (t-Bu), 1 -pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1 -butyl, 2-methyl-1 -butyl, 1 -hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, and n-icosyl. In particular embodiments, the term alkyl refers to Ci-i2alkyl (C1-12 hydrocarbons), yet more in particular to Ci-galkyl (C1-9 hydrocarbons), yet more in particular to C1-6 alkyl (C1-6 hydrocarbons) or C1-4 alkyl (C1-4 hydrocarbons) as further defined herein. Such embodiments may apply independently to terms comprising more than one alkyl moiety, e.g. embodiments of alkoxyalkyl include a.o. Ci-4alkoxy-Ci-6alkyl, Ci-ealkoxy-Ci-ealkyl or C1-6alkoxy-C1.4alkyl.The term "haloalkyl" as a group or part of a group, refers to an alkyl group having the meaning asdefined above wherein one, two, or three hydrogen atoms are each replaced with a halogen as defined herein. Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1 -trifluoroethyl and the like. The term "hydroxyalkyl" as a group or part of a group, refers to an alkyl group having the meaning as defined above wherein one, two, or three hydrogen atoms are each replaced with an hydroxyl as defined herein, i.e. mono-, di- and tri-hydroxy-alkyl respectively. Non-limiting examples of such hydroxyalkyl groups include hydroxymethyl, 1 -hydroxy-ethyl, 2-hydroxy-ethyl, 1,2-di-hydroxy ethyl, etc.

[0118] The term “alkoxy" or “alkyloxy”, as a group or part of a group, refers to a group having the formula -ORbwherein Rbis Ci-ealkyl as defined herein above. Non-limiting examples of suitable Ci-ealkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secbutoxy, tert-butoxy, pentyloxy and hexyloxy.

[0119] The term "hydroxyalkoxy" as a group or part of a group, refers to an alkyloxy (i.e. alkoxy) group having the meaning as defined above wherein one, two, or three hydrogen atoms are each replaced with an hydroxyl as defined herein, i.e. mono-, di- and tri-hydroxy-alkyloxy respectively. Non-limiting examples of such hydroxyalkyloxy groups include hydroxymethyloxy, 1-hydroxy-ethyloxy, 2-hydroxy-ethyloxy, 1,2-di-hydroxy ethyloxy, etc. The term "aminoalkoxy" as a group or part of a group, refers to an alkyloxy (i.e. alkoxy) group having the meaning as defined above wherein one, two, or three hydrogen atoms are each replaced with an amino group (-NH2) as defined herein, i.e. mono-, di- and tri-amino-alkyloxy respectively. Non-limiting examples of such aminoalkyloxy groups include aminomethyloxy, 1-amino-ethyloxy, 2-amino-ethyloxy, 1,2-di-amino-ethyloxy, etc.

[0120] The term “haloalkoxy”, as a group or part of a group, refers to a group of formula -O-Rc, wherein Rcis haloalkyl as defined herein. Non-limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1, 2, 2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy, 2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy.

[0121] The term “cycloalkyl” or “C3-18 cycloalkyl” as used herein and unless otherwise stated means a saturated hydrocarbon monovalent group having from 3 to 18 carbon atoms consisting of or comprising a C3-10 monocyclic or C7-18 polycyclic saturated hydrocarbon, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyltricycloheptyl, decalinyl, adamantyl and the like. In particular embodiments, the term cycloalkyl refers to C3-i2cycloalkyl (saturated cyclic C3-i2hydrocarbons), yet more in particular to Cs-gcycloalkyl (saturated cyclic Cs-ghydrocarbons), still more in particular to Cs-ecycloalkyl (saturated cyclic Cs-ehydrocarbons) as further defined herein above. For the avoidance of doubt, fused systemsof a cycloalkyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

[0122] The term “alkenyl” or “C2-i8alkenyl” as used herein is C2-C18 normal (primary), secondary or tertiary, linear, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond. Examples include, but are not limited to: ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2). The double bond may be in the cis or trans configuration. In particular embodiments, the term alkenyl refers to C2-i2alkenyl (C2-12 hydrocarbons), yet more in particular to C2-9 alkenyl (C2-9 hydrocarbons), still more in particular to C2-6 alkenyl (C2-6 hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond.

[0123] The term “alkenyloxy”, as a group or part of a group, refers to a group having the formula -ORdwherein Rdis alkenyl as defined herein above.

[0124] The term “cycloalkenyl” as used herein refers to a non-aromatic hydrocarbon group having from 5 to 18 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond and consisting of or comprising a C5-10 monocyclic or C7-18 polycyclic hydrocarbon. Examples include, but are not limited to: cyclopentenyl (-C5H7), cyclopentenylpropylene, methylcyclohexenylene and cyclohexenyl (-CeHg). The double bond may be in the cis or trans configuration. In particular embodiments, the term cycloalkenyl refers to C5-12 cycloalkenyl (cyclic C5-12 hydrocarbons), yet more in particular to C5-9 cycloalkenyl (cyclic C5-9 hydrocarbons), still more in particular to C5-6 cycloalkenyl (cyclic C5-6 hydrocarbons) as further defined herein above with at least one site of unsaturation, namely a carbon-carbon, sp2 double bond. For the avoidance of doubt, fused systems of a cycloalkenyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkenyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkenyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

[0125] The term “alkynyl” or “C2-i8alkynyl” as used herein refers to C2-C18 normal (primary), secondary, tertiary, linear, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. Examples include, but are not limited to: ethynyl (-OCH), 3-ethyl-cyclohept-1-ynylene, and 1-propynyl (propargyl, -CH2C=CH). In particular embodiments, the term alkynyl refers to C2-12 alkynyl (C2-12 hydrocarbons), yet more in particular to C2-9 alkynyl (C2-9 hydrocarbons) yet more in particularto C2-6 alkynyl (C2-6 hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond.

[0126] The term “alkynyloxy”, as a group or part of a group, refers to a group having the formula -ORewherein Reis alkynyl as defined herein above.

[0127] The term “cycloalkynyl” as used herein refers to a non-aromatic hydrocarbon group having from 5 to 18 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond and consisting of or comprising a C5-10 monocyclic or C7-18 polycyclic hydrocarbon. Examples include, but are not limited to: cyclohept- 1-yne, 3-ethyl-cyclohept-1-ynylene, 4-cyclohept-1-yn-methylene and ethylene-cyclohept-1-yne. In particular embodiments, the term cycloalkynyl refers to C5-10 cycloalkynyl (cyclic C5-10 hydrocarbons), yet more in particular to C5-9 cycloalkynyl (cyclic C5-9 hydrocarbons), still more in particular to C5-6 cycloalkynyl (cyclic C5-6 hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. For the avoidance of doubt, fused systems of a cycloalkynyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkynyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkynyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

[0128] The term “alkylene” as used herein each refer to a saturated, branched or straight chain hydrocarbon group of 1-18 carbon atoms (more in particular C1-12, Ci-gor C1-6 carbon atoms), and having two monovalent group centres derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene include, but are not limited to: methylene (-CH2-), 1 ,2-ethyl (-CH2CH2-), 1 ,3-propyl (-CH2CH2CH2-), 1 ,4-butyl (-CH2CH2CH2CH2-), and the like.

[0129] The term “alkenylene” as used herein each refer to a branched or straight chain hydrocarbon of 2-18 carbon atoms (more in particular C2-12, C2-gor C2-6 carbon atoms) with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond, and having two monovalent centres derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.

[0130] The term “alkynylene” as used herein each refer to a branched or straight chain hydrocarbon of 2-18 carbon atoms (more in particular C2-12, C2-gor C2-6 carbon atoms) with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond, and having two monovalent centres derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.

[0131] The term “heteroalkyl” as used herein refers to an alkyl wherein one or more carbon atoms are replaced by one or more heteroatoms independently selected from the group comprising oxygen, nitrogen and sulphur atom. The term heteroalkyl thus comprises -O-Rb, -NR°-Rb, -Ra-O-Rb, and -S-Rb, wherein Rais alkylene, Rbis alkyl, and R° is hydrogen or alkyl as defined herein. In particular embodiments, the term refers to Ci-i2heteroalkyl, Ci-gheteroalkyl or Ci-eheteroalkyl. In some embodiments heteroalkyl is selected from the group comprising alkyloxy, alkyl-oxy-alkyl, (mono- or di-)alkylamino, (mono- or di-)alkyl-amino-alkyl, alkylthio, and alkyl-thio-alkyl.

[0132] The term “heteroalkenyl” as used herein refers to an alkenyl wherein one or more carbon atoms are replaced by one or more heteroatoms independently selected from oxygen, nitrogen and sulphur atom. The term heteroalkenyl thus comprises -O-Rd, -NH-(Rd), -N(Rd)2, -N(Rb)(Rd), and -S-Rdwherein Rbis alkyl and Rdis alkenyl as defined herein. In particular embodiments, the term refers to C2-i2heteroalkenyl, C2-gheteroalkenyl or C2-6heteroalkenyl. In some embodiments heteroalkenyl is selected from the group comprising alkenyloxy, alkenyl-oxy-alkenyl, (mono- or di-)alkenylamino, (mono- or di-)alkenyl-amino-alkenyl, alkenylthio, and alkenyl-thio-alkenyl,

[0133] The term “heteroal kynyl” as used herein refers to an alkynyl wherein one or more carbon atoms are replaced by a heteroatom independently selected from oxygen, nitrogen and sulphur atom. The term heteroalkynyl thus comprises but is not limited to -O-Rd, -N(Rd)2, NHRd, -N(Rb)(Re), -N(Rd)(Re), and -S-Rdwherein Rbis alkyl, Reis alkynyl and Rdis alkenyl as defined herein. In particular embodiments, the term refers to C2-i2heteroalkynyl, C2-gheteroal kynyl or C2-eheteroalkynyl. In some embodiments the term heteroalkynyl is selected from the group comprising alkynyloxy, alkynyl-oxy-alkynyl, (mono- or di-)alkynylamino, (mono- or di-)alkynyl-amino-alkynyl, alkynylthio, alkynyl-thio-alkynyl.

[0134] The term “heteroalkylene” as used herein refers to an alkylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atoms.

[0135] The term “heteroalkenylene” as used herein refers to an alkenylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atoms.

[0136] The term “heteroalkynylene” as used herein refers to an alkynylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atom.

[0137] For each of the carbon, nitrogen and sulfur atoms present in a heteroalkyl, heteroalkenyl or heteroalkynyl group, optionally two or more hydrogen atoms on said carbon, nitrogen or sulfur atom of said group can be taken together to form a =0 or =S. The term heteroalkyl thus also includes, among other examples CH3-C(0)0-, CH3-C(O)O-CH2-, CH3-NH-C(0)-, CH3-C(0)-NH- CH3-NH-C(O)-CH2-, CH3-NH-C(S)-CH2-, CH3-NH-C(S)-NH-CH2-, CH3-NH-S(O)2-, CH3-NH-C(O)-NH-(CH2)Z-, CH3-C(O)-NH-C(O)-CH2-, CH3-NH-C(O)-O-CH2-, (CH3)2N-C(O)-O-CH2-and CH3-NH-S(O)2-NH-CH2-.

[0138] In some embodiments, each heteroatom selected from nitrogen and sulfur that is part of a heteroalkyl, heteroalkylene, heteroalkenyl, heteroalkenylene, heteroalkynyl or heteroalkynylene as defined herein is optionally oxidised and each such nitrogen is optionallyquaternized, and / or, at least one carbon atom of a heteroalkyl, heteroalkenyl or heteroalkynyl can be oxidised to form at least one C=O.

[0139] The term “aryl” as used herein means an aromatic hydrocarbon of 6-20 carbon atoms derived by the removal of hydrogen from a carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, derived from benzene, naphthalene, anthracene, biphenyl, and the like. In particular embodiments, the term aryl refers to a 6-14 carbon atoms membered aromatic cycle, yet more in particular refers to a 6-10 carbon atoms membered aromatic cycle. Fused systems of an aryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring, are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of an aryl ring with a heterocycle are considered as heterocycle irrespective of the ring that is bound to the core structure. Thus, indoline, dihydrobenzofurane, dihydrobenzo-thiophene and the like are considered as heterocycle according to the invention. Fused systems of an aryl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

[0140] The term “aryloxy”, as a group or part of a group, refers to a group having the formula -ORgwherein Rgis aryl as defined herein above.

[0141] The term “arylalkyl” or “arylalkyl-" as used herein refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethyl, and the like. The arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

[0142] The term “arylalkyloxy”, as a group or part of a group, refers to a group having the formula -O-Ra-Rgwherein Rgis aryl, and Rais alkylene as defined herein above.

[0143] The term “arylalkenyl” or “arylalkenyl-" as used herein refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl. The arylalkenyl group comprises 6 to 20 carbon atoms, e.g. the alkenyl moiety of the arylalkenyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

[0144] The term “arylalkynyl” or “arylalkynyl-" as used herein refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl. The arylalkynyl group comprises 6 to 20 carbon atoms, e.g. the alkynyl moiety of the arylalkynyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

[0145] The term “arylheteroalkyl” or “arylheteroalkyl-" as used herein refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl. The arylheteroalkyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkyl moiety of the arylheteroalkyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. In some embodiments arylheteroalkyl is selected from the groupcomprising aryl-O-alkyl, arylalkyl-O-alkyl, aryl-NH-alkyl, aryl-N(alkyl)2, arylalkyl-NH-alkyl, arylalkyl-N-(alkyl)2, aryl- S-alkyl, and arylalkyl-S-alkyl.

[0146] The term “arylheteroalkenyl” or “arylheteroalkenyl-" as used herein refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl. The arylheteroalkenyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkenyl moiety of the arylheteroalkenyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. In some embodiments arylheteroalkenyl is selected from the group comprising aryl-O-alkenyl, arylalkenyl-O-alkenyl, aryl-NH-alkenyl, aryl-N(alkenyl)2, arylalkenyl-NH-alkenyl, arylalkenyl-N-(alkenyl)2, aryl-S-alkenyl, and arylalkenyl-S-alkenyl.

[0147] The term “arylheteroalkynyl” or “arylheteroalkynyl-" as used herein refers to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl. The arylheteroalkynyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkynyl moiety of the arylheteroalkynyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. In some embodiments arylheteroalkynyl is selected from the group comprising aryl-O-alkynyl, arylalkynyl-O-alkynyl, aryl-NH-alkynyl, aryl-N(alkynyl)2, arylalkynyl-NH-alkynyl, arylalkynyl-N-(alkynyl)2, aryl-S-alkynyl, and arylalkynyl-S-alkynyl.

[0148] The term “heterocycle” or “heterocyclyl” as used herein refer to non-aromatic, fully saturated or partially unsaturated ring system of 3 to 18 (ring) atoms including at least one N, O, S, or P (i.e. C3-18, for example, 3 to 7 member monocyclic (C3-7), 7 to 11 member bicyclic (C7-11), or comprising a total of 3 to 10 ring atoms (C3-10)). Each ring of the heterocycle or heterocyclyl may have 1, 2, 3 or 4 heteroatoms selected from N, O and / or S, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized; and wherein at least one carbon atom of heterocyclyl can be oxidized to form at least one C=O. The heterocycle may be attached by any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocyclyls or heterocycles may be fused, bridged and / or joined through one or more spiro atoms. Fused systems of a heterocycle or heterocyclyl with an aryl ring are considered as heterocycle or heterocyclyl irrespective of the ring that is bound to the core structure. Fused systems of a heterocycle or heterocyclyl with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

[0149] Non limiting exemplary heterocycles or heterocyclic groups include piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, chromanyl (also known as 3,4-dihydrobenzo[b]pyranyl), 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolizinyl, 2-oxopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1 ,4-dithianyl, 1,3,5-trioxanyl, 1 H-pyrrolizinyl, tetrahydro-1, 1 -dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl. The term “aziridinyl” as used herein includes aziridin-1-yl and aziridin-2-yl. The term “oxyranyl” as used herein includes oxyranyl-2-yl. The term “thiiranyl” as used herein includes thiiran-2-yl. The term “azetidinyl” as used herein includes azetidin-1-yl, azetidin-2-yl and azetidin-3-yl. The term “oxetanyl” as used herein includes oxetan-2-yl and oxetan-3-yl. The term “thietanyl” as used herein includes thietan-2-yl and thietan-3-yl. The term “pyrrolidinyl” as used herein includes pyrrolidin-1 -yl, pyrrolidin-2-yl and pyrrolidin-3-yl. The term “tetrahydrofuranyl” as used herein includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. The term “tetrahydrothiophenyl” as used herein includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl. The term “succinimidyl” as used herein includes succinimid-1-yl and succininmid-3-yl. The term “dihydropyrrolyl” as used herein includes 2,3-dihydropyrrol-1 -yl, 2,3-dihydro-1 H-pyrrol-2-yl, 2,3-dihydro-1 H-pyrrol-3-yl, 2, 5-dihydropyrrol- 1 -yl, 2,5-dihydro-1 H-pyrrol-3-yl and 2,5-dihydropyrrol-5-yl. The term “2H-pyrrolyl” as used herein includes 2H-pyrrol-2-yl, 2H-pyrrol-3-yl, 2H-pyrrol-4-yl and 2H-pyrrol-5-yl. The term “3H-pyrrolyl” as used herein includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl and 3H-pyrrol-5-yl. The term “dihydrofuranyl” as used herein includes 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5-dihydrofuran-4-yl and 2,5-dihydrofuran-5-yl. The term “dihydrothiophenyl” as used herein includes 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,3-dihydrothiophen-4-yl, 2,3-dihydrothiophen-5-yl, 2,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5-dihydrothiophen-4-yl and 2,5-dihydrothiophen-5-yl. The term “imidazolidinyl” as used herein includes imidazolidin-1 -yl, imidazolidin-2-yl and imidazolidin-4-yl. The term “pyrazolidinyl” as used herein includes pyrazolidin-1 -yl, pyrazolidin-3-yl and pyrazolidin-4-yl. The term “imidazolinyl” as used herein includes imidazolin-1 -yl, imidazolin-2-yl, imidazolin-4-yl and imidazolin-5-yl. The term “pyrazolinyl” as used herein includes 1-pyrazolin-3-yl, 1-pyrazolin-4-yl, 2-pyrazolin-1-yl, 2-pyrazolin-3-yl, 2-pyrazolin-4-yl, 2-pyrazolin-5-yl, 3-pyrazolin-1-yl, 3-pyrazolin-2-yl, 3-pyrazolin-3-yl, 3-pyrazolin-4-yl and 3-pyrazolin-5-yl. The term “dioxolanyl” also known as “1,3-dioxolanyl” as used herein includes dioxolan-2-yl, dioxolan-4-yl and dioxolan-5-yl. The term “dioxolyl” also known as “1,3-dioxolyl” as used herein includes dioxol-2-yl, dioxol-4-yl and dioxol-5-yl. The term “oxazolidinyl” as used herein includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl and oxazolidin-5-yl. The term “isoxazolidinyl” as used herein includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl and isoxazolidin-5-yl. The term “oxazolinyl” as used herein includes 2-oxazolinyl-2-yl, 2-oxazolinyl-4-yl, 2-oxazolinyl-5-yl, 3-oxazolinyl-2-yl, 3-oxazolinyl-4-yl, 3-oxazolinyl-5-yl, 4-oxazolinyl-2-yl, 4-oxazolinyl-3-yl, 4-oxazolinyl-4-yl and 4-oxazolinyl-5-yl. The term “isoxazolinyl” as used herein includes 2-isoxazolinyl-3-yl, 2-isoxazolinyl-4-yl, 2-isoxazolinyl-5-yl, 3-isoxazolinyl-3-yl, 3-isoxazolinyl-4-yl, 3-isoxazolinyl-5-yl, 4-isoxazolinyl-2-yl, 4-isoxazolinyl-3-yl, 4-isoxazolinyl-4-yl and 4-isoxazolinyl-5-yl. The term “thiazolidinyl” as used herein includes thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl and thiazolidin-5-yl. The term “isothiazolidinyl” as used herein includes isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl and isothiazolidin-5-yl. The term “thiazolinyl” as used herein includes 2-thiazolinyl-2-yl, 2-thiazolinyl-4-yl, 2-thiazolinyl-5-yl, 3-thiazolinyl-2-yl, 3-thiazolinyl-4-yl, 3-thiazolinyl-5-yl, 4-thiazolinyl-2-yl, 4-thiazolinyl-3-yl, 4-thiazolinyl-4-yl and 4-thiazolinyl-5-yl. The term “isothiazolinyl” as used herein includes 2-isothiazolinyl-3-yl, 2-isothiazolinyl-4-yl, 2-isothiazolinyl-5-yl, 3-isothiazolinyl-3-yl, 3-isothiazolinyl-4-yl, 3-isothiazolinyl-5-yl, 4-isothiazolinyl-2-yl, 4-isothiazolinyl-3-yl, isothiazolinyl-4-yl and 4-isothiazolinyl-5-yl. The term “piperidyl” also known as “piperidinyl” as used herein includes piperid-1-yl, piperid-2-yl, piperid-3-yl and piperid-4-yl. The term “dihydropyridinyl” as used herein includes 1 ,2-dihydropyridin-1 -yl, 1 ,2-dihydropyridin-2-yl, 1,2-dihydropyridin-3-yl, 1 ,2-dihydropyridin-4-yl, 1 ,2-dihydropyridin-5-yl, 1 ,2-dihydropyridin-6-yl, 1.4-dihydropyridin- 1 -yl , 1 ,4-dihydropyridin-2-yl, 1 ,4-dihydropyridin-3-yl, 1 ,4-dihydropyridin-4-yl, 2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin- 5-yl, 2,3-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 3,4-dihydropyridin-2-yl, 3.4-dihydropyridin-3-yl, 3,4-dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl and 3,4-dihydropyridin- 6-yl. The term “tetrahydropyridinyl” as used herein includes 1.2.3.4-tetrahydropyridin- 1 -yl, 1.2.3.4-tetrahydropyridin-2-yl, 1.2.3.4-tetrahydropyridin-3-yl, 1.2.3.4-tetrahydropyridin-4-yl, 1.2.3.4-tetrahydropyridin-5-yl, 1.2.3.4-tetrahydropyridin-6-yl, 1.2.3.6-tetrahydropyridin- 1 -yl, 1.2.3.6-tetrahydropyridin-2-yl, 1.2.3.6-tetrahydropyridin-3-yl, 1.2.3.6-tetrahydropyridin-4-yl, 1.2.3.6-tetrahydropyridin-5-yl, 1.2.3.6-tetrahydropyridin-6-yl, 2.3.4.5-tetrahydropyridin-2-yl, 2.3.4.5-tetrahydropyridin-3-yl, 2.3.4.5-tetrahydropyridin-3-yl, 2.3.4.5-tetrahydropyridin-4-yl, 2.3.4.5-tetrahydropyridin-5-yl and 2,3,4,5-tetrahydropyridin-6-yl. The term “tetrahydropyranyl” also known as “oxanyl” or “tetrahydro-2H-pyranyl”, as used herein includes tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl. The term “2H-pyranyl” as used herein includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl and 2H-pyran-6-yl. The term “4H-pyranyl” as used herein includes 4H-pyran-2-yl, 4H-pyran-3-yl and 4H-pyran-4-yl. The term “3,4-dihydro-2H-pyranyl” as used herein includes 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl and 3,4-dihydro-2H-pyran-6-yl. The term “3,6-dihydro-2H-pyranyl” as used herein includes 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-5-yl and 3,6-dihydro-2H-pyran-6-yl. The term “tetrahydrothiophenyl”, as used herein includestetrahydrothiophen-2-yl, tetrahydrothiophenyl -3-yl and tetrahydrothiophenyl -4-yl. The term “2H-thiopyranyl” as used herein includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran- 4-yl, 2H-thiopyran-5-yl and 2H-thiopyran-6-yl. The term “4H-thiopyranyl” as used herein includes 4H-thiopyran-2-yl, 4H-thiopyran-3-yl and 4H-thiopyran-4-yl. The term “3,4-dihydro-2H-thiopyranyl” as used herein includes 3,4-dihydro-2H-thiopyran-2-yl, 3,4-dihydro-2H-thiopyran-3-yl, 3,4-dihydro-2H-thiopyran-4-yl, 3,4-dihydro-2H-thiopyran-5-yl and 3,4-dihydro-2H-thiopyran-6-yl. The term “3,6-dihydro-2H-thiopyranyl” as used herein includes 3,6-dihydro-2H-thiopyran-2-yl, 3,6-dihydro-2H-thiopyran-3-yl, 3,6-dihydro-2H-thiopyran-4-yl, 3,6-dihydro-2H-thiopyran-5-yl and 3,6-dihydro-2H-thiopyran-6-yl. The term “piperazinyl” also known as “piperazidinyl” as used herein includes piperazin-1 -yl and piperazin-2-yl. The term “morpholinyl” as used herein includes morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. The term “thiomorpholinyl” as used herein includes thiomorpholin-2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl. The term “dioxanyl” as used herein includes 1,2-dioxan-3-yl, 1,2-dioxan-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1 ,3-dioxan-5-yl and 1,4-dioxan-2-yl. The term “dithianyl” as used herein includes 1 ,2-dithian-3-yl, 1 ,2-dithian-4-yl, 1 ,3-dithian-2-yl, 1 ,3-dithian-4-yl, 1,3-dithian-5-yl and 1 ,4-dithian-2-yl. The term “oxathianyl” as used herein includes oxathian-2-yl and oxathian-3-yl. The term “trioxanyl” as used herein includes 1,2,3-trioxan-4-yl, 1,2,3-trioxan- 5-yl, 1,2,4-trioxan-3-yl, 1,2,4-trioxan-5-yl, 1,2,4-trioxan-6-yl and 1,3,4-trioxan-2-yl. The term “azepanyl” as used herein includes azepan-1-yl, azepan-2-yl, azepan-3-yl and azepan-4-yl. The term “homopiperazinyl” as used herein includes homopiperazin-1 -yl, homopiperazin-2-yl, homopiperazin-3-yl and homopiperazin-4-yl. The term “indolinyl” as used herein includes indolin-1 -yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, and indolin-7-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “isoindolinyl” as used herein includes isoindolin-1 -yl, isoindolin-2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6-yl, and isoindolin-7-yl. The term “3H-indolyl” as used herein includes 3H-indol-2-yl, 3H-indol-3-yl, 3H-indol-4-yl, 3H-indol-5-yl, 3H-indol-6-yl, and 3H-indol-7-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “tetrahydroquinolinyl” as used herein includes tetrahydroquinolin-1-yl, tetrahydroquinolin-2-yl, tetrahydroquinolin-3-yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl and tetrahydroquinolin-8-yl. The term “tetrahydroisoquinolinyl” as used herein includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl and tetrahydroisoquinolin-8-yl. The term “chromanyl” as used herein includes chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl and chroman-8-yl.The term “1H-pyrrolizine” as used herein includes 1 H-pyrrolizin-1 -yl, 1 H-pyrrolizin-2-yl, 1H-pyrrolizin-3-yl, 1 H-pyrrolizin-5-yl, 1 H-pyrrolizin-6-yl and 1 H-pyrrolizin-7-yl. The term “3H-pyrrolizine” as used herein includes 3H-pyrrolizin-1 -yl, 3H-pyrrolizin-2-yl, 3H-pyrrolizin-3-yl, 3H-pyrrolizin-5-yl, 3H-pyrrolizin-6-yl and 3H-pyrrolizin-7-yl.

[0150] The term “heteroaryl” refers to an aromatic ring system of 5 to 18 (ring) atoms including at least one N, O, S, or P (i.e. Cs-is), containing 1 or 2 rings which can be fused together or linked covalently, each ring typically containing 5 to 6 atoms; at least one of said rings is aromatic, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and wherein at least one carbon atom of said heteroaryl can be oxidized to form at least one C=O. Fused systems of a heteroaryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring, are considered as heteroaryl irrespective of the ring that is bound to the core structure. Fused systems of a heteroaryl ring with a heterocycle are considered as heteroaryl irrespective of the ring that is bound to the core structure. Fused systems of a hetero aryl ring with an aryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. Non-limiting examples of such heteroaryl, include: triazol-2-yl, pyridinyl, 1H-pyrazol-5-yl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1.2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2.3-dihydro-benzofuranyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl; preferably said heteroaryl group is selected from the group comprising pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, imidazolyl, indolyl, benzimidazolyl, s-triazinyl, oxazolyl, isothiazolyl, furyl, thienyl, triazolyl and thiazolyl ; more preferably, said heteroaryl group is selected from the group comprising pyridyl, pyrazinyl, pyrimidinyl, indolyl and benzimidazolyl. The term “pyrrolyl” (also called azolyl) as used herein includes pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl. The term “furanyl” (also called "furyl") as used herein includes furan-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl). The term “thiophenyl” (also called "thienyl") as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl). The term “pyrazolyl” (also called 1H-pyrazolyl and 1 ,2-diazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl or 1H-pyrazol-5-yl, pyrazol-4-yl and pyrazol-5-yl. The term “imidazolyl” as usedherein includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl and imidazol-5-yl. The term “oxazolyl” (also called 1,3-oxazolyl) as used herein includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl. The term “isoxazolyl” (also called 1,2-oxazolyl), as used herein includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. The term “thiazolyl” (also called 1,3-thiazolyl),as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl, 4-thiazolyl and 5-thiazolyl). The term “isothiazolyl” (also called 1, 2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl. The term “triazolyl” as used herein includes triazol-2-yl, 1 H-triazolyl and 4H-1 ,2,4-triazolyl, “1H-triazolyl” includes 1 H-1 ,2,3-triazol-1 -yl, 1H-1 ,2,3-triazol-4-yl, 1 H-1 ,2,3-triazol-5-yl, 1 H-1 ,2,4-triazol-1 -yl, 1 H-1 ,2,4-triazol-3-yl and 1 H-1, 2,4-triazol-5-yl. “4H-1,2,4-triazolyl” includes 4H-1 ,2,4-triazol-4-yl, and 4H-1 ,2,4-triazol-3-yl. The term “oxadiazolyl” as used herein includes 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl and 1,3,4-oxadiazol-2-yl. The term “thiadiazolyl” as used herein includes 1 ,2,3-thiadiazol-4-yl, 1 ,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl (also called furazan-3-yl) and 1,3,4-thiadiazol-2-yl. The term “tetrazolyl” as used herein includes 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term “oxatriazolyl” as used herein includes 1, 2,3,4-oxatriazol-5-yl and 1,2,3,5-oxatriazol-4-yl. The term “thiatriazolyl” as used herein includes 1.2.3.4-thiatriazol-5-yl and 1 ,2,3,5-thiatriazol-4-yl. The term “pyridinyl” (also called "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2-pyridyl, 3-pyridyl and 4-pyridyl). The term “pyrimidyl” as used herein includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl and pyrimid-6-yl. The term “pyrazinyl” as used herein includes pyrazin-2-yl and pyrazin-3-yl. The term “pyridazinyl as used herein includes pyridazin-3-yl and pyridazin-4-yl. The term “oxazinyl” (also called "1,4-oxazinyl") as used herein includes 1 ,4-oxazin-4-yl and 1,4-oxazin-5-yl. The term “dioxinyl” (also called "1,4-dioxinyl”) as used herein includes 1 ,4-dioxin-2-yl and 1.4-dioxin-3-yl. The term “thiazinyl” (also called "1,4-thiazinyl”) as used herein includes 1,4-thiazin-2-yl, 1 ,4-thiazin-3-yl, 1 ,4-thiazin-4-yl, 1 ,4-thiazin-5-yl and 1 ,4-thiazin-6-yl. The term “triazinyl” as used herein includes 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3-yl, 1 ,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1 ,2,3-triazin-4-yl and 1 ,2,3-triazin-5-yl. The term “imidazo[2,1-b][1,3]thiazolyl” as used herein includes imidazo[2,1-b][1,3]thiazoi-2-yl, imidazo[2,1-b][1,3]thiazol-3-yl, imidazo[2,1-b][1,3]thiazol-5-yl and imidazo[2,1-b][1,3]thiazol-6-yl. The term “thieno[3,2-b]furanyl” as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl. The term “thieno[3,2-b]thiophenyl” as used herein includes thieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl and thieno[3,2-b]thien-6-yl. The term “thieno[2,3-d][1,3]thiazolyl” as used herein includes thieno[2,3-d][1 ,3]thiazol-2-yl, thieno[2,3-d][1,3]thiazol-5-yl and thieno[2,3-d][1,3]thiazol-6-yl. The term “thieno[2,3-d]imidazolyl” as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl and thieno[2,3-d]imidazol-5-yl. The term “tetrazolo[1,5-a]pyridinyl” as usedherein includes tetrazolo[1,5-a]pyridine-5-yl, tetrazolo[1,5-a]pyridine-6-yl, tetrazolo[1,5-a]pyridine-7-yl, and tetrazolo[1,5-a]pyridine-8-yl. The term “indolyl” as used herein includes indol-1-yl, indol-2-yl, indol-3-yl, -indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl. The term “indolizinyl” as used herein includes indolizin-1 -yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl. The term “isoindolyl” as used herein includes isoindol-1 -yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl and isoindol-7-yl. The term “benzofuranyl” (also called benzo[b]furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl. The term “isobenzofuranyl” (also called benzo[c]furanyl) as used herein includes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl and isobenzofuran-7-yl. The term “benzothiophenyl” (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7-benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl). The term “isobenzothiophenyl” (also called benzo[c]thienyl) as used herein includes isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl and isobenzothien-7-yl. The term “indazolyl” (also called 1H-indazolyl or 2-azaindolyl) as used herein includes 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H-indazol-7-yl. The term “benzimidazolyl” as used herein includes benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl. The term “1 ,3-benzoxazolyl” as used herein includes 1.3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl and 1,3-benzoxazol-7-yl. The term “1 ,2-benzisoxazolyl” as used herein includes 1,2-benzisoxazol-3-yl, 1.2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1 ,2-benzisoxazol-6-yl and 1,2-benzisoxazol-7-yl. The term “2,1-benzisoxazolyl” as used herein includes 2,1-benzisoxazol-3-yl, 2,1-benzisoxazol-4-yl, 2,1-benzisoxazol-5-yl, 2,1-benzisoxazol-6-yl and 2,1-benzisoxazol-7-yl. The term “1,3-benzothiazolyl” as used herein includes 1,3-benzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl and 1,3-benzothiazol-7-yl. The term “1,2-benzoisothiazolyl” as used herein includes 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1.2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl and 1,2-benzisothiazol-7-yl. The term “2,1-benzoisothiazolyl” as used herein includes 2,1-benzisothiazol-3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6-yl and 2,1-benzisothiazol-7-yl. The term “benzotriazolyl” as used herein includes benzotriazol- 1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl. The term “1,2,3-benzoxadiazolyl” as used herein includes 1,2,3-benzoxadiazol-4-yl, 1,2,3-benzoxadiazol-5-yl, 1,2,3-benzoxadiazol-6-yl and 1.2.3-benzoxadiazol-7-yl. The term “2,1,3-benzoxadiazolyl” as used herein includes 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzoxadiazol-5-yl, 2,1,3-benzoxadiazol-6-yl and 2,1,3-benzoxadiazol-7-yl. The term “1,2,3-benzothiadiazolyl” as used herein includes 1,2,3-benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 1,2,3-benzothiadiazol-6-yl and 1,2,3-benzothiadiazol-7-yl. The term “2,1,3-benzothiadiazolyl” as used herein includes 2,1,3-benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-6-yl and 2,1,3-benzothiadiazol-7-yl. The term “thienopyridinyl” as used herein includes thieno[2,3-b]pyridinyl , thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl. The term “purinyl” as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl. The term “imidazo[1,2-a]pyridinyl”, as used herein includes imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-4-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl and imidazo[1,2-a]pyridin-7-yl. The term “1,3-benzodioxolyl”, as used herein includes 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, 1,3-benzodioxol-6-yl, and 1,3-benzodioxol-7-yl. The term “quinolinyl” as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl. The term “isoquinolinyl” as used herein includes isoquinolin-1 -yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. The term “cinnolinyl” as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl. The term “quinazolinyl” as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl. The term “quinoxalinyl” as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.

[0151] Heteroaryl and heterocycle or heterocyclyl as used herein includes by way of example and not limitation these groups described in Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C.W. and Scriven, E. “Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.

[0152] The term “heterocyclyloxy” or “heterocycleoxy”, as a group or part of a group, refers to a group having the formula -O-R' wherein R' is heterocyclyl as defined herein above.

[0153] The term “heterocyclylalkyloxy”, as a group or part of a group, refers to a group having the formula -O-Ra-R' wherein R' is heterocyclyl, and Rais alkyl as defined herein above.

[0154] The term “heteroaryloxy”, as a group or part of a group, refers to a group having the formula -O-Rkwherein Rkis heteroaryl as defined herein above.

[0155] The term “heteroarylalkyloxy”, as a group or part of a group, refers to a group having the formula -O-Ra-R' wherein R' is heteroaryl, and Rais alkyl as defined herein above.

[0156] The term “heterocyclylalkyl” or “heterocycle-alkyl” as a group or part of a group, refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with a heterocyclyl. A non-limiting example of a heterocyclylalkyl or heterocycle-alkyl group is 2-piperidinyl-methylene. The heterocyclylalkyl or heterocycle-alkyl group can comprise 6 to 20 atoms, e.g. the alkyl moiety is 1 to 6 carbon atoms and the heterocyclyl moiety is 3 to 14 atoms.

[0157] The term “heterocyclylalkenyl” or “heterocycle-alkenyl” as a group or part of a group refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heterocyclyl. The heterocyclylalkenyl or heterocycle-alkenyl group can comprise 6 to 20 atoms, e.g. the alkenyl moiety is 2 to 6 carbon atoms and the heterocyclyl moiety is 3 to 14 atoms. The term “heterocyclylalkynyl” or “heterocycle-alkynyl” as a group or part of a group refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heterocyclyl. The heterocyclylalkynyl or heterocycle-alkynyl group can comprise 6 to 20 atoms, e.g. the alkynyl moiety can comprise 2 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms.

[0158] The term “heterocyclylheteroalkyl” or “heterocycle-heteroalkyl” as a group or part of a group refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocyclyl. The heterocyclylheteroalkyl or heterocycle-heteroalkyl group can comprise 6 to 20 atoms (i.e. C6-C20), e.g. the heteroalkyl moiety can be Ci-Ce and the heterocyclyl moiety can comprise 3 to 14 atoms (i.e. be C3-C14). In some embodiments heterocyclylheteroalkyl or heterocycle-heteroalkyl is selected from the group comprising heterocyclyl-O-alkyl, heterocyclylalkyl-O-alkyl, heterocyclyl-NH-alkyl, heterocyclyl-N(alkyl)2, heterocyclylalkyl-NH-alkyl, heterocyclylalkyl-N-(alkyl)2, heterocyclyl-S-alkyl, and heterocyclylalkyl-S-alkyl.

[0159] The term “heterocyclylheteroalkenyl” or “heterocycle-heteroalkenyl” as a group or part of a group refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heterocyclyl. The heterocyclylheteroalkenyl or heterocycle-heteroalkenyl group can comprise 6 to 20 atoms (i.e. C6-C20), e.g. the heteroalkenyl moiety can be C2-C6 and the heterocyclyl moiety can comprise 3 to 14 atoms (i.e. be C3-C14). In some embodiments heterocyclyl-heteroalkenyl or heterocycle-heteroalkenyl is selected from the group comprising heterocyclyl-O-alkenyl, heterocyclylalkyl-O-alkenyl, heterocyclyl-NH-alkenyl, heterocyclyl-N(alkenyl)2, heterocyclylalkyl-NH-alkenyl, heterocyclylalkyl-N-(alkenyl)2, heterocyclyl-S-alkenyl, and heterocyclylalkenyl-S-alkenyl.

[0160] The term “heterocyclylheteroalkynyl” or “heterocycle-heteroalkynyl” as a group or part of a group refers to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heterocyclyl. The heterocyclylheteroalkynyl or heterocycle-heteroalkynyl group can comprise 6 to 20 atoms (i.e. be C6-C20), e.g. the heteroalkynyl moiety can be C2-C6 and the heterocyclyl moiety can comprise 3 to 14 atoms (i.e. be C3-C14). In some embodiments heterocyclyl-heteroalkynyl is selected from the group comprising heterocyclyl-O-alkynyl,heterocyclylalkynyl-O-alkynyl, heterocyclyl-NH-alkynyl, heterocyclyl-N(alkynyl)2, heterocyclylalkynyl-NH-alkynyl, heterocyclylalkynyl-N-(alkynyl)2, heterocyclyl-S-alkynyl, and heterocyclylalkynyl-S-alkynyl.

[0161] The term “heteroarylalkyl” as a group or part of a group refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl. An example of a heteroarylalkyl group is 2-pyridyl-methylene. The heteroarylalkyl group can comprise 6 to 20 atoms (i.e. C6-C20), e.g. the alkyl moiety of the heteroarylalkyl group can comprise 1 to 6 carbon atoms (i.e. Ci-Ce) and the heteroaryl moiety can comprise 5 to 14 atoms (i.e. C5-C14).

[0162] The term “heteroarylalkenyl” as a group or part of a group refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heteroaryl. The heteroarylalkenyl group can comprise 6 to 20 atoms (i.e. C6-C20), e.g. the alkenyl moiety of the heteroarylalkenyl group can comprise 2 to 6 carbon atoms and the heteroaryl moiety can comprise 5 to 14 atoms.

[0163] The term “heteroarylalkynyl” as a group or part of a group as used herein refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heteroaryl. The heteroarylalkynyl group comprises 6 to 20 atoms (i.e. C6-C20), e.g. the alkynyl moiety of the heteroaryl-alkynyl group is 2 to 6 carbon atoms (i.e. C2-C6) and the heteroaryl moiety is 5 to 14 atoms (i.e. C5-C14).

[0164] The term “heteroarylheteroalkyl” as a group or part of a group as used herein refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl. The heteroarylheteroalkyl group comprises 7 to 20 atoms (i.e. C7-C20), e.g. the heteroalkyl moiety of the heteroaryl-heteroalkyl group is 2 to 6 carbon atoms (i.e. C2-C6) and the heteroaryl moiety is 5 to 14 atoms (i.e. C5-C14). In some embodiments heteroaryl-heteroalkyl is selected from the group comprising heteroaryl-O-alkyl, heteroarylalkyl-O-alkyl, heteroaryl-NH-alkyl, heteroaryl-N(alkyl)2, heteroarylalkyl-NH-alkyl, heteroarylalkyl-N-(alkyl)2, heteroaryl-S-alkyl, and heteroarylalkyl-S-alkyl.

[0165] The term “heteroarylheteroalkenyl” as a group or part of a group as used herein refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heteroaryl. The heteroarylheteroalkenyl group comprises 8 to 20 atoms (i.e. C8-C20), e.g. the heteroalkenyl moiety of the heteroarylheteroalkenyl group is 3 to 6 carbon atoms (i.e. C3-Ce) and the heteroaryl moiety is 5 to 14 atoms (i.e. C5-C14). In some embodiments heteroarylheteroalkenyl is selected from the group comprising heteroaryl-O-alkenyl, heteroarylalkenyl-O-alkenyl, heteroaryl-NH-alkenyl, heteroaryl-N(alkenyl)2, heteroarylalkenyl-NH-alkenyl, heteroarylalkenyl-N-(alkenyl)2, heteroaryl-S-alkenyl, and heteroarylalkenyl-S-alkenyl.

[0166] The term “heteroarylheteroalkynyl” as a group or part of a group as used herein refers to aheteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heteroaryl. The heteroarylheteroalkynyl group comprises 8 to 20 atoms (i.e. C8-C20), e.g. the heteroalkynyl moiety of the heteroarylheteroalkynyl group is 2 to 6 carbon atoms (i.e. C2-C6) and the heteroaryl moiety is 5 to 14 atoms (i.e. C5-C14). In some embodiments heteroarylheteroalkynyl is selected from the group comprising heteroaryl-O-alkynyl, heteroarylalkynyl-O-alkynyl, heteroaryl-NH-alkynyl, heteroaryl-N(alkynyl)2, heteroarylal kynyl-NH-alkynyl, heteroarylalkynyl-N-(alkynyl)2, heteroaryl-S-alkynyl, and heteroarylal kynyl-S-alkynyl.

[0167] By way of example, carbon bonded heteroaryl or heterocyclic rings (or heterocycles) can be bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetra hydrofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heteroaryls and heterocyclyls include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example, nitrogen bonded heterocyclic rings are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or B-carboline. Still more typically, nitrogen bonded heteroaryls or heterocyclyls include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1 -piperidinyl.

[0168] As used herein and unless otherwise stated, the terms “alkoxy”, “cyclo-alkoxy”, “aryloxy”, “arylalkyloxy”, “heteroaryloxy” “heterocyclyloxy”, “alkylthio”, “cycloalkylthio”, “arylthio”, “arylalkylthio”, “heteroarylthio” and “heterocyclylthio” refer to substituents wherein an alkyl group, respectively a cycloalkyl, aryl, arylalkyl heteroaryl, or heterocyclyl (each of them such as defined herein), are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl and the like. The same definitions will apply for alkenyl and alkynyl instead of alkyl.

[0169] The term “alkylthio", as a group or part of a group, refers to a group having the formula -S-Rbwherein Rbis alkyl as defined herein above. Non-limiting examples of alkylthio groups include methylthio (-SCH3), ethylthio (-SCH2CH3), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like.The term “alkenylthio", as a group or part of a group, refers to a group having the formula -S-Rdwherein Rdis alkenyl as defined herein above.

[0170] The term “alkynylthio", as a group or part of a group, refers to a group having the formula -S-Rewherein Reis alkynyl as defined herein above.

[0171] The term “arylthio", as a group or part of a group, refers to a group having the formula -S-Rgwherein Rgis aryl as defined herein above.

[0172] The term “arylalkylthio", as a group or part of a group, refers to a group having the formula -S-Ra-Rgwherein Rais alkylene and Rgis aryl as defined herein above.

[0173] The term “heterocyclylthio", as a group or part of a group, refers to a group having the formula -S-R' wherein R' is heterocyclyl as defined herein above.

[0174] The term “heteroarylthio", as a group or part of a group, refers to a group having the formula -S-Rkwherein Rkis heteroaryl as defined herein above.

[0175] The term “heterocyclylalkylthio", as a group or part of a group, refers to a group having the formula -S-Ra-R' wherein Rais alkylene and R' is heterocyclyl as defined herein above.

[0176] The term “heteroarylalkylthio", as a group or part of a group, refers to a group having the formula -S-Ra-Rkwherein Rais alkylene and Rkis heteroaryl as defined herein above.

[0177] The term "aminoalkyl" as a group or part of a group, refers to an alkyl group having the meaning as defined above wherein one, two, or three hydrogen atoms are each replaced with an amino group (-NH2) as defined herein, i.e. mono-, di- and tri-amino-alkyl respectively. Non-limiting examples of such aminoalkyl groups include aminomethyl, 1 -amino-ethyl, 2-amino-ethyl, 1,2-di-amino-ethyl, etc.

[0178] The term “mono- or di-alkylamino”, as a group or part of a group, refers to a group of formula -N(R°)(Rb) wherein R° is hydrogen, or alkyl, Rbis alkyl. Thus, alkylamino include monoalkyl amino group (e.g. mono-alkylamino group such as methylamino and ethylamino), and di-alkylamino group (e.g. di-alkylamino group such as dimethylamino and diethylamino). Nonlimiting examples of suitable mono- or di-alkylamino groups include n-propylamino, isopropylamino, n-butylamino, / -butylamino, sec-butylamino, f-butylamino, pentylamino, n-hexylamino, di-n-propylamino, di- / -propylamino, ethylmethylamino, methyl-n-propylamino, methyl- / -propylamino, n-butylmethylamino, / -butylmethylamino, f-butylmethylamino, ethyl-n-propylamino, ethyl- / -propylamino, n-butylethylamino, i-butylethylamino, f-butylethylamino, di-n-butylamino, di- / -butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, and the like.

[0179] The term “mono- or di-arylamino”, as a group or part of a group, refers to a group of formula -N(Rg)(Rr) wherein Rgand Rrare each independently selected from hydrogen, aryl and alkyl, wherein at least one of Rgor Rris aryl.

[0180] The term “mono- or di-heteroarylamino”, as a group or part of a group, refers to a group of formula -N(RU)(RV) wherein Ruand Rvare each independently selected from hydrogen,heteroaryl and alkyl, wherein at least one of Ruor Rvis heteroaryl as defined herein.

[0181] The term “mono- or di-heterocyclylamino”, as a group or part of a group, refers to a group of formula -N(RW)(RX) wherein Rwand Rxare each independently selected from hydrogen, heterocyclyl and alkyl, wherein at least one of Rwor Rxis heterocyclyl as defined herein. As used herein and unless otherwise stated, the term “halogen” means any atom selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0182] Further to embodiments described herein below,

[0183] - each alkyl is C1-C18 alkyl, such as a C1-C12 alkyl; yet in particular a C1-C9 alkyl; still more in particular is a Ci-Ce alkyl, or a Ci-4alkyl; including when such alkyl is linked for example to aryl, heteroaryl or heterocycle as for example in arylalkyl, heteroarylalkyl and heterocycle-alkyl; - each alkenyl is C2-C18 alkenyl, such as a C2-C12 alkenyl; yet in particular C2-C9 membered alkenyl; still more in particular is C2-C6 alkenyl; including when such alkenyl is linked to for example aryl, heteroaryl or heterocycle as for example in arylalkenyl, heteroarylalkenyl and heterocycle-alkenyl;

[0184] - each alkynyl is C2-C18 alkynyl, such as a C2-C12 alkynyl; yet in particular a C2-Cgalkynyl; still more in particular a C2-C6 alkynyl; including when such alkynyl is linked to for example aryl, heteroaryl or heterocycle as for example in arylalkynyl, heteroarylalkynyl and heterocycle-alkynyl;

[0185] - each heteroalkyl is C1-C18 heteroalkyl, such as a C1-C12 heteroalkyl; yet in particular a C1-C9 heteroalkyl; still more in particular is a Ci-Ce heteroalkyl, or a Ci- heteroalkyl; including when such heteroalkyl is linked for example to aryl, heteroaryl or heterocycle as for example in arylheteroalkyl, heteroarylheteroalkyl and heterocycle-heteroalkyl;

[0186] - each heteroalkenyl is C2-C18 heteroalkenyl, such as a C2-C12 heteroalkenyl; yet in particular C2-C9 membered heteroalkenyl; still more in particular is C2-C6 heteroalkenyl; including when such heteroalkenyl is linked to for example aryl, heteroaryl or heterocycle as for example in arylheteroalkenyl, heteroarylheteroalkenyl and heterocycle-heteroalkenyl;

[0187] - each heteroalkynyl is C2-C18 heteroalkynyl, such as a C2-C12 heteroalkynyl; yet in particular a C2-C9 heteroalkynyl; still more in particular a C2-C6 heteroalkynyl; including when such heteroalkynyl is linked to for example aryl, heteroaryl or heterocycle as for example in arylheteroalkynyl, heteroarylheteroalkynyl and heterocycle-heteroalkynyl;

[0188] - each cycloalkyl is C3-C18 cycloalkyl, more in particular is a C3-C12 cycloalkyl; yet more in particular is a C3-C9 cycloalkyl; still more in particular is a C3-C6 cycloalkyl; including when such cycloalkyl is linked to alkyl, heteroalkyl, alkenyl or alkynyl such as in cycloalkylalkyl, cycloalkylheteroalkyl, cycloalkylalkenyl, or cycloalkylalkynyl;

[0189] - each cycloalkenyl is C5-C18 cycloalkenyl, more in particular is a C5-C12 cycloalkenyl; yet more in particular is a C5-C9 cycloalkenyl; still more in particular is a Cs-Ce cycloalkenyl;- each cycloalkynyl is C7-C18 cycloalkynyl, more in particular is a C7-C12 cycloalkynyl; yet more in particular is a C7-C9 cycloalkynyl;

[0190] - each aryl is C6-C20 aryl, more in particular is a C6-C14 aryl; yet more in particular is a Ce-C aryl; including when such aryl is linked to alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl, as in arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl or arylheteroalkynyl;

[0191] - each heteroaryl is 5 to 20 membered heteroaryl, more in particular is a 5 to 14 membered heteroaryl; yet more in particular is a 5 to 10 membered heteroaryl or a 5 to 8 membered heteroaryl; including when such heteroaryl is linked to alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl, such as in heteroarylalkyl, heteroarylalkenyl, heteroarylal kynyl, heteroarylheteroalkyl, heteroarylalkenyl or heteroarylheteroalkynyl;

[0192] - each heterocycle is 4 to 20 membered heterocycle, more in particular is a 4 to 14 membered heterocycle; yet more in particular is a 4 to 10, 4 to 8 or 5 to 7 membered heterocycle; including when such heterocycle is linked to alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl, as in heterocyclealkyl, heterocyclealkenyl, heterocycleal kynyl, heterocyclylheteroalkyl, heterocyclylheteroalkenyl or heterocyclylal kynyl.

[0193] The term “single bond” as used herein for a linking group i.e. in a way that a certain linking group is selected from a single bond, etc. in the formulas herein, refers to a molecule wherein the linking group is not present and therefore refers to compounds with a direct linkage via a single bond between the two moieties being linked by the linking group.

[0194] As used herein with respect to a substituting group, and unless otherwise stated, the terms “substituted” such as in “substituted alkyl”, “substituted alkenyl”, substituted alkynyl”, “substituted aryl”, “substituted heteroaryl”, “substituted heterocyclyl”, “substituted arylalkyl”, “substituted heteroaryl-alkyl”, “substituted heterocyclylalkyl” and the like refer to the chemical structures defined herein, and wherein the said alkyl, alkenyl, alkynyl, group and / or the said aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more substituents (preferable 1, 2, 3, 4, 5 or 6), meaning that one or more hydrogen atoms are each independently replaced with at least one substituent. Typical substituents include, but are not limited to and in a particular embodiment said substituents are being independently selected from the group consisting of halogen, amino, hydroxyl, sulfhydryl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroarylalkyl, heterocyclylalkyl, heteroarylalkenyl, heterocyclylalkenyl and heteroarylalkynyl, heterocyclylal kynyl, -X, -Z, -0; -OZ, =0, -SZ, -S’, =S, -NZ2, -N+Z3, =NZ, =N-OZ, -CX3(e.g. trifluoromethyl), -CN, -OCN, -SCN, -N=C=O, -N=C=S, -NO, -NO2, =N2, -N3, -NZC(O)Z, -NZC(S)Z, -NZC(O)O’, -NZC(O)OZ, -NZC(S)OZ, -NZC(O)NZZ, NZC(NZ)Z, NZC(NZ)NZZ, -C(O)NZZ, -C(NZ)Z, -S(O)2Q-, -S(O)2OZ, -S(O)2Z, -OS(O)2OZ, -OS(O)2Z, -0S(0)20-, -S(O)2NZZ, -S(O)(NZ)Z, -S(O)Z, -OP(O)(OZ)2, -P(O)(OZ)2, -P(0)(0-)2, -P(O)(OZ)(O-), -P(O)(OH)2, -C(O)Z, -C(O)X, -C(S)Z, -C(O)OZ, -0(0)0’ , -C(S)OZ, -C(O)SZ, -C(S)SZ, -C(O)NZZ, -C(S)NZZ, -C(NZ)NZZ, -OC(O)Z, -OC(S)Z, -00(0)0’, -OC(O)OZ, -OC(S)OZ, wherein each X is independently a halogen selected from F, Cl, Br, or I; and each Z is independently -H, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, protecting group or prodrug moiety, while two Z bonded to a nitrogen atom can be taken together with the nitrogen atom to which they are bonded to form a heteroaryl, or heterocyclyl. Alkyl(ene), alkenyl(ene), and alkynyl(ene) groups may also be similarly substituted.

[0195] Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected.

[0196] Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.

[0197] The term “heteroatom (s)” as used herein means an atom selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.

[0198] The term “hydroxy” as used herein means -OH.

[0199] The term “carbonyl” as used herein means carbon atom bonded to oxygen with a double bond, i.e., 0=0.

[0200] The term “amino” as used herein means the -NH2group.

[0201] The present invention provides novel compounds which have been shown to possess cGAS inhibitory activity. Therefore, these compounds constitute a useful class of new potent compounds that can be used in the treatment and / or prevention of cGAS mediated diseases in subjects, more specifically for the treatment and / or prevention of inflammation conditions and cancer.

[0202] The present invention furthermore relates to the compounds for use as medicines and to their use for the manufacture of medicaments for treating and / or preventing inflammation conditions and cancer. The present invention relates to the compounds for use as medicines for treating and / or preventing cGAS mediated diseases such as inflammation conditions and cancer in animals, mammals, more in particular in humans. The invention also relates to methods for the preparation of all such compounds and to pharmaceutical compositions comprising them in an effective amount. The present invention also relates to a method of treatment or prevention of inflammation conditions or cancer in humans by the administration of one or more such compounds, optionally in combination with one or more other medicines, to a patient in need thereof. The present invention also relates to the compounds for veterinary use and to theiruse as medicines for the prevention or treatment of diseases in a non-human mammal, such as inflammation conditions or cancer in non-human mammals.

[0203] Provided herein are compounds of formula (I) and any subgroup thereof as described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and / or prodrug thereof,

[0204]

[0205] wherein:

[0206] each dashed line ( ) represents an optional double bond and whereby two adjacent dashed line cannot form a double bond at the same time;

[0207] the dotted lines (

[0208]

[0209] ) represent the possible points of attachment of -Q-L-X; each E1, E2and E3is independently C or N;

[0210] T1is C, O or N; T2is C, N or a bond; T3is C, N or a bond; and, T4is C or N; wherein T2and T3are not both a bond, and, wherein one and only one of T1, T2, T3and T4is N;

[0211] R1is selected from the group comprising hydrogen, halogen, =0, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0212] wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, - OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, -C(O)OH, -C(O)O-alkyl, -NH2, -NHalkyl, and - N(alkyl)2;R2is selected from the group comprising hydrogen, halogen, =0, hydroxyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylaminoalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, -CONR2aR2band -CChR20;

[0213] wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylamino- alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -SCF3, -SF5, -N3, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl (such as -CF3, -CHF2), alkoxy, haloalkoxy (such as -OCF3, -OCHF2), hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -C(O)OR2c, -COR2d, -NR2aR2b(such as -NH2, -NHalkyl, and -N(alkyl)2), -NR2aCOR2d, -CONR2aR2b, and - 0R2c;

[0214] R2ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0215] R2bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0216] R2Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0217] R2dis selected from the group comprising heteroalkyl (e.g. hydroxyalkyl, alkyloxyalkyl), hydroxy, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; or R1and R2together with the carbon atoms to which they are attached can form a heterocyclyl (e.g. pyrrolidinyl),

[0218] wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, - CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;

[0219] or R2and X together with the atoms to which they are attached can form a heterocyclyl wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;R3is selected from the group comprising hydrogen, halogen, nitro, -CN, -NR3aR3b, - >

[0220]

[0221] IT*

[0222]

[0223] , oxo, hydroxyl, sulfhydryl, alkyl, alkenyl, alkynyl, heteroalkyl (e.g., alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl and alkoxyalkylamino), heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylheteroalkyl, heterocyclylheteroalkenyl and heterocyclylheteroalkynyl,

[0224] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl (e.g. alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl and alkoxyalkylamino), heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylheteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCFs, -SFs, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl (e.g. hydroxyalkyl, alkoxy, alkylthio), heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -C(O)OH, -C(O)R3i, -C(O)-O-CH2- O-CO-R3', -PO-(OR3i)2, -SO2F, -NR3aR3b(-NH2, -NHalkyl, and -N(alkyl)2);

[0225] cycle A is selected from the group comprising aryl (such as phenyl), cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl and heteroaryl;

[0226] - Y is NR3hor O;

[0227] each R6is independently selected from the group comprising hydrogen, halogen, -OH, - NR3aR3b, -SH, =S, -SCF3, -SFs, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl (e.g. alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- or di-)alkyl-amino-alkyl), heteroalkenyl, heteroalkynyl, -(CR3fR3g)q-O- (CR3fR3g)v-CO2R3c, hydroxyalkyl, -(CR3fR3g)q-NR3aSO2R3d, -CO2R3c, -(CR3fR3g)q-O- (CR3fR3g)v-aryl, -(CR3fR3g)q-O-(CR3fR3g)v-heteroaryl, -CONR3aS(O)2R3d, -S(O)2R3d, - (CR3fR3g)q-O-(CR3fR3g)v-CN, -C(O)R3d, aryl, heteroaryl, heterocyclyl, -C(O)NR3aR3b, oxo, - S(O)2NR3aR3b, -OR3cand -(CR3fR3g)q-O-(CR3fR3g)v-O-aryl,

[0228] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl (e.g. alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- or di-)alkyl-amino-alkyl), heteroalkenyl, heteroalkynyl, aryl, heteroaryl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, - CHF2, -OCF3, -OCHF2, -SCF3, -SFs, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, heteroalkyl (e.g. alkoxy, hydroxyalkyl, -NH2, -NHalkyl, and -N(alkyl)2), heteroalkenyl and heteroalkynyl;

[0229] R3ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di- )alkyl-amino, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, - SCh-alkyl, aryl, heteroaryl and heterocyclyl;

[0230] R3bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0231] R3Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkyl-COOH, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;

[0232] R3dis selected from the group comprising alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, alkoxy, (mono- or di-)alkyl-amino, (mono- or di-)alkyl-amino-alkyl, alkylthio, alkylthioalkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;

[0233] each R3fand R3gare each independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, -NH2, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;

[0234] R3his selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0235] R3' is selected from hydrogen, alkyl, cycloalkyl and aryl wherein each alkyl, cycloalkyl, and aryl is optionally further substituted with one or more halogen;

[0236] m is an integer selected from 0, 1 , 2, 3, 4 or 5

[0237] p is an integer selected from 0, 1, 2, 3, 4 or 5;

[0238] q is an integer selected from 0, 1, 2, 3, 4 or 5;

[0239] v is an integer selected from 0, 1 , 2, 3, 4 or 5;

[0240] Q is selected from -CO-, -SO2-, -SO(=NH)-;

[0241] L is selected from -CRLgRLh-, -NRLb-, or a single bond;

[0242] RLgis selected from the group comprising hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyalkyl, hydroxylalkenyl, hydroxyalkynyl, -NRLaRLb, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, -C(O)NRLaRLb, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, deuterium, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0243] RLhis selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, deuterium, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0244] RLais selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0245] RLbis selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0246] or RLgand RLhtogether with the carbon atoms to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl and heterocyclyl;

[0247] X is selected from the group comprising -ORXc, -NRXaRXb, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, -S(O)2Xd, -NRXbS(O)2Xd, -NRXbC(O)ORXc, -OC(O)RXd, -C(O)NRXaRXb, -C(O)ORXc, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkyl, alkenyl, alkynyl, (mono- or di-)alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl and -N3, wherein each of said heteroaryl, heterocyclyl, aryl, alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising hydroxyalkyl, -C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, - SCF3, -SF5, -P(O)H2, -S(O)2RXa, -S(O)RXa, cyano, nitro, -C(O)ORXc, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, (mono- or di-)alkyl-aminoalkoxy, -NRXaRXb(such as -NH2, -NHalkyl, and -N(alkyl)2);

[0248] RXais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,

[0249] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2;

[0250] RXbis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, - NH2, -NHalkyl, and -N(alkyl)2;

[0251] each RXcis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,

[0252] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2;

[0253] RXdis selected from the group comprising alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,

[0254] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy;

[0255] each RXeand RXfare independently selected from alkyl, alkenyl, alkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,

[0256] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl andheterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy;

[0257] n is an integer selected from 1, 2, 3, or 4;

[0258] each R4is independently selected from the group comprising halogen, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, -B(OH)2, -O-SO2-F, -SO2-F, cyano, nitro, -OR4c, -NR4aR4b, - NR4aS(O)2R4d, -NR4aSO2NR4aR4b, -NR4aC(O)R4c, -NR4aC(O)OR4c, -NR4aC(O)NR4aR4b, SR4c, -S(O)R4d, -S(O)2R4C, -S(O)2NR4aR4b, -S(O)(NR4a)R4c, -S(NR4a)(NR4a) R4c, -C(O)OR4c, -C(O)R4c, -C(O)NR3aR3b, -P(O)R4aR4b, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl haloalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl,

[0259] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxy, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -OH, =0, halogen, - SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -B(OH)2Icyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)OH, -C(O)Oalkyl, -C(O)NH2, - C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, -NHalkyl, and -N(alkyl)2;

[0260] or two R4together with the carbon atom(s) to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl,

[0261] wherein each of said cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, is unsubstituted or is substituted with one or more substituents each independently selected from R4e;

[0262] - R4ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl and aminoalkynyl;

[0263] - R4bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0264] - R4Cis selected from the group comprising hydrogen, alkyl, alkyl substituted with deuterium, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxyalkyl and (mono- or di-)alkyl-aminoalkyl; - R4dis selected from the group comprising alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;- R4eis independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxyalkoxyalkyl, -C(O)OH, -C(O)Oalkyl, -NHC(O)alkyl, -C(O)NH2, -C(O)NHalkyl, - C(O)N(alkyl)2, -NH2, -NHalkyl, and -N(alkyl)2;

[0265] wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl, alkoxy, alkoxyalkyl, -C(O)Oalkyl, -NHC(O)alkyl, -C(O)NHalkyl, -C(O)N(alkyl)2, -NHalkyl, and - N(alkyl)2 are optionally substituted with one of more substituents selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, azido, alkoxy, -NH2, -NHalkyl, and -N(alkyl)2;

[0266] R5is absent or is selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl-amino- alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl; wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl-amino-alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, - CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)OH, C(O)Oalkyl, - C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, - NHalkyl, and - N(alkyl)2;

[0267] or R3and R5together with the atoms to which they are attached form a heteroaryl or heterocyclyl wherein said heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, - OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, phenyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and - N(alkyl)2; and,

[0268] when E1, E2and E3are C, and, T1is C, T2is N, T3is a bond and T4is C, then E1and E3are both substituted with R4, wherein said two R4groups together form an aryl or heteroaryl, wherein said aryl and heteroaryl is unsubstituted or is substituted with one or more substituents each independently selected from R4e.In some embodiments, the compounds of the invention are compounds of formula (I) and any subgroup thereof as described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and / or prodrug thereof, wherein: wherein:

[0269] each dashed line (

[0270]

[0271] ) represents an optional double bond and whereby two adjacent dashed line cannot form a double bond at the same time;

[0272] the dotted lines (

[0273]

[0274] ) represent the possible points of attachment of -Q-L-X; each E1, E2and E3is independently C, CH, NH or N;

[0275] - T1is CH, C, O or N; T2is C, CH, CH2, N or a bond; T3is C, CH, CH2, N or a bond; and, T4is CH, C or N; wherein T2and T3are not both a bond, and, wherein one and only one of T1, T2, T3and T4is N;

[0276] R1is selected from the group comprising hydrogen, halogen, =0, alkyl, -C(O)O-alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, -C(O)OH, -C(O)O-alkyl, -NH2, -NHalkyl, and - N(alkyl)2;

[0277] R2is selected from the group comprising hydrogen, halogen, =0, hydroxyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylaminoalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, -CONR2aR2band - CO2R2C;

[0278] wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylamino- alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -SCF3, -SF5, -N3, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl (such as -CF3, -CHF2), alkoxy, haloalkoxy (such as -OCF3, -OCHF2), hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -C(O)OR2c, -COR2d, -NR2aR2b(such as -NH2, -NHalkyl, and -N(alkyl)2), -NR2aCOR2d, -CONR2aR2b, and -0R2c; R2ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl and cycloalkynyl;

[0279] R2bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0280] R2Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0281] R2dis selected from the group comprising hydroxyalkyl, alkyloxyalkyl, hydroxy, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0282] or R1and R2together with the carbon atoms to which they are attached can form a heterocyclyl (e.g. pyrrolidinyl),

[0283] wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, - CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;

[0284] or R2and X together with the atoms to which they are attached can form a heterocyclyl wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;

[0285] R3is selected from the group comprising hydrogen, halogen, nitro, -ON, -NR3aR3b, - (CR3fR3g)q-NR3aR3b, -NR3a-(CR3fR3g)q-NR3aR3b, -O-(CR3fR3g)q-NR3aR3b, -C(O)NR3aR3b, - (CR3fR3g)q-C(O)NR3aR3b, -NR3a-(CR3fR3g)q-C(O)NR3aR3b, -O-(CR3fR3g)q-C(O)NR3aR3b, -CO2R3C, -(CR3fR3g)q-CO2R3c, -NR3a-(CR3fR3g)q-CO2R3c, -O-(CR3fR3g)q-CO2R3c, -0R3c, - (CR3fR3g)q-OR3c, -NR3a-(CR3fR3g)q-OR3c, -O-(CR3fR3g)q-OR3c, -(CR3fR3g)q-C(O)R3c, -O- (CR3fR3g)q-C(O)R3c, -NR3a-(CR3fR3g)q-C(O)R3c, -O-(CR3fR3g)q-PO(OR3i)2, -NR3a-(CR3fR3g)q- PO(OR3i)2, -NR3aC(O)R3d, -(CR3fR3g)q-NR3aC(O)R3d, -NR3a-(CR3fR3g)q-NR3aC(O)R3d, - N(C(O)R3d)2, -SR3c, -S(O)R3c, -S(O)2R3C, -S(O)2-NR3aR3b, -NR3aS(O)2R3d, -(CR3fR3g)q- NR3aS(O)2R3d, -(CR3fR3g)q-S(O)2NR3a, -NR3a-(CR3fR3g)q-NR3aS(O)2R3d, -S(O)(NR3a)R3c, -S(O)(NR3a)NR3aR3b, -NR3aS(O)(NR3a)R3d, -(CR3fR3g)q-NR3aS(O)(NR3a)R3d, -(CR3fR3g)q-S(O)(NR3a)NR3a, -NR3a-(CR3fR3g)q-NR3aS(O)(NR3a)R3d, oxo, hydroxyl, sulfhydryl,

[0286]

[0287] alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, alkoxyalkylamino, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl andheterocyclylalkynyl,

[0288] wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, alkoxyalkylamino, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, - PO-(OR3i)2, -SO2F, -NR3aR3b(-NH2, -NHalkyl, and -N(alkyl)2);

[0289] cycle A is selected from the group comprising aryl (such as phenyl), cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl and heteroaryl;

[0290] - Y is NR3hor O;

[0291] each R6is independently selected from the group comprising hydrogen, halogen, -OH, - NR3aR3b, -SH, =S, -SCF3, -SFS, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- ordi-)alkyl-amino-alkyl, -(CR3fR3g)q-O-(CR3fR3g)v-CO2R3c, hydroxyalkyl, -(CR3fR3g)q- NR3aSO2R3d, -CO2R3C, -(CR3fR3g)q-O-(CR3fR3g)v-aryl, -(CR3fR3g)q-O-(CR3fR3g)v-heteroaryl, - CONR3aS(O)2R3d, -S(O)2R3d, -(CR3fR3g)q-O-(CR3fR3g)v-CN, -C(O)R3d, aryl, heteroaryl, heterocyclyl, -C(O)NR3aR3b, oxo, -S(O)2NR3aR3b, -0R3cand -(CR3fR3g)q-O-(CR3fR3g)v-O- aryl,

[0292] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- or di-)alkyl- amino-alkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;

[0293] R3ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di-)alkyl-amino, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, -SO2-alkyl, aryl, heteroaryl and heterocyclyl; R3bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0294] R3Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, alkyl-COOH, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;

[0295] R3dis selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, alkoxy, (mono- or di-)alkyl-amino, (mono- or di-)alkyl-amino-alkyl, alkylthio, alkylthioalkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;

[0296] each R3fand R3gare each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, -NH2, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;

[0297] R3his selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0298] R3' is selected from hydrogen, alkyl, cycloalkyl and aryl wherein each alkyl, cycloalkyl, and aryl is optionally further substituted with one or more halogen;

[0299] m is an integer selected from 0, 1 , 2, 3, 4 or 5

[0300] p is an integer selected from 0, 1, 2, 3, 4 or 5;

[0301] q is an integer selected from 0, 1, 2, 3, 4 or 5;

[0302] v is an integer selected from 0, 1 , 2, 3, 4 or 5;

[0303] Q is selected from -CO-, -SO2-, -SO(=NH)-; preferably Q is -CO-;

[0304] L is selected from -CRLgRLh-, -NRLb-, or a single bond;

[0305] RLgis selected from the group comprising hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxylalkenyl, hydroxyalkynyl, -NRLaRLb, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, -C(O)NRLaRLb, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, deuterium, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0306] RLhis selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, deuterium, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0307] RLais selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0308] RLbis selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0309] or RLgand RLhtogether with the carbon atoms to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl and heterocyclyl;

[0310] X is selected from the group comprising -ORXc, -NRXaRXb, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, -S(O)2Xd, -NRXbS(O)2Xd, -NRXbC(O)RXc, -NRXbC(O)ORXc, -OC(O)RXd, -C(O)NRXaRXb, -C(O)ORXc, hydroxyalkyl, hydroxyalkenyl,hydroxyal kynyl, alkyl, alkenyl, alkynyl, (mono- or di-)alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl and -N3,

[0311] wherein each of said heteroaryl, heterocyclyl, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyal kynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising hydroxyalkyl, - C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -P(O)H2, -S(O)2RXa, -S(O)RXa, cyano, nitro, -C(O)ORXc, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, (mono- or di- )alkyl-aminoalkoxy, -NRXaRXb(such as -NH2, -NHalkyl, and -N(alkyl)2);

[0312] RXais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,

[0313] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2;

[0314] RXbis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl,

[0315] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, - NH2, -NHalkyl, and -N(alkyl)2;

[0316] each RXcis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl,hydroxyal kynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,

[0317] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, - CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2;

[0318] RXdis selected from the group comprising alkyl, alkenyl, alkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from - CONRXaRXb, hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy;

[0319] each RXeand RXfare independently selected from alkyl, alkenyl, alkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,

[0320] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy;n is an integer selected from 1, 2, 3, or 4;

[0321] each R4is independently selected from the group comprising halogen, oxo, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, -B(OH)2, -O-SO2-F, -SO2-F, cyano, nitro, -OR4c, -NR4aR4b, - NR4aS(O)2R4d, -NR4aSO2NR4aR4b, -NR4aC(O)R4c, -NR4aC(O)OR4c, -NR4aC(O)NR4aR4b, SR4c, -S(O)R4d, -S(O)2R4C, -S(O)2NR4aR4b, -S(O)(NR4a)R4c, -S(NR4a)(NR4a) R4c, -C(O)OR4c, -C(O)R4c, -C(O)NR3aR3b, -P(O)R4aR4b, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl haloalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl,

[0322] wherein each of said alkyl, alkenyl, alkynyl, alkoxy, haloalkyl haloalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -B(OH)2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)OH, -C(O)Oalkyl, - C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, -NHalkyl, and -N(alkyl)2;

[0323] or two R4together with the atom(s) to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl,

[0324] wherein each of said cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, is unsubstituted or is substituted with one or more substituents each independently selected from R4e;

[0325] - R4ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl and aminoalkynyl;

[0326] - R4bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0327] - R4Cis selected from the group comprising hydrogen, alkyl, alkyl substituted with deuterium, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxyalkyl and (mono- or di-)alkyl-aminoalkyl;

[0328] - R4dis selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;

[0329] - R4eis independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxyalkoxyalkyl, -C(O)H, - C(O)OH, -C(O)Oalkyl, -NHC(O)alkyl, -C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, - NHalkyl, and -N(alkyl)2;wherein each of said alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl, alkoxy, alkoxyalkyl, -C(O)Oalkyl, -NHC(O)alkyl, - C(O)NHalkyl, -C(O)N(alkyl)2, -NHalkyl, and -N(alkyl)2 are optionally substituted with one of more substituents selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, - OCHF2, -SCF3, -SF5, cyano, nitro, azido, alkoxy, -NH2, -NHalkyl, and -N(alkyl)2;

[0330] R5is absent or is selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl-amino-alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl;

[0331] wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl- amino-alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, - CHF2, OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)OH, C(O)Oalkyl, -C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, - NHalkyl, and - N(alkyl)2;

[0332] or R3and R5together with the atoms to which they are attached form a heteroaryl or heterocyclyl wherein said heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, - OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, phenyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2; and,

[0333] when E1is C, E2is C or CH and E3is C, and, T1is C or CH, T2is N, T3is a bond and T4is C or CH, then E1and E3are both substituted with R4, wherein said two R4groups together form an aryl or heteroaryl, wherein said aryl and heteroaryl is unsubstituted or is substituted with one or more substituents each independently selected from R4e.

[0334] In some embodiments, the compounds of the invention are compounds of formula (I) and any subgroup thereof as described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and / or prodrug thereof, wherein: each dashed line (

[0335]

[0336] ) represents an optional double bond and whereby two adjacent dashed line cannot form a double bond at the same time;

[0337] the dotted lines ( ) represent the possible points of attachment of -Q-L-X;each E1, E2and E3is independently C, CH, NH or N;

[0338] - T1is CH, C, O or N; T2is C, CH, CH2, N or a bond; T3is C, CH, CH2, N or a bond; and, T4is CH, C or N; wherein T2and T3are not both a bond, and, wherein one and only one of T1, T2, T3and T4is N;

[0339] R1is selected from the group comprising hydrogen, halogen, =0, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably R1is selected from the group comprising hydrogen, halogen, =0, Ci-ealkyl, C2-6alkenyl, C2. ealkynyl, hydroxyCi-ealkyl, hydroxyC2-6alkenyl, hydroxyC2-6alkynyl, aminoCi-ealkyl, aminoC2-6alkenyl, aminoC2-6alkynyl, haloCi-ealkyl, haloC2-6alkenyl, haloC2-6alkynyl, C3- i2cycloalkyl, Cs-i2cycloalkenyl and Cs-i2cycloalkynyl;

[0340] wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, -C(O)OH, -C(O)O-alkyl, -NH2, -NHalkyl, and - N(alkyl)2; preferably each of said Ci-ealkyl, C2-ealkenyl, 02-ealkynyl, hydroxyCi-ealkyl, hydroxyC2-6alkenyl, hydroxyC2-ealkynyl, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2- ealkynyl, haloCi-ealkyl, haloC2-ealkenyl, haloC2-ealkynyl, C3-i2cycloalkyl, C5- i2cycloalkenyl and Cs-i2cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-6alkyl, 02-ealkenyl, 02-ealkynyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, aryl, -C(O)OH, -C(0)0-Ci-6alkyl, -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2;

[0341] R2is selected from the group comprising hydrogen, halogen, =0, hydroxyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylaminoalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, -CONR2aR2band - CC>22C; preferably R2is selected from the group comprising hydrogen, halogen, =0, hydroxyl, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2-ealkynyl, Ci-ealkyloxyCi- ealkyl, mono-Ci-6alkylaminoCi-ealkyl, di-Ci-ealkylaminoCi-ealkyl, C3-i2cycloalkyl, C5- i2cycloalkenyl, Cs-i2cycloalkynyl, haloCi-ealkyl, haloC2-ealkenyl, haloC2-ealkynyl, Ci-ealkoxy, haloCi-6alkoxy, -CONR2aR2band -CO2R2c;wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylamino- alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -N3, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -C(O)OR2c, -NH2, -NHalkyl, and -N(alkyl)2; - COR2d, -NR2aR2b, -NR2aCOR2d, -CONR2aR2b, and -OR2c; preferably each of said Ci- ealkyl, C2-ealkenyl, C2-ealkynyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2. ealkynyl, aminoCi-ealkyl, aminoC2-6alkenyl, aminoC2-ealkynyl, Ci-ealkyloxyCi-ealkyl, mono-Ci-ealkylaminoCi-ealkyl, di-Ci-ealkylaminoCi-ealkyl, C3-i2cycloalkyl, C5- i2cycloalkenyl, Cs-i2cycloalkynyl, haloCi-ealkyl, haloC2-ealkenyl, haloC2-ealkynyl, C1- ealkoxy, haloCi-ealkoxy, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -N3, cyano, nitro, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, -C(O)OH, -C(O)OR2c, -NH2, - NHalkyl, and -N(alkyl)2; -COR2d, -NR2aR2b, -NR2aCOR2d, -CONR2aR2b, and -0R2c; R2ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably R2ais selected from the group comprising hydrogen, Ci-ealkyl, 02-ealkenyl, 02-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl and C5-i2cycloalkynyl;

[0342] R2bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably R2bis selected from the group comprising hydrogen, Ci-ealkyl, C2-6alkenyl, 02-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl and C5-i2cycloalkynyl;

[0343] R2Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably R2cis selected from the group comprising hydrogen, Ci-ealkyl, 02-ealkenyl, 02-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl and C5-i2cycloalkynyl;

[0344] R2dis selected from the group comprising hydroxyalkyl, alkyloxyalkyl, hydroxy, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably R2ais selected from the group comprising hydroxy, hydrogen, Ci-ealkyl, 02-ealkenyl, 02-ealkynyl, C3. i2cycloalkyl, Cs-i2cycloalkenyl and Cs-i2cycloalkynyl;

[0345] or R1and R2together with the carbon atoms to which they are attached can form a heterocyclyl (e.g. pyrrolidinyl),wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, - CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2; preferably wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-ealkenyl, C2-6alkynyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, -C(O)OH, -NH2, - NHCi-ealkyl, and -N(Ci-6alkyl)2;

[0346] or R2and X together with the atoms to which they are attached can form a heterocyclyl wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2; preferably R2and X together with the atoms to which they are attached can form a heterocyclyl wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-ealkenyl, 02-ealkynyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, -C(O)OH, -NH2, -NHCi-ealkyl, and -N(Ci-6alkyl)2;

[0347] R3is selected from the group comprising hydrogen, halogen, nitro, -CN, -NR3aR3b, -(CR3fR3g)q-NR3aR3b, -NR3a-(CR3fR3g)q-NR3aR3b, -O-(CR3fR3g)q-NR3aR3b, -C(O)NR3aR3b, -(CR3fR3g)q-C(O)NR3aR3b, -NR3a-(CR3fR3g)q-C(O)NR3aR3b, -O-(CR3fR3g)q-C(O)NR3aR3b, -CO23C, -(CR3fR3g)q-CO2R3c, -NR3a-(CR3fR3g)q-CO2R3c, -O-(CR3fR3g)q-CO2R3c, -0R3c, -(CR3fR3g)q-OR3c, -NR3a-(CR3fR3g)q-OR3c, -O-(CR3fR3g)q-OR3c, -(CR3fR3g)q-C(O)R3c, -O-(CR3fR3g)q-C(O)R3c, -NR3a-(CR3fR3g)q-C(O)R3c, -O-(CR3fR3g)q-PO(OR3i)2, -NR3a-(CR3fR3g)q-PO(OR3i)2, -NR3aC(O)R3d, -(CR3fR3g)q-NR3aC(O)R3d, -NR3a-(CR3fR3g)q-NR3aC(O)R3d, -N(C(O)R3d)2, -SR3c, -S(O)R3c, -S(O)2R3c, -S(O)2-NR3aR3b, -NR3aS(O)2R3d, -(CR3fR3g)q-NR3aS(O)2R3d, -(CR3fR3g)q-S(O)2NR3a, -NR3a-(CR3fR3g)q-NR3aS(O)2R3d, -S(O)(NR3a)R3c, -S(O)(NR3a)NR3aR3b, -NR3aS(O)(NR3a)R3d, -(CR3fR3g)q-NR3aS(O)(NR3a)R3d, -(CR3fR3g)q-S(O)(NR3a)NR3a, -NR3a-(CR3fR3g)q-NR3aS(O)(NR3a)R3d, oxo, hydroxyl, sulfhydryl,

[0348] >

[0349]

[0350] , alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, alkoxyalkylamino, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl,haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl; preferably R3is selected from the group comprising hydrogen, halogen, nitro, -CN, -NR3aR3b, -(CR3fR3g)q-NR3aR3b, -NR3a-(CR3fR3g)q-NR3aR3b, -O-(CR3fR3g)q-NR3aR3b, -C(O)NR3aR3b, -(CR3fR3g)q-C(O)NR3aR3b, -NR3a-(CR3fR3g)q-C(O)NR3aR3b, -O-(CR3fR3g)q-C(O)NR3aR3b, -CO2R3c, -(CR3fR3g)q-CO2R3c, -NR3a-(CR3fR3g)q-CO2R3C, -O-(CR3fR3g)q-CO2R3c, -0R3c, -(CR3fR3g)q-OR3c, -NR3a-(CR3fR3g)q-OR3c, -O-(CR3fR3g)q-OR3c, -(CR3fR3g)q-C(O)R3c, -O-(CR3fR3g)q-C(O)R3c, -NR3a-(CR3fR3g)q-C(O)R3c, -O-(CR3fR3g)q-PO(OR3i)2, -NR3a-(CR3fR3g)q-PO(OR3i)2, -NR3aC(O)R3d, -(CR3fR3g)q-NR3aC(O)R3d, -NR3a-(CR3fR3g)q-NR3aC(O)R3d, -N(C(O)R3d)2, -SR3c, -S(O)R3c, -S(O)2R3c, -S(O)2-NR3aR3b, -NR3aS(O)2R3d, -(CR3fR3g)q-NR3aS(O)2R3d, -(CR3fR3g)q-S(O)2NR3a, -NR3a-(CR3fR3g)q-NR3aS(O)2R3d, -S(O)(NR3a)R3c, -S(O)(NR3a)NR3aR3b, -NR3aS(O)(NR3a)R3d, -(CR3fR3g)q-NR3aS(O)(NR3a)R3d, -(CR3fR3g)q-S(O)(NR3a)NR3a, -NR3a-(CR3fR3g)q-

[0351] NR3aS(O)(NR3a)R3d, oxo, hydroxyl, sulfhydryl,

[0352]

[0353] Ci-ealkyl, C2-6alkenyl, C2-ealkynyl, Ci-ealkoxy, Ci-ealkylamino, diCi-ealkylamino, Ci-ealkylaminoCi-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, thioCi-ealkyl, Ci-ealkoxyCi-ealkyl, Ci- 6alkyl-thio-Ci-6alkyl, Ci-ealkoxyCi-ealkylamino, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, haloCi-ealkyl, haloC2-ealkenyl, haloC2-ealkynyl, aryl, heteroaryl, heterocyclyl, arylCi-ealkyl, arylC2-6alkenyl, aryl C2-ealkynyl, heteroarylCi-ealkyl, heteroarylC2-6alkenyl, heteroarylC2-6alkynyl, heterocyclylCi-ealkyl, heterocyclylC2-6alkenyl and heterocyclylC2-ealkynyl,

[0354] wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, alkoxyalkylamino, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, - PO-(OR3i)2, -SO2F, -NR3aR3b(-NH2, -NHalkyl, and -N(alkyl)2); preferably each of said Ci-ealkyl, C2-6alkenyl, C2-ealkynyl, Ci^alkoxy, Ci-ealkylamino, diCi-ealkylamino, Ci- ealkylaminoCi-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, thioCi-ealkyl, Ci-ealkoxyCi-ealkyl, Ci- 6alkyl-thio-Ci-6alkyl, Ci-ealkoxyCi-ealkylamino, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, haloCi-ealkyl, haloC2-ealkenyl, haloC2-ealkynyl, aryl, heteroaryl, heterocyclyl, arylCi-ealkyl, arylC2-6alkenyl, aryl C2-ealkynyl, heteroarylCi-ealkyl, heteroarylC2-6alkenyl, heteroarylC2-6alkynyl, heterocyclylCi-ealkyl, heterocyclylC2- ealkenyl and heterocyclylC2-6alkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-ealkenyl, C2-6alkynyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, Ci-ealkylthio, C3- i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, heterocyclyl, -C(O)OH, -C(O)R3i, - C(O)-O-CH2-O-CO-R3i, -PO-(OR3i)2, -SO2F, -NR3aR3b(-NH2, -NHCi-6alkyl, and -N(Ci- ealkyl)2);

[0355] cycle A is selected from the group comprising aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl and heteroaryl; cycle A is selected from the group comprising aryl, C3- i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, heterocyclyl and heteroaryl;

[0356] - Y is NR3hor O; preferably Y is NH, NCi-ealkyl or O;

[0357] each R6is independently selected from the group comprising hydrogen, halogen, -OH, - NR3aR3b, -SH, =S, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- ordi-)alkyl-amino-alkyl, -(CR3fR3g)q-O-(CR3fR3g)v-CO2R3c, hydroxyalkyl, -(CR3fR3g)q- NR3aSO2R3d, -CO2R3C, -(CR3fR3g)q-O-(CR3fR3g)v-aryl, -(CR3fR3g)q-O-(CR3fR3g)v-heteroaryl, - CONR3aS(O)2R3d, -S(O)2R3d, -(CR3fR3g)q-O-(CR3fR3g)v-CN, -C(O)R3d, aryl, heteroaryl, heterocyclyl, -C(O)NR3aR3b, oxo, -S(O)2NR3aR3b, -0R3cand -(CR3fR3g)q-O-(CR3fR3g)v-O- aryl; preferably each R6is independently selected from the group comprising hydrogen, halogen, -OH, -NR3aR3b, -SH, =S, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-6alkenyl, C2- ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, Ci-ealkoxy, mono-Ci- ealkylamino, di-Ci-ealkylamino, Ci-ealkylthio, Ci-ealkylthioCi-ealkyl, Ci-ealkyloxyCi-ealkyl, mono-Ci-6alkyl-amino-Ci-6alkyl, di-Ci-ealkyl-amino-Ci-ealkyl, -(CR3fR3g)q-O-(CR3fR3g)v- CO2R3C, hydroxyCi-6alkyl, -(CR3fR3g)q-NR3aSO2R3d, -CO2R3c, -(CR3fR3g)q-O-(CR3fR3g)v-aryl, -(CR3fR3g)q-O-(CR3fR3g)v-heteroaryl, -CONR3aS(O)2R3d, -S(O)2R3d, -(CR3fR3g)q-O- (CR3fR3g)v-CN, -C(O)R3d, aryl, heteroaryl, heterocyclyl, -C(O)NR3aR3b, oxo, -S(O)2NR3aR3b, -0R3cand -(CR3fR3g)q-O-(CR3fR3g)v-O-aryl,

[0358] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- or di-)alkyl- amino-alkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2; preferably each of said Ci-ealkyl,C2-6alkenyl, C2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, Ci-ealkoxy, mono- Ci-ealkylamino, di-Ci-ealkylamino, Ci-ealkylthio, Ci-ealkylthioCi-ealkyl, Ci- ealkyloxyCi-ealkyl, mono-Ci-ealkyl-amino-Ci-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-ealkenyl, 02-ealkynyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, -C(O)OH, -NH2, -NHCi-ealkyl, and -N(Ci-6alkyl)2; R3ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di-)alkyl-amino, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, -S02-alkyl, aryl, heteroaryl and heterocyclyl; preferably R3ais selected from the group comprising hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, Ci-ealkoxy, mono-Ci-ealkyl-amino, di-Ci-ealkyl-amino, Ci-ealkyloxyCi-ealkyl, Ci-ealkylthioCi-ealkyl, mono-Ci-ealkyl-amino-Ci-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, haloCi-ealkyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2-ealkynyl, -SO2-C1-ealkyl, aryl, heteroaryl and heterocyclyl;

[0359] R3bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably R3bis selected from the group comprising hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl and C5-i2cycloalkynyl;

[0360] R3Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkyl-COOH, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl; preferably R3cis selected from the group comprising hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-i2cycloalkyl, C5-i2cycloalkenyl, Cs-i2cycloalkynyl, Ci-ealkyloxyCi-ealkyl, Ci-ealkylthioCi-ealkyl, mono-Ci-ealkyl-amino-Ci-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, haloCi-ealkyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, Ci-ealkyl-COOH, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2-ealkynyl, aryl, heteroaryl and heterocyclyl;

[0361] R3dis selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, alkoxy, (mono- or di-)alkyl-amino, (mono- or di-)alkyl-amino-alkyl, alkylthio, alkylthioalkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl; preferably R3dis selected from the group comprising Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-i2cycloalkyl, C5-i2cycloalkenyl, Cs-i2cycloalkynyl, Ci-ealkyloxyCi-ealkyl, Ci-ealkoxy, mono-Ci-ealkyl-amino,di-Ci-ealkyl-amino, mono-Ci-ealkyl-amino-Ci-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, Ci-ealkylthio, Ci-ealkylthioCi-ealkyl, haloCi-ealkyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-6alkynyl, aminoCi-ealkyl, aminoC2-6alkenyl, aminoC2-6alkynyl, aryl, heteroaryl and heterocyclyl;

[0362] each R3fand R3gare independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, -NH2, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl; preferably each R3fand R3gare independently selected from hydrogen, Ci-ealkyl, C2-6alkenyl, C2-ealkynyl, C3-i2cycloalkyl, Cs-^cycloalkenyl, Cs-i2cycloalkynyl, haloCi-ealkyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, -NH2, aminoCi-ealkyl, aminoC2-6alkenyl, aminoC2-ealkynyl, aryl, heteroaryl and heterocyclyl;

[0363] R3his selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably R3his selected from hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-i2cycloalkyl, Cs-^cycloalkenyl and Cs-i2cycloalkynyl;

[0364] R3' is selected from hydrogen, alkyl, cycloalkyl and aryl wherein each alkyl, cycloalkyl, and aryl is optionally further substituted with one or more halogen; preferably R3' is selected from hydrogen, Ci-ealkyl, C3-i2cycloalkyl, and aryl wherein each Ci-ealkyl, C3-i2cycloalkyl and aryl is optionally further substituted with one or more halogen;

[0365] m is an integer selected from 0, 1 , 2, 3, 4 or 5; preferably m is selected from 0, 1 , 2 and 3; p is an integer selected from 0, 1 , 2, 3, 4 or 5; preferably p is selected from 0, 1, 2 and 3; q is an integer selected from 0, 1 , 2, 3, 4 or 5; preferably q is selected from 0, 1, 2 and 3; v is an integer selected from 0, 1 , 2, 3, 4 or 5; preferably v is selected from 0, 1, 2 and 3;

[0366] Q is selected from -CO-, -SO2-, -SO(=NH)-;

[0367] L is selected from -CRLgRLh-, -NRLb-, or a single bond;

[0368] RLgis selected from the group comprising hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxylalkenyl, hydroxyalkynyl, -NRLaRLb, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, -C(O)NRLaRLb, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, deuterium, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably RLgis selected from the group comprising hydrogen, halogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, -NRLaRLb, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2-ealkynyl, haloCi-ealkyl, -C(O)NRLaRLb, Ci-ealkoxy, Ci-ealkylamino, diCi-ealkylamino, Ci-ealkylaminoCi-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, thioCi-ealkyl, Ci-ealkoxyCi.alkyl, Ci-ealkyl-thio-Ci-ealkyl, deuterium, C3-i2cycloalkyl, Cs-^cycloalkenyl and Cs-i2cycloalkynyl;

[0369] RLhis selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, deuterium, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably RLhis selected from hydrogen, halogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, deuterium, C3-i2cycloalkyl, Cs-^cycloalkenyl and Cs-i2cycloalkynyl;RLais selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably RLais selected from hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl and Cs-i2cycloalkynyl;

[0370] RLbis selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably RLbis selected from hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl and Cs-i2cycloalkynyl;

[0371] or RLgand RLhtogether with the carbon atoms to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl and heterocyclyl; preferably RLgand RLhtogether with the carbon atoms to which they are attached can form a C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl and heterocyclyl;

[0372] X is selected from the group comprising -ORXc, -NRXaRXb, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, -S(O)2Xd, -NRXbS(O)2Xd, -NRXbC(O)ORXc, -OC(O)RXd, -C(O)NRXaRXb, -C(O)ORXc, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkyl, alkenyl, alkynyl, (mono- or di-)alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl and -N3; preferably X is selected from the group comprising -ORXc, -NRXaRXb, aryl, heteroaryl, heterocyclyl, amino-Ci-ealkyl, aminoC2-6alkenyl, aminoC2-6alkynyl, -S(O)2RXd, -NRXbS(O)2RXd, -NRXbC(O)ORXc, -OC(O)RXd, -C(O)NRXaRXb, -C(O)ORXc, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, Ci-ealkyl, C2-6alkenyl, C2-ealkynyl, mono-Ci-ealkyl-amino-Ci-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, thioCi-ealkyl, Ci-ealkoxyCi-ealkyl, Ci-ealkyl-thio-Ci-ealkyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, and -N3;

[0373] wherein each of said heteroaryl, heterocyclyl, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising hydroxyalkyl, - C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -P(O)H2, -S(O)2RXa, -S(O)RXa, cyano, nitro, -C(O)ORXc, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, (mono- or di- )alkyl-aminoalkoxy, -NRXaRXb(such as -NH2, -NHalkyl, and -N(alkyl)2); preferably each of said aryl, heteroaryl, heterocyclyl, amino-Ci-ealkyl, aminoC2-ealkenyl, aminoC2- ealkynyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, Ci-ealkyl, C2- ealkenyl, 02-ealkynyl, mono-Ci-ealkyl-amino-Ci-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, thioCi-ealkyl, Ci-ealkoxyCi-ealkyl, Ci-ealkyl-thio-Ci-ealkyl C3-i2cycloalkyl, C5- i2cycloalkenyl, Cs-i2cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising hydroxyalkyl, - C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by alkyl, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -P(O)H2, -S(O)2RXa, -S(O)RXa, cyano, nitro, -C(O)ORXc, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, hydroxyCi-ealkoxy, aminoCi- ealkoxy, mono-Ci-ealkyl-aminoCi-ealkoxy, di-Ci-ealkyl-aminoCi-ealkoxy, -C(O)OH, - NRXaRXb(such as -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2);

[0374] RXais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl; preferably RXais selected from the group comprising hydrogen, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, haloCi-ealkyl, Ci-ealkoxyCi-ealkyl, aminoCi-ealkyl, aminoC2-6alkenyl, aminoC2-ealkynyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, heteroaryl, heterocyclyl, heteroarylCi-ealkyl, heteroarylC2-6alkenyl, heteroarylC2-6alkynyl, heterocyclylCi-ealkyl, heterocyclylC2-6alkenyl and heterocyclylC2-6alkynyl,

[0375] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2; preferably each of said Ci-ealkyl, C2-ealkenyl, C2-6alkynyl, haloCi-ealkyl, Ci-ealkoxyCi-ealkyl, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2-ealkynyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, C3- i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, heteroaryl, heterocyclyl, heteroarylCi- ealkyl, heteroarylC2-ealkenyl, heteroarylC2-ealkynyl, heterocyclylCi-ealkyl, heterocyclylC2-ealkenyl and heterocyclylC2-ealkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyCi-ealkyl, heteroaryl, heterocyclyl, Ci-ealkyl, C2-ealkenyl, 02-ealkynyl, C3- i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, - CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, O-Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, -NH2, -NHCi-ealkyl, and -N(Ci-ealkyl)2;

[0376] RXbis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably RXbis selected from the groupcomprising hydrogen, Ci-ealkyl, 02-salkenyl, 02-salkynyl, haloCi-salkyl, aminoCi-salkyl, aminoC2-6alkenyl, aminoC2-salkynyl, hydroxyCi-salkyl, hydroxyC2-salkenyl, hydroxyC2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl and Cs-^cycloalkynyl,

[0377] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, - NH2, -NHalkyl, and -N(alkyl)2; preferably each of said Ci-salkyl, 02-salkenyl, 02-salkynyl, haloCi-ealkyl, aminoCi-salkyl, aminoC2-salkenyl, aminoC2-salkynyl, hydroxyCi-salkyl, hydroxyC2-6alkenyl, hydroxyC2-salkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl and Cs- ^cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyCi-ealkyl, Ci-salkyl, C2-salkenyl, C2- salkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-^cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, C(O)OH, O-Ci-6alkyl, haloCi-ealkyl, Ci-salkoxy, haloCi-salkoxy, -NH2, -NHCi-salkyl, and -N(Ci-salkyl)2; each RXcis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl, preferably each RXcis selected from the group comprising hydrogen, Ci-salkyl, 02-salkenyl, 02-salkynyl, haloCi-ealkyl, Ci-salkoxyCi-salkyl, aminoCi-salkyl, aminoC2-6alkenyl, aminoC2-salkynyl, hydroxyCi-ealkyl, hydroxyC2-salkenyl, hydroxyC2-salkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-^cycloalkynyl, heteroaryl, heterocyclyl, heteroarylCi-salkyl, heteroarylC2-salkenyl, heteroarylC2-salkynyl, heterocyclylCi-salkyl, heterocyclylC2-salkenyl and heterocyclylC2-salkynyl,

[0378] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SFs, cyano, nitro, -C(O)OH, haloalkyl, alkoxy, haloalkoxy, - NH2, -NHalkyl, and -N(alkyl)2; preferably each of said Ci-salkyl, 02-salkenyl, 02-salkynyl, haloCi-salkyl, Ci-salkoxyCi-salkyl, aminoCi-salkyl, aminoC2-salkenyl, aminoC2-salkynyl,hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, C3-i2cycloalkyl, Cs- i2cycloalkenyl, Cs-i2cycloalkynyl, heteroaryl, heterocyclyl, heteroarylCi-ealkyl, heteroarylC2-6alkenyl, heteroarylC2-ealkynyl, heterocyclylCi-ealkyl, heterocyclylC2- ealkenyl and heterocyclylC2-6alkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyCi-ealkyl, heteroaryl, heterocyclyl, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-i2cycloalkyl, Cs- i2cycloalkenyl, Cs-i2cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, - OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, - NH2, -NHCi.6alkyl, and -N(Ci-6alkyl)2;

[0379] RXdis selected from the group comprising alkyl, alkenyl, alkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl, preferably RXdis selected from the group comprising Ci-ealkyl, C2-ealkenyl, 02-ealkynyl, haloCi-ealkyl, Ci-ealkoxyCi-ealkyl, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2-ealkynyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, C5-i2cycloalkynyl, heteroaryl, heterocyclyl, heteroarylCi-ealkyl, heteroarylC2-ealkenyl, heteroarylC2-ealkynyl, heterocyclylCi-ealkyl, heterocyclylC2-ealkenyl and heterocyclylC2-ealkynyl,

[0380] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from - CONRXaRXb, hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy; preferably each of said Ci-ealkyl, C2-6alkenyl, C2-ealkynyl, haloCi-ealkyl, Ci-ealkoxyCi-ealkyl, aminoCi-ealkyl, aminoC2- ealkenyl, aminoC2-ealkynyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, heteroaryl, heterocyclyl, heteroarylCi-ealkyl, heteroarylC2-ealkenyl, heteroarylC2-ealkynyl, heterocyclylCi-ealkyl, heterocyclylC2-ealkenyl and heterocyclylC2-ealkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyCi-ealkyl, heteroaryl, heterocycle, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3- i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloCi-ealkyl, Ci-ealkoxy and haloCi-ealkoxy; each RXeand RXfare independently selected from alkyl, alkenyl, alkynyl, haloalkyl,aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylal kynyl, preferably each RXeand RXfare independently selected from Ci-ealkyl, C2-6alkenyl, C2-ealkynyl, haloCi-ealkyl, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2-ealkynyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, heteroaryl, heterocyclyl, heteroarylCi-ealkyl, heteroarylC2-6alkenyl, heteroarylC2-6alkynyl, heterocyclylCi-ealkyl, heterocyclylC2-6alkenyl and heterocyclylC2-ealkynyl,

[0381] wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylal kynyl is unsubstituted or is substituted with one or more substituents each independently selected from hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy; preferably each of said Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, haloCi-ealkyl, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2-ealkynyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, C3-i2cycloalkyl, C5- i2cycloalkenyl, Cs-i2cycloalkynyl, heteroaryl, heterocyclyl, heteroarylCi-ealkyl, heteroarylC2-6alkenyl, heteroarylC2-ealkynyl, heterocyclylCi-ealkyl, heterocyclylC2- ealkenyl and heterocyclylC2-6alkynyl is unsubstituted or is substituted with one or more substituents each independently selected from hydroxyCi-ealkyl, heteroaryl, heterocycle, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, C5- i2cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy;

[0382] n is an integer selected from 1, 2, 3, or 4; preferably n is 1 , 2 or 3;

[0383] each R4is independently selected from the group comprising halogen, -SCF3, -SF5, -CF3,

[0384]

[0385] hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl, preferably each R4is independently selected from the group comprising halogen, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, -B(OH)2, -O-SO2-F, -SO2- F, cyano, nitro, -OR4c, -NR4aR4b, -NR4aS(O)2R4d, -NR4aSO2NR4aR4b, -NR4aC(O)R4c, - NR4aC(O)OR4c, -NR4aC(O)NR4aR4b, SR4c, -S(O)R4d, -S(O)2R4c, -S(O)2NR4aR4b, -S(O)(NR4a)R4c, -S(NR4a)(NR4a) R4c, -C(O)OR4c, -C(O)R4c, -C(O)NR3aR3b, -P(O)R4aR4b, Ci- ealkyl, C2-6alkenyl, C2-ealkynyl, haloCi-ealkyl, haloCi-ealkoxy, hydroxyCi-ealkyl, hydroxyC2- ealkenyl, hydroxyC2-ealkynyl, heteroaryl, heterocyclyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl and Cs-i2cycloalkynyl,

[0386] wherein each of said alkyl, alkenyl, alkynyl, haloalkyl haloalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxy, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -OH, =0, halogen, -SH, =S, -CF3, - CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -B(0H)2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, - C(O)OH, -C(O)Oalkyl, -C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, -NHalkyl, and - N(alkyl)2; preferably each of said Ci-ealkyl, C2-ealkenyl, 02-ealkynyl, haloCi-ealkyl, haloCi- ealkoxy, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, heteroaryl, heterocyclyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -B(0H)2, cyano, nitro, Ci- ealkyl, 02-ealkenyl, 02-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, hydroxyCi-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, -C(O)OH, -C(O)OCi-ealkyl, - C(O)NH2, -C(O)NHCi-6alkyl, -C(O)N(Ci-6alkyl)2, -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2; or two R4together with the carbon atom(s) to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl; preferably two R4together with the carbon atom(s) to which they are attached can form a C3-i2cycloalkyl, C5- i2cycloalkenyl, Cs-i2cycloalkynyl, C4-i2heterocyclyl, Ce-isaryl or Cs-isheteroaryl;

[0387] wherein each of said cycloalkyl, cycloalkenyl, cycloalkynyl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from R4e; preferably each of said C3-i2cycloalkyl, Cs-i2cycloalkenyl, C5- i2cycloalkynyl, C4-i2heterocyclyl, Ce-isaryl or Cs-isheteroaryl is unsubstituted or is substituted with one or more substituents each independently selected from R4e;

[0388] - R4ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl and aminoalkynyl; preferably R4ais selected from the group comprising hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, haloCi-ealkyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, aminoCi-ealkyl, aminoC2-ealkenyl and aminoC2-ealkynyl;

[0389] - R4bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably R4bis selected from the group comprising hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl and C5-i2cycloalkynyl;

[0390] - R4Cis selected from the group comprising hydrogen, alkyl, alkyl substituted with deuterium, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxyalkyl and (mono- or di-)alkyl-aminoalkyl; preferably R4cis selected from the group comprising hydrogen, Ci-ealkyl, Ci-ealkyl substituted with deuterium, C2-ealkenyl, C2-ealkynyl, haloCi- ealkyl, Ci-ealkoxyCi-ealkyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs- i2cycloalkynyl, mono-Ci-ealkyl-aminoCi-ealkyl and di-Ci-ealkyl-aminoCi-ealkyl;

[0391] - R4dis selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; preferably R4dis selected from the group comprising Ci-ealkyl, C2- ealkenyl, C2-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl and Cs-i2cycloalkynyl;

[0392] Each R4eis independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxyalkoxyalkyl, -C(O)OH, -C(O)Oalkyl, - NHC(O)alkyl, -C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, -NHalkyl, and -N(alkyl)2; preferably each R4eis independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-ealkenyl, C2- ealkynyl, C3-i2cycloalkyl, C3-i2cycloalkylCi-6alkyl, aryl, Cs-^heteroaryl, Cs-i2cycloalkenyl, C5- i2cycloalkynyl, hydroxyCi-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, Ci-ealkoxyCi- ealkyl, haloCi-ealkoxyCi-ealkyl, hydroxyCi-ealkoxyCi-ealkyl, -C(O)OH, -C(0)0Ci-6alkyl, - NHC(O)Ci.6alkyl, -C(O)NH2, -C(O)NHCi-6alkyl, -C(O)N(Ci.6alkyl)2, -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2;

[0393] R5is absent or is selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl-amino-alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl; preferably R5is absent or is selected from the group comprising hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, haloCi-ealkyl, Ci-ealkyloxyCi- ealkyl, mono-Ci-ealkyl-amino-Ci-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, hydroxyCi-ealkyl, hydroxyC2-ealkenyl, hydroxyC2-ealkynyl, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2- ealkynyl, Cs- cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, Cs- cycloalkylCi-ealkyl, C3- iocycloalkylC2-ealkenyl, C3- cycloalkylC2-6alkynyl, heterocyclylCi-ealkyl, heterocyclylC2- ealkenyl, heterocyclylC2-ealkynyl;

[0394] wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl- amino-alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl,aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, - OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)OH, C(O)Oalkyl, - C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, -NHalkyl, and -N(alkyl)2; preferably each of said Ci-ealkyl, C2-ealkenyl, C2-6alkynyl, haloCi-ealkyl, Ci-ealkyloxyCi-ealkyl, mono-Ci- ealkyl-amino-Ci-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, hydroxyCi-ealkyl, hydroxyC2- ealkenyl, hydroxyC2-ealkynyl, aminoCi-ealkyl, aminoC2-ealkenyl, aminoC2-ealkynyl, C3- locycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, Cs- cycloalkylCi-ealkyl, C3- iocycloalkylC2-6alkenyl, C3- cycloalkylC2-6alkynyl, heterocyclylCi-ealkyl, heterocyclylC2- ealkenyl, heterocyclylC2-6alkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-6alkenyl, 02-ealkynyl, C3-i2cycloalkyl, Cs-i2cycloalkenyl, Cs-i2cycloalkynyl, hydroxyCi-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, -C(O)OH, C(0)0Ci-6alkyl, -C(0)NH2, - C(O)NHCi.6alkyl, -C(O)N(Ci.6alkyl)2, -NH2, -NHCi-6alkyl, and -N(Ci.6alkyl)2;

[0395] or R3and R5together with the atoms to which they are attached form a heteroaryl or heterocyclyl wherein said heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, - OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, phenyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2; preferably R3and R5together with the atoms to which they are attached form a heteroaryl or heterocyclyl wherein said heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, - SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-ealkenyl, 02-ealkynyl, phenyl, hydroxyCi-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, -NH2, -NHCi-ealkyl, and -N(Ci-ealkyl)2; and when E1is C, E2is C or CH and E3is C, and, T1is C or CH, T2is N, T3is a bond and T4is C or CH, then E1and E3are both substituted with R4, wherein said two R4groups together form an aryl or heteroaryl, wherein said aryl and heteroaryl is unsubstituted or is substituted with one or more substituents each independently selected from R4e.

[0396] Preferred or particular statements (features), aspect and embodiments of the compounds of this invention are set herein below. Each statement, aspect and embodiment of the invention so defined may be combined with any other statement, aspect and / or embodiment, unless clearly indicated to the contrary. In particular, any feature being specifically referred to orindicated as being preferred, particular or advantageous may be combined with any other features or statements specifically referred to or indicated as being preferred, particular or advantageous. Hereto, the present invention is in particular captured by any one or any combination of one or more of the below statements and embodiments, with any other statement, aspect and / or embodiment.

[0397] The compound according to any one of the formulas, statements, embodiments or claims, wherein T1is N, T2is a bond or C, and, T3and T4are C.

[0398] The compound according to any one of the formulas, statements, embodiments or claims, wherein T1is N, T2is a bond, and, T3and T4are C.

[0399] The compound according to any one of the formulas, statements, embodiments or claims, wherein T4is N, T2is a bond or C, and, T1and T3are C.

[0400] The compound according to any one of the formulas, statements, embodiments or claims, wherein T4is N, T2is a bond, and, T1and T3are C.

[0401] The compound according to any one of the formulas, statements, embodiments or claims, wherein T1is C, T2is a bond, and, T3is N and T4is C.

[0402] The compound according to any one of the formulas, statements, embodiments or claims, wherein T2is N, and, T1, T3and T4are C.

[0403] The compound according to any one of the formulas, statements, embodiments or claims, wherein T3is N, and, T1, T3and T4are C.

[0404] The compound according to any one of the formulas, statements, embodiments or claims, wherein T1is N, T2is a bond, CH, CH2 or C, T3is CH, CH2 or C, and T4is CH or C.

[0405] The compound according to any one of the formulas, statements, embodiments or claims, wherein T1is N, T2is a bond, T3is CH, CH2 or C, and T4is CH or C.

[0406] The compound according to any one of the formulas, statements, embodiments or claims, wherein T4is N, T2is a bond, CH, CH2 or C, T1is CH or C, and T3is CH, CH2 or C.

[0407] The compound according to any one of the formulas, statements, embodiments or claims, wherein T4is N, T2is a bond, T1is CH or C, and T3is CH, CH2 or C.

[0408] The compound according to any one of the formulas, statements, embodiments or claims, wherein T1is CH or C, T2is a bond, T3is N and T4is CH or C.

[0409] The compound according to any one of the formulas, statements, embodiments or claims, wherein T2is N, and, T1is CH, T3is CH or CH2, and T4is CH or C.

[0410] The compound according to any one of the formulas, statements, embodiments or claims, wherein T3is N, and, T1is CH, T2is CH or CH2, and T4is CH or C.

[0411] The compound according to any one of the formulas, statements, embodiments or claims, wherein E1is N. The compound according to any one of the formulas, statements,embodiments or claims, wherein E1is N, and, E2and E3are C. The compound according to any one of the formulas, statements, embodiments or claims, wherein E2is N. The compound according to any one of the formulas, statements, embodiments or claims, wherein E2is N, and, E1and E3are C.

[0412] The compound according to any one of the formulas, statements, embodiments or claims, wherein E1is N or NH. The compound according to any one of the formulas, statements, embodiments or claims, wherein E1is N or NH, and, E2and E3are C or CH. The compound according to any one of the formulas, statements, embodiments or claims, wherein E2is N or NH. The compound according to any one of the formulas, statements, embodiments or claims, wherein E2is N or NH, and, E1and E3are C or CH.

[0413] The compound according to any one of the formulas, statements, embodiments or claims, wherein E2, E1and E3are C or CH.

[0414] t is to be understood that E1is C if substituted by R4, and CH if not, similarly E2is C if substituted by R4, and CH if not, similarly E3is C if substituted by R4, and CH if not.

[0415] The compound according to any one of the formulas, statements, embodiments or claims, wherein R1is selected from hydrogen, alkyl, or hydroxyalkyl; preferably R1is selected from hydrogen, Ci-ealkyl, or hydroxyCi-ealkyl.

[0416] In an embodiment, R1is selected from hydrogen, alkyl and hydroxyalkyl, such as Ci-4-alkyl and hydroxyCi-4-alkyl. In a further embodiment, R1is selected from hydrogen, methyl, hydroxymethyl, ethyl and (i- or n-) propyl. In a further embodiment, R1is a Ci-4-alkyl, such as methyl.

[0417] In some embodiments, T1is C and R1is stereo chemically defined in S-configuration.

[0418] In some embodiments, T1is CH and R1is stereo chemically defined in S-configuration.

[0419] The compound according to any one of the formulas, statements, embodiments or claims, wherein

[0420] R2is selected from the group comprising hydrogen, -CONR2aR2b, aminoalkyl, alkyl, hydroxyalkyl and heteroalkyl; preferably R2is selected from the group comprising hydrogen, -CONR2aR2b, aminoCi-ealkyl, Ci-ealkyl, hydroxyCi-ealkyl, Ci-ealkyloxyCi-ealkyl, mono-Ci-6alkylaminoCi-6alkyl and di-Ci-ealkylaminoCi-ealkyl;

[0421] R2ais selected from hydrogen or alkyl; preferably R2ais selected from hydrogen or Ci-ealkyl and

[0422] R2bis selected from hydrogen or alkyl; preferably R2bis selected from hydrogen or Ci-ealkyl. In some embodiments, R2is selected from the group comprising hydrogen, -CONR2aR2b, aminoalkyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, (mono- or di-alkyl)amino, (mono- or di-alkyl)amino-alkyl, alkylthio and alkylthioalkyl; R2ais selected from hydrogen or alkyl; and R2bisselected from hydrogen or alkyl; preferably R2is selected from the group comprising hydrogen, -CONR2aR2b, aminoCi-ealkyl, Ci-ealkyl, hydroxyCi-ealkyl, Ci-ealkoxy, Ci-ealkoxyCi-ealkyl, mono-Ci-ealkylamino, di-Ci-ealkylamino, mono-Ci-ealkylamino-Ci-ealkyl, di-Ci-ealkylamino-Ci-ealkyl, Ci-ealkylthio and Ci-ealkylthioCi-ealkyl; R2ais selected from hydrogen or Ci-ealkyl; and R2bis selected from hydrogen or Ci-ealkyl.

[0423] In some embodiments, R2is a Ci-4alkyl, such as methyl.

[0424] In further embodiments, T4is C and R2is stereochemically defined in S-configuration.

[0425] In further embodiments, T4is CH and R2is stereochemically defined in S-configuration.

[0426] The compound according to any one of the formulas, statements, embodiments or claims, wherein

[0427] R3is selected from the group comprising hydrogen, -NR3aR3b, -NR3a-(CR3fR3g)q-CONR3a, -

[0428] NR3a-(CR3fR3g)q-NR3aCOR3d, -SR3c, OR3c, alkyl,

[0429]

[0430] , oxo, -NR3aSO2R3d, halogen, -NR3aCOR3dand heteroalkyl (e.g. alkoxy, alkoxyalkyl, (mono- or di-alkyl)amino, (mono- or di-alkyl)amino-alkyl, alkylthio and alkylthioalkyl); preferably R3is selected from the group comprising hydrogen,

[0431] NR3a-(CR3fR3g)q-NR3aCOR3d, -SR3c, 0R3c

[0432]

[0433]

[0434] , oxo, -NR3aSO2R3d, halogen, -NR3aCOR3d, C2-i8heteroalkyl (such as Ci-ealkoxy, Ci-ealkoxyCi-ealkyl, mono-Ci-ealkylamino, di-Ci-ealkylamino, mono-Ci- ealkylamino-Ci-ealkyl, di-Ci-ealkylamino-Ci-ealkyl, Ci-ealkylthio and Ci-ealkylthioCi-ealkyl); cycle A is selected from the group comprising aryl (phenyl), 3- to 7-membered cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl;

[0435] - Y is NR3hor O;

[0436] each R6is independently selected from the group comprising hydrogen, -(CR3fR3g)q-O- (CR3fR3g)v-CO2R3c, hydroxyalkyl, -(CR3fR3g)q-NR3aSO2R3d, -CO2R3c, -(CR3fR3g)q-O- (CR3fR3g)v-heteroaryl, -CONR3aSO2R3d, -SO2R3d, -(CR3fR3g)q-O-(CR3fR3g)v-CN, -COR3d, heteroaryl, heteroalkyl (e.g. alkoxy, alkoxyalkyl, (mono- or di-alkyl)amino, (mono- or di- alkyl)amino-alkyl, alkylthio and alkylthioalkyl), aryl (phenyl), halo, alkyl, -CONR3aR3b, oxo, -SO2NR3aR3b, -OR3c, and -(CR3fR3g)q-O-(CR3fR3g)v-O-aryl; wherein each of said alkyl, aryl, heteroalkyl, or heteroaryl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, hydroxyl, alkoxy, haloalkyl and haloalkoxy; preferably each R6is independently selected from the groupcomprising hydrogen, -(CR3fR3g)q-O-(CR3fR3g)v-CO2R3c, hydroxyCi-ealkyl, -(CR3fR3g)q- NR3aSO2R3d, -CO2R3C, -(CR3fR3g)q-O-(CR3fR3g)v-heteroaryl, -CONR3aSO2R3d, -SO2R3d, - (CR3fR3g)q-O-(CR3fR3g)v-CN, -COR3d, Cs-i2heteroaryl, Ci-ealkoxy, Ci-ealkoxyCi-ealkyl, mono-Ci-6alkylamino, di-Ci-ealkylamino, mono-Ci-ealkylamino-Ci-ealkyl, di-Ci-ealkylamino- Ci-ealkyl, Ci-ealkylthio and Ci-ealkylthioCi-ealkyl, Ce-i2aryl, halo, Ci-ealkyl, -CONR3aR3b, oxo, -SO2NR3aR3b, -OR3c, and -(CR3fR3g)q-O-(CR3fR3g)v-O-aryl; wherein each of said Ci-ealkyl, Ce-i2aryl, Cs-i2heteroaryl, Ci-ealkoxy, Ci-ealkoxyCi-ealkyl, mono-Ci-ealkylamino, di-Ci- ealkylamino, mono-Ci-ealkylamino-Ci-ealkyl, di-Ci-ealkylamino-Ci-ealkyl, Ci-ealkylthio and Ci-ealkylthioCi-ealkyl, or heteroaryl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, hydroxyl, Ci- ealkoxy, haloCi-ealkyl and halo Ci-ealkoxy;

[0437] R3ais selected from hydrogen, alkyl, cycloalkyl, or hydroxyalkyl; preferably R3ais selected from hydrogen, Ci-ealkyl, Cs- cycloalkyl, or hydroxyCi-ealkyl;

[0438] R3bis selected from hydrogen or alkyl; preferably R3bis selected from hydrogen or Ci-ealkyl; R3cis selected from the group comprising alkyl, heteroalkyl (alkyloxyalkyl), haloalkyl, hydroxyalkyl, and hydrogen; preferably R3cis selected from the group comprising Ci-ealkyl, Ci-ealkyloxyCi-ealkyl, haloCi-ealkyl, hydroxyCi-ealkyl, and hydrogen;

[0439] R3dis selected from alkyl, heteroalkyl, cycloalkyl, or aryl; preferably R3dis selected from hydrogen, Ci-ealkyl, Ci-ealkoxy, Ci-ealkoxyCi-ealkyl, mono-Ci-ealkylamino, di-Ci- ealkylamino, mono-Ci-ealkylamino-Ci-ealkyl, di-Ci-ealkylamino-Ci-ealkyl, Ci-ealkylthio and Ci-ealkylthioCi-ealkyl, Cs- cycloalkyl, or aryl

[0440] each R3fand R3gare each independently selected from hydrogen or alkyl; preferably each R3fand R3gare each independently selected from hydrogen or Ci-ealkyl;

[0441] - R3his hydrogen or alkyl; preferably R3his hydrogen or Ci-ealkyl;

[0442] - m is an integer selected from 0, 1, 2, 3, or 4;

[0443] - p is an integer selected from 0, 1 or 2;

[0444] - q is an integer selected from 0, 1 or 2; and

[0445] - v is an integer selected from 0, 1 or 2.

[0446] The compound according to any one of the formulas, statements, embodiments or claims, wherein,

[0447] - R3is selected from hydrogen, -NR3aR3b, -(CR3fR3g)q-NR3aR3b, -NR3a-(CR3fR3g)q- C(O)NR3aR3b, -NR3a-(CR3fR3g)q-CO2R3c, -NR3a-(CR3fR3g)q-OR3c, -NR3a-(CR3fR3g)q- PO(OR3i)2, -NR3a-(CR3fR3g)q-NR3aC(O)R3d, -SR3c, -OR3c, -(CR3fR3g)q-OR3c,

[0448]

[0449] , oxo, -NR3aS(O)2R3d, -(CR3fR3g)q-NR3aS(O)2R3d,-NR3aC(O)R3d, -(CR3fR3g)q-NR3aC(O)R3d, -(CR3fR3g)q-CO2R3c, -(CR3fR3g)q-C(O)R3c, -(CR3fR3g)q-C(O)NR3aR3b, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl and alkoxyalkylamino, cycloalkyl; preferably R3is selected from hydrogen, -NR3aR3b, -(CR3fR3g)q-NR3aR3b, -NR3a-(CR3fR3g)q-C(O)NR3aR3b, -NR3a-(CR3fR3g)q-CO2R3c, -NR3a-(CR3fR3g)q-OR3c, -NR3a-(CR3fR3g)q-PO(OR3i)2, -NR3a-(CR3fR3g)q-NR3aC(O)R3d, -SR3c, -OR3c,

[0450] -(CR3fR3g)q-OR3c,

[0451]

[0452] oxo, -NR3aS(O)2R3d, - (CR3fR3g)q-NR3aS(O)2R3d, -NR3aC(O)R3d, -(CR3fR3g)q-NR3aC(O)R3d, -(CR3fR3g)q-CO2R3c, - (CR3fR3g)q-C(O)R3c, -(CR3fR3g)q-C(O)NR3aR3b, hydroxyl, Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, Ci-ealkoxy, Ci-ealkylamino, di-Ci-ealkylamino, Ci-ealkylaminoCi-ealkyl, di-Ci-ealkyl-amino- Ci-ealkyl, thioCi-ealkyl, Ci-ealkoxyCi-ealkyl, Ci-ealkyl-thio-Ci-ealkyl and Ci-ealkoxyCi-ealkylamino, Cs- cycloalkyl,

[0453] wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, alkoxyalkylamino and cycloalkyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, alkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxy, alkylthio, cycloalkyl, -C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, -PO-(OR3i)2, -NH2, -NHalkyl, and -N(alkyl)2; preferably wherein each of said Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Ci-ealkoxy, Ci- ealkylamino, di-Ci-ealkylamino, Ci-ealkylaminoCi-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, thio Ci-ealkyl, Ci-ealkoxyCi-ealkyl, Ci-ealkyl-thio-Ci-ealkyl and Ci-ealkoxyCi-ealkylamino, C3- locycloalkyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, Ci-ealkoxy, Ci-ealkylthio, Cs- cycloalkyl, - C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, -PO-(OR3i)2, -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2;

[0454] cycle A is selected from the group comprising aryl, Cs-ycycloalkyl, C4-i2heterocyclyl and C5-i2heteroaryl;

[0455] Y is NR3hor O;

[0456] each R6is independently selected from the group comprising hydrogen, halogen, alkyl, cycloalkyl, alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono-or di-)alkyl-amino-alkyl, -(CR3fR3g)q-O-(CR3fR3g)v-CO2R3c, hydroxyalkyl, -(CR3fR3g)q-NR3aSO2R3d, -C(O)OR3c, -(CR3fR3g)q-O-(CR3fR3g)v-aryl, -(CR3fR3g)q-O-(CR3fR3g)v-heteroaryl, -CONR3aS(O)2R3d, -S(O)2R3d, -(CR3fR3g)q-O-(CR3fR3g)v-CN, -C(O)R3d, aryl, heteroaryl, heterocyclyl, -C(O)NR3aR3b, oxo, -S(O)2NR3aR3b, -0R3cand -(CR3fR3g)q-O-(CR3fR3g)v-O-aryl; preferably each R6is independently selected from the group comprising hydrogen, halogen, Ci-ealkyl, Cs- cycloalkyl, Ci-ealkoxy, mono-Ci-ealkylamino, di- Ci-ealkylamino, Ci-ealkylthio, Ci-ealkylthioCi-ealkyl, Ci-ealkyloxyCi-ealkyl, mono-Ci-ealkylaminoCi-ealkyl, di-Ci-ealkylaminoCi-ealkyl, -(CR3fR3g)q-O-(CR3fR3g)v-CO2R3c, hydroxy Ci-6alkylaminoCi-6alkyl, -(CR3fR3g)q-NR3aSO2R3d, -C(O)OR3c, -(CR3fR3g)q-O-(CR3fR3g)v-aryl, -(CR3fR3g)q-O-(CR3fR3g)v-heteroaryl, -CONR3aS(O)2R3d, -S(O)2R3d, -(CR3fR3g)q-O-(CR3fR3g)v-CN, -C(O)R3d, aryl, heteroaryl, heterocyclyl, -C(O)NR3aR3b, oxo, -S(O)2NR3aR3b, -OR3cand -(CR3fR3g)q-O-(CR3fR3g)v-O-aryl,

[0457] wherein each of said alkyl, cycloalkyl, alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- or di-)alkyl-amino-alkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, - CHF2, -OCF3, -OCHF2, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2; preferably each of said Ci-ealkyl, Cs- cycloalkyl, Ci-ealkoxy, mono-Ci-ealkylamino, di-Ci-ealkylamino, C1- ealkylthio, Ci-ealkylthioCi-ealkyl, Ci-ealkyloxyCi-ealkyl, mono-Ci-ealkylaminoCi-ealkyl, di- Ci-ealkylaminoCi-ealkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, Ci-ealkyl, haloCi- ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, Cs- cycloalkyl, Cs- cycloalkenyl, C4- cycloalkynyl, -C(O)OH, -NH2, -NHCi-ealkyl, and -N(Ci-6alkyl)2;

[0458] R3ais selected from the group comprising hydrogen, alkyl, cycloalkyl, alkoxy, (mono- or di-)alkyl-amino, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, hydroxyalkyl and aminoalkyl; preferably hydrogen, Ci-ealkyl, Cs- cycloalkyl, Ci-ealkoxy, mono-Ci-ealkyl-amino, di-Ci-ealkyl-amino, Ci-ealkyloxyCi-ealkyl, Ci-ealkylthioCi-ealkyl, mono-Ci-ealkylaminoCi-ealkyl, di-Ci-ealkylaminoCi-ealkyl, hydroxyCi-ealkyl and aminoCi-ealkyl;

[0459] R3bis selected from the group comprising hydrogen and alkyl; preferably R3bis selected from the group comprising hydrogen and Ci-ealkyl;

[0460] R3cis selected from the group comprising hydrogen, alkyl, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, hydroxyalkyl, alkyl-COOH and aminoalkyl; preferably R3cis selected from the group comprising hydrogen, Ci-ealkyl, Ci-ealkyloxyCi-ealkyl, C1-ealkylthioCi-ealkyl, mono-Ci-ealkylaminoCi-ealkyl, di-Ci-ealkylaminoCi-ealkyl, hydroxyCi-ealkyl, Ci-ealkyl-COOH and aminoCi-ealkyl;

[0461] R3dis selected from the group comprising alkyl, cycloalkyl, alkyloxyalkyl, alkoxy, (mono- or di-)alkyl-amino, (mono- or di-)alkyl-amino-alkyl, alkylthio, alkylthioalkyl, hydroxyalkyl and aminoalkyl; preferably R3dis selected from the group comprising Ci-ealkyl, Cs- cycloalkyl, Ci-ealkyloxyCi-ealkyl, Ci-ealkoxy, mono-Ci-ealkylamino, di-Ci-ealkylamino, mono-Ci-ealkylaminoCi-ealkyl, di-Ci-ealkylaminoCi-ealkyl, Ci-ealkylthio, Ci-ealkylthioCi-ealkyl, hydroxyCi-ealkyl and aminoCi-ealkyl;

[0462] each R3fand R3gare each independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl -NH2, and aminoalkyl; preferably each R3fand R3gare each independently selected from hydrogen, Ci-ealkyl, Cs- cycloalkyl, hydroxyCi-ealkyl -NH2, and aminoCi- ealkyl;

[0463] R3his selected from hydrogen and alkyl; preferably R3his selected from hydrogen and Ci- ealkyl;

[0464] R3' is selected from hydrogen, alkyl, cycloalkyl and aryl wherein each alkyl, cycloalkyl, and aryl is optionally further substituted with one or more halogen; preferably R3' is selected from hydrogen, Ci-ealkyl, Cs- cycloalkyl and aryl wherein each Ci-ealkyl, Cs- cycloalkyl, and aryl is optionally further substituted with one or more halogen;

[0465] m is an integer selected from 0, 1 , 2, 3 or 4;

[0466] p is an integer selected from 0, 1 or 2;

[0467] q is an integer selected from 0, 1 or 2; or

[0468] v is an integer selected from 0, 1 or 2.

[0469] The compound according to any one of the formulas, statements, embodiments or claims, wherein R3is selected from hydrogen, alkyl, -NR3xR3yand -OR3z; preferably R3is selected from hydrogen, Ci-ealkyl, -NR3xR3yand -OR3zwherein:

[0470] alkyl is optionally substituted by one, two or three substituents independently selected from halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylthio, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, -PO-(OR3i)2, -NH2, -NHalkyl, and -N(alkyl)2; preferably Ci-ealkyl is optionally substituted by one, two or three substituents independently selected from halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, 02-ealkenyl, 02-ealkynyl, haloCi-ealkyl, Ci- ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, Ci-ealkylthio, Cs- cycloalkyl, Cs- cycloalkenyl, - C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, -PO-(OR3i)2, -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2;

[0471] each R3x, R3yand R3zare independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl; preferably each R3x, R3yand R3zare independently selected from hydrogen, Ci-ealkyl, 02-ealkenyl, 02-ealkynyl, Cs- cycloalkyl and heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are optionally further substituted by one, two or three substituents independently selected from halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl,cycloalkynyl, -C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, -PO-(OR3i)2, -NH2, -NHalkyl, and -N(alkyl)2; preferably each Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Cs- cycloalkyl and heterocyclyl are optionally further substituted by one, two or three substituents independently selected from halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, - SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, haloCi-ealkyl, Ci-ealkoxy, haloCi- ealkoxy, hydroxyCi-ealkyl, Ci-ealkoxy, Ci-ealkylthio, Cs- cycloalkyl, Cs- cycloalkenyl, - C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, -PO-(OR3i)2, -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2;

[0472] or, R3xand R3ytogether form a heterocycle optionally substituted with one, two or three substituents independently selected from comprising halogen, -OH, =0, -SH, =S, -CF3, - CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2; preferably R3xand R3ytogether form a heterocycle optionally substituted with one, two or three substituents independently selected from comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, Cs- cycloalkyl, C5- iocycloalkenyl, Cs- cycloalkynyl, -C(O)OH, -NH2, -NHCi-ealkyl, and -N(Ci-6alkyl)2.

[0473] The compound according to any one of the formulas, statements, embodiments or claims, wherein R3is selected from hydrogen, alkyl, -NR3xR3yand -0R3z; preferably R3is selected from hydrogen, Ci-ealkyl, -NR3xR3yand -0R3zwherein:

[0474] alkyl is optionally substituted by one, two or three substituents independently selected from halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylthio, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, -PO-(OR3i)2, -NH2, -NHalkyl, and -N(alkyl)2; preferably Ci-ealkyl is optionally substituted by one, two or three substituents independently selected from halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, haloCi-ealkyl, Ci- ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, Ci-ealkylthio, Cs- cycloalkyl, Cs- cycloalkenyl, - C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, -PO-(OR3i)2, -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2;

[0475] each R3x, R3yand R3zare independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl; preferably each R3x, R3yand R3zare independently selected from hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Cs- cycloalkyl and heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are optionally further substituted by one, two or three substituents independently selected from halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, -PO-(OR3i)2, -NH2, -NHalkyl, and -N(alkyl)2; preferably each Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Cs- cycloalkyl and heterocyclyl are optionally further substituted by one, two or three substituents independently selected from halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, - SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, haloCi-ealkyl, Ci-ealkoxy, haloCi- ealkoxy, hydroxyCi-ealkyl, Ci-ealkoxy, Ci-ealkylthio, Cs- cycloalkyl, Cs- cycloalkenyl, - C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, -PO-(OR3i)2, -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2;

[0476] or, R3xand R3ytogether form a heterocycle optionally substituted with one, two or three substituents independently selected from comprising halogen, -OH, =0, -SH, =S, -CF3, - CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2; preferably R3xand R3ytogether form a heterocycle optionally substituted with one, two or three substituents independently selected from comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, Cs- cycloalkyl, C5- iocycloalkenyl, Cs- cycloalkynyl, -C(O)OH, -NH2, -NHCi-ealkyl, and -N(Ci-6alkyl)2.

[0477] The compound according to any one of the formulas, statements, embodiments or claims, wherein R3is selected from hydrogen, amino, -NHCi-ealkyl, -N(Ci-ealkyl)2, -NR3a-(CR3fR3g)q-C(O)NR3aR3b, -NR3a-(CR3fR3g)q-CO2R3c, -NR3a-(CR3fR3g)q-OR3c, -NR3a-(CR3fR3g)q-PO(OR3i)2, - " "

[0478] >

[0479]

[0480] , oxo, -()2, -(), yroxy, i-6ay,2.6aeny,2-ealkynyl, Ci-ealkoxy, Ci-ealkylamino, diCi-ealkylamino and C3-i2cycloalkyl;

[0481] wherein each of said Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci-ealkoxy, Ci-ealkylamino, diCi- ealkylamino or C3-i2cycloalkyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -CF3, -CHF2, - OCF3, -OCHF2, cyano, nitro, Ci-4alkyl, haloCi-4alkyl, Ci-4alkoxy, haloCi-4alkoxy, hydroxyCi-4alkyl, C3-iocycloalkyl, heterocyclyl, -C(O)OH, -PO-(OH)2, -PO-(OCi-4alkyl)2, -NH2, -NHC1.

[0482] 4alkyl, and -N(Ci-4alkyl)2;

[0483] cycle A is selected from the group comprising aryl, C3-i2cycloalkyl, heterocyclyl and heteroaryl;preferably cycle A is selected from: aryl, Cs-wcycloalkyl,

[0484]

[0485]

[0486] Y is NH, NCi.6alkyl or O;

[0487] each R6is independently selected from the group comprising hydrogen, halogen, Ci-ealkyl, Ci-ealkoxy, Ci-ealkyloxyCi-ealkyl, -(CR3fR3g)q-O-(CR3fR3g)v-CO2R3c, hydroxyCi-ealkyl, -CC>2R3c, -(CR3fR3g)q-O-(CR3fR3g)v-heteroaryl, -CONR3aS(O)2R3d, -C(O)R3d, -C(O)NR3aR3b, oxo, -OR3c, wherein each of said Ci-ealkyl, Ci-ealkoxy, Ci-ealkyloxyCi-ealkyl, hydroxyCi-ealkyl, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -CF3, -CHF2, -OCF3, -OCHF2, cyano, Ci-4alkyl, haloCi-4alkyl, Ci-4alkoxy, haloCi-4alkoxy, hydroxyCi-4alkyl, -C(O)OH, -NH2, -NHCi-4alkyl, and -N(Ci-4alkyl)2;

[0488] R3ais selected from the group comprising hydrogen, Ci-ealkyl, hydroxyCi-ealkyl, aminoCi-ealkyl, -S02-Ci-ealkyl;

[0489] R3bis selected from the group comprising hydrogen, Ci-ealkyl;

[0490] R3Cis selected from the group comprising hydrogen, Ci-ealkyl, haloCi-ealkyl, hydroxyCi-ealkyl, Ci-ealkyl-COOH, aminoCi-ealkyl;

[0491] R3dis selected from the group comprising Ci-ealkyl, hydroxyCi-ealkyl, aminoCi-ealkyl; each R3fand R3gare independently selected from hydrogen, Ci-ealkyl, hydroxyCi-ealkyl, -NH2; R3his hydrogen;

[0492] R3' is hydrogen or Ci-ealkyl,

[0493] m is an integer selected from 0, 1, 2, or 3;

[0494] p is an integer selected from 0, or 1;

[0495] q is an integer selected from 0, 1, or 2;

[0496] v is an integer selected from 0, 1, or 2.The compound according to any one of the formulas, statements, embodiments or claims, wherein R3is selected from -NH2, -NHMe and -N(Me)2. The compound according to any one of the formulas, statements, embodiments or claims, wherein R3is hydrogen. The compound according to any one of the formulas, statements, embodiments or claims, wherein R3is C1-4alkyl, such as methyl.

[0497] The compound according to any one of the formulas, statements, embodiments or claims, wherein R3is not oxo. The compound according to any one of the formulas, statements, embodiments or claims, wherein R3is not hydrogen.

[0498] The compound according to any one of the formulas, statements, embodiments or claims, wherein Q is -CO-.

[0499] The compound according to any one of the formulas, statements, embodiments or claims, wherein

[0500] - L is -CRLgRLh- or-NRLb-;

[0501] RLgis selected from the group comprising hydrogen, alkyl, hydroxyalkyl, -NRLaRLb, aminoalkyl, heteroalkyl, haloalkyl and -C(O)NRLaRLb;

[0502] RLhis selected from hydrogen or alkyl;

[0503] RLais selected from hydrogen or alkyl; and

[0504] RLbis selected from hydrogen or alkyl.

[0505] The compound according to any one of the formulas, statements, embodiments or claims, wherein

[0506] RLgis selected from the group comprising hydrogen, alkyl, hydroxyalkyl, -NRLaRLb, aminoalkyl, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, haloalkyl -C(O)NRLaRLband deuterium; preferably RLgis selected from the group comprising hydrogen, Ci-ealkyl, hydroxyCi-ealkyl, -NRLaRLb, aminoCi-ealkyl, Ci-ealkoxy, Ci-ealkylamino, di-Ci-ealkylamino, Ci-ealkylaminoCi-ealkyl, di- Ci-ealkyl-amino-Ci-ealkyl, thioCi-ealkyl, Ci-ealkoxyCi-ealkyl, Ci-ealkyl-thio-Ci-ealkyl, haloCi- ealkyl, -C(O)NRLaRLband deuterium;

[0507] RLhis selected from hydrogen, deuterium or alkyl; preferably RLhis selected from hydrogen, deuterium or Ci-ealkyl;

[0508] RLais selected from hydrogen or alkyl; preferably RLais selected from hydrogen or Ci-ealkyl; and

[0509] RLbis selected from hydrogen or alkyl; preferably RLbis selected from hydrogen or Ci-ealkyl. The compound according to any one of the formulas, statements, embodiments or claims, wherein L is -CRLgRLh-, RLgis hydrogen, deuterium or Ci-4alkyl (e.g. methyl) and RLhis hydrogen or deuterium. In a further embodiment L is methylene or deuterated methylene (-CD2-).In some embodiments, such as where L is -CRLgRLh-, X is selected from -ORXcand -NRXaRXb. In some embodiments (such as but not limited to where L is -CRLgRLh-, and / or X is selected from -ORXcand -NRXaRXb, or, where the compound has structural formula (VI) or (VII)), RXais selected from the group comprising hydrogen, alkyl, alkyloxyalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl,

[0510] wherein each of said alkyl, alkyloxyalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, cycloalkyl, -OH, =0, halogen, -SH, =S, -C(O)OH, O-alkyl, alkoxy, -NH2, -NHalkyl, and -N(alkyl)2;

[0511] RXbis selected from the group comprising hydrogen, alkyl, aminoalkyl, hydroxyalkyl, and cycloalkyl,

[0512] wherein each of said alkyl, aminoalkyl, hydroxyalkyl, and cycloalkyl, is unsubstituted or is substituted with one or more substituents each independently selected from hydroxyalkyl, alkyl, cycloalkyl, -OH, =0, halogen, -SH, =S, -C(O)OH, alkoxy, -NH2, - NHalkyl, and -N(alkyl)2;

[0513] each RXcis selected from the group comprising hydrogen, alkyl, alkyloxyalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl,

[0514] wherein each of said alkyl, alkyloxyalkyl, aminoalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, deuterium, cycloalkyl, -OH, =0, halogen, -SH, =S, -C(O)OH, O-alkyl, alkoxy, -NH2, - NHalkyl, and -N(alkyl)2.

[0515] The compound according to any one of the formulas, statements, embodiments or claims,

[0516]

[0517]

[0518]

[0519] , aminoCi-ealkyl, -C(O)ONH2, hydroxyCi-ealkyl; wherein each of said groups is substituted or unsubstituted with one or more substituents each independently selected from the group comprising hydroxyCi-ealkyl, -C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by Ci-ealkyl, Ci-ealkyl, Cs- cycloalkyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, - OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, hydroxyCi-ealkoxy, aminoCi-ealkoxy, (mono- or di-)Ci-6alkyl-aminoCi-6alkoxy, -NH2, -NHCi.6alkyl, and -N(Ci-6alkyl)2.

[0520] The compound according to any one of the formulas, statements, embodiments or claims, wherein L is a single bond and X is a heterocycle or heteroaryl, wherein said heterocycle and heteroaryl are optionally substituted by one or more substituents independently selected from hydroxyCi-ealkyl, -C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by Ci-ealkyl, Ci-ealkyl, C2-6alkenyl, C2-ealkynyl, Cs- cycloalkyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, - OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkoxy, aminoCi-ealkoxy, mono-aminoCi-ealkoxy, di-aminoCi-ealkoxy, -NH2, -NHC1- ealkyl, and -N(Ci-6alkyl)2; and wherein RXaand RXbare as defined for any of the embodiments, statements or claims described herein.

[0521] In some embodiments, L is a single bond and X is a heterocycle or heteroaryl, wherein said heterocycle and heteroaryl are optionally substituted by one or more substituent R7, wherein each R7is independently selected from hydroxyCi-ealkyl, -C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by Ci-ealkyl, Ci-ealkyl, C2-ealkenyl, 02-ealkynyl, C3- locycloalkyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkoxy, aminoCi-ealkoxy, mono-aminoCi-ealkoxy, di-aminoCi-ealkoxy, -NH2, -NHCi-ealkyl, and -N(Ci-ealkyl)2; and wherein RXaand RXbare as defined for any of the embodiments, statements or claims described herein.In some embodiments,

[0522] the moiety L-X is according to

[0523]

[0524] Z is N or O;

[0525] cycle B is a heterocyclyl or heteroaryl, such as C4- heterocyclyl or C5-i2heteroaryl; and / or u is 0, 1, 2 or 3.

[0526] In further embodiments, Z is N.

[0527] In a further embodiment, each R7is independently selected from hydroxyalkyl, -C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by one or more alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, - OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, (mono- or di-)alkyl-aminoalkoxy, -NH2, -NHalkyl, and -N(alkyl)2; preferably each R7is independently selected from hydroxyCi-ealkyl, -C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by one or more Ci-ealkyl, Ci-ealkyl, C2-ealkenyl, C2- ealkynyl, Cs- cycloalkyl, Cs- cycloalkenyl, Cs- cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloCi-ealkyl, Ci-ealkoxy, haloCi- ealkoxy, hydroxyCi-ealkyl, hydroxyCi-ealkoxy, aminoCi-ealkoxy, mono-Ci-ealkyl-aminoCi- ealkoxy, di-Ci-ealkyl-aminoCi-ealkoxy, -NH2, -NHCi-ealkyl, and -N(Ci-6alkyl)2.

[0528] In some embodiments, such as where Q is -CO- and / or L is a single bond, X is a heteroaryl optionally substituted by one of more R7.

[0529] In some embodiments, moiety -L-X is according

[0530]

[0531] wherein cycle B is selected from

[0532]

[0533]

[0534] 10 In further embodiments, the optionally substituted cycle B is selected from H

[0535]

[0536] In yet further embodiments, the optionally substituted cycle B is selected from

[0537]

[0538] In alternative embodiments, the optionally substituted cycle B is

[0539]

[0540] In some embodiments, u is 0, 1 or 2.

[0541] In some embodiments, L is a single bond and X is a heterocycle or heteroaryl, wherein said heterocycle and heteroaryl are optionally substituted by one or more substituent R7, wherein each R7is independently selected from hydroxyCi-ealkyl, -C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by Ci-ealkyl, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3- locycloalkyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkoxy, aminoCi-ealkoxy, mono-aminoCi-6alkoxy, di-aminoCi-ealkoxy, -NH2, -NHCi-ealkyl, and -N(Ci-6alkyl)2; and wherein RXaand RXbare as defined for any of the embodiments, statements or claims described herein.

[0542] In some embodiments, each R7is independently selected from Ci-4-hydroxyalkyl, - C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by one or two Ci-4-alkyl, C1-4- alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -P(O)H2, -S(O)2RXa, -S(O)RXa, cyano, nitro, -C(O)ORXc, Ci-4-haloalkyl, Ci-4-alkoxy, Ci-4-haloalkoxy, Ci-4-hydroxyalkyl, Ci-4-hydroxyalkoxy, C1-4- aminoalkoxy, (mono- or di-)Ci-4-alkyl-amino- Ci-4-alkoxy, -NRXaRXb(such as -NH2, -NH-C1-4- alkyl, and -N(Ci-4-alkyl)2); or, two R7together form a Cs-s-cycloalkyl, or, 4-, 5- or 6-membered heterocyclyl wherein said cycloalkyl or heterocyclyl is optionally substituted with one, two or three substituents independently selected from halogen, Ci-4-alkyl, Ci-4-alkoxy or C1-4- haloalkyl.

[0543] In some embodiments, each R7is independently selected from hydroxyalkyl, -C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by one or more alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, - OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, (mono- or di-)alkyl-aminoalkoxy, -NH2, -NHalkyl, and -N(alkyl)2; preferably each R7is independently selected from hydroxyCi-ealkyl, -C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by one or more Ci-ealkyl, Ci-ealkyl, C2-ealkenyl, C2- ealkynyl, Cs- cycloalkyl, Cs- cycloalkenyl, Cs- cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloCi-ealkyl, Ci-ealkoxy, haloCi- ealkoxy, hydroxyCi-ealkyl, hydroxyCi-ealkoxy, aminoCi-ealkoxy, mono-Ci-ealkyl-aminoCi-ealkoxy, di-Ci-ealkyl-aminoCi-ealkoxy, -NH2, -NHCi-ealkyl, and -N(Ci-ealkyl)2.

[0544] In some embodiments, each R7is selected from halogen, cyano, nitro, -C(O)ORXcand halo C1-4alkyl.

[0545] In some embodiments, each R7is independently selected from hydroxyalkyl, alkyl, -OH, halogen, -SH, =S, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, (mono- or di-)alkyl-aminoalkoxy, -NH2, -NHalkyl, and -N(alkyl)2.

[0546] In some embodiments, each R7is independently selected from C1-4 alkyl (methyl), halogen, C1- 4 alkoxy (methoxy), halo-Ci-4 alkoxy, hydroxy-Ci-4 alkyl, hydroxy-Ci-4 alkoxy, C1-4 aminoalkoxy, (mono- or di-)-Ci-4 alkyl-amino-Ci-4 alkoxy, -NH2, -NH(CI-4 alkyl), and -N(CI-4 alkyl)2.

[0547] The compound according to any one of the formulas, statements, embodiments or claims, wherein

[0548] - X is selected from the group comprising -ORXc, -NRXaRXb, heteroaryl, heterocyclyl, aminoalkyl -SC>2RXd, -CONRXaRXb, -C(O)ORXc, hydroxyalkyl, and alkyl; wherein each of said heterocyclyl, heteroaryl and alkyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, alkoxy, hydroxyalkyl, alkyl, haloalkyl, amino, mono- or di-alkylamino, -CONRXaRXb, heteroaryl, and carboxyl; preferably X is selected from the group comprising -ORXc, - NRXaRXb, heteroaryl, heterocyclyl, aminoCi-ealkyl, -SO2RXd, -CONRXaRXb, -C(O)ORXc, hydroxyeCi-ealkyl, and Ci-ealkyl; wherein each of said heterocyclyl, heteroaryl and Ci-ealkyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, Ci-ealkoxy, hydroxyCi-ealkyl, Ci- ealkyl, haloCi-ealkyl, amino, mono-Ci-ealkylamino, di-Ci-ealkylamino, -CONRXaRXb, heteroaryl, and carboxyl;

[0549] RXais selected from hydrogen, hydroxyalkyl, alkyl, or heteroalkyl (alkyloxyalkyl); preferably RXais selected from hydrogen, hydroxyCi-ealkyl, Ci-ealkyl, or Ci-ealkyloxyCi-ealkyl;

[0550] RXbis selected from hydrogen or alkyl; preferably RXbis selected from hydrogen or Ci- ealkyl;

[0551] each RXcis selected from the group comprising hydrogen, alkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heteroalkyl (alkyloxyalkyl, mono- or di-alkyl aminoalkyl) and heteroarylalkyl, wherein each of said alkyl and cycloalkyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, -NH2 or hydroxyalkyl; preferably each RXcis selected from the group comprising hydrogen, Ci-ealkyl, aminoCi- ealkyl, hydroxyCi-ealkyl, Cs- cycloalkyl, Ci-ealkyloxyCi-ealkyl, mono-Ci-ealkylaminoCi- ealkyl, di-Ci-ealkylaminoCi-ealkyl and heteroarylCi-ealkyl, wherein each of said Ci-ealkyl and Cs- cycloalkyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, -NH2 or hydroxyCi-ealkyl; andRXdis selected from the group comprising alkyl, alkyl, cycloalkyl, and heteroaryl; preferably RXdis selected from the group comprising Ci-ealkyl ,C3- cycloalkyl and heteroaryl.

[0552] The compound according to any one of the formulas, statements, embodiments or claims, wherein

[0553] - Q is -CO-;

[0554] L is -CH2- or -NH-; and

[0555] - X is selected from the group comprising -ORXc, -NRXaRXb, heteroaryl, heterocyclyl, aminoalkyl -SO2RXd, -CONRXaRXb, -C(O)ORXc, hydroxyalkyl, and alkyl; wherein each of said heterocyclyl, heteroaryl and alkyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, alkoxy, hydroxyalkyl, alkyl, haloalkyl, amino, mono- or di-alkylamino, -CONRXaRXb, heteroaryl, and carboxyl;

[0556] each RXaand RXcis independently selected from hydrogen, alkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heteroaryl, heterocyclyl, heteroarylalkyl and heterocyclylalkyl;

[0557] wherein each of said alkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heteroaryl, heterocyclyl, heteroarylalkyl and heterocyclylalkyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, - OCHF2, - SCF3, -SF5, cyano, nitro, -C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, NHalkyl, and -N(alkyl)2;

[0558] RXbis selected from hydrogen or alkyl; and

[0559] RXdis selected from the group comprising alkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heteroaryl, heterocyclyl, heteroarylalkyl and heterocyclylalkyl;

[0560] wherein each of said alkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heteroaryl, heterocyclyl, heteroarylalkyl and heterocyclylalkyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, - OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2.

[0561] In some embodiments, -Q-L-X is selected from -C(0)-CH(RLg)-X, -C(O)-CH(RLg)-O-RXcor -C(O)-CH(RLg)-NRXaRXb.

[0562] In some embodiments, -Q-L-X is selected from -C(O)-CH(RLg)-OH, -C(0)-CH(RLg)-NH2, -0(0)-CH(RLg)-0Me, -C(O)-NH-NH2or -C(O)-NH-NH-Me.

[0563] The compound according to any one of the formulas, statements, embodiments or claims,wherein

[0564] each R4is independently selected from the group comprising halogen, -CF3, -OCF3, -CHF2, -OCHF2, alkyl, -OR4c, haloalkyl, -CN, haloalkoxy, hydroxyalkyl, heteroalkyl (alkyloxyalkyl) and cycloalkyl,

[0565] or two R4together with the carbon atom(s) to which they are attached can form a cycloalkyl, or a cycloalkenyl;

[0566] - R4cis selected from the group comprising alkyl, alkoxy, hydroxyalkyl and haloalkyl; and - n is an integer selected from 1, 2, 3, or 4.

[0567] The compound according to any one of the formulas, statements, embodiments or claims, wherein

[0568] each R4is independently selected from the group comprising -CF3, -OCF3, -CHF2, -B(OH)2, -O-SO2-F, -SO2-F, -OCHF2, alkyl, -OR4c, haloalkyl, -CN, haloalkoxy, hydroxyalkyl, haloalkoxy, hydroxyalkyl, alkyloxyCi-ealkyl and cycloalkyl; preferably each R4is independently selected from the group comprising halogen, -CF3, -OCF3, -CHF2, -OCHF2, -B(OH)2, -O-SO2-F, -SO2-F, alkyl, -OR4c, -NR4aC(O)R4c, haloCi-6alkyl, -CN, haloCi-6alkoxy, hydroxyCi-ealkyl, Ci-ealkyloxyCi-ealkyl and Cs- cycloalkyl;

[0569] or two R4together with the carbon atom(s) to which they are attached can form a cycloalkyl, a cycloalkenyl or heterocyclyl; preferably two R4together with the carbon atom(s) to which they are attached can form a Cs- cycloalkyl, a Cs- cycloalkenyl, or a heterocyclyl;

[0570] - R4cis selected from the group comprising alkyl, alkyl substituted with deuterium, alkoxyalkyl, hydroxyalkyl and haloalkyl; preferably R4cis selected from the group comprising Ci-ealkyl, -CD3, Ci-ealkoxyCi-ealkyl, hydroxyCi-ealkyl and haloCi-ealkyl; and - n is an integer selected from 1, 2, 3, or 4.

[0571] The compound according to any one of the formulas, statements, embodiments or claims, wherein R5is selected from the group comprising hydrogen, alkyl, haloalkyl, heteroalkyl (e.g., alkyloxyalkyl), hydroxyalkyl, aminoalkyl, cycloalkylalkyl, and heterocyclylalkyl; preferably R5is selected from the group comprising hydrogen, Ci-ealkyl, haloCi-ealkyl, Ci-ealkyloxyCi-ealkyl, mono-amino-Ci-6alkyl, di-amino-Ci-ealkyl, hydroxyCi-ealkyl, aminoCi-ealkyl, C3- cycloalkylalkyl, and heterocyclylalkyl.

[0572] In some embodiments, R5is selected from the group comprising hydrogen, alkyl, alkyloxyalkyl, hydroxyalkyl, aminoalkyl; preferably R5is selected from the group comprising hydrogen, C1-4alkyl, Ci-4alkyloxyCi-4alkyl, hydroxyCi-4alkyl, aminoCi-4alkyl.

[0573] The compound according to any one of the formulas, statements, embodiments or claims, wherein R5is absent.

[0574] The compound according to any one of the formulas, statements, embodiments or claims, wherein R5is not absent and R3is oxo.The compound according to any one of the formulas, statements, embodiments or claims, having structural formula (II) a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and / or prodrug thereof,

[0575]

[0576] wherein

[0577] R1, R2, R3, R4, R5, Q, L, X, T1, T2, T3, T4, E1, E2, the dotted lines and dashed lines are as defined for any one of the formulas, statements, embodiments or claims herein, each of R41and R42have independently the same meaning as R4, and

[0578] s is 0, 1 or 2.

[0579] The compound according to any one of the formulas, statements, embodiments or claims, having structural formula (Ila) a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and / or prodrug thereof,

[0580]

[0581] wherein

[0582] - R1, R2, R3, R5, Q, L, X, T1, T2, T3, T4, E1, E2, the dotted lines and dashed lines are as defined for any one of the formulas, statements, embodiments or claims herein,

[0583] each of R41and R42have independently the same meaning as R4, and

[0584] R43is absent or has the same meaning as R4.Also provided herein are compounds of formula (III) and any subgroup thereof, a stereoisomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and / or prodrug thereof,

[0585]

[0586] wherein

[0587] R1, R2, R3, R4e, R5, Q, L, X, T1, T2, T3, T4, E1and E2are as defined for any of the formulas, statements, embodiments or claims herein,

[0588] cycle C is an aryl or heteroaryl,

[0589] G is C, O or N;

[0590] R41has the same meaning as R4,

[0591] R43is absent or has the same meaning as R4, and,

[0592] - w is 0, 1, 2 or 3.

[0593] In further embodiments, G is O or N and cycle C is heteroaryl.

[0594] In some embodiments, R41is halogen (such as chlorine).

[0595] In some embodiments, R42is C1-4 alkoxy (such as methoxy) or haloalkoxyCi-4alkyl (such as trifluoromethoxy).

[0596] In some embodiments R43(when present) is halogen (such as fluorine or chlorine).

[0597] In further embodiments, R41is halogen and R42is C1-4 alkoxy, such as R41is chlorine and R42is methoxy.

[0598] In some embodiments, the compounds of the invention are compounds of formula (I), (II) or (III) and any subgroup thereof as described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and / or prodrug thereof, wherein:

[0599] each dashed line (

[0600]

[0601] ) represents an optional double bond and whereby two adjacent dashed line cannot form a double bond at the same time;

[0602] the dotted lines (

[0603]

[0604] ) represent the possible points of attachment of -Q-L-X; each E1, E2and E3is independently C, CH, NH or N;- T1is CH, C, O or N; T2is C, CH, CH2, N or a bond; T3is C, CH, CH2, N or a bond; and, T4is CH, C or N; wherein T2and T3are not both a bond, and, wherein one and only one of T1, T2, T3and T4is N;

[0605] R1is selected from the group comprising hydrogen, halogen, =0, Ci-ealkyl, -C(O)O-Ci- ealkyl, hydroxyCi-ealkyl, aminoCi-ealkyl, haloCi-ealkyl;

[0606] wherein each of said Ci-ealkyl, -C(O)O-Ci-6alkyl, hydroxyCi-ealkyl, aminoCi-ealkyl, haloCi- ealkyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, - CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, haloCi-ealkyl, Ci- ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, Cs-ecycloalkyl, aryl, -C(O)OH, -C(O)O-Ci-6alkyl, -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2;

[0607] R2is selected from the group comprising hydrogen, halogen, =0, hydroxyl, Ci-ealkyl, hydroxyCi-ealkyl, aminoCi-ealkyl, Ci-ealkyloxyCi-ealkyl, mono- or di-Ci-ealkylaminoCi-ealkyl, Cs-ecycloalkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, -CONR2aR2band -CO2R2c; wherein each of said Ci-ealkyl, hydroxyCi-ealkyl, aminoCi-ealkyl, Ci-ealkyloxyCi-ealkyl, mono- ordi-Ci-ealkylaminoCi-ealkyl, Cs-ecycloalkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi- ealkoxy, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, - SCF3, -SF5, -N3, cyano, nitro, Ci-ealkyl, haloCi-ealkyl (such as -CF3, -CHF2), Ci- ealkoxy, haloCi-ealkoxy (such as -OCF3, -OCHF2), hydroxyCi-ealkyl, Cs-ecycloalkyl, -C(O)OH, -C(O)OR2c, -COR2d, -NR2aR2b(such as -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2), -NR2aCOR2d, -CONR2aR2b, and -0R2c;

[0608] R2ais selected from the group comprising hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3- ecycloalkyl;

[0609] R2bis selected from the group comprising hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3- ecycloalkyl;

[0610] R2Cis selected from the group comprising hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, C3- ecycloalkyl;

[0611] R2dis selected from the group comprising hydroxyCi-ealkyl, Ci-ealkyloxyCi-ealkyl, hydroxy, hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Cs-ecycloalkyl;

[0612] R3is selected from the group comprising hydrogen, halogen, nitro, -CN, -NR3aR3b, - -NR3a- (CR3fR3g)q-NR3aC(O)R3d, -N(C(O)R3d)2, -NR3aS(O)2R3d, -(CR3fR3g)q-S(O)2NR3a, -NR3a-

[0613]

[0614] oxo, hydroxyl, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Ci-ealkoxy, Ci-ealkylamino, diCi-ealkylamino, Ci-ealkylaminoCi-ealkyl, di-Ci-ealkyl-amino-Ci-ealkyl, Ci-ealkoxyCi-ealkyl, Ci- ealkyl-Cs-ecycloalkyl, haloCi-ealkyl, Ce- aryl, 5 to 6 membered heteroaryl, 3 to 6 membered heterocyclyl, Ce-warylCi-ealkyl, 5 to 6 membered heteroarylCi-ealkyl, 3 to 6 membered heterocyclylCi-ealkyl,

[0615] cycle A is 3 to 6 membered heterocyclyl or 5 to 6 membered heteroaryl;

[0616] - Y is NR3hor O;

[0617] each R6is independently selected from the group comprising hydrogen, halogen, -OH, Ci- ealkyl, C2-6alkenyl, C2-6alkynyl, Cs-ecycloalkyl, Ci-ealkoxy, (mono- or di-)Ci-6alkylamino, Ci- ealkyloxyCi-ealkyl, -(CR3fR3g)q-O-(CR3fR3g)v-CO2R3c, hydroxyCi-ealkyl, Ce- aryl, 5 to 6 membered heteroaryl, 3 to 6 membered heterocyclyl,

[0618] R3ais hydrogen, Ci-ealkyl, C2-ealkenyl, or C2-ealkynyl;

[0619] R3bis hydrogen, Ci-ealkyl, C2-ealkenyl, or C2-ealkynyl;

[0620] R3Cis hydrogen, Ci-ealkyl, C2-ealkenyl, or C2-ealkynyl;

[0621] R3dis alkyl, Ci-ealkyl, C2-ealkenyl, or C2-6alkynyl;

[0622] each R3fand R3gare each independently selected from hydrogen, Ci-ealkyl , C2-ealkenyl, or C2-ealkynyl;

[0623] R3his selected from hydrogen, Ci-ealkyl, C2-ealkenyl, or C2-6alkynyl;

[0624] R3' is selected from hydrogen, Ci-ealkyl, Cs-ecycloalkyl and Ce- aryl;

[0625] m is an integer selected from 0, 1 , 2, 3, 4 or 5

[0626] p is an integer selected from 0, 1, 2, 3, 4 or 5;

[0627] q is an integer selected from 0, 1, 2, 3, 4 or 5;

[0628] v is an integer selected from 0, 1 , 2, 3, 4 or 5;

[0629] - Q is -CO-;

[0630] L is selected from -CRLgRLh-, -NRLb-, or a single bond;

[0631] RLgis hydrogen, Ci-ealkyl, C2-ealkenyl, or C2-6alkynyl;

[0632] RLhis selected from hydrogen, Ci-ealkyl, C2-ealkenyl, or C2-6alkynyl;

[0633] RLais selected from hydrogen, Ci-ealkyl, C2-ealkenyl, or C2-6alkynyl;

[0634] RLbis selected from hydrogen, Ci-ealkyl, C2-ealkenyl, or C2-6alkynyl;

[0635] X is selected from the group comprising -ORXc, -NRXaRXb, Ce-waryl, 5 to 6 membered heteroaryl, 3 to 6 membered heterocyclyl, 3 to 6 membered heterocyclylCi-ealkyl, aminoCi-6alkyl, -S(O)2RXd, -NRXbS(O)2RXd, -NRXbC(O)RXc, -NRXbC(O)ORXc, -OC(O)RXd, - C(O)NRXaRXb, -C(O)ORXc, hydroxyCi-ealkyl, Ci-ealkyl, C2-ealkenyl, or C2-6alkynyl, (mono- or di-)Ci-6alkyl-amino-Ci-ealkyl, Ci-ealkoxyCi-ealkyl, Cs-ecycloalkyl, and -N3,

[0636] wherein each of said Ce-waryl, 5 to 6 membered heteroaryl, 3 to 6 membered heterocyclyl, 3 to 6 membered heterocyclylCi-ealkyl, aminoCi-ealkyl, hydroxyCi-ealkyl, Ci-ealkyl, C2- ealkenyl, or C2-ealkynyl, (mono- or di-)Ci-ealkyl-amino-Ci-ealkyl, Ci-ealkoxyCi-ealkyl, C3-ecycloalkyl, and -N3, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising hydroxyalkyl, Ci-ealkyl, -OH, =0, halogen, -CF3, -CHF2, -OCF3, -OCHF2, -P(O)H2, -S(O)2RXa, -S(O)RXa, cyano, nitro, - C(O)ORXc, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, hydroxyCi-ealkyl, hydroxyCi- ealkoxy, aminoCi-ealkoxy, (mono- or di-)Ci-6alkyl-aminoCi-6alkoxy, -NRXaRXb(such as - NH2, -NHCi.6alkyl, and -N(Ci-6alkyl)2);

[0637] RXais hydrogen, Ci-ealkyl, C2-6alkenyl, or C2-6alkynyl;

[0638] RXbis hydrogen, Ci-ealkyl, C2-6alkenyl, or C2-6alkynyl;

[0639] each RXcis hydrogen, Ci-ealkyl, C2-6alkenyl, or C2-6alkynyl;

[0640] RXdis Ci-ealkyl, C2-6alkenyl, or C2-6alkynyl;

[0641] n is an integer selected from 1, 2, 3, or 4;

[0642] each R4is independently selected from the group comprising halogen, oxo, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, -B(OH)2I-O-SO2-F, -SO2-F, cyano, nitro, -0R4c, -NR4aR4b, - NR4aS(O)2R4d, -NR4aSO2NR4aR4b, -NR4aC(O)R4c, -NR4aC(O)OR4c, -NR4aC(O)NR4aR4b, SR4c, -S(O)R4d, -S(O)2R4C, -S(O)2NR4aR4b, -S(O)(NR4a)R4c, -S(NR4a)(NR4a) R4c, -C(O)OR4c, -C(O)R4c, -C(O)NR3aR3b, -P(O)R4aR4b, Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, Ci-6alkoxy, haloCi- ealkyl haloCi-ealkoxy, hydroxyCi-ealkyl, 5 to 6 membered-heteroaryl, 4 to 6 membered heterocyclyl;

[0643] wherein each of said Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci-ealkoxy, haloCi-ealkyl haloCi- ealkoxy, hydroxyCi-ealkyl, 5 to 6 membered-heteroaryl, 4 to 6 membered heterocyclyl; is unsubstituted or is substituted with one or more substituents each independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, - B(OH)2, cyano, nitro, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Cs-ecycloalkyl, hydroxyCi-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, -C(O)OH, -C(O)OCi-ealkyl, -C(O)NH2, - C(O)NHCi-6alkyl, -C(O)N(Ci-6alkyl)2, -NH2, -NHCi-6alkyl, and -N(Ci-6alkyl)2;

[0644] or two R4together with the atom(s) to which they are attached can form a 5 to 6-membered heteroaryl,

[0645] wherein each of said heteroaryl, is unsubstituted or is substituted with one or more substituents each independently selected from R4e;

[0646] - R4ais selected from the group comprising hydrogen, Ci-ealkyl, C2-6alkenyl, C2-ealkynyl; - R4bis selected from the group comprising hydrogen, Ci-ealkyl, C2-6alkenyl, C2-ealkynyl; - R4Cis selected from the group comprising hydrogen, Ci-ealkyl, Ci-ealkyl substituted with deuterium, C2-6alkenyl, C2-ealkynyl,

[0647] - R4dis selected from the group comprising Ci-ealkyl, C2-6alkenyl, C2-ealkynyl;

[0648] - R4eis independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, 3 to 6- membered heterocyclyl, Cs-ecycloalkyl, Cs-ecycloalkylCi-ealkyl, Ce- aryl, 5 to 6 memberedheteroaryl, hydroxyCi-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, Ci-ealkoxyCi-ealkyl, - C(O)H, -C(O)OH, -C(O)OCi.6alkyl, -NHC(O)Ci-6alkyl, -C(O)NH2, -C(O)NHCi-6alkyl, - C(O)N(Ci-6alkyl)2, -NH2, -NHCi-6alkyl, and -N(alkyl)2;

[0649] wherein each of said Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, 4 to 6-membered heterocyclyl, C3- ecycloalkyl, Cs-ecycloalkylCi-ealkyl, Ce- aryl, 5 to 6-membered heteroaryl, Ci-ealkoxy, Ci-6alkoxyCi-6alkyl, -C(O)OCi-6alkyl, -NHC(O)Ci-6alkyl, -C(O)NHCi-6alkyl, -C(O)N(Ci- ealkyl)2, -NHCi-ealkyl, and -N(alkyl)2are optionally substituted with one of more substituents selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, - SCF3, -SF5, cyano, nitro, azido, Ci-ealkoxy, -NH2, -NHCi-ealkyl, and -N(Ci-ealkyl)2; R5is absent or is hydrogen, or Ci-ealkyl;

[0650] when E1is C, E2is C or CH C and E3is C, and, T1is C or CH, T2is N, T3is a bond and T4is C or CH, then E1and E3are both substituted with R4, wherein said two R4groups together form a 5 or 6 membered heteroaryl, wherein said a 5 or 6 membered heteroaryl is unsubstituted or is substituted with one or more substituents each independently selected from R4e.

[0651] In a particular embodiment, the compounds of the invention are selected from the compounds listed in Table 1 or as described with their chemical name in Table 1 or in the examples.

[0652] A pharmaceutical composition comprising a compound according to any one of the formulas, statements, embodiments or claims herein and a pharmaceutically acceptable carrier, solvent, adjuvant or diluent.

[0653] A compound according to any one of the formulas, statements, embodiments or claims herein, or a pharmaceutical composition according to any one of the statements, embodiments or claims herein, for use as a medicament.

[0654] The present compounds used in the current invention may also exist in their stereochemically isomeric form, defining all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures, which are not interchangeable. Unless otherwise mentioned or indicated, the chemical designation of compounds encompasses the mixture of all possible stereochemically isomeric forms, which said compounds might possess. Said mixture may contain all diastereomers and / or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds used in the present invention either in pure form or in admixture with each other are intended to be embraced within the scope of the present invention including any racemic mixtures or racemates.

[0655] More generally, the invention relates to the compounds of the formulae described herein and embodiments, statements and aspects thereof being useful as agents having biological activityor as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a non-medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.

[0656] Compounds of the present disclosure are small molecule cGAS inhibitors or modulators. Small molecule cGAS inhibitors are useful, e.g., for the treatment of inflammation conditions, including with no limitations inflammatory disorders, auto-immune disorders, allergic diseases, inflammation of certain tissues or organs, fibrotic diseases and any other condition in which there is inflammation, more in particular associated with cGAS activity or activation. In a particular embodiment, the compounds of the invention are useful for the prevention or treatment of inflammatory, allergic or autoimmune diseases or diseases with an inflammation component such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis (LN), interferonopathies, psoriasis, insulin-dependent diabetes mellitus (IDDM), vasculitis, scleroderma, Aicardi Goutieres syndrome, dermatomyositis, sepsis, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome (SS), age related macular degeneration (AMD), Amyotrophic Lateral sclerosis (ALS), Fronto¬ temporal dementia (FTD), Alzheimer’s disease, Huntington’s disease and Parkinson’s disease. In other embodiments, cGAS inhibitors are useful for the treatment of cancers, such as cancers selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, oesophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer or prostate cancer. In some embodiments, solid cancers are characterized by the overexpression, genetic activation or the like of cGAS. cGAS inhibitors may also be useful to treat cancers that have developed resistance to prior treatments. This may include, for instance, the treatment of cancers that have developed resistance to chemotherapy, or to targeted therapy or to immunotherapy. Small molecule cGAS inhibitors may also be useful to treat a metastasized cancer. In some instances, the metastasized cancer is selected from metastasized uveal melanoma, oesophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, gastric cancer, medulloblastoma, ovarian cancer, oesophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer and meningioma.

[0657] The compounds of the invention according to any one of the formulas, statements, embodiments or claims herein or a pharmaceutical composition according to any one of the statements, embodiments or claims herein, are for use in treating or preventing a cGAS mediated disease, more in particular a disease with inappropriate activation of the cGAS-STING pathway or of the type I interferon (IFN) response. In a particular embodiment, acompound according to any one of the formulas, statements, embodiments or claims herein or a pharmaceutical composition according to any one of the statements, embodiments or claims herein, is for use in treating an inflammation condition or a disorder selected from inflammatory disorder, an autoimmune disorder, an allergic disease, a fibrotic disease or cancer. More in particular, the compound or pharmaceutical composition is for use according to any one of the formulas, statements, embodiments or claims herein, wherein the disorder is selected from the group comprising systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis (LN), interferonopathies, psoriasis, insulin-dependent diabetes mellitus (IDDM), vasculitis, scleroderma, Aicardi Goutieres syndrome, dermatomyositis, sepsis, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome (SS), age related macular degeneration (AMD), Amyotrophic Lateral sclerosis (ALS), Fronto¬ temporal dementia (FTD), Alzheimer’s disease, Huntington’s disease and Parkinson’s disease. The current inventions also relates to a method for treating or preventing a cGAS mediated disease in a subject in need thereof, the method comprising administering to a subject in need of such treatment an effective amount of one or more compounds according to any one of the formulas, statements, embodiments or claims herein or a pharmaceutical composition according to any one of the statements, embodiments or claims herein. In a particular embodiment, the method relates to inhibiting the cGAS / STING pathway or an aberrant type I interferon (IFN) response in a subject, the method comprising, comprising administering to a subject in need of such treatment an effective amount of one or more compounds according to any one of the formulas, statements, embodiments or claims herein or a pharmaceutical composition according to any one of the statements, embodiments or claims herein. In a particular embodiment, the inventions provides a method of treating an inflammation condition, the method comprising administering to a subject in need of such treatment an effective amount of one or more compounds according to any one of the formulas, statements, embodiments or claims herein or a pharmaceutical composition according to any one of the statements, embodiments or claims herein. It also provides a method for treating or preventing a disease according to any one of the statements, embodiments or claims herein, wherein the disorder is selected from the group comprising systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis (LN), interferonopathies, psoriasis, insulin-dependent diabetes mellitus (IDDM), vasculitis, scleroderma, Aicardi Goutieres syndrome, dermatomyositis, sepsis, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome (SS), age related macular degeneration (AMD), Amyotrophic Lateral sclerosis (ALS), Fronto-temporal dementia (FTD), Alzheimer’s disease, Huntington’s disease and Parkinson’s disease.

[0658] Small molecule cGAS inhibitors and pharmaceutical compositions comprising them may also be useful when combined, upon simultaneous administration, or subsequent administration,with other agents used for the treatment of diseases such as inflammatory disorders, autoimmune disorders, allergic diseases, fibrotic diseases, neurodegenerative diseases and cancer. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and / or adjunctive agents may be linked or conjugated to one another. In some embodiments, the additional medicine or therapeutic agent is an anti-inflammatory agent, anti-fibrotic agent or anti-allergic agent, or more general are selected from agents used for treating or preventing inflammation conditions such as anti- inflammatory agents, anti- fibrotic agents, anti-allergic agents / anti-histamines, bronchodilators, beta2 agonists / betamimetics, adrenergic agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, cytokine / chemokine receptor modulators (i.e. cytokine receptor antagonists), anti-TNF antibodies such as Adalimumab (Humira™), and anti-BAFF agents (such as Belimumab and Etanercept).

[0659] Examples of anti-inflammatory agents are NSAIDs and corticosteroids. NSAIDs are for example selected from ibuprofen, naproxen, diclofenac, meloxicam, celecoxib, acetylsalicylic acid (Aspirin™), indomethacin, mefenamic acid and etoricoxib. Corticosteroids can as an example be selected from Flunisolide, Beclomethasone, Triamcinolone, Budesonide, Fluticasone, Mometasone, Ciclesonide, Rofleponide and Dexametasone.

[0660] Antiallergic agents I anti-histamines can for example be selected from Epinastine, Cetirizine, Azelastine, Fexofenadine, Levocabastine, Loratadine, Ebastine, Desloratidine and Mizolastine. Anti-fibrotic agents are for example selected from Pirfenidone and tyrosine kinase inhibitors such as Nintedanib. Beta 2 agonists / betamimetics may be either long acting beta 2 Agonists (LABAs) or short acting beta agonists (SABAs). And are for example selected from Bambuterol, Bitolterol, Carbuterol, Clenbuterol, Fenoterol, Formoterol, Flexoprenalin, Ibuterol, Pirbuterol, Procaterol, Reproterol, Salmeterol, Sulfonterol, Terbutalin, Tolubuterol, Olodaterol, and Salbutamol, in particular Olodaterol. Anticholinergic agents are as an example selected from ipratropium salts, tiotropium salts, glycopyrronium salts, and theophylline, wherein tiotropium bromide is preferred in particular. Leukotriene modulators can for example be selected from Montelukast, Pranlukast, Zafirlukast, Ibudilast and Zileuton. JAK inhibitors can for example be selected from Baricitinib, Cerdulatinib, Fedratinib, Filgotinib, Gandotinib, Lestaurtinib, Momelotinib, Pacritinib, Peficitinib, Ruxolitinib, Tofacitinib, and Upadacitinib. Examples of anti-interleukin antibodies are anti-IL23 antibodies such as Risankizumab, anti-l L17 antibodies, anti-ILI antibodies, anti-l L4 antibodies, anti-IL13 antibodies, anti-IL-5antibodies, anti-l L-6 antibodies such as Tocilizumab (Actemra™), anti-l L-12 antibodies, anti-I L-15 antibodies.

[0661] In certain embodiments, the second agent is an anti-cancer agent. In certain embodiments, the second agent is a chemotherapeutic. "Anti-cancer agent" refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator, vaccine, cells) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells or in general an agent having utility in treating or preventing cancer and comprises chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, cancer vaccines and the like. In some embodiments, an anticancer agent is an agent approved by the FDA or EMA or similar regulatory agency of a country other than the USA or Europe, for treating cancer. Examples of anti-cancer agents include, but are not limited to EK inhibitors, EGFR inhibitors, RAS inhibitors, inhibitors of B-RAF, alkylating agents, nitrogen mustards, ethylenimine and methylmelamines, alkyl sulfonates, nitrosoureas, triazenes, anti-metabolites, pyrimidine analogues, purine analogues, plant alkaloids, topoisomerase inhibitors, antitumor antibiotics, platinum-based compounds, anthracenedione, substituted urea, methyl hydrazine derivative, adrenocortical suppressant, epipodophyllotoxins, inhibitors of mitogen-activated protein kinase signaling, mTOR inhibitors, agents that arrest cells in the G2-M phases and / or modulate the formation or stability of microtubules, antioestrogen, antiandrogen, monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies such as Alemtuzumab, Bevacizumab, Bretuximab vedotin, Cetuximab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Ipilimumab, Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab, Nivolumab, Pembrolizumab, Avelumab, durvalumab and pidilizumab), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti- CD20 monoclonal antibody conjugated tou qIn,9UY, or ‘-etc. ) and the like. Within the group of anti-cancer agents, “Chemotherapeutic" or "chemotherapeutic agent" refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. In a further embodiment, the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as47Sc,64Cu,67Cu,89Sr,86Y,87Y,90Y,105Rh,mAg,mln,117mSn,149Pm,153Sm,166Ho,177Lu,186R e,188Re,211At, and212Bi, optionally conjugated to antibodies directed against tumour antigens. The compounds of the invention can inhibit cGAS activity. The compounds have been shown to inhibit cGAS activity in cellular models and in an animal model

[0662] The compounds of the invention can optionally be bound covalently to an insoluble matrix and used for affinity chromatography (separations, depending on the nature of the groups of the compounds, for example compounds with pendant aryl are useful in hydrophobic affinityseparations).

[0663] When using one or more derivatives of the formulae as defined herein:

[0664] the active ingredients of the compound(s) may be administered to the animal or mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra-arterially, parenterally or by catheterization.

[0665] the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of diseases mediated by activity of cGAS in humans and other mammals (such as cancer, metabolic diseases and certain congenital disorders), preferably is a cGAS inhibiting amount of the compounds of the formulae, statements, aspects and embodiments as defined herein and corresponds to an amount which ensures a plasma level that is able to inhibit the cGAS activity and is in a particular embodiment between 1ng / ml and 100 mg / ml, more in particular between 1ng / ml and 1mg / ml, still more in particular between 1ng / ml and 1 g / ml.

[0666] Suitable dosages of the compounds or compositions of the invention should be used to treat or prevent the targeted diseases in a subject. Depending upon the pathologic condition to be treated and the patient’s condition, the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.

[0667] According to a particular embodiment of the invention, the compounds of the invention may be employed in combination with other therapeutic agents for the treatment or prophylaxis of diseases mediated by activity of cGAS in humans and other mammals. The invention therefore relates to the use of a composition comprising:

[0668] (a) one or more compounds of the formulae and aspects, statements and embodiments herein, and

[0669] (b) one or more further therapeutic or preventive agents that are used for the prevention or treatment of inflammatory disorders, auto-immune disorders, allergic diseases, fibrotic diseases and cancer and in general for inflammatory conditions also including diabetic diseases, metabolic diseases, cardiovascular diseases and neurodegenerative disorders as biologically active agents in the form of a combined preparation for simultaneous, separate or sequential use.

[0670] The compound or composition can be administered concurrently with, prior to, or subsequent to the one or more additional therapeutic agents, which are different from the compound described herein and may be useful as, e.g., combination therapies. Examples of such further therapeutic agents for use in combinations include anti-inflammatory agents, anti-auto-immune disorder agents, anti-allergic agents, anti-fibrotic agents, anti-diabetic agents, agents used for cardiovascular diseases, metabolic diseases, or neurodegenerative diseases and anti-cancer agents as described herein.The pharmaceutical composition or combined preparation according to this invention may contain the compounds of the present invention over a broad content range depending on the contemplated use and the expected effect of the preparation. Generally, the content of the derivatives of the present invention of the combined preparation is within the range of 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight. Those of skill in the art will also recognize that the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state - any and all protonated forms of the compounds are intended to fall within the scope of the invention. The term "pharmaceutically acceptable salts" as used herein means the therapeutically active non-toxic salt forms which the compounds of formulae herein are able to form. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+, Ca2+and Mg2+. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. The compounds of the invention may bear multiple positive or negative charges. The net charge of the compounds of the invention may be either positive or negative. Any associated counter ions are typically dictated by the synthesis and / or isolation methods by which the compounds are obtained. Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion. Moreover, as the compounds can exist in a variety of different forms, the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions). Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids to basic centres, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalogen acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric,malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e. 2-hydroxybenzoic), p-aminosalicylic and the like.

[0671] The compounds of the invention also include solvates thereof. As used herein and unless otherwise stated, the term “solvate” includes any combination which may be formed by a compound of formula (I) with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, ethers, nitriles and the like.

[0672] Finally, it is to be understood that the compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

[0673] In some embodiments, the pharmaceutically or physiologically acceptable salts of the compounds according to any of the formulae herein, in particular for use in a parental dosage form, are salts with one or more amino acids, especially the naturally-occurring amino acids found as protein components. The amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.

[0674] The compounds of the invention also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4+(wherein X is C1-C4 alkyl). Physiologically acceptable salts of a compound containing a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+and NX4+(wherein X typically is independently selected from H or a C1-C4 alkyl group). However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.

[0675] As used herein and unless otherwise stated...

Claims

CLAIMS1. A compound of formula (I), a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, hydrate, polymorph and / or prodrug thereof, Xwherein:each dashed line ( ) represents an optional double bond and whereby two adjacent dashed line cannot form a double bond at the same time;the dotted lines () represent the possible points of attachment of -Q-L-X; each E1, E2and E3is independently C, CH, NH or N;- T1is CH, C, O or N; T2is C, CH, CH2, N or a bond; T3is C, CH, CH2, N or a bond; and, T4is CH, C or N; wherein T2and T3are not both a bond, and, wherein one and only one of T1, T2, T3and T4is N;R1is selected from the group comprising hydrogen, halogen, =0, alkyl, -C(O)O-alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, - OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, -C(O)OH, -C(O)O-alkyl, -NH2, -NHalkyl, and - N(alkyl)2;R2is selected from the group comprising hydrogen, halogen, =0, hydroxyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylaminoalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, -CONR2aR2band -CChR20;wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylamino- alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -SCF3, -SF5, -N3, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl (such as -CF3, -CHF2), alkoxy, haloalkoxy (such as -OCF3, -OCHF2), hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -C(O)OR2c, -COR2d, -NR2aR2b(such as -NH2, -NHalkyl, and -N(alkyl)2), -NR2aCOR2d, -CONR2aR2b, and - 0R2c;R2ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;R2bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;R2Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;R2dis selected from the group comprising heteroalkyl (e.g. hydroxyalkyl, alkyloxyalkyl), hydroxy, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; or R1and R2together with the carbon atoms to which they are attached can form a heterocyclyl (e.g. pyrrolidinyl),wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, - CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;or R2and X together with the atoms to which they are attached can form a heterocyclyl wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;R3is selected from the group comprising hydrogen, halogen, nitro, -CN, -NR3aR3b, -i r*, oxo, hydroxyl, sulfhydryl, alkyl, alkenyl, alkynyl, heteroalkyl (e.g., alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl and alkoxyalkylamino), heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylheteroalkyl, heterocyclylheteroalkenyl and heterocyclylheteroalkynyl,wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl (e.g. alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl and alkoxyalkylamino), heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylheteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCFs, -SFs, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl (e.g. hydroxyalkyl, alkoxy, alkylthio), heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -C(O)OH, -C(O)R3i, -C(O)-O-CH2- O-CO-R3', -PO-(OR3i)2, -SO2F, -NR3aR3b(-NH2, -NHalkyl, and -N(alkyl)2);cycle A is selected from the group comprising aryl (such as phenyl), cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl and heteroaryl;- Y is NR3hor O;each R6is independently selected from the group comprising hydrogen, halogen, -OH, - NR3aR3b, -SH, =S, -SCF3, -SFs, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl (e.g. alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- or di-)alkyl-amino-alkyl), heteroalkenyl, heteroalkynyl, -(CR3fR3g)q-O- (CR3fR3g)v-CO2R3c, hydroxyalkyl, -(CR3fR3g)q-NR3aSO2R3d, -CO2R3c, -(CR3fR3g)q-O- (CR3fR3g)v-aryl, -(CR3fR3g)q-O-(CR3fR3g)v-heteroaryl, -CONR3aS(O)2R3d, -S(O)2R3d, - (CR3fR3g)q-O-(CR3fR3g)v-CN, -C(O)R3d, aryl, heteroaryl, heterocyclyl, -C(O)NR3aR3b, oxo, - S(O)2NR3aR3b, -OR3cand -(CR3fR3g)q-O-(CR3fR3g)v-O-aryl,wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl (e.g. alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- or di-)alkyl-amino-alkyl), heteroalkenyl, heteroalkynyl, aryl, heteroaryl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, - CHF2, -OCF3, -OCHF2, -SCF3, -SFs, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, heteroalkyl (e.g. alkoxy, hydroxyalkyl, -NH2, -NHalkyl, and -N(alkyl)2), heteroalkenyl and heteroalkynyl;R3ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di- )alkyl-amino, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, - SCh-alkyl, aryl, heteroaryl and heterocyclyl;R3bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;R3Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkyl-COOH, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;R3dis selected from the group comprising alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, alkoxy, (mono- or di-)alkyl-amino, (mono- or di-)alkyl-amino-alkyl, alkylthio, alkylthioalkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;each R3fand R3gare each independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, -NH2, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;R3his selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;R3' is selected from hydrogen, alkyl, cycloalkyl and aryl wherein each alkyl, cycloalkyl, and aryl is optionally further substituted with one or more halogen;m is an integer selected from 0, 1 , 2, 3, 4 or 5p is an integer selected from 0, 1, 2, 3, 4 or 5;q is an integer selected from 0, 1, 2, 3, 4 or 5;v is an integer selected from 0, 1 , 2, 3, 4 or 5;Q is selected from -CO-, -SO2-, -SO(=NH)-;L is selected from -CRLgRLh-, -NRLb-, or a single bond;RLgis selected from the group comprising hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyalkyl, hydroxylalkenyl, hydroxyalkynyl, -NRLaRLb, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, -C(O)NRLaRLb, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, deuterium, cycloalkyl, cycloalkenyl and cycloalkynyl;RLhis selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, deuterium, cycloalkyl, cycloalkenyl and cycloalkynyl;RLais selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;RLbis selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;or RLgand RLhtogether with the carbon atoms to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl and heterocyclyl;X is selected from the group comprising -ORXc, -NRXaRXb, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, -SRXc, aminoalkyl, aminoalkenyl, aminoalkynyl, -S(O)2Xd, -NRXbS(O)2RXd, -NRXbC(O)RXc, -NRXbC(O)ORXc, -OC(O)RXd, -C(O)NRXaRXb, -C(O)ORXc, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkyl, alkenyl, alkynyl, (mono- or di-)alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl and -N3,wherein each of said heteroaryl, heterocyclyl, heterocyclylalkyl, aryl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising hydroxyalkyl, -C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -P(O)H2, -S(O)2RXa, -S(O)RXa, cyano, nitro, -C(O)ORXc, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, (mono- or di-)alkyl-aminoalkoxy, -NRXaRXb(such as -NH2, -NHalkyl, and -N(alkyl)2);RXais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2;RXbis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, - NH2, -NHalkyl, and -N(alkyl)2;each RXcis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2;RXdis selected from the group comprising alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy;each RXeand RXfare independently selected from alkyl, alkenyl, alkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl,heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy;n is an integer selected from 1, 2, 3, or 4;each R4is independently selected from the group comprising halogen, oxo, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, -B(OH)2, -O-SO2-F, -SO2-F, cyano, nitro, -OR4c, -NR4aR4b, - NR4aS(O)2R4d, -NR4aSO2NR4aR4b, -NR4aC(O)R4c, -NR4aC(O)OR4c, -NR4aC(O)NR4aR4b, SR4c, -S(O)R4d, -S(O)2R4C, -S(O)2NR4aR4b, -S(O)(NR4a)R4c, -S(NR4a)(NR4a) R4c, -C(O)OR4c, -C(O)R4c, -C(O)NR3aR3b, -P(O)R4aR4b, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl haloalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -B(OH)2, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)OH, - C(O)Oalkyl, -C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, -NHalkyl, and -N(alkyl)2; or two R4together with the atom(s) to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl,wherein each of said cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, is unsubstituted or is substituted with one or more substituents each independently selected from R4e;- R4ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl and aminoalkynyl;- R4bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;- R4Cis selected from the group comprising hydrogen, alkyl, alkyl substituted with deuterium, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxyalkyl and (mono- or di-)alkyl-aminoalkyl; - R4dis selected from the group comprising alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;- R4eis independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxyalkoxyalkyl, -C(O)H, -C(O)OH, -C(O)Oalkyl, -NHC(O)alkyl, - C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, -NHalkyl, and -N(alkyl)2;wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl, alkoxy, alkoxyalkyl, -C(O)Oalkyl, -NHC(O)alkyl, -C(O)NHalkyl, -C(O)N(alkyl)2, -NHalkyl, and -N(alkyl)2 are optionally substituted with one of more substituents selected from - OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, azido, alkoxy, -NH2, -NHalkyl, and -N(alkyl)2;R5is absent or is selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl-amino- alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl; wherein each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl-amino-alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, - CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)OH, C(O)Oalkyl, - C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, - NHalkyl, and - N(alkyl)2;or R3and R5together with the atoms to which they are attached form a heteroaryl or heterocyclyl wherein said heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, - OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, phenyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and - N(alkyl)2; and,when E1is C, E2is C or CH and E3is C, and, T1is C or CH, T2is N, T3is a bond and T4is C or CH, then E1and E3are both substituted with R4, wherein said two R4groups together form an aryl or heteroaryl, wherein said aryl and heteroaryl is unsubstituted or is substitutedwith one or more substituents each independently selected from R4e.

2. A compound of formula (I), a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, hydrate, polymorph and / or prodrug thereof,wherein:each dashed line ( ) represents an optional double bond and whereby two adjacent dashed line cannot form a double bond at the same time;the dotted lines () represent the possible points of attachment of -Q-L-X; each E1, E2and E3is independently C, CH, NH or N;- T1is CH, C, O or N; T2is C, CH, CH2, N or a bond; T3is C, CH, CH2, N or a bond; and, T4is CH, C or N; wherein T2and T3are not both a bond, and, wherein one and only one of T1, T2, T3and T4is N;R1is selected from the group comprising hydrogen, halogen, =0, alkyl, -C(O)O-alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, -C(O)OH, -C(O)O-alkyl, -NH2, -NHalkyl, and - N(alkyl)2;R2is selected from the group comprising hydrogen, halogen, =0, hydroxyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylaminoalkyl, cycloalkyl, cycloalkenyl,cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, -CONR2aR2band -CO2R2C;wherein each of said alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, alkyloxyalkyl, mono- or di-alkylamino- alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -SCF3, -SF5, -N3, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl (such as -CF3, -CHF2), alkoxy, haloalkoxy (such as -OCF3, -OCHF2), hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -C(O)OR2c, -COR2d, -NR2aR2b(such as -NH2, -NHalkyl, and -N(alkyl)2), -NR2aCOR2d, -CONR2aR2b, and -0R2c; R2ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;R2bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;R2Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;R2dis selected from the group comprising hydroxyalkyl, alkyloxyalkyl, hydroxy, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;or R1and R2together with the carbon atoms to which they are attached can form a heterocyclyl (e.g. pyrrolidinyl),wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, - CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;or R2and X together with the atoms to which they are attached can form a heterocyclyl wherein said heterocyclyl is unsubstituted or substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;R3is selected from the group comprising hydrogen, halogen, nitro, -ON, -NR3aR3b, -(CR3fR3g)q-NR3aR3b, -NR3a-(CR3fR3g)q-NR3aR3b, -O-(CR3fR3g)q-NR3aR3b, -C(O)NR3aR3b, -(CR3fR3g)q-C(O)NR3aR3b, -NR3a-(CR3fR3g)q-C(O)NR3aR3b, -O-(CR3fR3g)q-C(O)NR3aR3b, -CO2R3C, -(CR3fR3g)q-CO2R3c, -NR3a-(CR3fR3g)q-CO2R3c, -O-(CR3fR3g)q-CO2R3c, -0R3c, -(CR3fR3g)q-OR3c, -NR3a-(CR3fR3g)q-OR3c, -O-(CR3fR3g)q-OR3c, -(CR3fR3g)q-C(O)R3c, -O-(CR3fR3g)q-C(O)R3c, -NR3a-(CR3fR3g)q-C(O)R3c, -O-(CR3fR3g)q-PO(OR3i)2, -NR3a-(CR3fR3g)q-PO(OR3i)2, -NR3aC(O)R3d, -(CR3fR3g)q-NR3aC(O)R3d, -NR3a-(CR3fR3g)q-NR3aC(O)R3d, - N(C(O)R3d)2, -SR3c, -S(O)R3c, -S(O)2R3C, -S(O)2-NR3aR3b, -NR3aS(O)2R3d, -(CR3fR3g)q- NR3aS(O)2R3d, -(CR3fR3g)q-S(O)2NR3a, -NR3a-(CR3fR3g)q-NR3aS(O)2R3d, -S(O)(NR3a)R3c, - S(O)(NR3a)NR3aR3b, -NR3aS(O)(NR3a)R3d, -(CR3fR3g)q-NR3aS(O)(NR3a)R3d, -(CR3fR3g)q- S(O)(NR3a)NR3a, -NR3a-(CR3fR3g)q-NR3aS(O)(NR3a)R3d, oxo, hydroxyl, sulfhydryl,, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, alkoxyalkylamino, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, alkoxyalkylamino, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, -C(O)OH, -C(O)R3i, -C(O)-O-CH2-O-CO-R3i, - PO-(OR3i)2, -SO2F, -NR3aR3b(-NH2, -NHalkyl, and -N(alkyl)2);cycle A is selected from the group comprising aryl (such as phenyl), cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl and heteroaryl;- Y is NR3hor O;each R6is independently selected from the group comprising hydrogen, halogen, -OH, - NR3aR3b, -SH, =S, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- ordi-)alkyl-amino-alkyl, -(CR3fR3g)q-O-(CR3fR3g)v-CO2R3c, hydroxyalkyl, -(CR3fR3g)q- NR3aSO2R3d, -CO2R3C, -(CR3fR3g)q-O-(CR3fR3g)v-aryl, -(CR3fR3g)q-O-(CR3fR3g)v-heteroaryl, - CONR3aS(O)2R3d, -S(O)2R3d, -(CR3fR3g)q-O-(CR3fR3g)v-CN, -C(O)R3d, aryl, heteroaryl, heterocyclyl, -C(O)NR3aR3b, oxo, -S(O)2NR3aR3b, -0R3cand -(CR3fR3g)q-O-(CR3fR3g)v-O- aryl,wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di-)alkylamino, alkylthio, alkylthioalkyl, alkyloxyalkyl, (mono- or di-)alkyl-amino-alkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising halogen, -OH, =0, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -C(O)OH, -NH2, -NHalkyl, and -N(alkyl)2;R3ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, (mono- or di-)alkyl-amino, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, -SO2-alkyl, aryl, heteroaryl and heterocyclyl; R3bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;R3Cis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, alkylthioalkyl, (mono- or di-)alkyl-amino-alkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkyl-COOH, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;R3dis selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, alkoxy, (mono- or di-)alkyl-amino, (mono- or di-)alkyl-amino-alkyl, alkylthio, alkylthioalkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;each R3fand R3gare each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, -NH2, aminoalkyl, aminoalkenyl, aminoalkynyl, aryl, heteroaryl and heterocyclyl;R3his selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;R3' is selected from hydrogen, alkyl, cycloalkyl and aryl wherein each alkyl, cycloalkyl, and aryl is optionally further substituted with one or more halogen;m is an integer selected from 0, 1 , 2, 3, 4 or 5p is an integer selected from 0, 1, 2, 3, 4 or 5;q is an integer selected from 0, 1, 2, 3, 4 or 5;v is an integer selected from 0, 1 , 2, 3, 4 or 5;Q is selected from -CO-, -SO2-, -SO(=NH)-; preferably Q is -CO-;L is selected from -CRLgRLh-, -NRLb-, or a single bond;RLgis selected from the group comprising hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxylalkenyl, hydroxyalkynyl, -NRLaRLb, aminoalkyl, aminoalkenyl, aminoalkynyl, haloalkyl, -C(O)NRLaRLb, alkoxy, alkylamino, dialkylamino, alkylaminoalkyl, di-alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, deuterium, cycloalkyl,cycloalkenyl and cycloalkynyl;RLhis selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, deuterium, cycloalkyl, cycloalkenyl and cycloalkynyl;RLais selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;RLbis selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;or RLgand RLhtogether with the carbon atoms to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl and heterocyclyl;X is selected from the group comprising -ORXc, -NRXaRXb, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, -S(O)2Xd, -NRXbS(O)2Xd, -NRXbC(O)RXc, -NRXbC(O)ORXc, -OC(O)RXd, -C(O)NRXaRXb, -C(O)ORXc, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, alkyl, alkenyl, alkynyl, (mono- or di-)alkyl-amino-alkyl, thioalkyl, alkoxyalkyl, alkyl-thio-alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl and -N3,wherein each of said heteroaryl, heterocyclyl, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyal kynyl is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising hydroxyalkyl, - C(O)NRXaRXb, heteroaryl, heterocyclyl, heterocyclyl substituted by alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -P(O)H2, -S(O)2RXa, -S(O)RXa, cyano, nitro, -C(O)ORXc, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, (mono- or di- )alkyl-aminoalkoxy, -NRXaRXb(such as -NH2, -NHalkyl, and -N(alkyl)2);RXais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2;RXbis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl,wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl and hydroxyalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXeRXf, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, C(O)OH, O-alkyl, haloalkyl, alkoxy, haloalkoxy, - NH2, -NHalkyl, and -N(alkyl)2;each RXcis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl,wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxyalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -CONRXaRXb, hydroxyalkyl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, -OH, =0, halogen, -SH, =S, - CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, -C(O)OH, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2;RXdis selected from the group comprising alkyl, alkenyl, alkynyl, haloalkyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from - CONRXaRXb, hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy;each RXeand RXfare independently selected from alkyl, alkenyl, alkynyl, haloalkyl,aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylal kynyl,wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyal kynyl, heteroaryl, heterocyclyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl and heterocyclylal kynyl is unsubstituted or is substituted with one or more substituents each independently selected from hydroxyalkyl, heteroaryl, heterocycle, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, sulfhydryl, -SCF3, -SF5, cyano, nitro, oxo, amino, -C(O)OH, halogen, hydroxyl, haloalkyl, alkoxy and haloalkoxy;n is an integer selected from 1, 2, 3, or 4;each R4is independently selected from the group comprising halogen, oxo, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, -B(OH)2, -O-SO2-F, -SO2-F, cyano, nitro, -OR4c, -NR4aR4b, - NR4aS(O)2R4d, -NR4aSO2NR4aR4b, -NR4aC(O)R4c, -NR4aC(O)OR4c, -NR4aC(O)NR4aR4b, SR4c, -S(O)R4d, -S(O)2R4C, -S(O)2NR4aR4b, -S(O)(NR4a)R4c, -S(NR4a)(NR4a) R4c, -C(O)OR4c, -C(O)R4c, -C(O)NR3aR3b, -P(O)R4aR4b, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl haloalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl,wherein each of said alkyl, alkenyl, alkynyl, alkoxy, haloalkyl haloalkoxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl and cycloalkynyl is unsubstituted or is substituted with one or more substituents each independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, -B(OH)2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)OH, -C(O)Oalkyl, - C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, -NHalkyl, and -N(alkyl)2;or two R4together with the atom(s) to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl,wherein each of said cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, is unsubstituted or is substituted with one or more substituents each independently selected from R4e;- R4ais selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl and aminoalkynyl;- R4bis selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;- R4Cis selected from the group comprising hydrogen, alkyl, alkyl substituted with deuterium, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxyalkyl and (mono- or di-)alkyl-aminoalkyl;- R4dis selected from the group comprising alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl;- R4eis independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxyalkoxyalkyl, -C(O)H, - C(O)OH, -C(O)Oalkyl, -NHC(O)alkyl, -C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, - NHalkyl, and -N(alkyl)2;wherein each of said alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl, alkoxy, alkoxyalkyl, -C(O)Oalkyl, -NHC(O)alkyl, - C(O)NHalkyl, -C(0)N(alkyl)2, -NHalkyl, and -N(alkyl)2are optionally substituted with one of more substituents selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, -OCF3, - OCHF2, -SCF3, -SF5, cyano, nitro, azido, alkoxy, -NH2, -NHalkyl, and -N(alkyl)2;R5is absent or is selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl-amino-alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl;wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, mono- or di-alkyl- amino-alkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminoalkyl, aminoalkenyl, aminoalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl, is unsubstituted or is substituted with one or more substituents each independently selected from the group comprising -OH, =0, halogen, -SH, =S, -CF3, - CHF2, OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -C(O)OH, C(O)Oalkyl, -C(O)NH2, -C(O)NHalkyl, -C(O)N(alkyl)2, -NH2, - NHalkyl, and - N(alkyl)2;or R3and R5together with the atoms to which they are attached form a heteroaryl or heterocyclyl wherein said heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from -OH, =0, halogen, -SH, =S, -CF3, -CHF2, - OCF3, -OCHF2, -SCF3, -SF5, cyano, nitro, alkyl, alkenyl, alkynyl, phenyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -NH2, -NHalkyl, and -N(alkyl)2; and,when E1is C, E2is C or CH and E3is C, and, T1is C or CH, T2is N, T3is a bond and T4is C or CH, then E1and E3are both substituted with R4, wherein said two R4groups together form an aryl or heteroaryl, wherein said aryl and heteroaryl is unsubstituted or is substituted with one or more substituents each independently selected from R4e.

3. A compound according to formula (II), a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, hydrate, polymorph and or prodrug thereof,whereinR1, R2, R3, R4, Q, L, X, T1, T2, T3, T4, E1, E2, the dotted lines and dashed lines are as defined for claim 1,each of R41and R42have independently the same meaning as R4, ands is 0, 1 or 2.

4. A compound according to formula (III), a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, hydrate, polymorph and or prodrug thereof,wherein- R1, R2, R3, R4e, R5, Q, L, X, T1, T2, T3, T4, E1and E2are as defined for claim 1,cycle C is an aryl or heteroaryl,G is C, O or N;each of R41has the same meaning as R4,R43is absent or has the same meaning as R4, and,- w is 0, 1, 2 or 3.

5. A compound a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, hydrate, polymorph and or prodrug thereof, selected from: (S)-7-chloro-2-(2-hydroxyacetyl)-1-methyl-2,3-dihydro-1H-furo[3,2-f]pyrrolo[3,4- c]quinoline-9-carboxamide(S)-1-(7-chloro-1-methyl-1,3-dihydro-2H-furo[3,2-f]pyrrolo[3,4-c]quinolin-2-yl)-2- hydroxyethan-1-one(S)-1-(4-chloro-10-methyl-8,10-dihydro-9H-oxazolo[4,5-f]pyrrolo[3,4-c]quinolin-9-yl)-2- methoxyethan-1-one(S)-1-(2-bromo-4-chloro-10-methyl-8,10-dihydro-9H-oxazolo[4,5-f]pyrrolo[3,4-c]quinolin- 9-yl)-2-methoxyethan-1-one(S)-1-(7-chloro-9-(hydroxymethyl)-1-methyl-1,3-dihydro-2H-furo[3,2-f]pyrrolo[3,4- c]quinolin-2-yl)-2-hydroxyethan-1-one(S)-1-(7-chloro-9-(methoxymethyl)-1-methyl-1,3-dihydro-2H-furo[3,2-f]pyrrolo[3,4- c]quinolin-2-yl)-2-methoxyethan-1-one(S)-1-(7-chloro-9-(hydroxymethyl)-1-methyl-1,3-dihydro-2H-furo[3,2-f]pyrrolo[3,4- c]quinolin-2-yl)-2-methoxyethan-1-one(S)-1-(9-(bromomethyl)-7-chloro-1-methyl-1,3-dihydro-2H-furo[3,2-f]pyrrolo[3,4-c]quinolin- 2-yl)-2-methoxyethan-1-one(S)-1-(4-chloro-10-methyl-2-phenyl-8,10-dihydro-9H-oxazolo[4,5-f]pyrrolo[3,4-c]quinolin- 9-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-3,10-dimethyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-1,10-dimethyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(1H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-2-(2-hydroxyethoxy)-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-2-(3-hydroxypropoxy)-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-10-methyl-2-(2,2,2-trifluoroethoxy)-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-2-(2-methoxyethoxy)-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-2-ethoxy-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin- 9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-2-(3-methoxypropoxy)-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-10-methyl-2-(2,2,3,3,3-pentafluoropropoxy)-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(1H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-2-isopropoxy-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(2-(2-azidoethoxy)-4,5-dichloro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(2-(2-aminoethoxy)-4,5-dichloro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-2-(2-(dimethylamino)ethoxy)-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4-chloro-10-methyl-8,10-dihydro-9H-pyrrolo[3,4-c][1,2,5]thiadiazolo[3,4-f]quinolin- 9-yl)-2-methoxyethan-1-one(S)-N-(4,5-dichloro-9-(2-methoxyacetyl)-10-methyl-1,8,9,10-tetrahydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-2-yl)-2-hydroxyacetamide(S)-5-chloro-10-(2-methoxyacetyl)-11-methyl-1,9,10,11-tetrahydro-2H-pyrrolo[3',4':4,5]pyrido[3,2-f]quinoxalin-2-one(S)-5-chloro-10-(2-methoxyacetyl)-11-methyl-1,9,10,11-tetrahydro-2H-pyrrolo[3',4':4,5]pyrido[3,2-f]quinoxalin-2-one(S)-1-(4-chloro-2-(2-methoxyethyl)-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4- c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-10-methyl-2-(methylamino)-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4- c]quinolin-9(3H)-yl)-2-methoxyethan-1-one- (S)-1-(5-chloro-11-methyl-2-(1H-pyrazol-4-yl)-9,11-dihydro-10H- pyrrolo[3',4':4,5]pyrido[3,2-f]quinoxalin-10-yl)-2-methoxyethan-1-onemethyl (S)-4,5-dichloro-9-(2-methoxyacetyl)-10-methyl-3,8,9,10-tetrahydroimidazo[4,5- f]pyrrolo[3,4-c]quinoline-2-carboxylate(S)-4,5-dichloro-9-(2-methoxyacetyl)-10-methyl-3,8,9,10-tetrahydroimidazo[4,5- f]pyrrolo[3,4-c]quinoline-2-carboxamide(S)-1-(4,5-dichloro-2-(hydroxymethyl)-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4- c]quinolin-9(3H)-yl)-2-methoxyethan-1-one(S)-1-(4,5-dichloro-2-methoxy-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin- 9(3H)-yl)-2-methoxyethan-1-one(S)-(4-chloro-5-fluoro-2-isopropyl-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4- c]quinolin-9(1H)-yl)(pyrimidin-2-yl)methanone((R)-azetidin-2-yl)((S)-4-chloro-5-fluoro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4- c]quinol in-9(1 H)-yl)methanone(S)-1-(4-chloro-5-fluoro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(1H)- yl)-2-methoxyethan-1-one(S)-(4-chloro-5-fluoro-2-methoxy-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4- c]quinolin-9(1H)-yl)(pyrimidin-2-yl)methanone(S)-1-(2,4-dichloro-5-fluoro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin- 9(3H)-yl)-2-hydroxyethan-1-onerac-((10R)-4-chloro-5-fluoro-2-(1-hydroxyethyl)-10-methyl-8,10-dihydroimidazo[4,5- f]pyrrolo[3,4-c]quinolin-9(3H)-yl)(pyrimidin-2-yl)methanone(S)-(4-chloro-2-(cyclopentylmethyl)-5-fluoro-10-methyl-8,10-dihydroimidazo[4,5- f]pyrrolo[3,4-c]quinolin-9(3H)-yl)(pyrimidin-2-yl)methanone(S)-(4-chloro-2-cyclopentyl-5-fluoro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4- c]quinolin-9(3H)-yl)(pyrimidin-2-yl)methanone(S)-(4-chloro-5-fluoro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(1H)- yl)(pyrimidin-2-yl)methanone(S)-1-(4-chloro-5-fluoro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)- yl)-2-hydroxyethan-1-one(S)-(4-chloro-5-fluoro-10-methyl-7-(methylamino)-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4- c]quinolin-9(1H)-yl)(pyrimidin-2-yl)methanone(S)-(4-chloro-5-fluoro-10-methyl-2-(1H-pyrazol-4-yl)-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(1H)-yl)(pyrimidin-2-yl)methanone(S)-(4-chloro-5-fluoro-10-methyl-2-(trifluoromethyl)-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(1H)-yl)(pyrimidin-2-yl)methanone(S)-(4-chloro-2-ethynyl-5-fluoro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(3H)-yl)(pyrimidin-2-yl)methanone(S)-N-(4-chloro-5-fluoro-10-methyl-9-(pyrimidine-2-carbonyl)-3,8,9,10-tetrahydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-2-yl)acetamide(S)-N-(4-chloro-5-fluoro-10-methyl-9-(pyrimidine-2-carbonyl)-3,8,9,10-tetrahydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-2-yl)-2,2,2-trifluoroacetamide6.7-dichloro-8-methoxy-1-methyl-3H-pyrrolo[2,3-c]quinoline-2-carbohydrazide6.7-dichloro-8-methoxy-1,3-dimethyl-3H-pyrrolo[2,3-c]quinoline-2-carbohydrazide 6.7-dichloro-8-methoxy-3H-pyrrolo[2,3-c]quinoline-2-carbohydrazide6.7-dichloro-8-methoxy-3-methyl-3H-pyrrolo[2,3-c]quinoline-2-carbohydrazide6.7-dichloro-8-methoxy-1H-pyrrolo[3,2-c]quinoline-2-carbohydrazide6.7-dichloro-8-methoxyfuro[3,2-c]quinoline-2-carbohydrazidetert-butyl 6,7-dichloro-2-(hydrazinecarbonyl)-3-hydroxy-8-methoxy-1 H-pyrrolo[3,2-c]quinoline-1 -carboxylate6.7-dichloro-1-ethyl-8-methoxy-1H-pyrrolo[3,2-c]quinoline-2-carbohydrazide6.7-dichloro-8-methoxy-1-methyl-1H-pyrrolo[3,2-c]quinoline-2-carbohydrazide(6,7-dichloro-8-methoxy-1H-pyrrolo[3,2-c]quinolin-2-yl)(pyrimidin-2-yl)methanone1-(6,7-dichloro-8-methoxy-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-methoxyethan-1-one(1-benzyl-6,7-dichloro-8-methoxy-1H-pyrrolo[3,2-c]quinolin-2-yl)(pyrimidin-2-yl)methanone6.7-dichloro-8-methoxy-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-2-carbohydrazide7-chloro-6-fluoro-8-methoxy-1H-pyrrolo[3,2-c]quinoline-2-carbohydrazide(S)-1-(3,4-dichloro-2-methoxy-9-methyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)-2-hydroxyethan-1-one(S)-1-(3,4-dichloro-2-methoxy-9-methyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)-2-methoxyethan-1-one(S)-1-(3-chloro-2-methoxy-4,9-dimethyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)-2-hydroxyethan-1-one(S)-1-(3-chloro-2-methoxy-4,9-dimethyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)-2-methoxyethan-1-one(S)-1-(3-chloro-2-methoxy-9-methyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)- 2-hydroxyethan-1-one(S)-1-(3-chloro-2-methoxy-9-methyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)-2-methoxyethan-1 -one(S)-3-chloro-8-(2-methoxyacetyl)-9-methyl-1,7,8,9-tetrahydro-2H-pyrrolo[3,4-c][1 ,5]naphthyridin-2-one(S)-3-chloro-8-(2-methoxyacetyl)-1 ,9-dimethyl-1 ,7,8,9-tetrahydro-2H-pyrrolo[3,4-c][1 ,5]naphthyridin-2-one(S)-(((3-chloro-8-(2-methoxyacetyl)-9-methyl-8,9-dihydro-7H-pyrrolo[3,4-c][1 ,5]naphthyridin-2-yl)oxy)methyl)boronic acid(S)-2-amino-1-(3,4-dichloro-2-methoxy-9-methyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)ethan-1-one(S)-N-(2-(3,4-dichloro-2-methoxy-9-methyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin- 8-yl)-2-oxoethyl)acetamide(S)-1-(4,5-dichloro-10-methyl-8,10-dihydro-9H-pyrrolo[3,4-h][1,2,4]triazolo[4,3-a][1,5]naphthyridin-9-yl)-2-methoxyethan-1-one(S)-1-(3,4-dichloro-9-methyl-2-(methylamino)-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)-2-methoxyethan-1-one(S)-1-(3,4-dichloro-2-(dimethylamino)-9-methyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)-2-methoxyethan-1-one(S)-1-(4-chloro-5,10-dimethyl-8,10-dihydro-9H-pyrrolo[3,4-h][1,2,4]triazolo[1,5-a][1,5]naphthyridin-9-yl)-2-methoxyethan-1-one(S)-1-(7-chloro-1-methyl-1,3-dihydro-2H-pyrrolo[3,4-c][1,6]naphthyridin-2-yl)-2-methoxyethan-1-one(S)-1-(7-chloro-8-methoxy-1-methyl-1,3-dihydro-2H-pyrrolo[3,4-c][1,8]naphthyridin-2-yl)- 2-methoxyethan-1 -one(S)-1-(7-chloro-8-methoxy-1-methyl-1,3-dihydro-2H-pyrrolo[3,4-c][1,8]naphthyridin-2-yl)- 2-hydroxyethan-1-one(S,E)-3-(8-methoxy-2-(2-methoxyacetyl)-1-methyl-7-oxo-1,2,3,7-tetrahydro-6H-pyrrolo[3,4-c][1 ,8]naphthyridin-6-yl)acrylic acid(S)-(3,4-dichloro-2-methoxy-9-methyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)(pyrimidin-2-yl)methanone(S)-(6-amino-3,4-dichloro-2-methoxy-9-methyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)(pyrimidin-2-yl)methanone(S)-(3,4-dichloro-2-methoxy-9-methyl-6-(methylamino)-7,9-dihydro-8H-pyrrolo[3,4-c][1,5]naphthyridin-8-yl)(pyrimidin-2-yl)methanone7,8-dichloro-3-(2-hydroxyacetyl)-9-methoxy-2,3,4,6-tetrahydrobenzo[c][2,7]naphthyridin- 5(1H)-one1-(7,8-dichloro-9-methoxy-1,4-dihydrobenzo[c][2,7]naphthyridin-3(2H)-yl)-2-hydroxyethan-1-oneN-(7,8-dichloro-3-(2-hydroxyacetyl)-9-methoxy-1 ,2,3,4-tetrahydrobenzo[c][2,7]naphthyridin-5-yl)methanesulfonamide(S)-3-((1-(7,8-dichloro-3-(2-hydroxyacetyl)-9-methoxy-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridin-5-yl)pyrrolidin-2-yl)methoxy)propanoic acid1-(7,8-dichloro-9-methoxy-3,4-dihydrobenzo[c][2,6]naphthyridin-2(1H)-yl)-2-hydroxyethan-1-one(S)-1-(7,8-dichloro-9-methoxy-1-methyl-3,4-dihydrobenzo[c][2,6]naphthyridin-2(1H)-yl)-2-methoxyethan-1-one(S)-1-(8-chloro-7-fluoro-9-methoxy-1-methyl-3,4-dihydrobenzo[c][2,6]naphthyridin-2(1H)-yl)-2-hydroxyethan-1-one(S)-1-(8-chloro-1-ethyl-7-fluoro-9-methoxy-3,4-dihydrobenzo[c][2,6]naphthyridin-2(1H)-yl)-2-hydroxyethan-1-one(S)-1-(8-chloro-7-fluoro-9-methoxy-1-methyl-3,4-dihydrobenzo[c][2,6]naphthyridin-2(1H)-yl)-2-methoxyethan-1-one(S)-(8-chloro-7-fluoro-9-methoxy-1-methyl-3,4-dihydrobenzo[c][2,6]naphthyridin-2(1H)-yl)(pyrimidin-2-yl)methanone(S)-(8-chloro-1-ethyl-7-fluoro-9-methoxy-3,4-dihydrobenzo[c][2,6]naphthyridin-2(1H)-yl)(pyrimidin-2-yl)methanone(S)-1-(8-chloro-1-ethyl-7-fluoro-9-methoxy-3,4-dihydrobenzo[c][2,6]naphthyridin-2(1H)-yl)-2-methoxyethan-1-one(S)-2-amino-1-(8-chloro-1-ethyl-7-fluoro-9-methoxy-3,4-dihydrobenzo[c][2,6]naphthyridin- 2(1 H)-yl)ethan-1-one(S)-1-(8-chloro-7-fluoro-9-methoxy-1-methyl-5-(methylamino)-3,4-dihydrobenzo[c][2,6]naphthyridin-2(1H)-yl)-2-hydroxyethan-1-one(S)-(8-chloro-7-fluoro-9-methoxy-1-methyl-5-(methylamino)-3,4-dihydrobenzo[c][2,6]naphthyridin-2(1H)-yl)(pyrimidin-2-yl)methanone(S)-1-(8-chloro-7-fluoro-9-methoxy-1,5-dimethyl-3,4-dihydrobenzo[c][2,6]naphthyridin- 2(1 H)-yl)-2-hydroxyethan-1-one(S)-(8-chloro-7-fluoro-9-methoxy-1,5-dimethyl-3,4-dihydrobenzo[c][2,6]naphthyridin- 2(1H)-yl)(pyrimidin-2-yl)methanone(S)-(2-amino-4-chloro-5-fluoro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin- 9(3H)-yl)(pyrimidin-2-yl)methanone(S)-N-(4-chloro-5-fluoro-10-methyl-9-(pyrimidine-2-carbonyl)-3,8,9,10-tetrahydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-2-yl)-2,2-difluoroacetamide(S)-1-(4-chloro-5-fluoro-10-methyl-9-(pyrimidine-2-carbonyl)-3,8,9,10-tetrahydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-2-yl)pyrrolidin-2-one(S)-(4-chloro-2-cyclopropyl-5-fluoro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin-9(1 H)-yl)(pyrimidin-2-yl)methanone(S)-1-(2-bromo-4-chloro-5-fluoro-10-methyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4- c]quinolin-9(1H)-yl)-2-hydroxyethan-1-one(S)-1-(4-chloro-5-fluoro-10-methyl-2-(2,2,2-trifluoroethyl)-8,10-dihydroimidazo[4,5- f]pyrrolo[3,4-c]quinolin-9(1H)-yl)-2-hydroxyethan-1-one(S)-4-chloro-5-fluoro-9-(2-hydroxyacetyl)-10-methyl-1,8,9,10-tetrahydroimidazo[4,5- f]pyrrolo[3,4-c]quinoline-2-carbonitrile(S)-1-(4-chloro-5-fluoro-2,10-dimethyl-8,10-dihydroimidazo[4,5-f]pyrrolo[3,4-c]quinolin- 9(1 H)-yl)-2-hydroxyethan-1-one(S)-1-(4,5-dichloro-2,10-dimethyl-8,10-dihydro-9H-oxazolo[5,4-f]pyrrolo[3,4-c]quinolin-9- yl)-2-methoxyethan-1-one(S)-1-(5-chloro-6-fluoro-2-(hydroxymethyl)-11-methyl-9,11 -dihydro-1 OH- pyrrolo[3',4':4,5]pyrido[3,2-f]quinoxalin-10-yl)-2-methoxyethan-1-one(S)-5-chloro-6-fluoro-10-(2-methoxyacetyl)-11-methyl-10,11-dihydro-9H- pyrrolo[3',4':4,5]pyrido[3,2-f]quinoxaline-2-carbaldehyde.

6. A pharmaceutical composition comprising a compound according to any one of the claims 1 to 5 and a pharmaceutically acceptable carrier, solvent, adjuvant or diluent.

7. A compound according to any of the claims 1 to 5, or a pharmaceutical composition according to claim 6 for use as a medicament.

8. A compound or a pharmaceutical composition for use as a medicament according to claim 7, for use in treating or preventing a cGAS mediated disease, more in particular a disease with inappropriate activation of a type I interferon (IFN) response.

9. A compound or a pharmaceutical composition for use as a medicament according to claim 8, wherein said cGAS mediated disease is selected from systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis (LN), interferonopathies, psoriasis, insulin-dependent diabetes mellitus (IDDM), vasculitis, scleroderma, Aicardi Goutieres syndrome, dermatomyositis, sepsis, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome (SS), age related macular degeneration (AMD), Amyotrophic Lateral sclerosis (ALS), Fronto-temporal dementia (FTD), Alzheimer’s disease, Huntington’s disease and Parkinson’s disease.

10. A method for treating or preventing a cGAS mediated disease in a subject in need thereof, the method comprising administering to a subject in need of such treatment an effective amount of one or more compounds according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6, wherein in particular said cGAS mediated disease is an inflammation condition, yet more in particular is selected fromsystemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis (LN), interferonopathies, psoriasis, insulin-dependent diabetes mellitus (IDDM), vasculitis, scleroderma, Aicardi Goutieres syndrome, dermatomyositis, sepsis, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome (SS), age related macular degeneration (AMD), Amyotrophic Lateral sclerosis (ALS), Fronto-temporal dementia (FTD), Alzheimer’s disease, Huntington’s disease and Parkinson’s disease.

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