Inhibitors of PTPN 2 / PTPN1 tyrosine phosphatase

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 PTPN2 and / or PTPN1, yet more in particular for the prevention or treatment of cancer or metabolic diseases. 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 PTPN2 and / or PTPN1, yet more in particular for the prevention or treatment of cancer or metabolic diseases. The present invention also relates to processes for the preparation of said compounds.

Description

SPC6350-1-NOVEL COMPOUNDSFIELD OF THE INVENTIONThe 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 PTPN2 and / or PTPN1 , yet more in particular for the prevention or treatment of 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 PTPN2 and / or PTPN 1 , yet more in particular for the prevention or treatment of cancer. 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.BACKGROUND OF THE INVENTIONTyrosine-protein phosphatase non-receptor type 2 (PTPN2), also known as T cell protein tyrosine phosphatase (TC-PTP), is an enzyme that in humans is encoded by the PTPN2 gene. It is a member of the PTP family of signaling proteins and regulates a variety of cellular processes by dephosphorylating either receptor protein tyrosine kinases, such as EGFR (epidermal growth factor receptor), CSF1 R (Colony stimulating factor 1 receptor), PDGFR (Platelet-derived growth factor receptor), IR (insulin receptor) or non-receptor protein tyrosine kinases, such as JAK (janus family kinases), Src (src family kinases), or STAT (signal transducers and activators of transcription) family kinases, either in the cytoplasm or nucleus (J. Song et al, Int. J. Mol. Sci 2022, 23(17), 10025).PTPN2 is associated with pathological processes, including inflammatory responses, immune disorders, and tumor development. The anti-inflammatory cytosolic protein tyrosine phosphatase, PTPN2, was identified as a cancer immunotherapy target after a CRISPR-Cas9- mediated genome editing study showed that deletion of PTPN2 in murine tumor cells promotes susceptibility of the tumor to checkpoint inhibitor therapy by enhancing IFNy-mediated effects on antigen presentation and growth suppression. Enhanced anti-PD-1 response was accompanied by the recruitment of cytotoxic CD8+ T cells, increased antigen presentation, as reflected by the increased expression of MHC-I on tumor cells, and the increased activation of recruited T-cells. PTPN2-deficient tumor cells expressed higher levels of IFN-y / STAT1 target genes, including those encoding T cell chemo-attractants as well as components of the antigen-processing and presentation pathway (Manguso, R.T. et al. Nature 2017, 547, 413-418). More recently, PTPN2SPC6350-2- deficiency has also been shown to enhance programmed T cell expansion and survival capacity of activated T cells (Flosbach, M. et al. Ce / / ep. 2020, 32, 107957). Hence, inhibitors of PTPN2 can be considered as a valuable approach as cancer immunotherapeutics.Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase-1 B (PTP1 B), has been shown to play a key role in insulin and leptin signaling and is a primary mechanism for down-regulating both the insulin and leptin receptor signaling pathways (Kenner K. A. et al., J Biol Chem 271 : 19810-19816, 1996). Animals deficient in PTPN1 have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high fat diet (Elchebly M. et al., Science 283: 1544-1548, 1999). Therefore, it is expected that PTPN1 inhibitors are useful for the treatment of metabolic diseases such as type 2 diabetes, obesity, and metabolic syndrome.Protein tyrosine phosphatases (PTPs) have been traditionally considered challenging drug targets due to the positively charged and highly conserved nature of their catalytic site. For the former reason potent orthosteric PTP inhibitors are negatively charged and often characterized by poor cell-permeability / bioavailability. Recent patent applications from Calico / Abbvie describe inhibitors of PTPN2 and / or PTPN1 : WO / 2020 / 186199A1 and WO / 2021 / 127499A1 describe small molecule inhibitors and WO / 2021 / 127586 proposed protein degradation via PROTACs targeting PTPN2. Kumquat recently disclosed PTPN2 inhibitors in WO / 2022 / 192598 and WO / 2023 / 096928A1 .However, there is still a great need for novel, alternative or better therapeutics for the prevention or treatment of cancer and potentially other disease indications mediated by PTPN2 and / or PTPN1. Therapeutics with better target engagement, (cellular) potency, less side-effects, 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.The present invention provides a class of novel compounds which can be used as inhibitors of PTPN2 and / or PTPN1 in cancer (immuno)therapy and potentially other disease indications mediated by PTPN2 and / or PTPN1.SUMMARY OF THE INVENTIONThe present disclosure is based on the unexpected finding that at least one of the above- mentioned problems can be solved by the below described compounds.In a first aspect, new compounds of formula (I) or derived formulas, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, hydrate, polymorph and / or prodrug thereof, are provided:SPC6350-3-wherein:- X1is N or C;X2is N or CR6; X3is N or CR8; X4is N or CR3; wherein maximum two groups selected from X2, X3and X4are nitrogen;- isanoptional double bond when valencies allow;R1is selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; cycloalkylheteroalkyl; cycloalkenylheteroalkyl; cycloalkynylheteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; heteroarylalkynyl; heteroarylalkenyl; heterocyclylalkyl; heterocyclylalkenyl; heterocyclylalkynyl; aryl heteroalkyl; heteroarylheteroalkyl; and heterocyclylheteroalkyl; whereby each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, cycloalkylheteroalkyl, cycloalkenylheteroalkyl, cycloalkynylheteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkynyl, heteroarylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, arylheteroalkyl, heteroarylheteroalkyl and heterocyclylheteroalkyl is unsubstituted or is substituted with one or more R4;R2is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and halogen; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl is optionally substituted with one or more halogen, alkyl, cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, - N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, -N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -0-C(=0)- NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; or, R1and R2taken together form a cycloalkyl; cycloalkenyl; cycloalkynyl; or heterocycle; wherein said cycloalkyl, cycloalkenyl, cycloalkynyl or heterocycle is unsubstituted or substituted with one or more R4;SPC6350-4- each R4is independently selected from halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ1, -SZ1, -NZ1Z2, -N(Z1)-S(=O)2-Z2, -N(Z1)- S(=O)(=NZ1)-Z2, -S(=O)2-NZ1Z2, -S(=O)(=NZ1)-NZ1Z2, -S(=NZ1)(=NZ1)-Z2, -N(Z1)-S(=O)2- NZ1Z2, -S(=O)2-Z2, -S(=O)-Z2, -S(=O)(=NZ1)-Z2, -N=S(=O)Z1Z2, -O-C(=O)-Z2, -C(=O)-O-Z2, - C(=O)-Z2, -O-C(=O)-NZ1Z2, -NZ1-C(=O)-O-Z2, -C(=O)-NZ1Z2, -NZ1-C(=O)-Z2, -NZ3C(O)NZ3Z4, -P(O)Z1Z2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, cycloalkyl-heteroalkyl, cycloalkylheteroalkenyl, cycloalkyl-heteroalkynyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, aryl-heteroalkyl, aryl-heteroalkenyl, aryl- heteroalkynyl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl-heteroalkyl, heteroaryl-heteroalkenyl, heteroaryl-heteroalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, heterocyclyl- heteroalkynyl, alkyl-oxy-alkyl, (mono or di)alkylamino, (mono or di-)alkyl-amino-alkyl, alkylthio, and alkyl-thio-alkyl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, cycloalkyl-heteroalkyl, cycloalkylheteroalkenyl, cycloalkyl-heteroalkynyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, aryl-heteroalkyl, aryl-heteroalkenyl, aryl- heteroalkynyl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl- heteroalkyl, heteroaryl-heteroalkenyl, heteroaryl-heteroalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl- heteroalkenyl, heterocyclyl-heteroalkynyl, alkyl-oxy-alkyl, (mono or di)alkylamino, (mono or di-)alkyl-amino-alkyl, alkylthio and alkyl-thio-alkyl is unsubstituted or is substituted with one or more R41; or two R4, optionally two R4on two adjacent atoms or on the same atom, can be taken together in order to form a 4-, 5-, 6-, 7- or 8-membered heterocycle or a 3-, 4-, 5-, 6-, 7- or 8- membered cycloalkyl, wherein said heterocycle and cycloalkyl is unsubstituted or is substituted with one or more R41; each Z1and Z2is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylal kynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocycly I heteroalkyl, heterocyclylheteroalkenyl, and heterocyclyl heteroal kynyl ; or, Z1and Z2, optionally bound to the same atom, together form a 4-, 5-, 6-, 7- or 8-membered heterocycle or a 3-, 4-, 5-, 6-, 7- or 8-membered cycloalkyl,SPC6350-5- wherein said heterocycle and cycloalkyl is unsubstituted or is substituted with one or more R41; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, 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 R41; each R41is independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, =0, =S, - SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, aryl, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, -OZ3, -NZ3Z4, -N(Z3)-S(=O)2-Z4, -N(Z3)-S(=O)(=NZ3)-Z4, -S(=O)2-NZ3Z4, -S(=O)(=NZ3)-NZ3Z4, -N(Z3)- S(=O)2-NZ3Z4, -S(=O)2-Z3, -S(=O)-Z3, -S(=O)(=NZ3)-Z4, -N=S(=O)Z3Z4, -O-C(=O)-Z3, -C(=O)- O-Z3, -C(=O)-Z3, -O-C(=O)-NZ3Z4, -NZ3-C(=O)-O-Z4, -C(=O)-NZ3Z4, -NZ3-C(=O)-Z4; or, two R41on two adjacent atoms or attached to the same atom together form a Cs-s-cycloalkyl or C4-8-heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclylalkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroarylalkynyl, aryl, aryl-alkyl, aryl-alkenyl and aryl-alkynyl is optionally substituted with one or more R42; each Z3and Z4is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, aryl-heteroalkyl, aryl-heteroalkenyl, arylheteroalkynyl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl-heteroalkyl, heteroaryl-heteroalkenyl, heteroaryl-heteroalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, and heterocyclylheteroalkynyl; wherein said each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl,SPC6350-6- heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocycly I heteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl is unsubstituted or is substituted with one or more R42; or, Z3and Z4bound to the same atom form a 4-, 5-, 6-, 7- or 8-membered heterocycle or a 3- , 4-, 5-, 6-, 7- or 8-membered cycloalkyl, wherein said heterocycle and cycloalkyl is unsubstituted or is substituted with one or more R42; each R42hydrogen, halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclylalkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl- alkynyl, aryl, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)- S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, - S(=O)-Z5, -S(=O)(=NZ5)-Z6, -N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)- NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; or, two R42on two adjacent atoms or attached to the same carbon atom together form a Cs-s-cycloalkyl or C4-8-heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclylalkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl- alkynyl, aryl, aryl-alkyl, aryl-alkenyl or aryl-alkynyl is optionally substituted by halogen, alkyl, cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, - S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, - N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; each Z5and Z6are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, aryl, aryl-alkyl, aryl-alkenyl and aryl-alkynyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclylalkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl- alkynyl, aryl, aryl-alkyl, aryl-alkenyl and aryl-alkynyl is optionally substituted with halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, C1- 4-alkyl, C3-7-cycloalkyl, -O-Ci-4-alkyl, -O-C3-7-cycloalkyl, -NH-Ci-4-alkyl, -N(Ci-4-alkyl)2, and -NH-C3-7-cycloalkyl;SPC6350-7-R5is selected from halogen, -OH, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl and heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl and heterocyclyl is optionally substituted by one or more R20;R3, R6, R7,R8, R9and R10are independently selected from hydrogen, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ca-w-heterocyclyl, -OR12, -OR15, -O-(Ci-6 alkyl)-OR15, - SR12, -N(R12)(R13), -C(=O)-OR12, -OC(=O)-N(R12)(R13), -N(R12)-C(=O)- N(R12)(R13), -N(R12)-C(=O)-OR12, -N(R12)-S(=O)2R12, -C(=O)R12, -S(=O)R12, -O-C(=O)-R12, - C(=O)-N(R12)(R13), -C(=O)C(=O)-N(R12)(R13), -N(R12)-C(=O)R12, -S(=O)2-R12,S(O)(NR12)R12, -S(=O)2-N(R12)(R13), and -S(=O)(=NR12)-N(R12)(R13), wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one, two, or three R20; or, R7and R8taken together form a cycloalkyl, heterocyclyl or heteroaryl, optionally substituted with one, two or three R20;R11is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl heteroalkyl, heterocyclyl, heterocyclyl- alkyl, heterocyclyl-heteroalkyl, (5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl, -C(=O)-OR12, -C(=O)- O-(Ci-6-alkyl)-OR15, -(Ci-6-alkyl)-OR15, -C(=O)R12, -C(=O)-N(R12)(R13),C(=O)C(=O)N(R12)(R13), -S(=O)2R12, -S(=O)(=NR12)R12, -S(=O)2N(R12)(R13), and - S(=O)(=NR12)N(R12)(R13), wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heterocyclyl, heterocyclyl- alkyl, and heterocyclyl-heteroalkyl are optionally substituted with one, two, or three R20; each R12is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl are optionally substituted with one, two, or three R20;R13is independently selected at each occurrence from hydrogen, alkyl, and haloalkyl; or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;R15is independently selected at each occurrence from hydrogen, (5-methyl-2-oxo-1,3-dioxol- 4-yl)methyl, -C(=O)-OR12, -C(=O)-R12, -P(=O)(Y-R16)(Y-R17), -CH2P(O)(Y-R16)(Y-R17), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl are optionally substituted with one, two, or three R20; each Y is independently selected at each occurrence from -O- and -N(R12)-;R16and R17are independently selected at each occurrence from hydrogen, alkyl and phenyl, wherein alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, cyano, cycloalkyl, heterocycle, -OR12, -SR12, -SPC6350-8-N(R12)(R13), -C(=O)-OR12, -O-C(=O)-N(R12)(R13), -N(R12)-C(=O)-N(R12)(R13), -N(R12)-C(=O)- OR12, -N(R12)-S(=O)2R12, -N(R12)-S(=O)2N(R12)(R13), -S-S-R12, -S-C(=O)R12, -C(=O)R12, - S(=O)R12, -O-C(=O)R12, -O-C(=O)-OR12, -C(=O)-N(R12)(R13), -C(=O)C(=O)N(R12)(R13), - N(R12)-C(=O)R12, -S(=O)2R12, -S(=O)(=NR12)R12, -S(=O)2-N(R12)(R13), -S(=O)(=NR12)- N(R12)(R13), -P(=O)(OR12)2, -P(=O)(R12)2, -O-P(=O)(OR12)2, =0, =S, and =NR12; or R16and R17are taken together with the atoms to which they are attached to form a heterocycle optionally substituted with one, two, or three R20;R20is independently selected at each occurrence from halogen, oxo, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl heteroalkyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl-heteroalkyl, -OR22, -SR22, - N(R22)(R23), =NR22, =C(R21)2, -C(=O)OR22, -O-C=(O)-N(R22)(R23), -N(R22)-C(=O)-N(R22)(R23), -N(R22)-C(=O)-OR22, -N(R22)S(=O)2R22, -C(=O)R22, -S(=O)R22, -OC(=O)R22, -C(=O)N(R22)(R23), -C(=O)C(=O)N(R22)(R23), -N(R22)C(=O)R22, -S(=O)2R22, -S(=O)(=NR22)R22, -S(=O)2N(R22)(R23), -S(=O)(=NR22)N(R22)(R23), and -O-CH2-C(=O)-OR22; or, two R20attached to the same or adjacent atoms optionally join to form cycloalkyl or heterocycle;- wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl heteroalkyl, heterocyclyl, heterocyclyl-alkyl and heterocyclyl- heteroalkyl are optionally substituted with one or more substituents independently selected from halogen, oxo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)-C(=O)-N(R22)(R23), -N(R22)-C(=O)- OR22, -N(R22)-S(=O)2.R22, -C(=O)-R22, -S(=O)R22, -O-C(=O)R22, -C(=O)-N(R22)(R23), - C(=O)C(=O)N(R22)(R23), -N(R22)C(=O)R22, -S(=O)2R22, -S(=O)(=NR22)R22,S(=O)2N(R22)(R23), and -S(=O)(=NR22)N(R22)(R23);R21is independently selected at each occurrence from hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl, or two R21are taken together with the carbon atom to which they are attached to form cycloalkyl or heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, alkyl, haloalkyl, and -OH;R22is independently selected at each occurrence from hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl;R23is independently selected at each occurrence from hydrogen and alkyl; or R22and R23attached to the same nitrogen atom form heterocycle.The present disclosure provides new compounds which have been shown to possess inhibitory activity on PTPN2 and / or PTPN1. The present disclosure furthermore demonstrates that these compounds efficiently inhibit the activity of PTPN2 and / or PTPN1. Therefore, these compounds constitute a useful class of new potent compounds that can be used in the treatmentSPC6350-9- and / or prevention of PTPN2 and / or PTPN1 mediated disorders in animals, mammals and humans, more specifically for the treatment and / or prevention of (i) cancer, more specifically lung cancer, breast cancer, head and neck cancer, oesophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer, skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, yet more specifically colon cancer, kidney cancer, pancreatic cancer, breast cancer, melanoma, head and neck squamous cell carcinoma and non-small cell lung cancer and (ii) metabolic diseases.The present disclosure 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 PTPN2 and / or PTPN1 mediated diseases, in particular (i) cancer and (ii) metabolic diseases in animals or mammals, more in particular in humans. 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 PTPN2 and / or PTPN1 mediated disorders and to the method of preparation of manufacturing of said pharmaceutical compositions.The present invention also relates to a method of treatment or prevention of PTPN2 and / or PTPN1 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 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 is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti- PD-L1 antibody and an anti- CTLA-4 antibody.When reference is made to the treatment or prevention of PTPN2 and / or PTPN1 mediated diseases, this in particular embodiment refers to (i) cancer, more in particular lung cancer, breast cancer, head and neck cancer, oesophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer, skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, yet more in particular colon cancer, kidney cancer, pancreatic cancer, breast cancer, melanoma, head and neck squamous cell carcinoma and non-small cell lung cancer and (ii) metabolic diseases, more specifically nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type-2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome or Kearns-Sayre disease in animals or mammals, more in particular in humans.SPC6350-10-More in particular in relation to the treatment or prevention of cancer, 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 immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti- PD-L1 antibody and an anti-CTLA-4 antibody. In particular related to the treatment or prevention of metabolic diseases comprises the treatment or prevention of type-2 diabetes 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 obesity in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein. For example, disclosed herein is a method of inhibiting further weight gain in an overweight or obese 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.DETAILED DESCRIPTION OF THE INVENTIONThe present invention will be further described and in some instances with respect to particular embodiments, but the invention is not limited thereto.The term “PTPN2 and / or PTPN1 mediated diseases” or “PTPN2 and / or PTPN1 mediated disorders” refers to diseases, disorders or conditions in which PTPN2 and / or PTPN1 signaling is active or activated and whereby PTPN2 and / or PTPN1 activity or activation is contributing, driving, sustaining, enabling or the like such disease. PTPN2 and / or PTPN1 mediated diseases includes cancer, but also includes metabolic diseases or any other disease, disorder or ailment favorably responsive to PTPN2 or PTPN1 inhibitor treatment.The term "cancer" as used herein refers to all types of animal, more specifically human cancers, neoplasm or (malignant) tumors including carcinomas, sarcomas, lymphomas, leukemias, germ cell tumors 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 tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, 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,SPC6350-11- 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 tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal 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 Tumors, Lobular Carcinoma, Ductal Carcinoma, cancer of the pancreatic stellate cells, cancer of the hepatic stellate cells, or prostate cancer.The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngealSPC6350-12- carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet- ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamouscell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy- cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblasts leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound, pharmaceutical composition, or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumorSPC6350-13- sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.The term "melanoma" refers to a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.PTPN2 and / or PTPN1 mediated diseases also includes cancers that have developed resistance to prior treatments such has EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors, RAS inhibitors, immunomodulatory agents and others.The term “metabolic disease" as used herein refers to a disease or condition affecting a metabolic process in a subject and includes non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns- Sayre disease. In some embodiments, the treatment or prevention of a metabolic disease comprises decreasing or eliminating a symptom of such metabolic disease comprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like.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 PTPN2 and / or PTPN1. 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 indicia of such disease, disorder or condition, here in particular mediated through PTPN2 and / or PTPN1. 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 someSPC6350-14- 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.The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, such as a patient, who has been the object of treatment, observation or experiment or who is in need of such treatment.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 or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease or disorder being treated.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.The term “antagonist” or “inhibitor” as used herein in reference to inhibitors of the PTPN2 and / or PTPN1 activity or activation, refers to a compound capable of producing, depending on the circumstance, a functional antagonism or inhibition of PTPN2 and / or PTPN1 activity or activation.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.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.SPC6350-15-In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms generally optimally present in the substituent or linker; it is understood that where otherwise indicated in the present application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.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 hydrolyzed 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).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 an ordered 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. Protected compounds, when biologically active, 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 are referred herein as “prodrugs”. Another function of a protecting group is thus to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Prodrugs typically alter the pharmacokinetic properties of the parent drug, e.g. 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.Accordingly, in some embodiments, various precursor or “prodrug” forms of the compounds as defined herein are provided. A prodrug of a compound herein described may be in the form of a chemical species which itself is not significantly biologically-active, but which when delivered to the animal, mammal or human will undergo a chemical reaction catalyzed by theSPC6350-16- normal function of the body of the fish, inter alia, enzymes present in the stomach or in blood serum, said chemical reaction having the effect of releasing a compound as defined herein. The term “pro-drug” thus relates to these species which are converted in vivo into the active pharmaceutical ingredient.The prodrugs provided herein can have any form suitable to the formulator, for example, esters are non-limiting common pro-drug forms. In the present case, however, the pro-drug may necessarily exist in a form wherein a covalent bond is cleaved by the action of an enzyme present at the target locus. For example, a C-C covalent bond may be selectively cleaved by one or more enzymes at said target locus and, therefore, a pro-drug in a form other than an easily hydrolysable precursor, inter alia an ester, an amide, and the like, may be used. The counterpart of the active pharmaceutical ingredient in the pro-drug can have different structures such as an amino acid or peptide structure, alkyl chains, sugar moieties and others as known in the art.For the purpose of the present invention the term “therapeutically suitable pro-drug” is defined herein as “a compound modified in such a way as to be transformed in vivo to the therapeutically active form, whether by way of a single or by multiple biological transformations, when in contact with the tissues of the animal, mammal or human to which the pro-drug has been administered, and without undue toxicity, irritation, or allergic response, and achieving the intended therapeutic outcome ”.More specifically the term “prodrug”, as used herein, relates to an inactive or significantly less active derivative of a compound such as represented by the structural formulae herein described, which undergoes spontaneous or enzymatic transformation within the body in order to release the pharmacologically active form of the compound. For a comprehensive review, reference is made to Rautio J. et al. (“Prodrugs: design and clinical applications” Nature Reviews Drug Discovery, 2008, doi: 10.1038 / nrd2468).The term “alkyl” or “Ci-isalkyl” as used herein means C1-C18 normal, 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 Ci-ealkyl (C1-6 hydrocarbons) or Ci-4-alkyl as further defined herein above.The term "haloalkyl" as a group or part of a group, refers to an alkyl group having theSPC6350-17- meaning as defined above wherein one, two, three or more 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 “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, sec-butoxy, tertbutoxy, pentyloxy and hexyloxy.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.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), such as to Cs- -cycloalkyl (saturated cyclic C3-9- hydrocarbons), to Cs-s-cycloalkyl (saturated cyclic Cs-s-hydrocarbons), or to Cs-ecycloalkyl (saturated cyclic Cs-ehydrocarbons). For the avoidance of doubt, fused systems of 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.The term “alkenyl” or “C2-i8alkenyl” as used herein is C2-C18 normal, 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-i2hydrocarbons), yet more in particular to C2-9 alkenyl (C2-9 hydrocarbons), still more in particular to C2-6 alkenyl (C2-6hydrocarbons) 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.SPC6350-18-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.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.The term “alkynyl” or “C2-i8alkynyl” as used herein refers to C2-C18 normal, 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, -CH2OCH). 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 particular to 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.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.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 theSPC6350-19- 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.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-g or C1-6 carbon atoms), and having two monovalent group centers 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.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 centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.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 centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.“Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” refer to substituted or unsubstituted alkyl, alkenyl and alkynyl groups, respectively, in which one or more, such as 1 , 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized. If given, a numerical range refers to the chain length in total thus including both carbon and heteroatoms. For example, a 3- to 8-membered heteroalkyl group, i.e. C3-8 heteroalkyl, has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.Unless stated otherwise in the specification, any alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, heteroalkyl, heteroalkenyl and heteroalkynyl, as such or as part of a broader group, may be linear or branched.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. TypicalSPC6350-20- 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, dihydrobenzothiophene 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.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.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.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.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 group comprising 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.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 aryl heteroalkenyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkenyl moiety of the aryl heteroalkenyl 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,SPC6350-21- arylalkenyl-O-alkenyl, aryl-NH-alkenyl, aryl-N(alkenyl)2, arylalkenyl-NH-alkenyl, arylalkenyl-N- (alkenyl)2, aryl-S-alkenyl, and arylalkenyl-S-alkenyl.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.The term “heterocycle” or “heterocyclyl” as used herein refer to non-aromatic, fully saturated or partially unsaturated ring system of 3 to 18 atoms including at least one N, O, S, or P (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or comprising a total of 3 to 10 ring atoms). 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 at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multiring 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. If given, a numerical range refers to the total number of ring atoms including both carbon and heteroatoms. For example, a C3-11- heterocyclyl refers to a 3- to 11- membered heterocycle, thus a heterocycle for which the total number of ringatoms, including both carbon as well as heteroatoms N, O and / or S, is 3 to 11. 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-SPC6350-22- 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,SPC6350 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, 4-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 includes1 .2-dihydropyridin- 1 -yl, 1 ,2-di hydropyridin-2-yl , 1.2-dihydropyridin-3-yl, 1.2-dihydropyridin-4-yl,1 .2-dihydropyridin-5-yl, 1.2-di hydropyridin-6-yl , 1.4-dihydropyridin-1 -yl, 1.4-dihydropyridin-2-yl,1 .4-dihydropyridin-3-yl, 1.4-di hydropyridin-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 includes tetrahydrothiophen-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-SPC6350-24-2H-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 includes1.2.3-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 and1.3.4-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 “1 H- pyrrolizine” as used herein includes 1 H-pyrrolizin-1 -yl, 1 H-pyrrolizin-2-yl, 1 H-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.The term “heterocyclylalkyl” or “heterocycle-alkyl” as a group or part of a group, refers toSPC6350-25- 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 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.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.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, e.g. the heteroalkyl moiety can comprise 1 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms. 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.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, e.g. the heteroalkenyl moiety can comprise 2 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms. In some embodiments heterocyclylheteroalkenyl 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.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, e.g. the heteroalkynyl moiety can comprise 2 to 6 carbon atoms andSPC6350-26- the heterocyclyl moiety can comprise 3 to 14 atoms. 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.The term “heteroaryl” refers to an aromatic ring system of 5 to 18 atoms including at least one N, O, S, or P, 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. In an analogous way as for heterocycles, if given, a numerical range for a heteroaryl refers to the total number of ring atoms including both carbon and heteroatoms.Non-limiting examples of such heteroaryl, include: triazol-2-yl, pyridinyl, 1 H-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 usedSPC6350-27- herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl). The term “pyrazolyl” (also called 1 H-pyrazolyl and 1 ,2-diazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl or 1 H-pyrazol-5-yl, pyrazol-4-yl and pyrazol-5-yl. The term “imidazolyl” as used herein 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 41-1-1 ,2,4- triazolyl, “1 H-triazolyl” includes 1 H-1 ,2,3-triazol-1-yl, 1 H-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 1 H-tetrazol-1-yl, 1 H-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-SPC6350-28- 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 used herein 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 1 H-indazolyl or 2-azaindolyl) as used herein includes 1 H- indazol-1 -yl, 1 H-indazol-3-yl, 1 H-indazol-4-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-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-SPC6350-29- 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 and2.1.3-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.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.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, e.g. the alkyl moiety of the heteroarylalkyl group can comprise 1 to 6 carbon atoms and the heteroaryl moiety can comprise 5 to 14 atoms.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 heteroaryl-alkenyl group can comprise 6 to 20 atoms, e.g. the alkenyl moiety of the heteroaryl-SPC6350-30- alkenyl group can comprise 2 to 6 carbon atoms and the heteroaryl moiety can comprise 5 to 14 atoms.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, e.g. the alkynyl moiety of the heteroaryl-alkynyl group is 2 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.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, e.g. the heteroalkyl moiety of the heteroaryl-heteroalkyl group is 2 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms. 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.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 heteroaryl heteroalkenyl group comprises 8 to 20 atoms, e.g. the heteroalkenyl moiety of the heteroarylheteroalkenyl group is 3 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms. 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.The term “heteroarylheteroalkynyl” as a group or part of a group as used herein refers to a heteroalkynyl 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, e.g. the heteroalkynyl moiety of the heteroarylheteroalkynyl group is 2 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms. In some embodiments heteroarylheteroalkynyl is selected from the group comprising heteroaryl-O-alkynyl, heteroarylalkynyl-O-alkynyl, heteroaryl-NH-alkynyl, heteroaryl-N(alkynyl)2, heteroarylalkynyl-NH-alkynyl, heteroarylalkynyl-N-(alkynyl)2, heteroaryl-S-alkynyl, and heteroarylalkynyl-S-alkynyl.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 3SPC6350-31- 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, 1 H-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.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.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.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.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.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.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.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.The term “heterocyclylalkylthio", as a group or part of a group, refers to a group having theSPC6350-32- formula -S-Ra-R' wherein Rais alkylene and R' is heterocyclyl as defined herein above.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.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.The term “mono- or di-arylamino”, as a group or part of a group, refers to a group of formula -N(Rq)(Rr) wherein Rqand Rrare each independently selected from hydrogen, aryl, or alkyl, wherein at least one of Rqor Rris aryl.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, or alkyl, wherein at least one of Ruor Rvis heteroaryl as defined herein.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, or 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).The terminology regarding a chemical group “which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N” as used herein, refers to a group where one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom and thus includes, depending on the group to which is referred, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroalkenyl, arylheteroalkynyl, heteroarylalkynyl, among others. This term therefore comprises, depending on the group to which is referred, as an example alkoxy, alkenyloxy, alkynyloxy, alkyl-O-alkylene, alkenyl-O-alkylene, arylalkoxy, benzyloxy, heteroaryl-alkoxy, heterocyclyl-alkoxy, among others.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 singleSPC6350-33- bond between the two moieties being linked by the linking group.As used herein with respect to a substituting group, and unless otherwise stated, the terms “substituted” means that one or more hydrogen atoms are each independently replaced with at least one substituent. “Optionally substituted” means the group to which it refers is either unsubstituted or substituted with one or more substituents, typically independently selected from a specified group of substitutents. 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, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroarylalkyl, heterocyclylalkyl, heteroarylalkenyl, heterocyclylalkenyl and heteroarylalkynyl, heterocyclylalkynyl, -X, -Z, -O; -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, -N02, =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(0)20’, -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(0)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, 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.Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected.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.As used herein and unless otherwise stated, the term “solvate” includes any combination which may be formed by a derivative of this invention 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.The term “heteroatom(s)” as used herein, and unless specified otherwise, means an atom selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.The term “hydroxy” as used herein means -OH.SPC6350-34-The term “carbonyl” as used herein means carbon atom bonded to oxygen with a double bond, i.e., C=O.The term “amino” as used herein means the -NH2 group.The present invention provides novel compounds which have been shown to possess PTPN2 and / or PTPN1 inhibitory activity. Therefore, these compounds constitute a useful class of new potent compounds that can be used in the treatment and / or prevention of PTPN2 and / or PTPN1 mediated diseases in subjects, more specifically for the treatment and / or prevention of cancer and metabolic diseases, among other diseases.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 cancer or metabolic diseases. The present invention relates to the compounds for use as medicines for treating and / or preventing PTPN2 and / or PTPN1 mediated diseases such as cancer or metabolic diseases 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 cancer or metabolic diseases 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 their use as medicines for the prevention or treatment of diseases in a non-human mammal, such as cancer and metabolic diseases in non-human mammals.Overall the compounds provided herein are as specified in the summary. It is understood that the crossed double bond of formula (I) indicates that the stereochemistry on the double bond is undefined.Particular statements (features) 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. For example, any embodiment defined for R1may be combined with any embodiment defined for R2, R3, Z1, Z2, Z3, etc. Any feature indicated as being preferred, particular or advantageous may be combined with any other features or statements 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.In some embodiments, the compounds are compounds of formula (I) and any subgroup thereof as described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceuticallySPC6350-35- acceptable salt), solvate, polymorph and / or prodrug thereof,wherein:- X1is N or C;X2is N or CR6; X3is N or CR8; X4is N or CR3; wherein maximum two groups selected from X2, X3and X4are nitrogen;- is an optional double bond when valencies allow;R1is selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; cycloalkylheteroalkyl; cycloalkenylheteroalkyl; cycloalkynylheteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; heteroarylalkyl; heterocyclylalkyl; arylheteroalkyl; heteroarylheteroalkyl; and heterocyclylheteroalkyl; whereby each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, cycloalkylheteroalkyl, cycloalkenylheteroalkyl, cycloalkynylheteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylheteroalkyl, heteroarylheteroalkyl, and heterocyclylheteroalkyl is unsubstituted or is substituted with one or more R4;R2is selected from hydrogen, alkyl and halogen; or, R1and R2taken together form a cycloalkyl; cycloalkenyl; cycloalkynyl; or heterocycle; wherein said cycloalkyl, cycloalkenyl, cycloalkynyl or heterocycle is unsubstituted or substituted with one or more R4; each R4is independently selected from halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ1, -SZ1, -NZ1Z2, -N(Z1)-S(=O)2-Z2, -N(Z1)- S(=O)(=NZ1)-Z2, -S(=O)2-NZ1Z2, -S(=O)(=NZ1)-NZ1Z2, -S(=NZ1)(=NZ1)-Z2, -N(Z1)-S(=O)2- NZ1Z2, -S(=O)2-Z2, -S(=O)-Z2, -S(=O)(=NZ1)-Z2, -N=S(=O)Z1Z2, -O-C(=O)-Z2, -C(=O)-O-Z2, - C(=O)-Z2, -O-C(=O)-NZ1Z2, -NZ1-C(=O)-O-Z2, -C(=O)-NZ1Z2, -NZ1-C(=O)-Z2, -NZ3C(O)NZ3Z4, -P(O)Z1Z2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, cycloalkyl-heteroalkyl, cycloalkyl-SPC6350-36- heteroalkenyl, cycloalkyl-heteroalkynyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, aryl-heteroalkyl, aryl-heteroalkenyl, aryl- heteroalkynyl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl-heteroalkyl, heteroaryl-heteroalkenyl, heteroaryl-heteroalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, heterocyclyl- heteroalkynyl, alkyl-oxy-alkyl, (mono or di)alkylamino, (mono or di-)alkyl-amino-alkyl, alkylthio, and alkyl-thio-alkyl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, cycloalkyl-heteroalkyl, cycloalkylheteroalkenyl, cycloalkyl-heteroalkynyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, aryl-heteroalkyl, aryl-heteroalkenyl, aryl- heteroalkynyl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl- heteroalkyl, heteroaryl-heteroalkenyl, heteroaryl-heteroalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl- heteroalkenyl, heterocyclyl-heteroalkynyl, alkyl-oxy-alkyl, (mono or di)alkylamino, (mono or di-)alkyl-amino-alkyl, alkylthio and alkyl-thio-alkyl is unsubstituted or is substituted with one or more R41; or two R4, optionally two R4on the same atom, can be taken together in order to form a 4-, 5-, 6-, 7- or 8-membered heterocycle or a 3-, 4-, 5-, 6-, 7- or 8-membered cycloalkyl, wherein said heterocycle and cycloalkyl is unsubstituted or is substituted with one or more R41; each Z1and Z2is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocycly I heteroalkyl, heterocyclylheteroalkenyl, and heterocyclyl heteroalkynyl ; or, Z1and Z2, optionally bound to the same atom, together form a 4-, 5-, 6-, 7- or 8-membered heterocycle or a 3-, 4-, 5-, 6-, 7- or 8-membered cycloalkyl, wherein said heterocycle and cycloalkyl is unsubstituted or is substituted with one or more R41; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylheteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl isSPC6350-37- unsubstituted or is substituted with one or more R41; each R41is independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, =0, =S, - SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, aryl, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, -OZ3, -NZ3Z4, -N(Z3)-S(=O)2-Z4, -N(Z3)-S(=O)(=NZ3)-Z4, -S(=O)2-NZ3Z4, -S(=O)(=NZ3)-NZ3Z4, -N(Z3)- S(=O)2-NZ3Z4, -S(=O)2-Z3, -S(=O)-Z3, -S(=O)(=NZ3)-Z4, -N=S(=O)Z3Z4, -O-C(=O)-Z3, -C(=0)- 0-Z3, -C(=O)-Z3, -O-C(=O)-NZ3Z4, -NZ3-C(=O)-O-Z4, -C(=O)-NZ3Z4, -NZ3-C(=O)-Z4; or, two R41attached to the same atom together form a Cs-s-cycloalkyl or C4-8-heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl- alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl- alkynyl, aryl, aryl-alkyl, aryl-alkenyl and aryl-alkynyl is optionally substituted with one or more R42; each Z3and Z4is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, aryl-heteroalkyl, aryl-heteroalkenyl, aryl- heteroalkynyl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl-heteroalkyl, heteroaryl-heteroalkenyl, heteroaryl-heteroalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, and heterocyclyl- heteroalkynyl; wherein said each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclyl heteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl is unsubstituted or is substituted with one or more R42; or, Z3and Z4bound to the same atom form a 4-, 5-, 6-, 7- or 8-membered heterocycle or a 3- , 4-, 5-, 6-, 7- or 8-membered cycloalkyl, wherein said heterocycle and cycloalkyl is unsubstituted or is substituted with one or more R42; each R42hydrogen, halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl- alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl-SPC6350-38- alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl- alkynyl, aryl, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)- S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, - S(=O)-Z5, -S(=O)(=NZ5)-Z6, -N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)- NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; or, two R42attached to the same carbon atom together form a Cs-s-cycloalkyl or C4-8-heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl- alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl- alkynyl, aryl, aryl-alkyl, aryl-alkenyl or aryl-alkynyl is optionally substituted by halogen, alkyl, cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, - S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, - N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; each Z5and Z6are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, aryl, aryl-alkyl, aryl-alkenyl and aryl-alkynyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl- alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl- alkynyl, aryl, aryl-alkyl, aryl-alkenyl and aryl-alkynyl is optionally substituted with halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, C1- 4-alkyl, C3-7-cycloalkyl, -O-Ci-4-alkyl, -O-C3-7-cycloalkyl, -NH-Ci-4-alkyl, -N(Ci-4-alkyl)2, and -NH-C3-7-cycloalkyl;R5is selected from halogen, -OH, amino, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is optionally substituted by one or more R20;R3, R6, R7,R8, R9and R10are independently selected from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Cs-w-heterocyclyl, -OR12, -OR15, -0-(Ci-6 alkyl)-OR15, - SR12, -N(R12)(R13), -C(=O)-OR12, -OC(=O)-N(R12)(R13), -N(R12)-C(=O)- N(R12)(R13), -N(R12)-C(=O)-OR12, -N(R12)-S(=O)2R12, -C(=O)R12, -S(=O)R12, -O-C(=O)-R12, - C(=O)-N(R12)(R13), -C(=O)C(=O)-N(R12)(R13), -N(R12)-C(=O)R12, -S(=O)2.R12,S(O)(NR12)R12, -S(=O)2-N(R12)(R13), and -S(=O)(=NR12)-N(R12)(R13), wherein alkyl, alkenyl,SPC6350-39- alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one, two, or three R20; or, R7and R8taken together form a cycloalkyl, heterocyclyl or heteroaryl, optionally substituted with one, two or three R20;R11is selected from hydrogen, -CN, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl heteroalkyl, heterocyclyl, heterocyclyl- alkyl, heterocyclyl-heteroalkyl, (5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl, -C(=O)-OR12, -C(=O)- O-(Ci-6-alkyl)-OR15, -(Ci-6-alkyl)-OR15, -C(=O)R12, -C(=O)-N(R12)(R13),C(=O)C(=O)N(R12)(R13), -S(=O)2R12, -S(=O)(=NR12)R12, -S(=O)2N(R12)(R13), and - S(=O)(=NR12)N(R12)(R13), wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heterocyclyl, heterocyclyl- alkyl, and heterocyclyl-heteroalkyl are optionally substituted with one, two, or three R20; each R12is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl are optionally substituted with one, two, or three R20;R13is independently selected at each occurrence from hydrogen, alkyl, and haloalkyl; or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;R15is independently selected at each occurrence from (5-methyl-2-oxo-1,3-dioxol-4- yl)methyl, -C(=O)-OR12, -C(=O)-R12, -P(=O)(Y-R16)(Y-R17), and -CH2P(O)(Y-R16)(Y-R17); each Y is independently selected at each occurrence from -O- and -N(R12)-;R16and R17are independently selected at each occurrence from hydrogen, alkyl and phenyl, wherein alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, cycloalkyl, heterocycle, -OR12, -SR12, - N(R12)(R13), -C(=O)-OR12, -O-C(=O)-N(R12)(R13), -N(R12)-C(=O)-N(R12)(R13), -N(R12)-C(=O)- OR12, -N(R12)-S(=O)2R12, -N(R12)-S(=O)2N(R12)(R13), -S-S-R12, -S-C(=O)R12, -C(=O)R12, - S(=O)R12, -O-C(=O)R12, -O-C(=O)-OR12, -C(=O)-N(R12)(R13), -C(=O)C(=O)N(R12)(R13), - N(R12)-C(=O)R12, -S(=O)2R12, -S(=O)(=NR12)R12, -S(=O)2-N(R12)(R13), -S(=O)(=NR12)- N(R12)(R13), -P(=O)(OR12)2, -P(=O)(R12)2, -O-P(=O)(OR12)2, =0, =S, and =NR12; or R16and R17are taken together with the atoms to which they are attached to form a heterocycle optionally substituted with one, two, or three R20;R20is independently selected at each occurrence from halogen, oxo, -CN, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl heteroalkyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl-heteroalkyl, -OR22, -SR22, - N(R22)(R23), =NR22, =C(R21)2, -C(=O)OR22, -O-C=(O)-N(R22)(R23), -N(R22)-C(=O)-N(R22)(R23), -N(R22)-C(=O)-OR22, -N(R22)S(=O)2R22, -C(=O)R22, -S(=O)R22, -OC(=O)R22, -C(=O)N(R22)(R23), -C(=O)C(=O)N(R22)(R23), -N(R22)C(=O)R22, -S(=O)2R22, -S(=O)(=NR22)R22,SPC6350-40--S(=O)2N(R22)(R23), -S(=O)(=NR22)N(R22)(R23), and -O-CH2-C(=O)-OR22; or, two R20attached to the same or adjacent atoms optionally join to form cycloalkyl or heterocycle;- wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl heteroalkyl, heterocyclyl, heterocyclyl-alkyl and heterocyclyl- heteroalkyl are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, alkyl, haloalkyl, alkoxy, haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)-C(=O)-N(R22)(R23), -N(R22)-C(=O)-OR22, - N(R22)-S(=O)2.R22, -C(=O)-R22, -S(=O)R22, -O-C(=O)R22, -C(=O)-N(R22)(R23), -C(=O)C(=O)N(R22)(R23), -N(R22)C(=O)R22, -S(=O)2R22, -S(=O)(=NR22)R22,S(=O)2N(R22)(R23), and -S(=O)(=NR22)N(R22)(R23);R21is independently selected at each occurrence from hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl, or two R21are taken together with the carbon atom to which they are attached to form cycloalkyl or heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, alkyl, haloalkyl, and -OH;R22is independently selected at each occurrence from hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl;R23is independently selected at each occurrence from hydrogen and alkyl; or R22and R23attached to the same nitrogen atom form heterocycle.In some embodiments, R2is selected from hydrogen, alkyl and halogen.In some embodiments, each R4is independently selected from halogen, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, Cs-s-cycloalkyl-Ci-e-alkyl, C3-s-cycloalkyl-C2-6- alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-Ci-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl- C2-6-alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-i2-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, C5-12- heteroaryl-C2-6-alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl, aryl-C2. 6-alkynyl, -OZ1, -NZ1Z2, -N(Z1)-S(=O)2-Z2, -N(Z1)-S(=O)(=NZ1)-Z2, -S(=O)2-NZ1Z2, -S(=O)(=NZ1)- NZ1Z2, -N(Z1)-S(=O)2-NZ1Z2, -S(=O)2-Z2, -S(=O)-Z2, -S(=O)(=NZ1)-Z2, -N=S(=O)Z1Z2, -O-C(=O)- Z2, -C(=O)-O-Z2, -C(=O)-Z2, -O-C(=O)-NZ1Z2, -NZ1-C(=O)-O-Z2, -C(=O)-NZ1Z2, -NZ1-C(=O)-Z2; or, two R4attached to the same carbon atom together form a Cs-s-cycloalkyl or C4-i2-heterocyclyl; wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8- cycloalkyl-Ci-6-alkyl, C3-s-cycloalkyl-C2-6-alkenyl, C3-s-cycloalkyl-C2-6-alkynyl, C4-8- cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4- i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-i2-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6-SPC6350-41- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally further substituted with one, two, three or four R41.In some embodiments, each R4is independently selected from halogen, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, Cs-s-cycloalkyl-Ci-e-alkyl, C3-8-cycloalkyl-C2-6- alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-Ci-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl- C2-6-alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, C5-12- heteroaryl-C2-6-alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl, aryl-C2- 6-alkynyl, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, -S(=O)(=NZ5)- NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, -N=S(=O)Z5Z6, -O-C(=O)- Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; or, two R4attached to the same carbon atom together form a Cs-s-cycloalkyl or C4-i2-heterocyclyl; wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8- cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-e-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-8- cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4- 12-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally further substituted with one, two, three or four R41.In some embodiments, each R41is independently selected from halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, Cs-s-cycloalkyl-Ci-e-alkyl, C3-s-cycloalkyl-C2-6-alkenyl, C3-8- cycloalkyl-C2-6-alkynyl, C4-s-cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-8- cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6- alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, C5-12- heteroaryl-C2-6-alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl, aryl-C2- 6-alkynyl, -OZ3, -NZ3Z4, -N(Z3)-S(=O)2-Z4, -N(Z3)-S(=O)(=NZ3)-Z4, -S(=O)2-NZ3Z4, -S(=O)(=NZ3)- NZ3Z4, -N(Z3)-S(=O)2-NZ3Z4, -S(=O)2-Z3, -S(=O)-Z3, -S(=O)(=NZ3)-Z4, -N=S(=O)Z3Z4, -0-C(=0)- Z3, -C(=O)-O-Z3, -C(=O)-Z3, -O-C(=O)-NZ3Z4, -NZ3-C(=O)-O-Z4, -C(=O)-NZ3Z4, -NZ3-C(=O)-Z4; or, two R41attached to the same carbon atom together form a Cs-s-cycloalkyl or C4-i2-heterocyclyl wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, C3-8- cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-s-alkenyl, Cs-s-cycloalkyl-Cs-s-alkynyl, C4-8- cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4- 12-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12-SPC6350-42- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally further substituted with one, two, three or four R42.In some embodiments, each R41is independently selected from halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, Cs-s-cycloalkyl-Ci-e-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8- cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-Ci-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8- cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6- alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, C5-12- heteroaryl-C2-6-alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl, aryl-C2- 6-alkynyl, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, -S(=O)(=NZ5)- NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, -N=S(=O)Z5Z6, -0-C(=0)- Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; or, two R41attached to the same carbon atom together form a Cs-s-cycloalkyl or C4-i2-heterocyclyl wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8- cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-e-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-8- cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4- 12-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally further substituted with one, two, three or four R42.In some embodiments, each R42is independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, Ci-6-alkyl, C2-6- alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, Cs-s-cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl- C2-6-alkenyl, Cs-s-cycloalkyl-Cs-s-alkynyl, C4-s-cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6- alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-12- heterocyclyl-C2-6-alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6- alkyl, Cs-i2-heteroaryl-C2-6-alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6- alkenyl, aryl-C2-6-alkynyl, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, - N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=0)- NZ5Z6, -NZ5-C(=O)-Z6; or, two R42attached to the same carbon atom together form a Cs-s- cycloalkyl or C4-i2-heterocyclyl, wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8-SPC6350-43- cycloalkyl-Ci-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8- cycloalkenyl-Ci-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, C4- 12-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally substituted by halogen, Ci-6-alkyl, Cs-s-cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ4Z5, -N(Z5)- S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2- NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, -N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6.In some embodiments, each Z5and Z6are independently selected from hydrogen, Ci-6-alkyl, C2- 6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, Cs-s-cycloalkyl-Ci-e-alkyl, Cs-s-cycloalkyl- C2-6-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-s-cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6- alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-12- heterocyclyl-C2-6-alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6- alkyl, Cs-i2-heteroaryl-C2-6-alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6- alkenyl and aryl-C2-6-alkynyl; wherein said Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8- cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-e-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-8- cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4- 12-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally substituted with halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, Ci-4-alkyl, Cs-7-cycloalkyl, -O-Ci-4-alkyl, -O-C3-7- cycloalkyl, -NH-Ci-4-alkyl, -N(Ci-4-alkyl)2, and -NH-Cs-7-cycloalkyl.SPC6350-44-In some embodiments, the compound of formula (I) have formula (II)wherein B is a cycloalkyl or heterocyclyl.In some embodiments, cycle B is a 3-, 4-, 5-, 6-, 7- or 8-membered cycloalkyl; a 4-, 5-, 6-, 7- or 8-membered cycloalkenyl; a 5-, 6-, 7- or 8-membered cycloalkynyl; or a 4-, 5-, 6-, 7- or 8- membered heterocycle.In some embodiments, compounds are according to formula (Ila) or (lib)(Ila) (lib).In some embodiments, R4is selected from- -S(=O)(=NZ1)-Z2; -S(=O)2-NZ1Z2; -S(=O)(=NZ1)-NZ1Z2; -S(=NZ2)2-Z1; -S(=O)2-Z2; -S(=O)-Z2; - C(=O)-O-Z2; -C(=O)-Z2; -C(=O)-NZ1Z2; and,Ci-6-alkyl, Ca-s-cycloalkyl-Ci-ealkyl or C4-8-heterocyclyl-Ci-6alkyl, optionally substituted by a group selected from -OZ3, -NZ3Z4, -N(Z3)-S(=O)2-Z4, -N(Z3)-S(=O)(=NZ3)-Z4, -S(=O)2-NZ3Z4, - S(=O)(=NZ3)-NZ3Z4, -N(Z3)-S(=O)2-NZ3Z4, -S(=O)2-Z3, -S(=O)-Z3, -S(=O)(=NZ3)-Z4, - N=S(=O)Z3Z4, -O-C(=O)-Z3, -C(=O)-O-Z3, -C(=O)-Z3, -O-C(=O)-NZ3Z4, -NZ3-C(=O)-O-Z4, - C(=O)-NZ3Z4and -NZ3-C(=O)-Z4.In a further embodiment, each Z1, Z2, Z3and Z4is independently selected from alkyl, alkenyl, alkynyl, heterocyclyl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heterocyclyl and heteroaryl is optionally further substituted with 1 , 2 or 3 substitutents independently selected fromSPC6350 halogen, -OH, -O-alkyl, -NH2, -NHalkyl, -N(alkyl)2, -SH, -S-alkyl, -CF3, -CHF2, -OCF3, -OCHF2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl.In some embodiments, compounds are according to formula (lie) wherein each Q7and Q8are asR4as defined for any of the embodiments herein(He).In some embodiments Q8is independently selected from halogen (fluor), Ci-6-alkyl, C2-6-alkenyl, C3.8-cycloalkyl, C4-8-heterocyclyl-OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2- NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, - N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)- NZ5Z6, -NZ5-C(=O)-Z6; or, two Q8together form a C3-8-cycloalkyl or C4-8-heterocyclyl; wherein each Ci-6-alkyl, C2-6-alkenyl, C3-8-cycloalkyl, C4-8-heterocyclyl, is optionally further substituted with one, two, three or four groups independently selected from halogen, C1-6- alkyl, C3-8-cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, - OCHF2, cyano, nitro, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2- NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)- Z6, -N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O- Z6, -C(=O)-NZ5Z6, and -NZ5-C(=O)-Z6.In some embodiments, Q7is selected from Ci-6-al kyl , C3-8-cycloalkyl, and C3-8-cycloalkyl-Ci-4-alkyl, each optionally substituted with halogen, haloalkyl, hydroxy, Ci-4-alkoxy, -O-C3-7-cycloalkyl, mono- or di-Ci-4-alkylamino and -NH-C3-7-cycloalkyl.Further to embodiments described herein,- each alkyl is C1-C18 alkyl, such as a Ci-Ci2alkyl; 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-Cis alkenyl, such as a C2-Ci2alkenyl; yet in particular C2-Cg membered alkenyl; still more in particular is C2-Ce alkenyl; including when such alkenyl is linked to forSPC6350-46- example aryl, heteroaryl or heterocycle as for example in arylalkenyl, heteroarylalkenyl and heterocycle-alkenyl;- each alkynyl is C2-C18 alkynyl, such as a C2-C12 alkynyl; yet in particular a C2-C9 alkynyl; 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;- 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;- 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 C5-C18 cycloalkynyl, more in particular is a C5-C12 cycloalkynyl; yet more in particular is a C5-C9 cycloalkynyl; still more in particular is a Cs-Ce cycloalkynyl;- 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;- 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 or alkynyl such as in heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl;- 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, and alkynyl as in heterocyclealkyl, heterocyclealkenyl, heterocyclealkynyl.Structures of example compounds that contain stereocentres are drawn and named with absolute stereochemistry, if known. In case of unknown absolute stereochemistry the compounds can be either racemic, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry.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 activity or 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.Compounds of the present disclosure are small molecule PTPN2 and / or PTPN 1 inhibitors.SPC6350-47-Small molecule PTPN2 and / or PTPN1 inhibitors are useful, e.g., for the treatment of cancer, including with no limitations, lung cancer, breast cancer, head and neck cancer, oesophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer, skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesotheliomas, and / or sarcomas. In other embodiments, small molecule PTPN2 and / or PTPN1 inhibitors are useful for the treatment of cancers selected from colon cancer, kidney cancer, pancreatic cancer, breast cancer, multiple myeloma or cancers of secretory cells. In more particular embodiments, the compounds of the invention are useful for the treatment of cancers selected from colon cancer, kidney cancer, pancreatic cancer, breast cancer, melanoma, head and neck squamous cell carcinoma and non-small cell lung cancer. Still in more particular embodiments, the compounds of the invention are useful for the treatment of colon cancer, melanoma and lung cancer. In some embodiments, solid cancers are characterized by the overexpression of PTPN2 and / or PTPN1.Small molecule PTPN2 and / or PTPN1 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 PTPN2 and / or PTPN1 inhibitors may also be useful to treat a metastasized cancer. In some instances, the metastasized cancer is selected from metastasized uveal melanoma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer and meningioma.In some embodiments, small molecule PTPN2 and / or PTPN1 inhibitors are useful, e.g., for the treatment of metabolic disorders, such as non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes) and metabolic syndrome. In some embodiments, the treatment or prevention of a metabolic disease comprises decreasing or eliminating a symptom of such metabolic disease comprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like.Small molecule PTPN2 and / or PTPN1 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 cancer and metabolic diseases. Co-administration includes administering two active agentsSPC6350-48- 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 certain embodiments, the second agent is an anti-cancer agent. In certain embodiments, the second agent is a chemotherapeutic. In other embodiments, the second agent is a (cancer) immunotherapy or (cancer) immunotherapeutic agent. In again other embodiments, the second agent is an agent for treating a metabolic disease. In particular embodiments, the second agent is an anti-diabetic agent. In some embodiments, the second agent is an anti-obesity agent."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.Cancer immunotherapy refers to the use of the immune system to treat cancer. Types of immunotherapy used to treat cancer include compound-base, cell-based, antibody-based, and cytokine therapies. Exemplary immunotherapies or immunotherapeutic agent that may be useful when combined with the compounds of the invention include, but are not limited a compounds (e.g., a ligand, an antibody) that inhibits the immune checkpoint blockade pathway. In some embodiments, the immunotherapeutic agent is a compound that inhibits the indoleamine 2,3- dioxygenase (IDO) pathway. In some embodiments, the immunotherapeutic agent is a compound that agonizes the STING pathway. Cancer immunotherapy (e.g., anti-tumor immunotherapy or anti-tumor immunotherapeutics) includes but is not limited to, immune checkpoint antibodies (e.g., PD-1 antibodies, PD-L1 antibodies, PD-L2 antibodies, CTLA-4 antibodies, TIM3 antibodies, LAG3 antibodies, TIGIT antibodies); and cancer vaccines (e.g., anti-tumor vaccines or vaccines based on neoantigens such as a peptide or RNA vaccine). Cell-based therapies (e.g., cancer vaccines), usually involve the removal of immune cells from a subject suffering from cancer, either from the blood or from a tumor. Immune cells specific for the tumor will be activated, grown, and returned to a subject suffering from cancer where the immune cells provide an immune response against the cancer. Cell types that can be used in this way are e.g., natural killer cells, lymphokine- activated killer cells, cytotoxic T-cells, dendritic cells, CAR-T therapies (e.g., chimeric antigenSPC6350-49- receptor T-cells which are T-cells engineered to target specific antigens), TIL therapy (e.g., administration of tumor-infiltrating lymphocytes), TCR gene therapy, protein vaccines, and nucleic acid vaccines. An exemplary cell-based therapy is Provenge. In some embodiments, the cellbased therapy is a CAR-T therapy. Interleukin-2 and interferon-alpha are examples of cytokines, proteins that regulate and coordinate the behavior of the immune system. Cancer vaccines with neoantigens might also be combined with the compounds of the invention. Neoantigens are antigens encoded by tumor-specific mutated genes.The invention described herein comprises, in some embodiments, administering in combination with a compound of the invention a cancer immunotherapy. In some embodiments, the immunotherapeutic agent is a compound (e.g., an inhibitor or antibody) that inhibits the immune checkpoint blockade pathway. Immune checkpoint proteins, under normal physiological conditions, maintain self-tolerance (e.g., prevent autoimmunity) and protect tissues from damage when the immune system is responding to e.g., pathogenic infection. Immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism (Pardoll, Nature Rev. Cancer, 2012, 12, 252-264). Agonists of co- stimulatory receptors or antagonists of inhibitory signals (e.g., immune checkpoint proteins), provide an amplification of antigen-specific T-cell responses. Antibodies that block immune checkpoints do not target tumor cells directly but typically target lymphocyte receptors or their ligands to enhance endogenous antitumor activity.

[0241] Exemplary checkpoint blocking antibodies include but are not limited to, anti-CTLA-4, anti-PD-1 , anti-LAG3 (e.g., antibodies against lymphocyte activation gene 3), and anti-TIM3 (e.g., antibodies against T-cell membrane protein 3). Exemplary anti-CTLA-4 antibodies include but are not limited to, ipilimumab and tremelimumab. Exemplary anti-PD-1 ligands include but are not limited to, PD-L1 (e.g., B7-H1 and CD274) and PD-L2 (e.g., B7-DC and CD273). Exemplary anti- PD-1 antibodies include but are not limited to, nivolumab (e.g., MDX- 1106, BMS-936558, or ONO-4538)), CT-011 , AMP-224, pembrolizumab (trade name Keytruda), and MK-3475. Exemplary PD-L1 -specific antibodies include but are not limited to,BMS936559 (e.g., MDX-1105), MEDI4736 and MPDL-3280A. Exemplary checkpoint blocking antibodies also include but are not limited to, IMP321 and MGA271.

[0242] T-regulatory cells (e.g., CD4+, CD25+, or T-reg) are also involved in policing the distinction between self and non-self (e.g., foreign) antigens, and may represent an important mechanism in suppression of immune response in many cancers. T-reg cells can either emerge from the thymus (e.g., “natural T-reg”) or can differentiate from mature T- cells under circumstances of peripheral tolerance induction (e.g., “induced T-reg”). Strategies that minimize the action of T-reg cells would therefore be expected to facilitate the immune response to tumors.IDO pathway inhibitors. The IDO pathway regulates immune response by suppressing T cell function and enabling local tumor immune escape. IDO expression by antigen-presentingSPC6350-50- cells (APCs) can lead to tryptophan depletion, and resulting antigen-specific T cell energy and regulatory T cell recruitment. Some tumors even express IDO to shield themselves from the immune system. A compound that inhibits IDO or the IDO pathway activates the immune system to attack the cancer (e.g., tumor in a subject). Exemplary IDO pathway inhibitors include indoximod, epacadostat and EOS200271.STING pathway agonists. Stimulator of interferon genes (STING) is an adaptor protein that plays an important role in the activation of type I interferons in response to cytosolic nucleic acid ligands. Evidence indicates involvement of the STING pathway in the induction of antitumor immune response. For example, activation of the STING-dependent pathway in cancer cells can result in tumor infiltration with immune cells and modulation of the anticancer immune response. STING agonists are being developed as a class of cancer therapeutics. Exemplary STING agonists include MK-1454 and ADU-S100.In some embodiments, the immunotherapeutic agent is a co-stimulatory inhibitor or antibody, e.g. by depleting or activating anti-4-1 BB, anti-OX40, anti-GITR, anti-CD27 and anti- CD40, and variants thereof. Also immunostimulants (e.g., Bacillus Calmette- Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.) are considered to be covered by immunotherapeutic agents.Other examples of anti-cancer agents include, but are not limited to MEK inhibitors, EGFR inhibitors, RAS inhibitors, inhibitors of B-RAF, alkylating agents, nitrogen mustards, ethylenimine and methylmelamines, alkyl sulfonates, nitrosoureas, triazenes, anti-metabolites, pyrimidine analogs, purine analogs, plant alkaloids, topoisomerase inhibitors, antitumor antibiotics, platinumbased 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, antiestrogen, 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 qln,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.SPC6350-51-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,186Re,188Re,211At, and212Bi, optionally conjugated to antibodies directed against tumor antigens.The compounds of the invention can inhibit PTPN2 and / or PTPN1 activity. The compounds have been shown to inhibit PTPN2 and / or PTPN1 activity in cellular models and in an animal model. The compounds have also been shown to have an inhibitory effect on cancer cell lines and on the growth of cancer in an animal cancer model.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 affinity separations).When using one or more derivatives of the formulae as defined herein: 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. the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of diseases mediated by activity of PTPN2 and / or PTPN1 in humans and other mammals (such as cancer, metabolic diseases and certain congenital disorders), preferably is a PTPN2 and / or PTPN1 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 PTPN2 and / or PTPN1 activity and is in a particular embodiment between 1 ng / 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.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 subunits per day or may be administered at more than one day intervals.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 PTPN2 and / or PTPN1 in humans and other mammals (such as cancer and metabolic disorders). The invention therefore relates to the use of a composition comprising:SPC6350-52-(a) one or more compounds of the formulae and aspects, statements and embodiments herein, and(b) one or more further therapeutic or preventive agents that are used for the prevention or treatment of cancer or metabolic diseases as biologically active agents in the form of a combined preparation for simultaneous, separate or sequential use.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-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 counterSPC6350-53- 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 centers, 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. Furthermore, this term also includes the solvates which the compounds of formulae herein as well as their salts are able to form, such as for example hydrates, alcoholates and the like. 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.Also included within the scope of this invention are the salts of the parental compounds 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.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 an 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 presentSPC6350-54- invention.The compounds herein provided 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.As used herein and unless otherwise stated, the term "enantiomer" means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (e.g. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.The term "isomers" as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formulae herein may possess, but not including position isomers. Typically, the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well. Unless otherwise stated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds of formulae herein may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S-configuration, and multiple bonds may have either c / s- or trans-configuration.Pure isomeric forms of the said compounds are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In particular, the term "stereoisomerically pure" or "chirally pure" relates to compounds having a stereoisomeric excess of at least about 80% (e.g. at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question.Separation of stereoisomers is accomplished by standard methods known to those in the art. One enantiomer of a compound of the invention can be separated substantially free of itsSPC6350-55- opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents ("Stereochemistry of Carbon Compounds," (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302). Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions. Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl- b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. Alternatively, by method (2), the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compound. A method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy- a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal- and reversephase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96 / 15111). Under method (3), a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives. Commercially available polysaccharide based chiral stationary phases are ChiralCel™ CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak™ AD, AS, OP(+) and OT(+). Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like. ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) "Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. of Chromatogr. 513:375-378).SPC6350-56-The terms c / s and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of the substituents on a ring moiety. The absolute stereochemical configuration of the compounds of the formulae described herein may easily be determined by those skilled in the art while using well-known methods such as, for example, X-ray diffraction.Alternatively, in some embodiments, stereoisomeric forms of compounds provided herein are defined by their optical rotation and labeled or named either “(+)-[compound name]” or “(d)- [compound name]” when dextrorotary, or, “(-)-[compound name]” or “(l)-[compound name]” when levorotary. Optical rotation is determined using a polarimeter in methods such as the one described in Part A of the examples hereunder.The present invention also includes isotopically labelled compounds, which are identical to those recited in the formulas recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as2H,3H,13C,11C,14C,15N,180,170,31P,32P,35S,18F, and36CI, respectively. Compounds of the present invention and pharmaceutically acceptable salts of said compounds or which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of the formulas of this invention may generally be prepared by carrying out the procedures disclosed in the examples and preparations described herein, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. Accordingly, deuterated forms of the compounds described herein are encompassed by the present disclosure.Also encompassed within the invention are modifications of the compounds of the formula (I) or other formulas, embodiments, aspects or parts thereof or metabolites thereof using PROTAC technology (Schapira M. et al, Nat. Rev. Drug Discov. 2019, 18(12), 949-963). Specifically, the PROTAC technology designs a bifunctional small molecule, one end of which is a compound of the general formula (I) or other formulas, embodiments, aspects or parts thereofSPC6350-57- or metabolites thereof, and the other end of which is connected with a ligand of E3 ubiquitin ligase through a connecting chain, to form a target-induced protein degradation complex. Because this degradation has a catalytic effect, a lower dosage can achieve efficient degradation. The compound of the general formula (I) or other formulas, embodiments, aspects or parts thereof or metabolites thereof can be connected via a linker arm (e.g. long-chain ethylene glycol with the length of 2-10, long-chain propylene glycol with the length of 2-10 and long-chain fatty alkane with the length of 2-10) to a ligand of E3 ubiquitin ligase such as e.g. thalidomide analogs.The compounds of the invention may be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.Subsequently, the term "pharmaceutically acceptable carrier" as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and / or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, e.g. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, e.g. carriers and additives which do not create permanent damage to mammals. The pharmaceutical compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and / or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents, may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm,SPC6350-58- namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.Suitable surface-active agents, also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and / or anionic materials having good emulsifying, dispersing and / or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C10-C22), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable from coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl group having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol / ethylene oxide adducts. Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates are the sodium, calcium or alcoholamine salts of dodecylbenzene sulphonic acid or dibutyl-naphthalenesulphonic acid or a naphthalene-sulphonic acid / formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and / or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl -choline and their mixtures.Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and / or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionicSPC6350-59- surfactants are nonylphenol -polyethoxyethanol, castor oil polyglycolic ethers, polypropylene / polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon groups optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one Cs- 22alkyl (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and / or hydroxy-lower alkyl.A more detailed description of surface-active agents suitable for this purpose may be found for instance in "McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Crop., Ridgewood, New Jersey, 1981), "Tensid-Taschenbucw1, 2 d ed. (Hanser Verlag, Vienna, 1981) and "Encyclopaedia of Surfactants, (Chemical Publishing Co., New York, 1981).Compounds of the invention and their pharmaceutically acceptable salts (hereafter collectively referred to as the active ingredients) may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). The preferred route of administration may vary with for example the condition of the recipient.While it is possible for the active ingredients to be administered alone it is preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients. The carrier(s) optimally are "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount ofSPC6350-60- the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues e.g. mouth and skin, the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w / w (including active ingredient(s) in a range between 0.1 % and 20% in increments of 0.1% w / w such as 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w and most preferably 0.5 to 10% w / w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of a polyhydric alcohol, e.g. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus the cream should optionally be a non- greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-SPC6350-61- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w / w. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc.), which is administered in the manner in which snuff is taken, e.g. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.SPC6350-62-Preferred unit dosage formulations are those containing a daily dose or unit daily subdose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.Compounds of the invention can be used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention ("controlled release formulations") in which the release of the active ingredient can be controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given invention compound. Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.Additional ingredients may be included in order to control the duration of action of the active ingredient in the composition. Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl methacrylate and the other above-described polymers. Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on. Depending on the route of administration, the pharmaceutical composition may require protective coatings. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof.In view of the fact that, when several active ingredients are used in combination, they do not necessarily bring out their joint therapeutic effect directly at the same time in the mammal to be treated, the corresponding composition may also be in the form of a medical kit or package containing the two ingredients in separate but adjacent repositories or compartments. In the latter context, each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.SPC6350-63-In some embodiments, the compound is selected from the compounds listed in Table 1 and as described with their chemical name below (generated with ChemBioDraw 16.0).CpdOOl : (E)-5-(2-fluoro-6-hydroxy-3-(1-(pyrrolidin-3-ylidene)ethyl)phenyl)-1 ,2,5-thiadiazolidin-3- one 1 ,1 -dioxideCpd002: (Z)-5-(2-fluoro-6-hydroxy-3-(1-(pyrrolidin-3-ylidene)ethyl)phenyl)-1 ,2,5-thiadiazolidin-3- one 1 ,1 -dioxideCpd003: 5-(2-fluoro-3-(fluoro(pyrrolidin-3-ylidene)methyl)-6-hydroxyphenyl)-1 ,2,5-thiadiazolidin- 3-one 1 ,1 -dioxideCpd004: (E)-5-(3-((4-cyclopropylpyrrolidin-3-ylidene)fluoromethyl)-2-fluoro-6-hydroxyphenyl)-1 ,2,5-thiadiazolidin-3-one 1 , 1 -dioxideCpd005: (E)-5-(2-fluoro-3-(fluoro(1-methylpyrrolidin-3-ylidene)methyl)-6-hydroxyphenyl)-1 ,2,5- thiadiazolidin-3-one 1 ,1 -dioxideCpd006: (E)-5-(3-((4-cyclopropyl-1-methylpyrrolidin-3-ylidene)fluoromethyl)-2-fluoro-6- hydroxyphenyl)-1 ,2,5-thiadiazolidin-3-one 1 , 1 -dioxideCpd007: (E)-5-(2-fluoro-3-(fluoro(6-azaspiro[3.4]octan-8-ylidene)methyl)-6-hydroxyphenyl)-1 ,2,5-thiadiazolidin-3-one 1 , 1 -dioxideCpd008: 5-(2-fluoro-3-(fluoro(piperidin-4-ylidene)methyl)-6-hydroxyphenyl)-1 ,2,5-thiadiazolidin-3-one 1 ,1 -dioxideCpd009: (E)-5-(2-fluoro-3-(fluoro(pyrrolidin-3-ylidene)methyl)-6-hydroxyphenyl)isothiazolidin-3- one 1 ,1 -dioxideCpdO1O: (E)-5-(2-fluoro-3-(fluoro(6-azaspiro[3.4]octan-8-ylidene)methyl)-6- hydroxyphenyl)isothiazolidin-3-one 1 , 1 -dioxideCpdO11 : (Z)-5-(2-chloro-3-((4-cyclopropylpyrrolidin-3-ylidene)fluoromethyl)-6-hydroxyphenyl)-1 ,2,5-thiadiazolidin-3-one 1 , 1 -dioxideCpd012: (Z)-5-(2-fluoro-6-hydroxy-3-(1-(pyrrolidin-3-ylidene)propyl)phenyl)-1 ,2,5-thiadiazolidin- 3-one 1 ,1 -dioxideCpd013: (E)-5-(2-fluoro-6-hydroxy-3-(1-(pyrrolidin-3-ylidene)propyl)phenyl)-1 ,2,5-thiadiazolidin- 3-one 1 ,1 -dioxideCpd014: (E)-5-(3-(chloro(pyrrolidin-3-ylidene)methyl)-2-fluoro-6-hydroxyphenyl)-1 ,2,5- thiadiazolidin-3-one 1 ,1 -dioxideCpdO15: (E)-5-(2-chloro-3-(fluoro(pyrrolidin-3-ylidene)methyl)-6-hydroxyphenyl)-1 ,2,5- thiadiazolidin-3-one 1 ,1 -dioxideCpd016: (Z)-5-(3-(2-cyclopropyl-1-fluorovinyl)-2-fluoro-6-hydroxyphenyl)-1 ,2,5-thiadiazolidin-3- one 1 ,1 -dioxideCpd017: (Z)-5-(2-fluoro-3-(1-fluoro-2-(3-fluorophenyl)vinyl)-6-hydroxyphenyl)-1 ,2,5- thiadiazolidin-3-one 1 ,1 -dioxideSPC6350-64-Cpd018: (Z)-5-(3-(4-amino-1-fluoro-3-methylbut-1-en-1-yl)-2-fluoro-6-hydroxyphenyl)-1 ,2,5- thiadiazolidin-3-one 1 ,1 -dioxideCpd019: (Z)-5-(3-(2-cyclohexyl-1-fluorovinyl)-2-fluoro-6-hydroxyphenyl)-1 ,2,5-thiadiazolidin-3- one 1 ,1 -dioxide Cpd020: (E)-(2-(1 ,1-dioxido-4-oxo-1 ,2,5-thiadiazolidin-2-yl)-3-fluoro-4-(fluoro(6- azaspiro[3.4]octan-8-ylidene)methyl)phenoxy)methyl dihydrogen phosphateThe present invention relates to methods for the preparation of the compounds, comprising the steps of coupling a leaving group-containing compound of formula (A1) with a alkenyl derivative thereby obtaining compound of formula (A2), wherein X1 , X2, X3, X4, R1 , R2, R5, R9, R10 and R11 have the meaning according to any one of the formula or embodiments presented herein, LG is a leaving-goup (typically an halogen, such as Cl, Br, I).The compounds of the present invention may be prepared according to the general proceduresScheme A: all X3, X4are as described for the compounds of the present invention, particularly hydrogen, and its embodiments, statements and formulae. PG is protecting group. LG is a leaving group, typically an halogen (Cl, Br, I). Y is an ester protecting group (like methyl, ethyl, t-Bu and the like).A nitro compound 1 may be reacted with a primary alcohol of general formula PGiOH (like benzylalcohol, MeOH, 4-methoxybenzylalcohol and the like) in the presence of a base (like NaH, K2CO3, CS2CO3, DBU and the like) in a suitable solvent (e.g., DCM, THF, toluene and the like) at a temperature ranging from -78°C to 100°C to provide intermediates of formula 2. IntermediatesSPC6350-65- of formula 2 may be halogenated with a suitable halogenating agent (e.g. Bromine, N- bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and the like) in a polar aprotic solvent (e.g. dichloromethane, tetra hydrofuran and the like) at a temperature ranging from 0 to 100°C to provide the intermediates of formula 3. Reduction of intermediates of formula 3 with a reducing agent (e.g., hydrogen gas, ammonium formate, cyclohexadiene, metal (like Zn, Fe) in acidic conditions and the like) using a catalyst (more preferably Pd or Pt) in a protic or aprotic solvent (e.g., THF, EtOH, EtOAc, dioxane and the like) may provide anilines of formula 4. Anilines of formula 4 may be reacted with ester derivatives having a leaving group LG (like Br, Cl, OMs and the like) and where Y is an ester protecting group (like methyl, ethyl, t-Bu and the like) in the presence of a base (e.g. DI PEA, K2CO3, CS2CO3, DBU and the like) in a polar aprotic solvent (e.g., CH3CN, THF, DCM and the like) at a temperature ranging from 0°C to 100°C to provide intermediates of formula 5. Anilines of formula 5 may react with chlorosulfonyl isocyanate in the presence of a suitable alcohol derivative (tBuOH, benzylalcohol and the like) to provide sulfonylureas of formula 8. Removal of the N-protecting group PG2 may be performed following procedures known to the skilled in the art (e.g. treatment in presence of an acid such as HCI or TFA if PG2 = Boc, hydrogenolysis if PG2 = cBz) to provide sulfonylureas intermediates of formula 9. Intermediates of formula 9 can themselves undergo an intermolecular cyclisation in the presence of a base (like NaOMe, NaOEt, NaH and the like) in a aprotic or protic polar solvent (e.g. THF, MeOH, EtOH and the like) at a temperature ranging from -78°C to 100°C to provide intermediates of formula 10. Intermediates similar to those of formula 10, with X2different than C- F, R7different than OPG1 can be synthesized according to similar procedure (X2, R7as described for the compounds of the present invention).In another embodiment, compounds of the present invention may also be synthesized accordingSPC6350-66-Scheme B: R3 (different than H) is as described for the compounds of the present invention and its embodiments and formulae. PG is protecting group. LG is leaving group, typically an halogen (Cl, Br, I, ...). Y is an ester protecting group (like methyl, ethyl, t-Bu and the like).A nitro compound 11 may be reacted with a primary alcohol of general formula PGiOH (like benzylalcohol, MeOH, 4-methoxybenzylalcohol and the like) in the presence of a base (like NaH, K2CO3, CS2CO3, DBU and the like) in a suitable solvent (e.g., DCM, THF, toluene and the like) at a temperature ranging from -78°C to 100°C to provide intermediates of formula 12. Intermediates of formula 12 may be halogenated with a suitable halogenating agent (e.g. Bromine, N- bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and the like) in a polar aprotic solvent (e.g. dichloromethane, tetra hydrofuran and the like) at a temperature ranging from 0 to 100°C to provide the intermediates of formula 13. Reduction of intermediates of formula 13 with a reducing agent (e.g., hydrogen gas, ammonium formate, cyclohexadiene, metal (like Zn, Fe) in acidic conditions and the like) using a catalyst (more preferably Pd or Pt) in a protic or aprotic solvent (e.g., THF, EtOH, EtOAc, dioxane and the like) may provide anilines of formula 14. Anilines of formula 14 may be reacted with ester derivatives having a leaving group LG (like Br, Cl, OMs and the like) and where Y is an ester protecting group (like methyl, ethyl, t-Bu and the like) in the presence of a base (e.g. DI PEA, K2CO3, CS2CO3, DBU and the like) in a polar aprotic solvent (e.g., CH3CN, THF, DCM and the like) at a temperature ranging from 0°C to 100°C to provide intermediates of formula 15. Anilines of formula 15 may be halogenated with a suitable halogenating agent (e.g. Bromine, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and the like) in a polar aprotic solvent (e.g. dichloromethane, tetra hydrofuran and the like) at a temperature ranging from 0 to 100°C to provide intermediates of formula 16. Intermediates of general formula 16 may be reacted further with appropriate coupling agents selected from, but not limited, to boronic acids, boronic esters, boroxines, organozinc reagents, organotin reagents, amines and alcohols in combination with suitable Pd or Cu based catalysts to afford intermediates of general formula 17. Anilines of formula 17 may react with chlorosulfonyl isocyanate in the presence of a suitable alcohol derivative (tBuOH, benzylalcohol and the like) to provide sulfonylureas of formula 18. Removal of the N-protecting group PG2 may be performed following procedures known to the skilled in the art (e.g. treatment in presence of an acid such as HCI or TFA if PG2 = Boc, hydrogenolysis if PG2 = cBz) to provide sulfonylureas intermediates of formula 19. Intermediates of formula 19 can themselves undergo an intermolecular cyclisation in the presence of a base (like NaOMe, NaOEt, NaH and the like) in a aprotic or protic polar solvent (e.g. THF, MeOH, EtOH and the like) at a temperature ranging from -78°C to 100°C to provide intermediates of formula 20. Intermediates similar to those of formula 20, with X2different than OF, R7different than OPG1 can be synthesized according to similar procedure (X2, R7as described for the compounds of the present invention).SPC6350-67-In another embodiment, compounds of the present invention may also be synthesized accordingScheme C: all X3, X4, R1, R2, R5are as described for the compounds of the present invention and its embodiments, statements and formulae. LG is a leaving group, typically an halogen (Br, I, Cl). T is a boron atom under the form of boronic acid or ester and PG = protecting group.Phenols derivatives of formula 21 may be obtained by removal of the O-protecting group from intermediates of general 10 following procedures known to the skilled in the art (e.g. treatment with BBra or BCh, hydrogenation with H2 in the presence of Pd / C and the like). Alkenes derivatives of formulae 22 or 23 may be obtained by reaction of an halogenated intermediate of formula 21 and boronic derivatives (such as boronic acids or boronic esters, either commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below) in the presence of a Pd catalyst (e.g. Pd(PPha)4, PdCh(PPh3)2, Pd(ddpf)Ci2, Pd(dtbpf)Ch and the like) and a base (e.g K3PO4, K2CO3, CS2CO3 and the like) in a suitable solvent (e.g dioxane, water, toluene, DMF, DMSO and the like) at a temperature ranging from 0°C to 150°C. Alkenes derivatives of formula 22 may themselves undergo functional group transformation (using a series of chemical reactions well known to those skilled in the art or as set forth in the examples) to deliver alkenes derivatives of formula 23. Compounds similar to those of formula 23 with X2different than CF, R7different than OH and X1different than N can be synthesized according to similar procedure (X2, R7, X1as described for the compounds of the present invention).In another embodiment, compounds of the present invention may also be synthesized according to the general procedure outlined in Scheme D.SPC6350Scheme D: all X3, X4, R1, R2, R5are as described for the compounds of the present invention and its embodiments, statements and formulae. LG is a leaving group, typically an halogen (Br, I, Cl). T is a boron atom under the form of boronic acid or ester and PG = protecting group.Alkenes derivatives of formulae 24 or 25 may be obtained by reaction of an halogenated intermediate of formula 10 and boronic derivatives (such as boronic acids or boronic esters, either commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below) in the presence of a Pd catalyst (e.g. Pd(PPha)4, PdCh(PPh3)2, Pd(ddpf)Ci2, Pd(dtbpf)Ch and the like) and a base (e.g K3PO4, K2CO3, CS2CO3 and the like) in a suitable solvent (e.g dioxane, water, toluene, DMF, DMSO and the like) at a temperature ranging from 0°C to 150°C. Alkenes derivatives of formula 24 may themselves undergo functional group transformation (using a series of chemical reactions well known to those skilled in the art or as set forth in the examples) to deliver alkenes derivatives of formula 25. Compounds of interest having a formula 23 may be obtained after removal of the O-protecting group following procedures known to the skilled in the art (e.g. treatment with BBrs or BCI3, hydrogenation with H2 in the presence of Pd / C and the like) as described in Scheme D. Compounds similar to those of formula 23 with X2different than CF, R7different than OH and X1different than N can be synthesized according to similar procedure (X2, R7, X1as described for the compounds of the present invention).The general schemes depicted above should be considered as non-limiting examples. It will be understood that compounds of the invention may be obtained through other methods, which are known to people skilled in the art.Abbreviations used in the description, particularly in the Schemes and Examples, are as follows:SPC6350-69-SPC6350-70-The following examples are provided for the purpose of illustrating the present invention and by no means should be interpreted to limit the scope of the present invention. Table 1 : Structures of example compounds of the invention and their respective codesSPC6350-71-*The crossed bond indicates that the stereochemistry on the double bond, (E) or (Z), is not defined.Structures of example compounds that contain stereocentres are drawn and named with absolute stereochemistry, if known. In case of unknown absolute stereochemistry the compounds can be either racemic, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, orSPC6350-72- a pure enantiomer of unknown stereochemistry.ExamplesPart A represent the preparation of the compounds of the invention whereas Part B represents the pharmacological examples.Part A: Experimental chemistry proceduresThe compounds of the invention can be prepared while using a series of chemical reactions well known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified further. The processes described further are only meant as examples and by no means are meant to limit the scope of the present invention.All reagents which are not explicitly described were either commercially available (the details of suppliers such as for example ABCR, Apollo Scientific, BLD, Combi-Blocks, Enamine, FluoroChem-DougDiscovery, MatrixScientific, Maybridge, Merck, TCI etc. can be found in the SciFinder® Database for example) and used as received without further purification, unless otherwise stated or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys® Database or the SciFinder® Database respectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.The reactions were, if necessary, carried out under an inert atmosphere (mostly argon and N2). Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. The number of equivalents of reagents and the amounts of solvents employed as well as the reaction temperatures and times can vary slightly between different reactions carried out by analogous methods. The work-up and purification methods were adapted according to the characteristic properties of each compound and can vary slightly for analogous methods. The yields of the compounds prepared are not optimized. The indication “equivalents" ("eq." or “eq” or “equiv.”) means molar equivalents, “RT“ or “rt” means room temperature T (23 + / - 7 °C), “M“ are indications of concentration in mol / l, “sol.“ means solution, "cone." means concentrated, “sat.” means saturated. The mixing ratios of solvents are usually stated in the volume I volume ratio.Key analytical characterization was carried out by means of 1 H-NMR spectroscopy and / or mass spectrometry (MS, m / z for [M+H]+ and / or [M-H]-) for all the exemplary compounds and selected intermediate products. In certain cases, where e.g. regioisomers and / or diastereomers couldSPC6350-73- be / were formed during the reaction, additional analytics, such as, e.g. 13C NMR and NOE (nuclear overhauser effect) NMR experiments were performed. NMR data were recorded using Bruker Avance 400MHz or 600MHz NMR spectrometers (TopSpin-softwares).1H data were calibrated using tetramethylsilane as an internal calibration reference. The chemical shifts 6- values are expressed in parts per million (ppm). The following acronyms were used: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), brs (broadened singulet).The LC / MS analyses mentioned in the experimental part were performed on Waters systems combining either a Waters Acquity LIPLC H-Class Plus system, a Waters Acquity LIPLC l-Class Plus system, a Waters Acquity Premier system, a Waters Alliance e2695 system or a Waters 2545 system or a Waters 1290 Infinity using ad hoc detectors, columns and chromatographic conditions.The LC-MS analyses of the final compounds were performed on a Waters system combining: a Acquity LIPLC H-Class equipped with a Acquity LIPLC PDA Detector (range 190-420 nm), a Acquity LIPLC ELS Detector and a Acquity TQ Detector (ESI / ESCi)LC-MS “Method A” (HSS - Acidic 5%). Column: UPLC HSS C18 (2.1x50mm, 1.8pm) thermostated at 40°C; Mobile phase A: 0.1% formic acid in water ; Mobile phase B: acetonitrile ; Gradient (Time / % of B) 0 / 5, 3.18 / 50, 4 / 90, 5 / 90 ; Flow rate 0.5 mL / min; UV detection: from 190 nm to 420 nm ; MS conditions: Ionisation Mode: Positive and Negative Electrospray Ionisation (ESI+ / ESI-); Scan Range: 100 to 1000 m / z, ES+ / -All the preparative HPLC purifications mentioned in this experimental part were carried out either with aWaters system combining a Waters 2545 Binary Gradient Module, a Waters 2489 UV / Visible Detector ((dual wavelength detection at 210 nm and 254 nm), a System Fluidics Organizer, a 515 HPLC Pump, a Waters 2767 Sample Manager and a Waters MS3100 Mass detectorWaters Alliance e2695 instrument equipped with either a 2996 or a 2998 PDA detector- Acquity Arc-HPLC equipped with a 2998 PDA detector- Agilent techn. 1260 Infinity II equipped with a PDA detectorExamples of intermediates for the synthesis of the compounds of the invention and their preparation.Synthesis of lnt-01 : 5-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-1 ,2,5-thiadiazolidin-3-one 1 ,1- dioxideSPC6350-74-Step-1 : To a stirred solution of benzyl alcohol (7.19 mL, 69 mmol) in THF (250 mL), was added NaH (60% in mineral oil, 3.04 g, 76 mmol) at 0 °C. After 15 min, 1 ,3-difluoro-2-nitrobenzene (1.10 g, 63 mmol) dissolved in dry THF (50 mL) was added dropwise to the above reaction mixture at 0 °C. The resulting reaction mixture was slowly allowed to RT. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with ice cold water (300 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the crude product. Similarly, two more batches were performed following the exact procedure. The crude product of the three batches were combined and purified by column chromatography on silica gel eluting with a gradient of EtOAc in PE (4-5%) to yield 1-(benzyloxy)-3-fluoro-2-nitrobenzene (49.5 g from three batches).1 H NMR (400 MHz, CDCI3) 6 ppm 7.40-7.32 (m, 6H), 6.87-6.81 (m, 2H), 5.20 (s, 2H).19F NMR (376 MHz, CDCI3) 6 ppm -122.4 (t)Step-2: To a stirred solution of 1-(benzyloxy)-3-fluoro-2-nitrobenzene (25 g, 101 mmol) in AcOH (600 mL) and DCM (600 mL), was added Br2 (104.3 mL, 2.02 mol) at -10 °C. The reaction mixture was slowly allowed to reach RT. After completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0 °C, quenched with ice-water (200 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with a saturated solution of NaHSOs, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Similarly, 1 more batch was performed on same scale following the exact same procedure.The crude material of the 2 batches were combined, pentane (300 mL) was added to the resulting residue and stirred for 30 min. The solid obtained was filtered and further stirred with a mixture of pentane (100 mL) and diethyl ether (100 mL) for 30 min. The solid was again filtered and dried under vacuum to afford 1-(benzyloxy)-4-bromo-3-fluoro-2-nitrobenzene (33 g from 2 batches), which was used as such in the next step without further purification.1 H NMR (400 MHz, CDCI3) 6 ppm 7.98-7.94 (t, 1 H), 7.44-7.31 (m, 6H), 5.35 (s, 2H).19F NMR (376 MHz, CDCI3) 6 ppm -117.5 (d)Step-3: To a stirred solution of 1-(benzyloxy)-4-bromo-3-fluoro-2-nitrobenzene (25 g, 76.7 mmol)SPC6350-75- in ethanol (250 mL) and H2O (100 mL), were added iron powder (12.8 g, 229.9 mmol) and NH4CI (42 g, 383.3 mmol) at RT. The resulting reaction mixture was heated at 90°C. After completion of the reaction (TLC monitoring), the reaction mixture was filtered through a celite bed and the bed was washed thoroughly with EtOH. The filtrate was concentrated under reduced pressure, diluted with water (200 mL) and extracted with EtOAc (2 x 250 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc in PE (0-30%) to yield 22 g of 6-(benzyloxy)-3-bromo- 2-fluoroaniline.1 H NMR (400 MHz, CDCh) 6 ppm 7.48 (d, 2H), 7.38 (t, 2H), 7.32 (t, 1 H), 6.77-6.73 (m, 2H), 5.14 (s, 2H), 4.99 (brs, 2H).19F NMR (376 MHz, CDCh) 6 ppm -128.1 (d).Step-4: To a stirred solution of 6-(benzyloxy)-3-bromo-2-fluoroaniline (40 g, 135.1 mmol), in acetonitrile (400 mL), were added DI PEA (95.6 mL, 540 mmol) followed by ethyl 2-bromoacetate (29.8 mL, 270 mmol) at RT. The reaction mixture was then stirred at 80°C. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with a saturated NaHCCh solution at 0°C and then concentrated under reduced pressure. The obtained crude product was diluted with water (150 mL) and extracted with EtOAc (2x300 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc in PE (0-5%). The obtained compound was again purified by reverse phase C18 column chromatography eluting with a gradient of CH3CN in H2O containing 0.1 % FA (0-50%). The pure fractions were concentrated and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 22 g of ethyl (6-(benzyloxy)-3-bromo-2-fluorophenyl)glycinate.1 H NMR (400 MHz, CDCh) 6 ppm 7.47-7.45 (m, 2H), 7.42-7.38 (m, 2H), 7.35-7.32 (m, 1 H), 6.87 (t, 1 H), 6.78 (dd, 1 H), 5.37-5.33 (m, 1 H), 5.14 (s, 2H), 4.09-4.04 (m, 4H), 1.14 (t, 3H).19F NMR (376 MHz, CDCh) 6 ppm -126.8 (d)Step-5: To a stirred solution of chlorosulfonyl isocyanate (9.54 g, 109.8 mmol) in DCM (150 mL) was added tBuOH (10.42 mL, 109.9 mmol) dropwise at 0°C. The reaction mixture was stirred for 30 min at the same temperature under N2 atmosphere. This pre-reagent mixture was added to a stirred solution of ethyl (6-(benzyloxy)-3-bromo-2-fluorophenyl)glycinate (21 g, 54.94 mmol) and triethylamine (23 mL, 164.8 mmol) in DCM (150 mL) at O°C. The resulting reaction mixture was allowed to RT. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with water (150 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc in PE (8- 50%) to yield 22 g of ethyl N-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-N-(N-(tert-SPC6350-76- butoxycarbonyl)sulfamoyl) glycinate.1 H NMR (400 MHz, CDCI3) 6 ppm 11.40 (s, 1 H), 7.62-7.66 (m, 1 H), 7.45-7.46 (m, 2H), 7.35-7.41 (m, 2H), 7.31-7.33 (m, 1 H), 6.91-6.94 (m, 1 H), 5.19-5.29 (q, 2H), 4.68-4.73 (d, 1 H), 4.34-4.38 (d, 1 H), 3.97-4.07 (m, 2H), 1.32 (s, 9H), 1.09-1.17 (m, 3H)Step-6: To a stirred solution of ethyl N-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-N-(N-(tert- butoxycarbonyl)sulfamoyl)glycinate (21 g, 37.4 mmol, 1.0 eq) in DCM (200 mL), was added TFA (42.4 mL, 561 mmol, 15 eq) at 0°C. The resulting reaction mixture was then stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was concentrated under reduced pressure, quenched with a saturated NaHCCh aqueous solution and extracted with DCM (3 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc in PE (0-50%). The pure fractions were combined and concentrated under reduced pressure. The obtained residue was dissolved in DCM (40 mL) and PE (80 mL) was slowly added. The white precipitated solid was filtered and dried under vacuum to provide 12 g of ethyl N-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-N-sulfamoylglycinate.1 H NMR (400 MHz, CDCI3) 6 ppm 7.57-7.61 (q, 1 H), 7.49 (d, 2H), 7.41 (t, 2H), 7.31-7.34 (m, 1 H), 7.08 (bs, 2H), 6.95-6.97 (dd, 1 H), 5.18 (s, 2H), 4.19-4.42 (dd, 2H), 3.98-4.04 (m, 2H), 1.10 (t, 3H) Step-7: To a stirred solution of ethyl N-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-N- sulfamoylglycinate (12 g, 26.0 mmol, 1.0 eq) in THF (120 mL), was added sodium methoxide (25% solution in methanol, 8.43 mL, 39.0 mmol, 1.5 eq) at 0°C. The resulting reaction mixture was stirred at 0°C. After completion of the reaction (TLC monitoring), the reaction mixture was acidified with AcOH (0.5 mL) and evaporated under reduced pressure to obtain a crude residue, which was triturated with pentane followed by Et20 to afford 11 g of 5-(6-(benzyloxy)-3-bromo-2- fluorophenyl)-1 ,2,5-thiadiazolidin-3-one 1 ,1 -dioxide lnt-01.1 H NMR (400 MHz, CDCI3) 6 ppm 7.55 (t, 1 H), 7.49 (d, 2H), 7.38-7.28 (m, 3H), 6.93 (dd, 1 H), 5.18 (s, 2H), 3.99 (s, 2H)19F NMR (376 MHz, CDCI3) 6 ppm -109.8 (d)Synthesis of lnt-02: 5-(3-bromo-2-fluoro-6-hydroxyphenyl)-1 ,2,5-thiadiazolidin-3-one 1 ,1 -dioxideTo a stirred solution of 5-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-1 ,2,5-thiadiazolidin-3-one 1 ,1- dioxide lnt-01 (3.0 g, 7.23 mmol, 1 eq.) in DCM (50 mL) was added BBrs (1 M in DCM, 21.7 mL, 21 .7 mmol, 3 eq.) dropwise at -78°C and the resulting reaction mixture was stirred at -78°C. AfterSPC6350-77- completion of the reaction (TLC monitoring), the reaction mixture was quenched with a 7M NH3 solution in MeOH at -78°C and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography eluting with a gradient of CH3CN in H2O (10- 20%) to yield 2.2 g of 5-(2-fluoro-6-hydroxy-3-(4-methylpent-1-yn-1-yl)phenyl)-1 ,2,5- thiadiazolidin-3-one 1 ,1 -dioxide lnt-02.1 H NMR (400 MHz, DMSO-d6) 5 ppm: 7.79 (br s , 2H), 7.39 (t, 1 H), 6.69 (dd, 1 H), 3.98 (s, 2H)Examples of compounds of the invention and their preparationExample 1 : Synthesis of Cpd001 and Cpd002Step-1 : A stirred solution of TMP CAS# 768-66-1 (4.00 g, 28.37 mmol, 1 eq.) in THF (80 mL), was cooled down to -78°C, treated dropwise with a 2.5M n-BuLi solution in hexane (13.62 mL, 34.04 mmol, 1 .2 eq.) and the resulting mixture was left under stirring for 30min warming up to RT. The mixture was cooled down to 0°C before a solution of bis(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)methane CAS# 78782-17-9 (8 g, 28.37 mmol, 1 eq.) in THF (50 mL) was slowly added and stirring was pursued for 10min. Finally iodomethane (1.77 mL, 28.369 mmol, 1 eq.) was added at 0 °C and the resulting reaction mixture was allowed to stir at RT for 1 h. The crude mixture containing the desired intermediate 2,2'-(ethane-1 ,1-diyl)bis(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane) was kept under inert atmosphere and used as such in the next step.A stirred solution of TMP CAS# 768-66-1 (4.41 g, 31.21 mmol, 1.1 eq.) in THF (50 mL) was cooled down to -78°C and slowly treated dropwise with a 2.5M solution of n-BuLi in hexane (12.99 mL, 34.04 mmol, 1.2 eq.) and the reaction mixture was allowed to warm up to -30°C over a 30 min period. Then the solution from step-1 A (crude 2,2'-(ethane-1 ,1-diyl)bis(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane) was added dropwise and stirring was pursed for another 30min period. Finally a solution of tert-butyl 3-oxopyrrolidine-1 -carboxylate CAS# 101385-93-7 (5.26 g, 28.37 mmol, 1 eq.) in THF (30 mL) was added at -30 °C and the resulting reaction mixture was allowed to stir for 16h at RT. After reaction completion (monitored by TLC), the reaction mixture was cooled to 0 °C and carefully quenched adding a sat NH4CI aq. solution. The insolubles were filtered of, the liquor was concentrated and the residue was then taken up in EtOAc and partitioned with water.SPC6350-78-The aqueous layer was back extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over Na2SC>4 and concentrated. The crude product was purified by chromatography over silica gel using a gradient elution of EtOAc (6-7%) in PE to yield 1.3 g of a E / Z mixture of tert-butyl 3-(1-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) ethylidene) pyrrolidine-1 -carboxylate.1H NMR (400 MHz, CDCI3) 6 ppm: 4.21-3.94 (m, 2H), 3.47 (br. s., 2H), 2.85-2.56 (m, 2H), 1.70 (s, 3H), 1.48 (s, 9H), 1.23 (s, 12H).Step-2: To a stirred solution of 5-(3-bromo-2-fluoro-6-hydroxyphenyl)-1 ,2,5-thiadiazolidin-3-one 1 ,1-dioxide lnt-02 (500 mg, 1.54 mmol, 1.0 eq.), (E+Z) tert-butyl 3-(1-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl) ethylidene) pyrrolidine-1 -carboxylate (1.24 g, 3.85 mmol, 2.5 eq.) and K3PO4 (1.306 g, 6.152 mmol, 4 eq.) in a previously degassed mixture of dioxane (20 mL) and water (5 mL) was added under inert atmosphere Pd(dtbpf)Ch CAS# 95408-45-0 (100 mg, 0.15 mmol, 0.1 eq.) and the resulting reaction mixture was stirred at 90 °C for 16 h. After reaction completion (monitored by TLC), the crude reaction mixture was cooled to RT and filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by reverse phase column chromatography over C18 mofidied silica gel using a gradient elution of acetonitrile (10-30%) in water to yield 380 mg of a E / Z mixture of tert-butyl 3-(1-(3-(1 ,1-dioxido-4-oxo-1 ,2,5-thiadiazolidin-2-yl)-2-fluoro-4-hydroxyphenyl) ethylidene) pyrrolidine-1 -carboxylate.LC-MS: exact m / z (calcd): 441 ; m / z (obsd): 440 [M+H]+Step-3: A stirred solution (E+Z) tert-butyl 3-(1-(3-(1 ,1-dioxido-4-oxo-1 ,2,5-thiadiazolidin-2-yl)-2- fluoro-4-hydroxyphenyl) ethylidene) pyrrolidine-1 -carboxylate (350 mg, 0.79 mmol, 1 eq.) in a mixture of DCM (25 mL) and dioxane (25 mL) was slowly treated dropwise at 0°C with a 4N HCI solution in dioxane (1.98 mL, 7.93 mmol, 10 eq.) and the resulting reaction mixture was left under stirring for 16h at RT. Upon completion of the reaction (monitored by TLC), the reaction mixture was concentrated, the residue was suspended in Et20, sonicated for 5min and filtered off to give the crude compound. The crude compound was purified by Prep-HPLC (Method: Mobile phase A: MOBILE PHASE A O mM Ammonium bicarbonate in water, Mobile phase B: acetonitrile, Column: X-SELECT cash phenyl hexyl (19x250mm, 5 pm), Flow: 13 mL / min, Method: (T. / % B): (0 / 5, 4 / 5, 10 / 30, 14 / 30, 14.1 / 99, 18 / 99, 18.1 / 5, 23 / 5), Temperature: Ambient.) to yield35 mg of first eluting (E)-5-(2-fluoro-6-hydroxy-3-(1-(pyrrolidin-3-ylidene)ethyl)phenyl)-1 ,2,5- thiadiazolidin-3-one 1 ,1-dioxide (-trans, 35 mg) Cpd001LC-MS (Method A): r.t 1.57 min.; m / z 342 [M+H]+; m / z 340 [M-H]’1H NMR (400 MHz, DMSO-cfe) 6 ppm: 8.84 (br. s., 2H), 7.01 (t, 1 H), 6.69 (d, 1 H), 3.96 (s, 2H), 3.86 (brs, 2H), 3.20 (t, 2H), 2.33 (t, 2H), 1.91 (s, 3H)19F NMR (376 MHz, DMSO-cfe) 6 ppm: -118.0 (d) and 75 mg of second eluting (Z)-5-(2-fluoro-6-hydroxy-3-(1-(pyrrolidin-3-ylidene)ethyl)phenyl)-SPC6350-79-1 ,2,5-thiadiazolidin-3-one 1 ,1 -dioxide Cpd002LC-MS (Method A): r.t 1.83 min.; m / z 342 [M+H]+; m / z 340 [M-H]’1H NMR (400 MHz, DMSO-cfe) 6 ppm: 8.89 (br. s., 2H), 7.01 (t, 1 H), 6.69 (d, 1 H), 3.96 (s, 2H),3.53 (brs, 2H), 3.32 (t, 2H), 2.64 (t, 2H), 1.95 (s, 3H)19F NMR (376 MHz, DMSO- cfe) 6 ppm: -118.0 (d)Example 2: Synthesis of Cpd003Step-1 : To a stirred solution of tert-butyl 3-oxopyrrolidine-1 -carboxylate CAS# 101385-93-7 (2.0 g, 10.80 mmol, 1 eq.), triphenylphosphine (8.50 g, 32.39 mmol, 3 eq.) and tribromofluoromethane (8.77 g, 32.39 mmol, 3 eq.) in THF (20 mL) was slowy added over a 30min period at RT a 1M diethylzinc solution in hexanes (32.39 mL, 32.39 mmol, 3 eq.) by means of a syringe pump and the resulting reaction mixture was allowed to stir at RT 2 h. Upon completion of the reaction (monitored by TLC), the crude reaction mixture was cooled to 0°C, carefully quenched adding MeOH and the mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel using a gradient elution of EtOAc (5-10%) in PE to yield 1.4 g of a E / Z mixture of tert-butyl 3- (bromofluoromethylene)pyrrolidine-l -carboxylate.1H NMR (400 MHz, CDCI3) 6 ppm: 4.07 (s, 1 H), 3.90 (s, 1 H), 3.58-3.49 (m, 2H), 2.70-2.66 (m, 1 H), 2.56-2.51 (m, 1 H), 1.47 (s, 9H).Step-2: To a stirred solution of E / Z tert-butyl 3-(bromofluoromethylene) pyrrolidine-1 -carboxylate (1.4 g, 5 mmol, 1.0 eq.), bis(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)methane CAS# 78782- 17-9 (1.27 g, 5 mmol, 1.0 eq.) and potassium acetate (1.23 g, 12.49 mmol, 2.5 eq.) in degassed dioxane (15 mL) were added Pd(dppf)Cl2.CH2Cl2 CAS# 95464-05-4 (0.20 g, 0.25 mmol, 0.05 eq.) followed by tricyclohexylphosphine (0.14 g, 0.50 mmol, 0.1 eq.) and the resulting reaction mixture was left under stirring for 16h at 90 °C. Upon completion of the reaction, monitored by TLC, the reaction mixture was cooled down to RT and filtered through a pad of Celite. The filtering cake was rinsed twice with dioxane and the resulting liquor was concentrated under reduced pressure to yield the crude tert-butyl 3-(fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-SPC6350-80- yl)methylene)pyrrolidine-1 -carboxylate which was used as such in the next step.Step-3: To a stirred solution of 5-(3-bromo-2-fluoro-6-hydroxyphenyl)-1 ,2,5-thiadiazolidin-3-one 1 ,1 -dioxide lnt-02 (400 mg, 1.23 mmol, 1.0 eq.), tert-butyl 3-(fluoro(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)methylene)pyrrolidine-1 -carboxylate (603 mg, 1.85 mmol, 1.5 eq.) and K3PO4 (782.51 mg, 3.69 mmol, 3 eq.) in a previously degassed mixture of dioxane (10 mL) and water (3 mL) was added under inert atmosphere Pd(dtpbf)Ch CAS# 95408-45-0 (80.1 mg, 0.12 mmol, 0.1 eq.) and the resulting mixture was heated up to 90°C for 16h. Upon completion of the reaction (monitored by TLC), the crude mixture was cooled down to RT and concentrated under reduced pressure. The crude compound was purified by reverse phase column chromatography over C18 modified silica gel using a gradient elution of acetonitrile (10-30%) in water to yield 150 mg of tertbutyl 3-((3-(1 , 1 -dioxido-4-oxo-1 ,2,5-thiadiazolidin-2-yl)-2-fluoro-4- hydroxyphenyl)fluoromethylene) pyrrolidine-1 -carboxylate.LC-MS: exact m / z (calcd): 445; m / z (obsd): 444 [M-HpStep-4: A stirred solution of tert-butyl 3-((3-(1 ,1-dioxido-4-oxo-1 ,2,5-thiadiazolidin-2-yl)-2-fluoro- 4-hydroxyphenyl)fluoromethylene)pyrrolidine-1-carboxylate (150 mg, 0.34 mmol, 1.0 eq.) in dioxane (6 mL) was cooled to 0°C and treated dropwise with a 4N HCI solution in dioxane (0.42 mL, 1.68 mmol, 5.0 eq.) and the resulting reaction mixture was allowed to stir at RT for 5h. Upon completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by Prep-HPLC (method: MOBILE PHASE A: 10 mM Ammonium bicarbonate (Aq), MOBILE PHASE B: acetonitrile, COLUMN: xselect csh C18(19x250mm, 5pm, FLOW: 13 mL / min, Method: (T / % OF B): 0 / 10, 2 / 10, 10 / 35, 12 / 35, 12.1 / 98, 15 / 98, 15.1 / 10, 18 / 10, Temperature: Ambient) to yield 6 mg of 5-(2-fluoro-3-(fluoro(pyrrolidin-3- ylidene)methyl)-6-hydroxyphenyl)-1 ,2,5-thiadiazolidin-3-one 1 ,1 -dioxide Cpd003 LC-MS (Method A): r.t 1.71 min.; m / z 346 [M+H]+; m / z 344 [M-Hp1H NMR (400 MHz, DMSO-cfe) 6 ppm: 8.86 (br. s., 2H), 7.24 (t, 1 H), 6.77 (d, 1 H), 3.97 (s, 2H), 3.65 (br. s., 2H), 3.26 (t, 2H), 2.73 (t, 2H)19F NMR (376.56 MHz, DMSO-cfe) 6 ppm: -98.94 (s), -115.69 (t)SPC6350-81-Table 2: Analytical LC-MS and NMR data for example compounds of the inventionPart B: Experimental pharmacology procedures / procedures for determining biological activity of the compounds of the inventionExample 3: Activity of the compounds of the invention as PTPN2 and / or PTPN1 inhibitors Phosphatase activity assay to determine potency against PTPN2.Compound activity was determined using a GST-tagged PTPN2 protein (TC45, accession # NP_002819.2) (Active motif, Cat# 31592) in an in vitro enzymatic reaction. The enzymatic assay used to determine potency was the phosphatase (PTP) activity inhibition assay. The assay is performed using a buffer comprising 50mM HEPES pH7.5, 2mM EDTA, 3mM DTT and 100mM NaCI and as phosphated substrate 10 pM 6,8-Difluoro-4-Methylumbelliferyl Phosphate (DiFMUP) (ThermoFisher, Cat# D6567) was used.The assay is carried out at room temperature in 384-well plate. The compounds were dispensed on a white 384-well plate at varying concentrations (10 point, 1 : 5 dilution). Next, PTPN2 enzyme was added at final concentration of 4 nM and incubated with compound for 10 minutes at room temperature. Then, the reaction is initiated by adding the substrate (DIFMUP) mix to each well of reaction plate to the final concentration of 10 pM , followed by incubation at room temperature for 30 minutes. Finally, a guench solution was added to the reaction plates and the phosphatase activity of the PTPN2 enzyme is assessed by monitoring the appearance of the fluorescent product 6,8-difluoro-7-hydroxyl-4-coumarin (DiFMU) from DiFMUP using the EnVision® multimode plate reader (PerkinElmer, Cat# 2105-0010) with excitation of 360 nm and emission at 450 nm for DiFMU. The % of DIFMU conversion (the amount of phosphorylated substrate which was de-phosphorylated by PTPN2) was plotted against the concentration of theSPC6350-82- small molecule PTPN2 inhibitor, and the data were fitted using a four-parameter equation. Each plate had a positive control (no PTPN2 enzyme) and a negative control (DMSO + PTPN2 enzyme), which were used to calculate % of inhibition. The % inhibition was then used to determine the IC50 values of the compounds disclosed here for the specific PTPN2 enzyme. Phosphatase activity assay to determine potency against PTPN1.Compound activity was determined using a GST-tagged PTPN1 protein (PTP1 B, accession # NP_002818.1) (Active motif, Cat# 81034) in an in vitro enzymatic reaction. The enzymatic assay used to determine potency was the phosphatase (PTP) activity inhibition assay. The assay is performed using a buffer comprising 50mM HEPES pH7.5, 2mM EDTA, 3mM DTT and 100mM NaCI and as phosphated substrate 10 pM 6,8-Difluoro-4-Methylumbelliferyl Phosphate (DiFMUP) (ThermoFisher, Cat# D6567) was used.The assay is carried out at room temperature in 384-well plate. The compounds were dispensed on a white 384-well plate at varying concentrations (10 point, 1 : 5 dilution). Next, PTPN1 enzyme was added at final concentration of 2 nM and incubated with compound for 10 minutes at room temperature. Then, the reaction is initiated by adding the substrate (DIFMUP) mix to each well of reaction plate to the final concentration of 10 pM, followed by incubation at room temperature for 30 minutes. Finally, a quench solution was added to the reaction plates and the phosphatase activity of the PTPN1 enzyme is assessed by monitoring the appearance of the fluorescent product 6,8-difluoro-7-hydroxyl-4-coumarin (DiFMU) from DiFMUP using the EnVision® multimode plate reader (PerkinElmer, Cat# 2105-0010) with excitation of 360 nm and emission at 450 nm for DiFMU. The % of DIFMU conversion (the amount of phosphorylated substrate which was de-phosphorylated by PTPN2) was plotted against the concentration of the small molecule PTPN1 inhibitor, and the data were fitted using a four-parameter equation. Each plate had a positive control (no PTPN1 enzyme) and a negative control (DMSO + PTPN1 enzyme), which were used to calculate % of inhibition. The % inhibition was then used to determine the IC50 values of the compounds disclosed here for the specific PTPN1 enzyme. Activities of example compounds of the invention in the PTPN2 and PTPN1 inhibition assays are depicted in the table below.SPC6350-83-Table 3: PTPN2 and PTPN1 inhibitory activity of compounds of the invention. “A” represents IC50 <500 nM; “B” represents an IC50 of 500nM < IC50 s 2 pM and “C” represents IC50 > 2 pM.Example 4: Activity of the compounds of the invention to potentiate / enhance IFNy- induced / mediated tumor growth inhibitionIFNy is a cytokine that is produced by immune cells, like T cells or NK cells. It plays a crucial role in regulating anti-tumor immune responses and it has been shown to have anti-proliferative and anti-tumor effects in various cancer types, including melanoma and colorectal cancer. Notably, tumor growth is promoted when IFNy signaling is impaired, whereas enhancing IFNy signaling leads to greater inhibition of tumor growth. Since PTPN2 and PTPN1 act as negative regulators of cytokine signaling, including IFNy signaling, by dephosphorylating JAK and STAT proteins, the compounds of the invention facilitate tumor growth arrest in the presence of IFNy. Compounds of the present invention amplify mouse B16F10 melanoma and human T84 colorectal cancer cells growth inhibition in the presence of IFNy.Mouse B16F10 cells IFNy-lnduced Growth Inhibition AssayB16F10 mouse melanoma cells (ATCC Cat# CRL-6475) are seeded at density of 1500 cells per well in two 96-well white bottom plates (Greiner, Cat# 655083) in 100 pL total volume of RPMI 1640 + 10% FBS. Cells are allowed to adhere for 3 hours at 37oC + 5% CO2. Next, compounds are resuspended in DMSO at 10 mM were diluted in 1 : 3 dilutions in DMSO ranging from 10 mM to 0.0002 mM and DMSO only controls are included. The compound / DMSO dilutions are further diluted 1 : 25 in RPMI 1640 + 10% FBS, and 50 pL of these dilutions are added in duplicates to cells of both plates. Final compound concentration range from 100 pM to 0.002 pM with a final DMSO concentration of 1%. Compounds are only dosed in the inner 60-wells avoiding the outer 1-well perimeter of the plate to minimize edge effects. Next, 50 pL of mouse IFNy (Roche, Cat# 11276905001) is added to the first plate at a concentration of 2 ng / mL for a final assay concentration of 0.5 ng / mL of IFNy. Media only (50 pL of RPMI 1640 + 10% FBS) is added to the second plate and both IFNy treated and non- IFNy control plates are maintained in a 37°C + 5% CO2 incubator. After 5 days of incubation, plates are leveled up to 50 pL and 50 pL of ATPIiteSPC6350-84-(PerkinElmer, Cat# 6016949) is added to determine cell growth. After incubation for 10 minutes at room temperature under shaking, luminescence signal is measured using the EnVision® multimode plate reader (PerkinElmer, Cat# 2105-0010). For each compound, the percent growth inhibition at every compound dose level is calculated relative to the "DMSO / with IFNy” control and used to determine the IC50.Human T84 cells IFNy-lnduced Growth Inhibition AssayT84 human colorectal carcinoma cells (ATCC Cat# CCL-248) are seeded in a 96-well format. Before cell seeding, plates are coated with 40ul of 40 pg / mL rat tail collagen type I (Gibco, Cat# A10483-01) in 20 mM acetic acid and allowed for 1 hour in room temperature for achieving a thin collagen layer. Next, plates are washed 3 times with PBS and T84 cells are seeded at density of 3500 cells per well in two 96-well white bottom plates (Greiner, Cat# 655083) in 100 pL total volume of DMEM / F12 + 10% FBS. Cells are allowed to adhere for 3 hours at 37oC + 5% CO2. Next, compounds resuspended in DMSO at 10 mM are diluted in 1 : 3 dilutions in DMSO ranging from 10 mM to 0.0002 mM and DMSO only controls are included. The compound / DMSO dilutions are further diluted 1 : 25 in DMEM / F12 + 10% FBS, and 50 pL of these dilutions are added in triplicates to cells of both plates. Final compound concentration range from 100 pM to 0.002 pM with a final DMSO concentration of 1 %. Compounds are only dosed in the inner 60-wells avoiding the outer 1-well perimeter of the plate to minimize edge effects. After, 50 pL of human IFNy (Roche, Cat# 1104596001) are added to the first plate at a concentration of 20 ng / mL for a final assay concentration of 5 ng / mL of IFNy. Media only (50 pL of RPMI 1640 + 10% FBS) is added to the second plate and both IFNy treated and non- IFNy control plates are maintained in a 37°C + 5% CO2 incubator. After 4 days of incubation, plates are leveled up to 50 pL and 50 pL of ATPIite (PerkinElmer, Cat# 6016949) are added to determine cell growth. After incubation for 10 minutes at room temperature under shaking, luminescence signal is measured using the EnVision® multimode plate reader (PerkinElmer, Cat# 2105-0010). For each compound, the percent growth inhibition at every compound dose level is calculated relative to the "DMSO / with IFNy” control and used to determine the IC50.Example 5: T cell activation activity of the compounds of the invention as antitumor response evidenced by enhanced phosphorylation of STAT1 in human Jurkat T cells stimulated with IFNyIFNy in T cells promotes activation of multiple signaling pathways associated with T cell activation and antitumor responses. A key target of this signaling is phosphorylation of the transcriptional factor STAT1. STAT1 is also a direct target of PTPN2 and PTPN1 which serve as negative regulators of IFNy signaling. A PTPN2 / N1 inhibitor is expected to increase the phosphorylation ofSPC6350-85-STAT1 upon stimulation with IFNy.To assess the ability of compounds of the invention to stimulate T cell activation as evidenced by increase in pSTATI signaling, human Jurkat T cells (DSMZ, Cat# ACC282) are seeded at a density of 150.000 cells per well in a 96-well Il-bottom plate in 25 pL total volume of RPMI + 1 % FCS. Next, compounds resuspended in DMSO at 10 mM are diluted in 1 :3 dilutions in DMSO ranking from 10 mM to 0.005 mM and DMSO only controls are included. The compound / DMSO dilutions are further diluted in 1 :74 in RPMI + 1 % FCS, and 10 pL of these increasing concentrations of the compound dilutions are added in duplicates to cells and incubated for 2.5 hours at 37°C. Final compound concentration ranges from 30 pM to 0.014 pM with a final DMSO concentration of 0.3%.To induce STAT1 phosphorylation, 10 pL of human IFNy (Roche Cat# 1104096001) is added at a concentration of 22.5 ng / ml for a final assay concentration of 5 ng / ml IFNy. After 30 minutes incubation, 15 pL / well of 4x supplemented lysis buffer (PerkinElmer, Cat# 64KL2FDF) is added and samples are incubated for 1 hour at room temperature under shaking. After homogenization by pipetting up and down, 16 pL of cell lysates are subsequently transferred from the 96-well cellassay plate to a 384-small volume (SV) white detection plate for the detection of Phospho-STAT 1 by HTRF Phospho-STAT1 (Tyr701) cellular kit (PerkinElmer Cat# 63ADK026PEH) ending with quadruples per cpd dilution.In particular, 4 pL of premixed Phospho-STAT1 (Tyr701) antibody solutions (vol / vol), using 2 different specific antibodies, one labelled with Eu3+-Cryptate (donor) and the second with d2 (acceptor), are prepared in the detection buffer and added in the detection plates. After overnight incubation at room temperature, the fluorescence emission at two different wavelengths (665nm and 620nm) is measured using the EnVision® multimode plate reader (PerkinElmer, Cat# 2105- 0010). The amount of STAT 1 phosphorylation is assessed by calculating the ratio of the acceptor and donor emission signals for each individual well. For each compound the percentage of STAT 1 phosphorylation enhancement at every compound dose level is calculated relative to the "DMSO / with IFNY" control. Compound dose-response curves are determined using a four- parameter logistic non-linear regression model from which half maximal effective concentrations (ECso) were calculated.Protein tyrosine phosphatases PTPN2 and PTPN1 serve as negative regulators for various cellular pathways, including JAK / STAT-mediated cytokine signaling involving IFNy, IFNa, and IL2. Inhibition of PTPN2 / N1 is anticipated to enhance STAT phosphorylation by delaying the dephosphorylation of STAT proteins. To assess the impact of compounds on IFNy signaling, the phosphorylation of the direct target of PTPN2 / N1 , STAT1 , was measured as proximal translational marker in human Jurkat T cells. The Jurkat T cell line facilitates high-throughput assessment of PTPN2 / N1 inhibitors in potentiating the activation of human T cells in a doseSPC6350-86- dependent manner with determination of half maximal effective concentrations. In human Jurkat T cells treated with active compounds, a dose dependent enhancement of STAT1 phosphorylation after stimulation with IFNy was observed. The results demonstrate that the exemplified compounds disclosed herein (e.g. PTPN2 / N1 inhibitors) are capable of enhancing T cell activation associated with IFNy-induced STAT1 phosphorylation. The activities of the example compounds of the invention are shown in the table below.Table 4: Activity of the compounds of the invention in the pSTATI assay. “A” represents an IC50 < 5 pM; “B” represents an IC50 of 5 pM < IC50 < 30 pM and “C” represents an IC50 > 30 pM.Example 6: Activation of primary human T cells by compounds of the invention as evidenced by enhanced expression of activation markers and increased production of cytotoxic effector molecules and antitumor cytokinesEnhancing T cell activation and function is a main strategy in novel immune oncology approaches aimed at promoting effective tumor immunity. In vitro assays utilizing primary T cells are frequently employed to evaluate the effects of compounds on T cell activation and function.Primary human CD3+ T cells are isolated from PBMCs using a StemCell T cell isolation kit ( StemCell technologies, Grenoble, France) according to manufacturer’s instructions. Isolated T cells (150.000 cell / well) are re-suspended in RPM1 1640 supplemented with 10% FBS and seeded into antiCD28 / antiCD3 coated 96-well flat-bottom cell culture wells. Directly after seeding, the PTPN2 / 1 inhibitors are added at concentrations ranging from 3 - 30 pM. The same amount of DMSO only is added to controls. After 4 and 24 hours of stimulation, cells are re-stimulated with PMA (50 ng / mL) and lonomycin (1 pM) in the presence of Brefeldin A (3 ug / mL) to stain for a panel of different cytokines (e.g TNFa+ and IFNy+) and T cell activation and suppression markers (e.g GrzB, Perforin, PD1 , CTL4). After 3 hours incubation, the cells are stained with Zombie NIR Fixable Viability Kit (Biolegend, San Diego, CA) diluted in Dulbecco’s PBS for 10 minutes on ice to exclude dead cells followed by staining for surface markers for 15 minutes on ice using the following flow cytometry antibodies in FACS buffer (PBS, 2% FCS, 2mM EDTA): Brilliant Violet (BV) 450-labeled anti-CD45, Brilliant Utraviolet (BUV) 661-labeled anti-CD3, Brilliant Violet (BV) 570-labeled anti-CD4, PE-TexasRed-labeled anti-CD8, Brilliant Blue 630-labelled anti-CD69,SPC6350-87-BV605-CTL4 and Pacific Blue -PD1. Cells are washed in FACS buffer, permeabilized with Fixation / Permeabilization Buffer (FoxP3 / transcriptional Factor Staining Buffer Set, eBioscience) and stained intracellularly with PE-labeled anti-pSTAT1 , PerCP-Cy5.5-labeled anti-Granzyme B, PE-Cy7-labelled anti-IFNy and BV781 -labelled anti-TNFa diluted in Permeabilization buffer for 15 minutes on ice. After staining, cells are washed with Permeabilization buffer, and the samples are acquired on a BD Symphony flow cytometer (BD Biosciences, San Jose, CA) and analyzed with FlowJo V10 software (FlowJo, Ashland, OR). The frequency of the direct target engagement marker pSTATI , along with the activation and suppression markers within CD4+ and CD8+ T cell populations, is evaluated in primary human T cells treated with either vehicle or the compound. An increase in T cell activation markers, coupled with elevated production of cytotoxic effector molecules and antitumor cytokines, indicates enhanced T cell cytotoxic activity.Example 7: In vivo immune cell activation by compounds of the invention upon systemic dosing in miceIn vivo compound treatment and assessment of target engagement and immune cell activation: Wild type C57BI / 6 female mice are sacrificed on day 1 , after a single oral dose with either a PTPN2 / 1 inhibitor or a vehicle control (n = 5 mice / group). After 6 hours post compound or vehicle administration, spleens are excised and dissociated over 100um strainers, red blood cells lysed, and single cell suspensions are prepared. The cells are stimulated with PMA (50 ng / mL) and lonomycin (1 uM) in the presence of Brefeldin A (3 ug / mL) to stain for cytokines (e.g TNFa and IFNy) and activation markers in T and myeloid cells. After 3.5 hours incubation, the cells are stained with Zombie NIR Fixable Viability Kit (Biolegend, San Diego, CA) diluted in Dulbecco’s PBS for 10 minutes on ice to exclude dead cells followed by staining for surface markers for 15 minutes on ice using the following flow cytometry antibodies in FACS buffer (PBS, 2% FCS, 2mM EDTA): Brilliant Utraviolet (BUV)661 -labeled anti-CD3, Brilliant Violet(BV)-labeled anti CD4, PE- TexasRed-labeled anti-CD8, Alexa Fluor700-labeled anti-MHCll, PE-Cy5 labeled anti F4 / 80, eFluor450-CD11c, BV570-labeled anti-B220, BUV563-labeled anti-Ly6G, BV605-labeled anti- CD11 b. Cells were washed in FACS buffer, permeabilized with Fixation / Permeabilization Buffer (FoxP3 / transcriptional Factor Staining Buffer Set; eBioscience) and stained intracellularly with PE-labeled anti-pSTAT1 , APC-labelled-pSTAT5, PerCP-Cy5.5-labeled anti-Granzyme B, PE- Cy7-labelled anti-IFNy, Fitc-labelled anti-Perforrin, and BV785-labelled anti-TNFa diluted in Permeabilization buffer for 15 minutes on ice. After staining, cells are washed with Permeabilization buffer, and the samples were acquired on a BD Symphony flow cytometer (BD Biosciences, San Jose, CA) and analysed with FlowJo V10 software (FlowJo, Ashland, OR). The mean fluorescence intensity (MFI) and / or the frequency of pSTAT1+ and pSTAT5+ cells within T cell populations and macrophages in animals treated with vehicle or compound are evaluated asSPC6350-88- markers of target engagement. Similarly, the MFI and / or the frequency of Granzyme B+, Perforin+, TNFa+, and IFNy+ cells within splenic T cell populations, as well as MHC-II+ cells within macrophages, are assessed as markers of immune cell activation.In vivo immune activation in splenic CD8+ T cells is characterized by elevated levels of STAT 1 and STAT5 phosphorylation following the administration of PTPN2 / 1 inhibitors. This immune activation is further associated with enhanced cytotoxic activity of CD8+ T cells, as evidenced by increased expression of Granzyme B, I FNy, and TNFa, which mediate cytotoxic CD8+ T cell responses.Example 8: In vivo efficacy of PTPN2 / 1 inhibitors of the invention in syngeneic subcutaneous MC38 mouse tumor model and impact on pharmacodynamic markers.Tumor Cell Inoculation and Treatments: Cells are grown to passage 3 in vitro. A total of 3 x 105viable MC-38 cells (1 OOul, re-suspended in cell culture medium) are injected subcutaneously into the left and right flanks of 9-12 week old female C57BI / 6 mice on day 0. Treatments are initiated on day 6. Dosing of mice is conducted orally. Mice are dosed with either PTPN2 / 1 inhibitors or vehicle controls (n = 5 mice / group).Assessment of inhibition of tumor growth inhibition: Tumor volume is calculated every 2ndday. Measurements of the length (L) and width (W) of the tumor is taken via electronic caliper and the volume is calculated according to the ellipsoid equation: V = % x n x L / 2 x (W / 2)2. Mice are euthanized on day 13 post tumor inoculation. Tumor growth inhibition (TGI) is calculated as TGI = 1-(Mean TVTimepoint (Treatment) I Mean TVTimepoint (vehicle) for each time point that tumor volumes is measured.Assessment of tumor infiltrating CD8+ T cell activation: Mice are sacrificed on day 14 of the study and tumors are excised. Tumors are digested in digestion solution (0.5 mg / mL collagenase type IV (Sigma Aldrich) and 0.05 mg / mL DNAse I) to obtain single cell suspensions. Next, tumor single cell suspensions are re-stimulated with PMA (50ng / mL) and lonomycin (1 uM) in the presence of Brefeldin A (3 ug / mL) to stain for cytokines (e.g TNFa+ and IFNy+) and T cell activation and immunosuppression markers (e.g GrzB, CTL4, PD1). After 3.5 hours incubation, tumor cells are stained with Zombie NIR Fixable Viability Kit (Biolegend, San Diego, CA) diluted in Dulbecco’s PBS for 10 minutes on ice to exclude dead cells followed by staining for surface markers for 15 minutes on ice using the following flow cytometry antibodies in FACS buffer (PBS, 2% FCS, 2mM EDTA): Brilliant Violet(BV)480-labeled anti-CD45, Brilliant Utraviolet (BUV)661 -labeled anti-CD3, BV570-labeled anti CD4, PE-TexasRed-labeled anti-CD8, BV605-CTL4, Pacific Blue-PD1 , Alexa Fluor700-FoxP3. Cells are washed in FACS buffer, permeabilized with Fixation / Permeabilization Buffer (FoxP3 / transcriptional Factor Staining Buffer Set; eBioscience) and stained intracellularlySPC6350-89- with PE-labeled anti-pSTAT1, PerCP-Cy5.5-labeled anti-Granzyme B and PE-Cy7-labelled anti- IFNy, BV785-TNFa diluted in Permeabilization buffer for 15 minutes on ice. After staining, cells are washed with Permeabilization buffer, and the samples are acquired on a BD Symphony flow cytometer (BD Biosciences, San Jose, CA) and analysed with FlowJo V10 software (FlowJo, Ashland, OR). The frequency and mean fluorescence intensity (MFI) levels of different activation and suppression markers within intratumor T cell populations in vehicle or compound treated animals are assessed.Anti-tumor efficacy in the MC38 mouse model is demonstrated by substantial inhibition of tumor growth. Enhanced activation of intratumoral CD8+ T cells is evidenced by increased STAT1 phosphorylation and elevated levels of immunoactivation markers

Claims

SPC6350CLAIMS1. A compound of formula (I), a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), a solvate, a hydrate, a polymorph, an isotope, and / or a prodrug thereof,wherein:- X1is N or C;X2is N or CR6; X3is N or CR8; X4is N or CR3; wherein maximum two groups selected from X2, X3and X4are nitrogen;- isanoptional double bond when valencies allow;R1is selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; cycloalkylheteroalkyl; cycloalkenylheteroalkyl; cycloalkynylheteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; heteroarylalkynyl; heteroarylalkenyl; heterocyclylalkyl; heterocyclylalkenyl; heterocyclylalkynyl; aryl heteroalkyl; heteroarylheteroalkyl; and heterocyclylheteroalkyl; whereby each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkynylalkyl, cycloalkylheteroalkyl, cycloalkenylheteroalkyl, cycloalkynylheteroalkyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkynyl, heteroarylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, arylheteroalkyl, heteroarylheteroalkyl and heterocyclylheteroalkyl is unsubstituted or is substituted with one or more R4;R2is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and halogen; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl is optionally substituted with one or more halogen, alkyl, cycloalkyl, hydroxyl, sulfhydryl, =0,SPC6350-91-=S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, - N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, -N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)- NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; or, R1and R2taken together form a cycloalkyl; cycloalkenyl; cycloalkynyl; or heterocycle; wherein said cycloalkyl, cycloalkenyl, cycloalkynyl or heterocycle is unsubstituted or substituted with one or more R4; each R4is independently selected from halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ1, -SZ1, -NZ1Z2, -N(Z1)-S(=O)2-Z2, -N(Z1)- S(=O)(=NZ1)-Z2, -S(=O)2-NZ1Z2, -S(=O)(=NZ1)-NZ1Z2, -S(=NZ1)(=NZ1)-Z2, -N(Z1)-S(=O)2- NZ1Z2, -S(=O)2-Z2, -S(=O)-Z2, -S(=O)(=NZ1)-Z2, -N=S(=O)Z1Z2, -O-C(=O)-Z2, -C(=O)-O-Z2, - C(=O)-Z2, -O-C(=O)-NZ1Z2, -NZ1-C(=O)-O-Z2, -C(=O)-NZ1Z2, -NZ1-C(=O)-Z2, -NZ3C(O)NZ3Z4, -P(O)Z1Z2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, cycloalkyl-heteroalkyl, cycloalkylheteroalkenyl, cycloalkyl-heteroalkynyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, aryl-heteroalkyl, aryl-heteroalkenyl, aryl- heteroalkynyl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl-heteroalkyl, heteroaryl-heteroalkenyl, heteroaryl-heteroalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, heterocyclyl- heteroalkynyl, alkyl-oxy-alkyl, (mono or di)alkylamino, (mono or di-)alkyl-amino-alkyl, alkylthio, and alkyl-thio-alkyl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, cycloalkyl-heteroalkyl, cycloalkylheteroalkenyl, cycloalkyl-heteroalkynyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, aryl-heteroalkyl, aryl-heteroalkenyl, aryl- heteroalkynyl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl- heteroalkyl, heteroaryl-heteroalkenyl, heteroaryl-heteroalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl- heteroalkenyl, heterocyclyl-heteroalkynyl, alkyl-oxy-alkyl, (mono or di)alkylamino, (mono or di-)alkyl-amino-alkyl, alkylthio and alkyl-thio-alkyl is unsubstituted or is substituted with one or more R41; or two R4, optionally two R4on two adjacent atoms or on the same atom, can be taken together in order to form a 4-, 5-, 6-, 7- or 8-membered heterocycle or a 3-, 4-, 5-, 6-, 7- or 8- membered cycloalkyl, wherein said heterocycle and cycloalkyl is unsubstituted or is substituted with one or more R41; each Z1and Z2is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl,SPC6350-92- heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylal kynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocycly I heteroalkyl, heterocyclylheteroalkenyl, and heterocyclyl heteroal kynyl ; or, Z1and Z2, optionally bound to the same atom, together form a 4-, 5-, 6-, 7- or 8-membered heterocycle or a 3-, 4-, 5-, 6-, 7- or 8-membered cycloalkyl, wherein said heterocycle and cycloalkyl is unsubstituted or is substituted with one or more R41; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, 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 R41; each R41is independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, =0, =S, - SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, aryl, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, -OZ3, -NZ3Z4, -N(Z3)-S(=O)2-Z4, -N(Z3)-S(=O)(=NZ3)-Z4, -S(=O)2-NZ3Z4, -S(=O)(=NZ3)-NZ3Z4, -N(Z3)- S(=O)2-NZ3Z4, -S(=O)2-Z3, -S(=O)-Z3, -S(=O)(=NZ3)-Z4, -N=S(=O)Z3Z4, -O-C(=O)-Z3, -C(=O)- O-Z3, -C(=O)-Z3, -O-C(=O)-NZ3Z4, -NZ3-C(=O)-O-Z4, -C(=O)-NZ3Z4, -NZ3-C(=O)-Z4; or, two R41on two adjacent atoms or attached to the same atom together form a Cs-s-cycloalkyl or C4-8-heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclylalkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroarylalkynyl, aryl, aryl-alkyl, aryl-alkenyl and aryl-alkynyl is optionally substituted with one or more R42; each Z3and Z4is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, aryl-heteroalkyl, aryl-heteroalkenyl, arylheteroalkynyl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl-heteroalkyl, heteroaryl-heteroalkenyl, heteroaryl-heteroalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl,SPC6350-93- heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, and heterocyclyl- heteroalkynyl; wherein said each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocycly I heteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl is unsubstituted or is substituted with one or more R42; or, Z3and Z4bound to the same atom form a 4-, 5-, 6-, 7- or 8-membered heterocycle or a 3- , 4-, 5-, 6-, 7- or 8-membered cycloalkyl, wherein said heterocycle and cycloalkyl is unsubstituted or is substituted with one or more R42; each R42hydrogen, halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclylalkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroarylalkynyl, aryl, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)- S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, - S(=O)-Z5, -S(=O)(=NZ5)-Z6, -N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)- NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; or, two R42on two adjacent atoms or attached to the same carbon atom together form a Cs-s-cycloalkyl or C4-8-heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclylalkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroarylalkynyl, aryl, aryl-alkyl, aryl-alkenyl or aryl-alkynyl is optionally substituted by halogen, alkyl, cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, - S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, - N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; each Z5and Z6are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, aryl, aryl-alkyl, aryl-alkenyl and aryl-alkynyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl,SPC6350-94- cycloalkyl-alkenyl, cycloalkyl-alkynyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl- alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl- alkynyl, aryl, aryl-alkyl, aryl-alkenyl and aryl-alkynyl is optionally substituted with halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, C1- 4-alkyl, C3-7-cycloalkyl, -O-Ci-4-alkyl, -O-C3-7-cycloalkyl, -NH-Ci-4-alkyl, -N(Ci-4-alkyl)2, and -NH-C3-7-cycloalkyl;R5is selected from halogen, -OH, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl and heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl and heterocyclyl is optionally substituted by one or more R20;R3, R6, R7,R8, R9and R10are independently selected from hydrogen, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Cs-w-heterocyclyl, -OR12, -OR15, -O-(Ci-6 alkyl)-OR15, - SR12, -N(R12)(R13), -C(=O)-OR12, -OC(=O)-N(R12)(R13), -N(R12)-C(=O)- N(R12)(R13), -N(R12)-C(=O)-OR12, -N(R12)-S(=O)2R12, -C(=O)R12, -S(=O)R12, -O-C(=O)-R12, - C(=O)-N(R12)(R13), -C(=O)C(=O)-N(R12)(R13), -N(R12)-C(=O)R12, -S(=O)2-R12,S(O)(NR12)R12, -S(=O)2-N(R12)(R13), and -S(=O)(=NR12)-N(R12)(R13), wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one, two, or three R20; or, R7and R8taken together form a cycloalkyl, heterocyclyl or heteroaryl, optionally substituted with one, two or three R20;R11is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl heteroalkyl, heterocyclyl, heterocyclyl- alkyl, heterocyclyl-heteroalkyl, (5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl, -C(=O)-OR12, -C(=O)- O-(Ci-6-alkyl)-OR15, -(Ci-6-alkyl)-OR15, -C(=O)R12, -C(=O)-N(R12)(R13),C(=O)C(=O)N(R12)(R13), -S(=O)2R12, -S(=O)(=NR12)R12, -S(=O)2N(R12)(R13), and - S(=O)(=NR12)N(R12)(R13), wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heterocyclyl, heterocyclyl- alkyl, and heterocyclyl-heteroalkyl are optionally substituted with one, two, or three R20; each R12is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl are optionally substituted with one, two, or three R20;R13is independently selected at each occurrence from hydrogen, alkyl, and haloalkyl; or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;R15is independently selected at each occurrence from hydrogen, (5-methyl-2-oxo-1,3-dioxol- 4-yl)methyl, -C(=O)-OR12, -C(=O)-R12, -P(=O)(Y-R16)(Y-R17), -CH2P(O)(Y-R16)(Y-R17), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl, wherein alkyl,SPC6350-95- alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl are optionally substituted with one, two, or three R20; each Y is independently selected at each occurrence from -O- and -N(R12)-;R16and R17are independently selected at each occurrence from hydrogen, alkyl and phenyl, wherein alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, cyano, cycloalkyl, heterocycle, -OR12, -SR12, - N(R12)(R13), -C(=O)-OR12, -O-C(=O)-N(R12)(R13), -N(R12)-C(=O)-N(R12)(R13), -N(R12)-C(=O)- OR12, -N(R12)-S(=O)2R12, -N(R12)-S(=O)2N(R12)(R13), -S-S-R12, -S-C(=O)R12, -C(=O)R12, - S(=O)R12, -O-C(=O)R12, -O-C(=O)-OR12, -C(=O)-N(R12)(R13), -C(=O)C(=O)N(R12)(R13), - N(R12)-C(=O)R12, -S(=O)2R12, -S(=O)(=NR12)R12, -S(=O)2-N(R12)(R13), -S(=O)(=NR12)- N(R12)(R13), -P(=O)(OR12)2, -P(=O)(R12)2, -O-P(=O)(OR12)2, =0, =S, and =NR12; or R16and R17are taken together with the atoms to which they are attached to form a heterocycle optionally substituted with one, two, or three R20;R20is independently selected at each occurrence from halogen, oxo, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl heteroalkyl, heterocyclyl, heterocyclyl-alkyl, heterocyclyl-heteroalkyl, -OR22, -SR22, - N(R22)(R23), =NR22, =C(R21)2, -C(=O)OR22, -O-C=(O)-N(R22)(R23), -N(R22)-C(=O)-N(R22)(R23), -N(R22)-C(=O)-OR22, -N(R22)S(=O)2R22, -C(=O)R22, -S(=O)R22, -OC(=O)R22, -C(=O)N(R22)(R23), -C(=O)C(=O)N(R22)(R23), -N(R22)C(=O)R22, -S(=O)2R22, -S(=O)(=NR22)R22, -S(=O)2N(R22)(R23), -S(=O)(=NR22)N(R22)(R23), and -O-CH2-C(=O)-OR22; or, two R20attached to the same or adjacent atoms optionally join to form cycloalkyl or heterocycle;- wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl heteroalkyl, heterocyclyl, heterocyclyl-alkyl and heterocyclyl- heteroalkyl are optionally substituted with one or more substituents independently selected from halogen, oxo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)-C(=O)-N(R22)(R23), -N(R22)-C(=O)- OR22, -N(R22)-S(=O)2.R22, -C(=O)-R22, -S(=O)R22, -O-C(=O)R22, -C(=O)-N(R22)(R23), - C(=O)C(=O)N(R22)(R23), -N(R22)C(=O)R22, -S(=O)2R22, -S(=O)(=NR22)R22,S(=O)2N(R22)(R23), and -S(=O)(=NR22)N(R22)(R23);R21is independently selected at each occurrence from hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl, or two R21are taken together with the carbon atom to which they are attached to form cycloalkyl or heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, alkyl, haloalkyl, and -OH;R22is independently selected at each occurrence from hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl;R23is independently selected at each occurrence from hydrogen and alkyl;SPC6350-96- or R22and R23attached to the same nitrogen atom form heterocycle.

2. A compound according claim 1 , wherein each R4is independently selected from halogen, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8- cycloalkyl, C4-8-cycloalkenyl, Cs-s-cycloalkyl-Ci-e-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8- cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-Ci-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8- cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl- C2-6-alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, C5-12- heteroaryl-C2-6-alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, -OZ1, -NZ1Z2, -N(Z1)-S(=O)2-Z2, -N(Z1)-S(=O)(=NZ1)-Z2, -S(=O)2-NZ1Z2, - S(=O)(=NZ1)-NZ1Z2, -N(Z1)-S(=O)2-NZ1Z2, -S(=O)2-Z2, -S(=O)-Z2, -S(=O)(=NZ1)-Z2, - N=S(=O)Z1Z2, -O-C(=O)-Z2, -C(=O)-O-Z2, -C(=O)-Z2, -O-C(=O)-NZ1Z2, -NZ1-C(=O)-O-Z2, - C(=O)-NZ1Z2, -NZ1-C(=O)-Z2; or, two R4attached to the same carbon atom together form a Cs-s-cycloalkyl or C4-i2-heterocyclyl; wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8- cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-e-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-8- cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4- 12-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally further substituted with one, two, three or four R41;- Z1and Z2are independently selected from hydrogen, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs- s-cycloalkyl, C4-8-cycloalkenyl, Cs-s-cycloalkyl-Ci-e-alkyl, Cs-s-cycloalkyl-Cs-e-alkenyl, C3-8- cycloalkyl-C2-6-alkynyl, C4-s-cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-8- cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl- C2-6-alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, C5-12- heteroaryl-C2-6-alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8- cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-e-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-8- cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4- 12-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6-SPC6350-97- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally further substituted with one, two, three or four R41; each R41is independently selected from halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, Cs-s-cycloalkyl-Ci-e-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6- alkynyl, C4-8-cycloalkenyl-Ci-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6- alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, - OZ3, -NZ3Z4, -N(Z3)-S(=O)2-Z4, -N(Z3)-S(=O)(=NZ3)-Z4, -S(=O)2-NZ3Z4, -S(=O)(=NZ3)-NZ3Z4, - N(Z3)-S(=O)2-NZ3Z4, -S(=O)2-Z3, -S(=O)-Z3, -S(=O)(=NZ3)-Z4, -N=S(=O)Z3Z4, -O-C(=O)-Z3, - C(=O)-O-Z3, -C(=O)-Z3, -O-C(=O)-NZ3Z4, -NZ3-C(=O)-O-Z4, -C(=O)-NZ3Z4, -NZ3-C(=O)-Z4; or, two R41attached to the same carbon atom together form a Cs-s-cycloalkyl or C4-i2-heterocyclyl wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8- cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-e-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-8- cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4- 12-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally further substituted with one, two, three or four R42;Z3and Z4are independently selected from hydrogen, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs- s-cycloalkyl, C4-8-cycloalkenyl, Cs-s-cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-e-alkenyl, C3-8- cycloalkyl-C2-6-alkynyl, C4-s-cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-8- cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl- C2-6-alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, C5-12- heteroaryl-C2-6-alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8- cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-e-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-8- cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4- 12-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6-SPC6350-98- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally further substituted with one, two, three or four R42; each R42is independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, =0, =S, - SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, Cs-s-cycloalkyl-Ci-e-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8- cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-Ci-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8- cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl- C2-6-alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, C5-12- heteroaryl-C2-6-alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, - S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, - N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O-Z6, - C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; or, two R42attached to the same carbon atom together form a Cs-s-cycloalkyl or C4-i2-heterocyclyl; wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8- cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-e-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-8- cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6-alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4- 12-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally substituted by halogen, Ci-6-al kyl , Cs-s-cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ4Z5, -N(Z5)- S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2- NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, -N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; each Z5and Z6are independently selected from hydrogen, Ci-6-alkyl, C2-6-alkenyl, C2-6- alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, Cs-s-cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-s- alkenyl, Cs-s-cycloalkyl-Cs-s-alkynyl, C4-s-cycloalkenyl-Ci-6-alkyl, C4-s-cycloalkenyl-C2-6- alkenyl, C4-s-cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-12- heterocyclyl-C2-6-alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-12-heteroaryl-Ci- 6-alkyl, Cs-i2-heteroaryl-C2-6-alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2- 6-alkenyl and aryl-C2-6-alkynyl; wherein said Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, C3-8- cycloalkyl-Ci-6-alkyl, Cs-s-cycloalkyl-Cs-s-alkenyl, Cs-s-cycloalkyl-Cs-s-alkynyl, C4-8-SPC6350 cycloalkenyl-Ci-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, C4- 12-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-i2-heterocyclyl-C2-6-alkenyl, C4-12- heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, Cs-i2-heteroaryl-Ci-6-alkyl, Cs-i2-heteroaryl-C2-6- alkenyl, Cs-i2-heteroaryl-C2-6-alkynyl, aryl, aryl-Ci-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6- alkynyl is optionally substituted with halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, Ci-4-alkyl, Cs-y-cycloalkyl, -O-Ci-4-alkyl, -O-C3-7- cycloalkyl, -NH-Ci-4-alkyl, -N(Ci-4-alkyl)2, and -NH-Cs-y-cycloalkyl.

3. A compound according to formula (II), a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), a solvate, a hydrate, a polymorph, an isotope, and / or a prodrug thereof,whereinCycle B is a 3-, 4-, 5-, 6-, 7- or 8-membered cycloalkyl; a 4-, 5-, 6-, 7- or 8-membered cycloalkenyl; a 5-, 6-, 7- or 8-membered cycloalkynyl; or a 4-, 5-, 6-, 7- or 8-membered heterocycle ; m is 0, 1 , 2, 3 or 4; and- X1, X2, X3, X4, R4, R7, R9, R10, R11and dotted line are as defined for claim 1 or 2.

4. A compound according to any of claims 1 , 2 or 3 wherein the compound is of formula (Ila) or(Ila) (lib).

5. A compound according to any of the preceding claims whereinR4is selected from-S(=O)(=NZ1)-Z2; -S(=O)2-NZ1Z2; -S(=O)(=NZ1)-NZ1Z2; -S(=NZ2)2-Z1; -S(=O)2-Z2; -S(=O)-Z2; -SPC6350-100-C(=O)-O-Z2; -C(=O)-Z2; -C(=O)-NZ1Z2; and, Ci-6-alkyl, C3-8-cycloalkyl-Ci-6alkyl or C4-8- heterocyclyl-Ci-ealkyl, optionally substituted by a group selected from -OZ3, -NZ3Z4, -N(Z3)- S(=O)2-Z4, -N(Z3)-S(=O)(=NZ3)-Z4, -S(=O)2-NZ3Z4, -S(=O)(=NZ3)-NZ3Z4, -N(Z3)-S(=O)2- NZ3Z4, -S(=O)2-Z3, -S(=O)-Z3, -S(=O)(=NZ3)-Z4, -N=S(=O)Z3Z4, -O-C(=O)-Z3, -C(=O)-O-Z3, - C(=O)-Z3, -O-C(=O)-NZ3Z4, -NZ3-C(=O)-O-Z4, -C(=O)-NZ3Z4and -NZ3-C(=O)-Z4; and each Z1, Z2, Z3and Z4is independently selected from alkyl, alkenyl, alkynyl, heterocyclyl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heterocyclyl and heteroaryl is optionally further substituted with 1 , 2 or 3 substituents independently selected from halogen, -OH, -O-alkyl, - NH2, -NHalkyl, -N(alkyl)2, -SH, -S-alkyl, -CF3, -CHF2, -OCF3, -OCHF2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl.

6. A compound according to any of claims 1 to 4 wherein two R4, optionally two R4on the same atom, are taken together in order to form an 4-, 5-, 6-, 7- or 8-membered heterocycle or a 3-, 4-, 5-, 6-, 7- or 8-membered cycloalkyl, optionally substituted with 1 , 2 or 3 substituents independently selected from halogen, -OH, -O-alkyl, -NH2, -NHalkyl, -N(alkyl)2, -SH, -S-alkyl, -CF3, -CHF2, -OCF3, -OCHF2, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl.

7. A compound according to any of claims 1 to 6 wherein the compound is of formula (He)wherein each Q7and Q8are as R4as defined for any of claims 1 to 6.

8. A compound according to claim 7, wherein each Q8is independently selected from halogen (fluor), Ci-6-alkyl, C2-6-alkenyl, C3-8-cycloalkyl, C4-8-heterocyclyl-OZ5, -NZ4Z5, -N(Z5)-S(=O)2- Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6- S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)-Z6, -N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)-O-Z6, -C(=O)-NZ5Z6, -NZ5-C(=O)-Z6; or, two Q8together form a C3-8-cycloalkyl or C4-8-heterocyclyl;SPC6350-101- wherein each Ci-6-alkyl, C2-6-alkenyl, Cs-s-cycloalkyl, C4-8-heterocyclyl, is optionally further substituted with one, two, three or four groups independently selected from halogen, C1-6- alkyl, Cs-s-cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, - OCHF2, cyano, nitro, -OZ5, -NZ4Z5, -N(Z5)-S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2- NZ5Z6, -S(=O)(=NZ5)-NZ5Z6, -N(Z5)-S(=O)2-NZ5Z6-S(=O)2-Z5, -S(=O)-Z5, -S(=O)(=NZ5)- Z6, -N=S(=O)Z5Z6, -O-C(=O)-Z5, -C(=O)-O-Z5, -C(=O)-Z5, -O-C(=O)-NZ5Z6, -NZ5-C(=O)- O-Z6, -C(=O)-NZ5Z6, and -NZ5-C(=O)-Z6.

9. A compound according to claim 7 or 8, wherein Q7is selected from Ci-6-alkyl, Cs-s-cycloalkyl, and C3-8-cycloalkyl-Ci-4-alkyl, each optionally substituted with halogen, haloalkyl, hydroxy, C1- 4-alkoxy, -O-Cs-y-cycloalkyl, mono- or di-Ci-4-alkylamino and -NH-Cs-y-cycloalkyl.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient, an effective amount of a compound according to any one of claims 1-9.

11. The compound according to any one of claims 1-9, or a pharmaceutical composition according to claim 10, for use as a medicine.

12. The compound or pharmaceutical composition according to claim 11 , for use in the prevention or treatment of a PTPN2 and / or PTPN1 mediated disorder in an animal, mammal or human.

13. The compound or pharmaceutical composition for use according to claim 12, wherein the PTPN2 and / or PTPN1 mediated disorders is selected from the group comprising cancer and metabolic diseases.

14. The compound or pharmaceutical composition for use according to claim 12, wherein the PTPN2 and / or PTPN1 mediated disorders is selected from the group comprising lung cancer, breast cancer, head and neck cancer, oesophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer, skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer.

15. A method for the prevention or treatment of a PTPN2 and / or PTPN1 activation mediated disorders in an animal, mammal or human comprising administering to said animal, mammal or human in need for such prevention or treatment an effective dose of a compound according to any one of claims 1-9.

16. A method of treatment or prevention of PTPN2 and / or PTPN1 activation mediated disorder according to claim 15 comprising administering to a patient in need thereof an effective doseSPC6350-102- of a compound according to any one of claims 1-9, in combination with one or more other anticancer agents, more specifically immunotherapeutic agents.

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