Inhibitors of PTPN2 and / or PTPN1

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

SPC6349-1-INHIBITORS OF PTPN2 AND / OR PTPN1FIELD 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), CSF1R (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, PTPN2 deficiency has also been shown to enhance programmed T cell expansion and survival capacity of activated T cells (Flosbach, M. et al. Cell Rep. 2020, 32, 107957). Hence, inhibitors of PTPN2SPC6349-2-can be considered as a valuable approach as cancer immunotherapeutics.Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B), 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. etal., 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 formula (la), (lb) or (II), a stereoisomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, hydrate, polymorph and / or prodrug thereof, are provided:SPC6349-3-wherein:^njTj r represents a double bond ( ) or a triple bond ();- 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;- when - uTj r is a triple bond, then R2is not present;- when - uTj r is a double bond, then 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, -NZ5Z6, -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;SPC6349-4-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 the same atom or on two adjacent atoms, 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, heterocyclylheteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl;SPC6349-5-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;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;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 R41attached to the same atom together form a cycloalkyl or 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, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl,SPC6349-6-heterocyclylalkynyl, heterocyclylheteroalkyl, 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, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, aryl, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, -OZ5, -NZ5Z6, -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 cycloalkyl or heterocyclyl;wherein each 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 optionally substituted by one or more halogen, alkyl, cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ5Z6, -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, 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;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,SPC6349-7-heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylheteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl is optionally substituted with halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, - OCF3, -CHF2, -OCHF2, cyano, nitro, alkyl, cycloalkyl, -O- alkyl, -O- cycloalkyl, -NH-alkyl, - N(alkyl)2, and -NH-cycloalkyl;R3, R6, R7,R8, R9and R10are independently selected from hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -OR12, -OR15, -O-(C1-6 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, heterocyclylalkyl, heterocyclyl-heteroalkyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, -C(=O)-OR12, -C(=O)-O-(C1-6-alkyl)-OR15, -(C1-6-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, heterocyclylalkyl, 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 a 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 substituentsSPC6349-8-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;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 treatmentSPC6349-9-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.More in particular in relation to the treatment or prevention of cancer, the inventionSPC6349-10-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, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, or melanoma. Additional examples include, cancer of theSPC6349-11-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, nasopharyngeal 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, SchneiderianSPC6349-12-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' tumor 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,SPC6349-13-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 some embodiments, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. For example certain methods herein treat cancer by decreasing or reducing or preventing the occurrence, growth, metastasis, or progression of cancer or decreasing a symptom of cancer.SPC6349-14-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.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 acidicSPC6349-15-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 the 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 presentSPC6349-16-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-ealkyl (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 the 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.SPC6349-17-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.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-i2cycloalkenyl (cyclic C5-12 hydrocarbons), yet more in particular to C5-9 cycloalkenyl (cyclic C5-9SPC6349-18-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 (-C≡CH), 3-ethyl-cyclohept-1-ynylene, and 1-propynyl (propargyl, -CH2C≡CH). In particular embodiments, the term alkynyl refers to C2-12 alkynyl (C2-12 hydrocarbons), yet more in particular to C2-9 alkynyl (C2-9 hydrocarbons) yet more in 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 the avoidance of doubt, fused systems of a cycloalkynyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkynyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkynyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.The term “alkylene” as used herein each refer to a saturated, branched or straight chain hydrocarbon group of 1-18 carbon atoms (more in particular C1-12, Ci-gor C1-6 carbon atoms), and having two monovalent group 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.SPC6349-19-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. Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, derived from benzene, naphthalene, anthracene, biphenyl, and the like. In particular embodiments, the term aryl refers to a 6-14 carbon atoms membered aromatic cycle, yet more in particular refers to a 6-10 carbon atoms membered aromatic cycle. Fused systems of an aryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring, are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of an aryl ring with a heterocycle are considered as heterocycle irrespective of the ring that is bound to the core structure. Thus, indoline, dihydrobenzofurane, 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 replacedSPC6349-20-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 arylheteroalkenyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms. In some embodiments arylheteroalkenyl is selected from the group comprising aryl-O-alkenyl, arylalkenyl-O-alkenyl, aryl-NH-alkenyl, aryl-N(alkenyl)2, arylalkenyl-NH-alkenyl, arylalkenyl-N-(alkenyl)2, aryl-S-alkenyl, and arylalkenyl-S-alkenyl.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 heteroatomsSPC6349-21-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-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-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydropyrrol-1 -yl, 2,5-dihydro-1H-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-SPC63495-yl. The term “dihydrofuranyl” as used herein includes 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5-dihydrofuran-4-yl and 2,5-dihydrofuran-5-yl. The term “dihydrothiophenyl” as used herein includes 2.3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,3-dihydrothiophen-4-yl, 2,3-dihydrothiophen-5-yl, 2,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5-dihydrothiophen-4-yl and 2,5-dihydrothiophen-5-yl. The term “imidazolidinyl” as used herein includes imidazolidin-1-yl, imidazolidin-2-yl and imidazolidin-4-yl. The term “pyrazolidinyl” as used herein includes pyrazolidin-1 -yl, pyrazolidin-3-yl and pyrazolidin-4-yl. The term “imidazolinyl” as used herein includes imidazolin-1 -yl, imidazolin-2-yl, imidazolin-4-yl and imidazolin-5-yl. The term “pyrazolinyl” as used herein includes 1-pyrazolin-3-yl, 1-pyrazolin-4-yl, 2-pyrazolin-1-yl, 2-pyrazolin-3-yl, 2-pyrazolin-4-yl, 2-pyrazolin-5-yl, 3-pyrazolin-1-yl, 3-pyrazolin-2-yl, 3-pyrazolin-3-yl, 3-pyrazolin-4-yl and 3-pyrazolin-5-yl. The term “dioxolanyl” also known as “1,3-dioxolanyl” as used herein includes dioxolan-2-yl, dioxolan-4-yl and dioxolan-5-yl. The term “dioxolyl” also known as “1,3-dioxolyl” as used herein includes dioxol-2-yl, dioxol-4-yl and dioxol-5-yl. The term “oxazolidinyl” as used herein includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl and oxazolidin-5-yl. The term “isoxazolidinyl” as used herein includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl and isoxazolidin-5-yl. The term “oxazolinyl” as used herein includes 2-oxazolinyl-2-yl, 2-oxazolinyl-4-yl, 2-oxazolinyl-5-yl, 3-oxazolinyl-2-yl, 3-oxazolinyl-4-yl, 3-oxazolinyl-5-yl, 4-oxazolinyl-2-yl, 4-oxazolinyl-3-yl, 4-oxazolinyl-4-yl and 4-oxazolinyl-5-yl. The term “isoxazolinyl” as used herein includes 2-isoxazolinyl-3-yl, 2-isoxazolinyl-4-yl, 2-isoxazolinyl-5-yl, 3-isoxazolinyl- 3-yl, 3-isoxazolinyl-4-yl, 3-isoxazolinyl-5-yl, 4-isoxazolinyl-2-yl, 4-isoxazolinyl-3-yl, 4-isoxazolinyl- 4-yl and 4-isoxazolinyl-5-yl. The term “thiazolidinyl” as used herein includes thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl and thiazolidin-5-yl. The term “isothiazolidinyl” as used herein includes isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl and isothiazolidin-5-yl. The term “thiazolinyl” as used herein includes 2-thiazolinyl-2-yl, 2-thiazolinyl-4-yl, 2-thiazolinyl-5-yl, 3-thiazolinyl-2-yl, 3-thiazolinyl-4-yl, 3-thiazolinyl-5-yl, 4-thiazolinyl-2-yl, 4-thiazolinyl-3-yl, 4-thiazolinyl-4-yl and 4-thiazolinyl-5-yl. The term “isothiazolinyl” as used herein includes 2-isothiazolinyl-3-yl, 2-isothiazolinyl-4-yl, 2-isothiazolinyl-5-yl, 3-isothiazolinyl-3-yl, 3-isothiazolinyl-4-yl, 3-isothiazolinyl-5-yl, 4-isothiazolinyl-2-yl, 4-isothiazolinyl-3-yl, 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 includes 1.2-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-ylSPC6349and 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-2H-thiopyran-4-yl, 3,4-dihydro-2H-thiopyran-5-yl and 3,4-dihydro-2H-thiopyran-6-yl. The term “3,6-dihydro-2H-thiopyranyl” as used herein includes 3,6-dihydro-2H-thiopyran-2-yl, 3,6-dihydro-2H-thiopyran-3-yl, 3,6-dihydro-2H-thiopyran-4-yl, 3,6-dihydro-2H-thiopyran-5-yl and 3,6-dihydro-2H-thiopyran-6-yl. The term “piperazinyl” also known as “piperazidinyl” as used herein includes piperazin-1 -yl and piperazin-2-yl. The term “morpholinyl” as used herein includes morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. The term “thiomorpholinyl” as used herein includes thiomorpholin-2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl. The term “dioxanyl” as used herein includes 1,2-dioxan-3-yl, 1,2-dioxan-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl and 1,4-dioxan-2-yl. The term “dithianyl” as used herein includes 1,2-dithian-3-yl, 1,2-dithian-4-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl, 1,3-dithian-5-yl and 1,4-dithian-2-yl. The term “oxathianyl” as used herein includes oxathian-2-yl and oxathian-3-yl. The term “trioxanyl” as used herein includes 1.2.3-trioxan-4-yl, 1,2,3-trioxan-5-yl, 1,2,4-trioxan-3-yl, 1,2,4-trioxan-5-yl, 1,2,4-trioxan-6-yl and 1.3.4-trioxan-2-yl. The term “azepanyl” as used herein includes azepan-1-yl, azepan-2-yl, azepan-3-yl and azepan-4-yl. The term “homopiperazinyl” as used herein includes homopiperazin-1 -yl, homopiperazin-2-yl, homopiperazin-3-yl and homopiperazin-4-yl. The term “indolinyl” as used herein includes indolin-1 -yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl,SPC6349-24-indolin-6-yl, and indolin-7-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “isoindolinyl” as used herein includes isoindolin-1 -yl, isoindolin-2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6-yl, and isoindolin-7-yl. The term “3H-indolyl” as used herein includes 3H-indol-2-yl, 3H-indol-3-yl, 3H-indol-4-yl, 3H-indol-5-yl, 3H-indol-6-yl, and 3H-indol-7-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “tetrahydroquinolinyl” as used herein includes tetrahydroquinolin-1-yl, tetrahydroquinolin-2-yl, tetrahydroquinolin-3-yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl and tetrahydroquinolin-8-yl. The term “tetrahydroisoquinolinyl” as used herein includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl and tetrahydroisoquinolin-8-yl. The term “chromanyl” as used herein includes chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl and chroman-8-yl. The term “1H-pyrrolizine” as used herein includes 1 H-pyrrolizin-1 -yl, 1 H-pyrrolizin-2-yl, 1 H-pyrrolizin-3-yl, 1H-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 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 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. TheSPC6349-25-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 and the heterocyclyl moiety can comprise 3 to 14 atoms. In some embodiments heterocyclylheteroalkynyl 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, 1H-pyrazol-5-yl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,SPC6349-26-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2, 1 -b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1.2.3-benzoxadiazolyl, 2, 1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl; preferably said heteroaryl group is selected from the group comprising pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, imidazolyl, indolyl, benzimidazolyl, s-triazinyl, oxazolyl, isothiazolyl, furyl, thienyl, triazolyl and thiazolyl; more preferably, said heteroaryl group is selected from the group comprising pyridyl, pyrazinyl, pyrimidinyl, indolyl and benzimidazolyl.The term “pyrrolyl” (also called azolyl) as used herein includes pyrrol-1 -yl, pyrrol-2-yl and pyrrol-3-yl. The term “furanyl” (also called "furyl") as used herein includes furan-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl). The term “thiophenyl” (also called "thienyl") as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl). The term “pyrazolyl” (also called 1H-pyrazolyl and 1,2-diazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl or 1H-pyrazol-5-yl, pyrazol-4-yl and pyrazol-5-yl. The term “imidazolyl” as 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 4H-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 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term “oxatriazolyl” as used herein includes 1,2,3,4-oxatriazol-5-yl and 1,2,3,5-oxatriazol-4-yl. The term “thiatriazolyl” asSPC6349-27-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]thiazol-2-yl, imidazo[2,1-b][1,3]thiazol-3-yl, imidazo[2,1-b][1,3]thiazol-5-yl and imidazo[2,1-b][1,3]thiazol-6-yl. The term “thieno[3,2-b]furanyl” as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl. The term “thieno[3,2-b]thiophenyl” as used herein includes thieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl and thieno[3,2-b]thien-6-yl. The term “thieno[2,3-d][1,3]thiazolyl” as used herein includes thieno[2,3-d][1,3]thiazol-2-yl, thieno[2,3-d][1,3]thiazol-5-yl and thieno[2,3-d][1,3]thiazol-6-yl. The term “thieno[2,3-d]imidazolyl” as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl and thieno[2,3-d]imidazol-5-yl. The term “tetrazolo[1,5-a]pyridinyl” as 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 1H-indazolyl or 2-azaindolyl) as used herein includes 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl,SPC63492H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H-indazol-7-yl. The term “benzimidazolyl” as used herein includes benzimidazol-1-yl, benzimidazol- 2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl. The term “1,3-benzoxazolyl” as used herein includes 1,3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl and 1,3-benzoxazol-7-yl. The term “1,2-benzisoxazolyl” as used herein includes 1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1,2-benzisoxazol-6-yl and 1,2-benzisoxazol-7-yl. The term “2,1-benzisoxazolyl” as used herein includes 2,1 -benzisoxazol-3-yl, 2,1 -benzisoxazol-4-yl, 2, 1 -benzisoxazol-5-yl, 2,1 -benzisoxazol-6-yl and 2,1-benzisoxazol-7-yl. The term “1,3-benzothiazolyl” as used herein includes 1,3-benzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl and 1,3-benzothiazol-7-yl. The term “1,2-benzoisothiazolyl” as used herein includes 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl and 1,2-benzisothiazol-7-yl. The term “2,1 -benzoisothiazolyl” as used herein includes 2,1-benzisothiazol- 3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6-yl and 2,1-benzisothiazol-7-yl. The term “benzotriazolyl” as used herein includes benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl. The term “1,2,3-benzoxadiazolyl” as used herein includes 1,2,3-benzoxadiazol-4-yl, 1,2,3-benzoxadiazol-5-yl, 1.2.3-benzoxadiazol-6-yl and 1,2,3-benzoxadiazol-7-yl. The term “2,1,3-benzoxadiazolyl” as used herein includes 2, 1,3-benzoxadiazol-4-yl, 2,1,3-benzoxadiazol-5-yl, 2,1,3-benzoxadiazol-6-yl and 2.1.3-benzoxadiazol-7-yl. The term “1,2,3-benzothiadiazolyl” as used herein includes 1,2,3-benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 1,2,3-benzothiadiazol-6-yl and 1,2,3-benzothiadiazol-7-yl. The term “2,1,3-benzothiadiazolyl” as used herein includes 2,1,3-benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-6-yl and 2,1,3-benzothiadiazol-7-yl. The term “thienopyridinyl” as used herein includes thieno[2,3-b]pyridinyl, thieno[2, 3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl. The term “purinyl” as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl. The term “imidazo[1,2-a]pyridinyl”, as used herein includes imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-4-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl and imidazo[1,2-a]pyridin-7-yl. The term “1,3-benzodioxolyl”, as used herein includes 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, 1,3-benzodioxol-6-yl, and 1,3-benzodioxol-7-yl. The term “quinolinyl” as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl. The term “isoquinolinyl” as used herein includes isoquinolin-1 -yl, isoquinolin-3-yl, isoquinolin- 4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. The term “cinnolinyl” as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl. The term “quinazolinyl” as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl. The term “quinoxalinyl” as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.SPC6349-29-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 heteroarylalkenyl 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.SPC6349-30-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 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heteroaryls and heterocyclyls include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example, nitrogen bonded heterocyclic rings are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or B-carboline. Still more typically, nitrogen bonded heteroaryls or heterocyclyls include 1-aziridyl, 1-azetedyl, 1 -pyrrolyl, 1 -imidazolyl, 1-pyrazolyl, and 1 -piperidinyl.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.SPC6349-31-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 the 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(Rg)(Rr) wherein Rgand Rrare each independently selected from hydrogen, aryl, or alkyl, wherein at least one of Rgor 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 selectedSPC6349-32-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 single 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, -0; -OZ, =0, -SZ, -S; =S, -NZ2, -N+Z3, =NZ, =N-OZ, -CX3(e.g. trifluoromethyl), -CN, -OCN, -SCN, -N=C=O, -N=C=S, -NO, -NO2, =N2, -N3, -NZC(O)Z, -NZC(S)Z, -NZC(O)O’, -NZC(O)OZ, -NZC(S)OZ, -NZC(O)NZZ, NZC(NZ)Z, NZC(NZ)NZZ, -C(O)NZZ, -C(NZ)Z, -S(O)2O’, -S(O)2OZ, -S(O)2Z, -OS(O)2OZ, -OS(O)2Z, -OS(O)2O-, -S(O)2NZZ, -S(O)(NZ)Z, -S(O)Z, -OP(O)(OZ)2, -P(O)(OZ)2, -P(O)(O-)2, -P(O)(OZ)(O-), -P(O)(OH)2, -C(O)Z, -C(O)X, -C(S)Z, -C(O)OZ, -0(0)0; -C(S)OZ, -C(O)SZ, -C(S)SZ, -C(O)NZZ, -C(S)NZZ, -C(NZ)NZZ, -OC(O)Z, -OC(S)Z, -00(0)0; -OC(O)OZ, -OC(S)OZ, wherein each X is independently a halogen selected from F, Cl, Br, or I; and each Z is independently -H, alkyl, alkenyl, alkynyl, 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.SPC6349-33-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.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.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 embodimentSPC6349-34-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 of formula (I) and any subgroup thereof as described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and / or prodrug thereof,wherein:represents a double bond ( ) or a triple bond ( );- 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; 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;- when - uTj r is a triple bond, then R2is not present;- when - uTj r is a double bond, then 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 orSPC6349-35-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, on the same or adjacent atoms, 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, heterocyclylheteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl;wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocycle, arylalkyl, arylalkenyl,SPC6349-36-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;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;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 R41attached to the same or adjacent atoms together form a cycloalkyl or 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, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylheteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl is unsubstituted or is substituted with one or more R42;SPC6349-37-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, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, aryl, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, -OZ5, -NZ5Z6, -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 adjacent or to the same atoms together form a cycloalkyl or heterocyclyl;wherein each 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 heterocyclyl heteroalkynyl is optionally substituted by halogen, alkyl, cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, - SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ5Z6, -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, 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;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 isSPC6349-38-optionally substituted with halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, - OCF3, -CHF2, -OCHF2, cyano, nitro, alkyl, cycloalkyl, -O- alkyl, -O- cycloalkyl, -NH-alkyl, - N(alkyl)2, and -NH-cycloalkyl;R3, R6, R7,R8, R9and R10are independently selected from hydrogen, halogen, -CN, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -OR12, -OR15, -O-(C1-6 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, -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-(C1-6-alkyl)-OR15, -(C1-6-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 a 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)-SPC6349-39-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, -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.It is understood that when represents a double bond ( ), the conformation can be either E or Z.In some embodiments, R2, if not taken together with R1, is 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, C3-8-cycloalkyl-C1-6-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-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-SPC6349-40-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 or adjacent atoms together form a Cs-s-cycloalkyl or C4-8-heterocyclyl;wherein each C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, C4-12-heterocyclyl, C4-12-heterocyclyl-C1-6-alkyl, C4-12-heterocyclyl-C2-6-alkenyl, C4-12-heterocyclyl-C2-6-alkynyl, C5-12-heteroaryl, C5-12-heteroaryl-C1-6-alkyl, C5-12-heteroaryl-C2-6-alkenyl, C5-12-heteroaryl-C2-6-alkynyl, aryl, aryl-C1-6-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, C3-8-cycloalkyl-C1-6-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-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, -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 R4attached to the same or adjacent atoms together form a Cs-s-cycloalkyl or C4-8-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 R4is 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-6-alkyl, Cs-s-cycloalkyl-C2-6-alkenyl, Cs-s-cycloalkyl-Cs-s-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, C4-i2-heterocyclyl, C4-i2-heterocyclyl-Ci-6-alkyl, C4-12-SPC6349-41-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, -NZ5Z6, -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 or adjacent atoms together form a C3-8-cycloalkyl or C4-8-heterocyclyl;wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, C3-8- 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, C1-6-alkyl, Cs-s-cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3I-OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ5Z6, -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 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, C3-8-cycloalkyl-C1-6-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, -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 or adjacent atoms together form a Cs-s-cycloalkyl or C4-8-heterocyclyl;wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, 04-s-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- 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-SPC6349-42-alkynyl is optionally further substituted with one, two, three or four R42.In some embodiments, each R41is 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, C3-8-cycloalkyl-C1-6-alkyl, Cs-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, C4-12-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, -NZ5Z6, -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 R41attached to the same or adjacent atoms together form a C3-8-cycloalkyl or C4-8-heterocyclyl;wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, C3-8- 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, C1-6-alkyl, Cs-s-cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ5Z6, -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 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-e-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-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, -NZ5Z6, -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 or adjacent atoms together form a Cs-s-cycloalkyl or C4-8-heterocyclyl;SPC6349-43-wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, C3-8- 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, C1-6-alkyl, Cs-s-cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ5Z6, -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, Z1and Z2are independently selected from hydrogen, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, Cs-s-cycloalkyl-C2-6-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-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,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, Z1and Z2are 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-C2-6-alkenyl, Cs-s-cycloalkyl-Cs-s-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-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,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-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-SPC6349-44-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, Z1and Z2are independently selected from hydrogen, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, Cs-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, C4-12-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,wherein each Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-8-cycloalkenyl, C3-8- 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 further 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-Cs-y-cycloalkyl.In some embodiments, Z3and Z4are independently selected from hydrogen, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Cs-s-cycloalkyl, C4-s-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, Cs-s-cycloalkyl-C2-6-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-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,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 Z3and Z4are 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-SPC6349-45-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-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, C4-12-heterocyclyl-C2-6-alkenyl, C4-i2-heterocyclyl-C2-6-alkynyl, Cs-12-heteroaryl, C5-12-heteroaryl-C1-6-alkyl, C5-12-heteroaryl-C2-6-alkenyl, C5-12-heteroaryl-C2-6-alkynyl, aryl, aryl-C1-6-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, 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 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.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, C3-8-cycloalkyl-C1-6-alkyl, Cs-s-cycloalkyl-C2-6-alkenyl, Cs-s-cycloalkyl-Cs-e-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-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, C5-12-heteroaryl-C1-6-alkyl, C5-12-heteroaryl-C2-6-alkenyl, C5-12-heteroaryl-C2-6-alkynyl, aryl, aryl-C1-6-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.In some embodiments, the compound is according to formula (II)SPC6349(H)whereinB 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, R10and R11are as defined for any of the embodiments herein. In further embodiments, the compound is of formula (Ila) or (lib)In yet further embodiments, the compound is of formula (He)(He)wherein each Q7and Q8are as R4as defined for any of the embodiments herein.In some embodiments for compounds according to formula (He), each Q8is independently selected from halogen (fluor), Ci-6-alkyl, C2-6-alkenyl, Cs-s-cycloalkyl, C4-8-heterocyclyl-OZ5, -NZ5Z6, -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 Cs-s-cycloalkyl or C4-8-heterocyclyl;SPC6349wherein 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, -NZ5Z6, -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 for compounds according to formula (He), Q7is selected from Ci-6-alkyl, Cs-s-cycloalkyl, and C3-8-cycloalkyl-Ci-4-alkyl, each optionally substituted with halogen, haloalkyl, hydroxy, Ci-4-alkoxy, -O-Cs-y-cycloalkyl, mono- or di-Ci-4-alkylamino and -NH-Cs-y-cycloalkyl. In some embodiments, the compound is according to formula (III),whereinR1is C3-i2-cycloalkyl, C3-i2-heterocycle, C4-i2-cycloalkenyl, C4-i2-cycloalkynyl, Ce-12-aryl or C5- 12-heteroaryl, wherein said cycloalkyl, heterocycle, cycloalkenyl, cycloalkynyl, aryl or heteroaryl is optionally substituted by one or more R4;- X1, X2, X3, X4, R4, R7, R9, R10and R11are as defined for claim 1 or 2.In some embodiments for compound according to formula (III), R1is selected fromIn further embodiments for compound according to formula (III), R1is selected fromSPC6349-48-In further embodiments for compound according to formula (III), 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 further embodiments, 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 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.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 for example aryl, heteroaryl or heterocycle as for example in arylalkenyl, heteroarylalkenyl and heterocycle-alkenyl;- each alkynyl is C2-Cis alkynyl, such as a C2-Ci2alkynyl; yet in particular a C2-Cg alkynyl; still more in particular a C2-Ce 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-Cis cycloalkyl, more in particular is a C3-Ci2cycloalkyl; yet more in particular is a C3-Cg cycloalkyl; still more in particular is a C3-Ce cycloalkyl;- each cycloalkenyl is C5-C18 cycloalkenyl, more in particular is a Cs-Ci2cycloalkenyl; 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 Cs-Ci2cycloalkynyl; yet more in particular is a C5-C9 cycloalkynyl; still more in particular is a Cs-Ce cycloalkynyl;- each aryl is Ce-C2o 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 orSPC6349-49-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.In some embodiments, the compounds have a structure according to the formula (I) further defined by embodiments herein provided, and wherein:when X1is N; X2is C(F); X3is C(H); R7is -OH and X4is C(R3) wherein R3is hydrogen or alkyl; R9, R10and R11are hydrogen; and - is a single bond,then:R1is substituted by at least one R4, or, when R1and R2taken together form a cycloalkyl, cycloalkenyl, cycloalkynyl or heterocycle, said cycloalkyl, cycloalkenyl, cycloalkynyl or heterocycle is substituted with at least one R4;and;said at least one R4is selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, cycloalkylheteroalkyl, cycloalkyl-heteroalkenyl, cycloalkyl-heteroalkynyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, aryl-heteroalkyl, arylheteroalkenyl, 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, cycloalkyl- 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, (monoSPC6349-50-or di-)alkyl-amino-alkyl, alkylthio, and alkyl-thio-alkyl is substituted by at least one R41that is not selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, - CF3, -O-alkyl, -OCF3, -CHF2; -OCHF2, cyano, nitro, -C(O)OH, -NH2, -NHalkyl, -N(alkyl)2, - S(O)2alkyl, and -NHS(O)2alkyl;OR,- said at least one R4is selected from -OZ1, -SZ1, -NZ1Z2, -N(Z1)-S(=O)2-Z2, -S(=O)2-NZ1Z2, - S(=NZ1)(=NZ1)-Z2, -N(Z1)-S(=O)2-NZ1Z2, -S(=O)2-Z2, -S(=O)-Z2, -S(=O)(=NZ1)-Z2, -C(=O)-O- Z2, -C(=O)-Z2, -NZ1-C(=O)-O-Z2, -C(=O)-NZ1Z2, -NZ1-C(=O)-Z2, -NZ3C(O)NZ3Z4, -P(O)Z1Z2, wherein Z1and / or Z2are substituted by at least one R41that is not selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, -CF3, -O-alkyl, -OCF3, -CHF2; - OCHF2, cyano, nitro, -C(O)OH, -NH2, -NHalkyl, -N(alkyl)2,OR,- said at least one R4is selected from -N(Z1)-S(=O)(=NZ1)-Z2, -S(=O)(=NZ1)-NZ1Z2, - N=S(=O)Z1Z2, -O-C(=O)-Z2and -O-C(=O)-NZ1Z2.In some embodiments, the compounds are 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-(pyrrolidin-3-ylidenemethyl)phenyl)isothiazol-3(2H)- one 1,1 -dioxideCpd002: (Z)-5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3-ylidenemethyl)phenyl)isothiazol-3(2H)- one 1,1 -dioxideCpd003: 5-(4-(aminomethyl)-3-(cyclopropylethynyl)-2-fluoro-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1 -dioxideCpd004: 5-(3-(cyclopropylethynyl)-2-fluoro-6-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl)- 1,2,5-thiadiazolidin-3-one 1, 1 -dioxideCpd005: (Z)-5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3-ylidenemethyl)phenyl)isothiazolidin-3- one 1,1 -dioxideCpd006: (Z)-5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3-ylidenemethyl)phenyl)isothiazolidin-3- one 1,1 -dioxideCpd007: (E)-5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3-ylidenemethyl)phenyl)isothiazolidin-3- one 1,1 -dioxideCpd008: 5-(3-(cyclopropylethynyl)-2-fluoro-6-hydroxyphenyl)isothiazolidin-3-one 1,1- dioxideCpd009: 5-(3-(cyclopropylethynyl)-2-fluoro-6-hydroxyphenyl)isothiazolidin-3-one 1,1- dioxideSPC6349-51-Cpd010: 5-(4-(azetidin-3-ylmethyl)-3-(cyclopropylethynyl)-2-fluoro-6-hydroxyphenyl)- 1,2,5-thiadiazolidin-3-one 1, 1 -dioxideCpd011: 5-(3-(cyclopropylethynyl)-2-fluoro-6-hydroxy-4-((methylamino)methyl)phenyl)- 1,2,5-thiadiazolidin-3-one 1, 1 -dioxideCpd012: 5-(4-(2-aminoethyl)-3-(cyclopropylethynyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxideCpd013: 5-(3-(cyclopropylethynyl)-2-fluoro-6-hydroxy-4-(piperidin-2-ylmethyl)phenyl)- 1,2,5-thiadiazolidin-3-one 1, 1 -dioxideCpd014: 5-(3-(cyclopropylethynyl)-2-fluoro-6-hydroxy-4-methylphenyl)isothiazolidin-3-one 1,1 -dioxideCpd015: 5-(3-((1 H-pyrazol-4-yl)ethynyl)-2-fluoro-6-hydroxyphenyl)isothiazolidin-3-one 1,1 -dioxideCpd016: 5-(2-fluoro-6-hydroxy-3-(pyridin-3-ylethynyl)phenyl)isothiazolidin-3-one 1,1-dioxideCpd017: 5-(3-(cyclopentylethynyl)-2-fluoro-6-hydroxy-4-methylphenyl)isothiazolidin-3-one 1,1 -dioxideCpd018: (E)-5-(3-(2-cyclopropylvinyl)-2-fluoro-6-hydroxyphenyl)isothiazolidin-3-one 1,1-dioxideCpd019: (E)-5-(2-fluoro-3-(3-fluorostyryl)-6-hydroxy-4-methylphenyl)isothiazolidin-3-one 1,1 -dioxideCpd020: (Z)-5-(3-((4-cyclopropylpyrrolidin-3-ylidene)methyl)-2-fluoro-6-hydroxyphenyl)isothiazolidin-3-one 1, 1 -dioxideCpd021: (E)-5-(2-chloro-3-((4-cyclopropylpyrrolidin-3-ylidene)methyl)-6-hydroxyphenyl)isothiazolidin-3-one 1, 1 -dioxideCpd022: (Z)-5-(2-fluoro-6-hydroxy-3-((1-methylpyrrolidin-3-ylidene)methyl)phenyl)isothiazolidin-3-one 1, 1 -dioxideCpd023: (Z)-5-(3-((4-cyclopropyl-1-methylpyrrolidin-3-ylidene)methyl)-2-fluoro-6-hydroxyphenyl)isothiazolidin-3-one 1, 1 -dioxideCpd024: (Z)-5-(3-((6-azaspiro[3.4]octan-8-ylidene)methyl)-2-fluoro-6-hydroxyphenyl)isothiazolidin-3-one 1, 1 -dioxideCpd025: 5-(4-(aminomethyl)-2-fluoro-6-hydroxy-3-(((1R,5S,6S)-3-((4-methylpiperazin-1-yl)sulfonyl)-3-azabicyclo[3.1,0]hexan-6-yl)ethynyl)phenyl)isothiazolidin-3-one 1, 1 -dioxide Cpd026: (E)-5-(4-(2-aminoethyl)-3-(2-cyclopropylvinyl)-2-fluoro-6-hydroxyphenyl)isothiazolidin-3-one 1, 1 -dioxideCpd027: 5-(4-(2-aminoethyl)-2-fluoro-6-hydroxy-3-(((1R,5S,6S)-3-((4-methylpiperazin-1-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxideSPC6349-52-Cpd028: 5-(2-chloro-3-((3-chlorophenyl)ethynyl)-6-hydroxyphenyl)-1,2, 5-thiadiazolidin-3- one 1,1 -dioxideCpd029: 5-(4-(aminomethyl)-3-(cyclopentylidenemethyl)-2-fluoro-6- hydroxyphenyl)isothiazolidin-3-one 1, 1 -dioxideCpd030: (Z)-(4-((6-azaspiro[3.4]octan-8-ylidene)methyl)-2-(1,1-dioxido-3- oxoisothiazolidin-5-yl)-3-fluorophenoxy)methyl dihydrogen phosphateCpd031: 5-(6-fluoro-5-(((1 R,5S,6s)-3-(piperidin-4-ylsulfonyl)-3-azabicyclo[3.1,0]hexan-6- yl)ethynyl)-2H-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1, 1 -dioxideCpd032: 5-(6-fluoro-5-(((1R,5S,6s)-3-((4-methylpiperazin-1-yl)sulfonyl)-3- azabicyclo[3.1.0]hexan-6-yl)ethynyl)-2H-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1- dioxideCpd033: 5-(6-fluoro-5-(((1R,5S,6s)-3-(piperazin-1-ylsulfonyl)-3-azabicyclo[3.1.0]hexan-6- yl)ethynyl)-2H-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1, 1 -dioxideCpd034: 5-(6-fluoro-5-(((1 R,5S,6s)-3-(methylsulfonyl)-3-azabicyclo[3.1,0]hexan-6- yl)ethynyl)-2H-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1, 1 -dioxideCpd035: 5-(5-(cyclopropylethynyl)-6-fluoro-2H-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxideCpd036: (Z)-5-(5-((4-cyclopropylpyrrolidin-3-ylidene)methyl)-6-fluoro-2H-indazol-7-yl)- 1,2,5-thiadiazolidin-3-one 1, 1 -dioxideCpd037: (E)-5-(6-fluoro-5-(pyrrolidin-3-ylidenemethyl)-2H-indazol-7-yl)-1,2,5- thiadiazolidin-3-one 1,1 -dioxideCpd038: (Z)-5-(6-fluoro-5-(pyrrolidin-3-ylidenemethyl)-2H-indazol-7-yl)-1,2,5- thiadiazolidin-3-one 1, 1 -dioxide.In some embodiments, the compounds have a structure according to the formula (I) further defined by embodiments herein provided, and wherein when X1is N; X2is C(F); X3is C(H); R7is -OH and X4is C(R3); R9, R10and R11are hydrogen; and - is a single bond; then R3is not hydrogen or unsubstituted alkyl.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.SPC6349-53-Compounds of the present disclosure are small molecule PTPN2 and / or PTPN 1 inhibitors. 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), 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) 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 agentsSPC6349-54-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 antigen receptor T-cells which are T-cells engineered to target specific antigens), TIL therapy (e.g.,SPC6349-55-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 cell¬ based 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-presenting 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 theSPC6349-56-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, platinum¬ based compounds, anthracenedione, substituted urea, methyl hydrazine derivative, adrenocortical suppressant, epipodophyllotoxins, inhibitors of mitogen-activated protein kinase signaling, mTOR inhibitors, agents that arrest cells in the G2-M phases and / or modulate the formation or stability of microtubules, 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 to111In,90Y, or131I· etc. ) and the like. Within the group of anti-cancer agents, “Chemotherapeutic" or "chemotherapeutic agent" refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.In a further embodiment, the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as47Sc,64Cu,67Cu,89Sr,86Y,87Y,90Y,105Rh,mAg,mln,117mSn,149Pm,153Sm,166Ho,177Lu,186Re,188Re,211At, and212Bi, optionally conjugated to antibodies directed against tumor antigens.SPC6349-57-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 1ng / ml and 100 mg / ml, more in particular between 1ng / ml and 1mg / ml, still more in particular between 1ng / ml and 1 g / ml.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:(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 theSPC6349-58-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 counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions). Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids to basic 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-SPC6349-59-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 present 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 withinSPC6349-60-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 frans-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 its 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 inducedSPC6349-61-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 reverse-phase 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).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 replacedSPC6349-62-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,18O,17O,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 fortheir 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 thereof 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 asSPC6349-63-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, 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 sulphonicSPC6349-64-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-ionic 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 appropriateSPC6349-65-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 of 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 creamSPC6349-66-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 diisoadipate, 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 500SPC6349-67-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.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 polymericSPC6349substance 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.The 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.Accordingly, the disclosure also 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 or an alkynyl derivative thereby obtaining compound of formula (A2) wherein R1, R2, R3, R6, R7, R8, R9, R10and R11have the meaning according to any one of the formula or embodiments presented herein.Couplingreaction(A2)(A1)The compounds of the present invention may be prepared according to the general procedures outlined in below Schemes.SPC6349-69-Scheme 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. Intermediates 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, tetrahydrofuran 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 X2 different than CF, R7 different than OPG1 can be synthesized according to similar procedure (X2, R7 as described for the compounds of the present invention).SPC6349In another embodiment, compounds of the present invention may also be synthesized accordingScheme 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 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 11 may be reacted with a primary alcohol of general formula PG1OH (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, butSPC6349-71-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 X2 different than CF, R7 different than OPG1 can be synthesized according to similar procedure (X2, R7 as 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 C.Coupling reaction24Scheme C: all X3, X4are as described for the compounds of the present invention and its embodiments, statements and formulae. LG is 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 (optional).A boronic derivative compound 21 (either commercially available or synthesized by the person skilled in the art) may be reacted with a reagent 22 in a coupling reaction in the presence of a Pd catalyst (e.g. Pd(PPh3)4, PdCI2(PPh3)2, Pd(ddpf)CI2, Pd(dtbpf)CI2 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 to provide intermediates of formula 23. Optional reduction of double bond can provide intermediates of formula 24.Intermediates similar to those of formula 23 or 24, with X2different than CF, X1different than C and R7different than OPG1 can be synthesized according to similar procedure (X2, X1, R7as 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.SPC6349Scheme D: all X1, X3, X4, R1, R2, R5are as described for the compounds of the present invention and its embodiments, statements and formulae. LG is leaving group, typically an halogen (Br, I, Cl). PG = protecting group (optional).Phenols derivatives of formula 26 may be obtained by removal of the O-protecting group from intermediates of general formula 25 following procedures known to the skilled in the art (e.g. treatment with BBrs or BCh, hydrogenation with H2 in the presence of Pd / C and the like). Derivatives of formulae 27 or 28 may be obtained by reaction of an intermediate of formula 26 with either 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, Cs2CO3and 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 or with a suitable terminal alkyne (either commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below or also generated in situ from an appropriated terminally silylated alkyne in the presence of a fluoride source in the reaction medium (CsF, TBAF and the like)) in the presence of a Pd catalyst (e.g. PdCh(PPh3)2, Pd(ddpf)Ci2, Pd(dtbpf)Ch, PdCl2(CH3CN)2 and the like), optionally a Cu catalyst (Cui and the like) and a base (e.g EtsN, K2CO3, Cs2CO3and the like) in a polar aprotic solvent (e.g CH3CN, DMF, DMSO and the like) at a temperature ranging from 0°C to 100°C. Derivatives of formula 27 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 derivatives of formula 28.Compounds similar to those of formula 28 with X2different than CF, R7different than OH 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 according to the general procedure outlined in Scheme E.SPC6349Scheme E: all X1, X3, X4, R1, R2, R5are as described for the compounds of the present invention and its embodiments, statements and formulae. LG is leaving group, typically an halogen (Br, I, Cl). PG = protecting group (optional).Derivatives of formulae 29 or 30 may be obtained by reaction of an halogenated intermediate of formula 25 with either 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, Cs2CO3and 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 or with a suitable terminal alkyne (either commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below or also generated in situ from an appropriated terminally silylated alkyne in the presence of a fluoride source in the reaction medium (CsF, TBAF and the like)) in the presence of a Pd catalyst (e.g. PdCh(PPh3)2, Pd(ddpf)Ci2, Pd(dtbpf)Ch, PdCl2(CH3CN)2 and the like), optionally a Cu catalyst (Cui and the like) and a base (e.g EtsN, K2CO3, Cs2CO3and the like) in a polar aprotic solvent (e.g CH3CN, DMF, DMSO and the like) at a temperature ranging from 0°C to 100°C. Derivatives of formula 29 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 30. Compounds of interest having a formula 28 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 28 with X2different than CF, R7different than OH can be synthesized according to similar procedure (X2, R7as described for the compounds of the present invention).Abbreviations used in the description, particularly in the Schemes and Examples, are as follows:SPC6349-74-Abbreviation DefinitionAcOH acetic acid aq. aqueous Bn benzyl Boc tert-butyloxycarbonyl br. s. broad singuletcBz carboxybenzylcone. concentrated DCM dichloromethaneDIPEA diisopropylethylamine CAS# 7087-68-5 DMAP 4-dimethylaminopyridine CAS# 1122-58-3 DME 1,2-dimethoxyethane DMF N, N-dimethylformamide DMSO dimethyl sulfoxideDppf 1,1'-bis(diphenylphosphino)ferrocene Dtbpf 1, 1 '-Bis(di-tert-butylphosphino)ferrocene En enantiomerEt ethyl Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol Eq equivalent FA formic acid H hour HPLC high performance liquid chromatography iPr iso-propyl iPrOH propan-2-ol KOtBu potassium tert-butoxideLDA lithium diisopropylamideSPC6349-75- Abbreviation DefinitionLG leaving groupMe methylMeOH methanolMin minutem / z mass-to-charge ratio n-BuLi n-butyllithiumNEt3 triethylamineNIS N-iodosuccinimideNMP N-methyl-2-pyrrolidone Pd / C palladium on carbonPE Petroleum etherPG protecting groupr.t. retention timeRT room temperatureSat saturatedTBAF tetrabutylammonium iodide Temp temperaturetBu tert-butyltBuOH tert-butanolTf trifluoromethanesulfonyl TFA trifluoroacetic acidTHF tetra hydrofuranTLC thin layer chromatography TMP 2,2,6,6-Tetramethylpiperidine CAS# 768-66-1 Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneXPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl The following examples are provided for the purpose of illustrating the present invention and bySPC6349-76-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 codes P / \ / o _ " OStructure and Compound Code Structure and Compound Code Structure and Compound Code 4’n_^ o y o x o— o oFA OX' *JJO= o'-- ° s-NHFO=s-NH Z_kFO=s-NH [I1oH < NJ XX\^OH Cpd002 H2NXXOHCpd001 Cpd003o oFO=s-NHFO=s-NH Z\ / \X / X=O< J XX XXHN \^OH Cpd005 HN^ <^< OH Cpd006oFA ° A ° O=s-NH Z_\FO=s-NH Z_kFO=s-NH ^^^ I XX^0^^x Jv^XX^0HN' J^' || XXXXX^ ~'' C> HCpd007 Cpd008 Cpd009A ° A °Z_\FO~s- NH Z_\FO=s-NH AFO=0S'NH X^x Nj=2 NX°HN— \ [| H T |_N.’ OH Cpd011 HjN'^^^^OH Cpd010Cpd012A °Z A-S.FOa °g-NH Z_kFO=s-NH HN'n 0NXXF 0=S-NHX^KXX-X0J-L XX^01 1 l x XX^XX^ H ^^OH Cpd014Cpd013 Cpd0150° °F O=S-NH \> L F O=s-NHFO=S'NH X^X-X^0XXs0XX XX^'^ OH XXQHCpd017Cpd016 Cpd018o ■r X-7 ° oFO=VNH JFO=s-NHC| O=£-NH L. JI 1 1 / =o XX^ H0F^^^Xxi N jf^ [|H CN^T X ^X<OHCpd019 Cpd020Cpd021oF<-7 ° 0 O=s-NH xyFO=s-NHFO=s^NH z\X^X'X=oX / ^^XX-X^0SX^^X^XX^0Cr XX < J XXHN-' XX0HCpd022 Cpd023 Cpd024SPC6349-77-Structure and Compound Code Structure and Compound Code Structure and Compound Code L _N_o _x*\ I IFO=s-NH o' ' O F O='s-NH A. ^■V-X,z FO*s-NHH2XXXH2NJLOHH N Y TICpd025 Cpd026 Cpd027 ° oAFO. JL Cl O^-NH O^s-NH zx F O=s-NHx / ji r ^>=o I T CJ JL JLH (NY^ r k^>ix / x, °P< OH NH2° ° OH Cpd028Cpd029 Cpd030HNC / L0'9cA"\'H0F O^-NH w ° d' O Y-A.,F0^-NH F O^-NH A ^^xAxj'A^0Q VN1LX LX'' H U '—N-NH V NNH Cpd031O Cpd032 Cpd0330 A0^7 0Z_XFO~s-NH \7FO=S'NH °*SA^X"HoLmwFO^-NH N xk0k ^x A_Nx^° H / / \ _ Io c y, \ / or- — < j J T\ / Q. - I THNn / ° VN^-NH VN^NHNH Cpd036Cpd035Cpd034Z^JZ 0FO~s-NH'k=0Hl\k k / L.I <N^NHCpd038Structures 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.In one embodiment, the compounds have the structure of formula (IX), including any tautomeric and stereochemically isomeric form, isotopically labeled derivative, or a pharmaceutically acceptable salt or solvate thereof:SPC6349-78-wherein,^njTj r represents a double bond ( ) or a triple bond ( );- when - uTj r is a triple bond, then R2is not present;- when - uTj r is a double bond, then R2is selected from hydrogen;R1is selected from heterocycle; cycloalkyl; aryl; heteroaryl; multiring heterocycle; whereby each of said heterocycle, cycloalkyl, aryl, heteroaryl, or multiring heterocycle; is unsubstituted or is substituted with one or more R4;each R4is independently selected from -S(=O)-Z2, cycloalkyl, halogen, or alkyl;- Z2is independently selected from alkyl, or heterocycle, wherein said heterocycle is unsubstituted or is substituted with one or more R41;each R41is independently alkyl;R3is selected from hydrogen, or alkyl optionally substituted with one, two, or three R20; R20is independently selected at each occurrence from heterocyclyl, -N(R22)(R23), or -O- P(=O)(OH)2;R22is independently selected at each occurrence from hydrogen, or alkyl;R23is independently selected at each occurrence from hydrogen and alkyl;each R15is independently selected from hydrogen, or alkyl optionally substituted with one, two, or three R20.In one embodiment, the compounds have the structure of formula (X), including any tautomeric and stereochemically isomeric form, isotopically labeled derivative, or a pharmaceutically acceptable salt or solvate thereof:a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), a solvate, a hydrate, thereof, Wherein,represents a double bond ( ) or a triple bond( );- when - uTj r is a triple bond, then R2is not present;- when - uTj r is a double bond, then R2is selected from hydrogen;R1is cycloalkyl or heterocycle; whereby each of said cycloalkyl or heterocycle is unsubstituted or is substituted with one or more R4;SPC6349-79-each R4is independently selected from -S(=O)-Z2, or cycloalkyl;Z2is independently selected from alkyl, or heterocycle, wherein said heterocycle is unsubstituted or is substituted with one or more R41;each R41is independently alkyl.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 1H-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 could 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 usingSPC6349-80-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 UPLC H-Class Plus system, a Waters Acquity UPLC I-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 UPLC H-Class equipped with a Acquity UPLC PDA Detector (range 190-420 nm), a Acquity UPLC 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+ / - LC-MS “Method B” (BEH - Neutral 5%). Column: UPLC BEH Premier C18 (2.1x50mm, 1.7pm) thermostated at 40°C; Mobile phase A: 5 mM aqueous solution of ammonium acetate (adjusted to pH 7 with aq. ammonia) + 5% acetonitrile; Mobile phase B: acetonitrile; Gradient (Time / % of B) 0 / 16, 3.18 / 58, 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+ / - LC-MS “Method C” (XBridge - ABC 20 min). Column: X Bridge C18 (4.6x150mm, 3.5pm) thermostated at 35°C; Mobile phase A: 10 mM aqueous solution of ammonium bicarbonate; Mobile phase B: acetonitrile; Gradient (Time / % of B) 0 / 5,1 / 5,3 / 15,7 / 55,11 / 98.16 / 98,16.01 / 5,20 / 5; Flow rate 1.0 mL / min; UV detection; MS conditions: Ionisation Mode: Positive and Negative Electrospray Ionisation (ESI+ / ESI-); Scan Range: 100 to 1500 m / z, ES+ / - LC-MS “Method D” (BEH - FA 4 min). Column: UPLC BEH C18 (2.1x50mm, 1.7pm) thermostated at35°C; Mobile phase A: 0.05% formic acid in water; Mobile phase B: 0.05% formic acid in acetonitrile; Gradient (Time / % of B) 0 / 3, 0.4 / 3, 2 / 98, 3.4 / 98, 3.5 / 3, 4 / 3; Flow rate 0.6 mL / min; UV detection; MS conditions: Ionisation Mode: Positive and Negative Electrospray Ionisation (ESI+ / ESI-); Scan Range: 100 to 1500 m / z, ES+ / - LC-MS “Method E” (XBridge - ABC 8 min). Column: Xbridge C18 (75x4.6mm, 3.5pm) thermostated at 35°C; Mobile phase A: 10 mM aqueous solution of ammonium bicarbonate; Mobile phase B: acetonitrile; Gradient (Time / % of B) 0 / 5, 0.5 / 5, 1.0 / 15, 4.0 / 98, 7.0 / 98, 7.5 / 5, 8.0 / 5; Flow rate 1.3 mL / min; UV detection: from 190 nm to 420 nm; MS conditions: Ionisation Mode:SPC6349Positive and Negative Electrospray Ionisation (ESI+ / ESI-); Scan Range: 100 to 1500 m / z, ES+ / - UPLC “Method F” (BEH - FA 10 min). Column: UPLC BEH C18 (2.1x100mm, 1.7pm) thermostated at50°C; Mobile phase A: 0.05% formic acid in water; Mobile phase B: 0.05% formic acid in acetonitrile; Gradient (Time / % of B) 0 / 3, 8.5 / 100, 9 / 100, 9.5 / 3, 10 / 3; Flow rate 0.550 mL / min; UV detection: from 190 nm to 420 nm.LC-MS “Method G” (BEH - ABC 3.5 min). Column: BEH C18 (100x2.1mm, 1.7pm) thermostated at 55°C; Mobile phase A: 0.1% aqueous solution of ammonium bicarbonate in 95% water + 5% acetonitrile; Mobile phase B: acetonitrile; Gradient From 100% A to 5% A in 2.10min, to 0% A in 0.9min, to 5% A in 0.5min; Flow rate 0.6 mL / min; UV detection: from 210 nm to 400 nm; MS conditions: Ionisation Mode: Positive and Negative Electrospray Ionisation (ESI+ / ESI-); Scan Range: 100 to 1500 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-01Et0H-H20, 90 °C Step-2Boc^ CpS-N=C=O NH OtBuOH. TEA TFA NaQMe (30 % MeQH) DCM, 0 °C-RT DCM, 0°C-RT THF, 0°CStep-4 Step-5 Step-6Step-1: To a stirred solution of 5-bromo-1,3-difluoro-2-nitrobenzene (10.0 g, 42.0 mmol, 1 eq.) and benzyl alcohol (4.99 g, 46.2 mmol, 1.1 eq) in THF (150 mL), cooled to -50°C, was added dropwise a KOtBu solution (1.6 M in THF) (28.9 mL, 46.2 mmol). The resultant reaction mixtureSPC6349-82-was stirred at same temperature for 1 h. After completion of the reaction (TLC monitoring), the reaction mixture was poured in H2O (250 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water, then brine, dried over Na2SC>4 and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc (1-2%) in PE to yield 9.0 g of 1-(benzyloxy)-5-bromo-3-fluoro-2-nitrobenzene.1H NMR (400 MHz, CDCI3) 6 ppm 7.42-7.35 (m, 5H), 7.05 (s, 2H), 5.18 (s, 2H).Step-2: A stirred solution of 1-(benzyloxy)-5-bromo-3-fluoro-2-nitrobenzene (9.0 g, 27.6 mmol, 1 eq.) and Fe powder (4.62 g, 82.8 mmol, 3 eq.) in a 2:1 ethanokwater mix (150 mL) was treated at RT with ammonium chloride (7.38 g, 138 mmol, 5 eq.) and the resultant mixture was then heated to 90 °C and stirred for 2 h. After reaction completion (TLC monitoring), the reaction mixture was cooled to RT, quenched with a sat. aq NaHCO3solution, filtered through celite bed and the bed was washed with EtOAc (150 mL). The filtrate was evaporated, diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer were washed with water (150 mL), brine (150 mL), dried over sodium sulphate and concentrated to yield 8.1 g of crude 2-(benzyloxy)-4-bromo-6-fluoroaniline which was used as such in the next step.Step-3: To a stirred solution of 2-(benzyloxy)-4-bromo-6-fluoroaniline (8.10 g, 27.4 mmol, 1 eq.) in DMF (130 mL), at RT, was added DIPEA (14.5 mL, 82.0 mmol, 3 eq) followed by the addition of ethyl bromoacetate (6.85 g, 41.0 mmol, 1.5 eq). The resulting mixture was then heated at 60°C and stirred for 16 h (TLC monitoring). Again, ethyl bromo acetate (2.28 g, 13.7 mmol, 0.5 eq) was added and stirring was continued at 60°C. After completion of the reaction (TLC monitoring), the reaction mixture was cooled to RT, diluted with water (200 mL) and extracted with EtOAc (2x250 mL). The combined organic layers were washed with ice cold water (3 x 150 mL), brine (150 mL), dried over Na2SO4 and concentrated. The crude residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc (2-3%) in PE to yield 6.0 g of ethyl (2-(benzyloxy)-4-bromo-6-fluorophenyl)glycinate.1H NMR (400 MHz, CDCI3) 6 ppm 7.49-7.42 (t, 2H), 7.42-7.36 (m, 2H), 7.33 (m, 1H), 7.09-6.96 (m, 2H), 5.23-5.19 (m, 1H), 5.16 (s, 2H), 4.07-4.00 (m, 4H), 1.15-1.11 (t, 3H).Step-4: A stirred solution of chlorosulfonyl isocyanate CAS# 1189-71-5 (2.74 mL, 31.4 mmol, 2 eq.) in DCM (25 mL) was treated with t-BuOH (2.97 mL, 31.4 mmol, 2 eq) at 0°C and resulting reaction mixture was stirred for 30 min at same temperature. This pre-reagent mixture was added to a stirred solution of ethyl (2-(benzyloxy)-4-bromo-6-fluorophenyl)glycinate (6.0 g, 15.7 mmol, 1 eq) in DCM (45 mL) and Et3N (6.6 mL, 47.1 mmol, 3 eq) at 0°C. The resulting reaction mixture was then allowed to reach RT. After completion of the reaction (TLC monitoring), the reaction mixture was poured in water (150 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with water (75 mL), brine (75 mL), dried over Na2SC>4 and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc (8-10%) in PE to yield 5.7 g of ethyl / V-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-SPC6349N-(N-(tert-butoxycarbonyl) sulfamoyl) glycinate.1H NMR (400 MHz, CDCI3) 6 ppm 11.35 (s, 1H), 7.47-7.45 (d, 2H), 7.42-7.40 (m, 2H), 7.35-7.32 (m, 1H), 7.24 (d, 1H), 7.18 (d, 1H), 5.29-5.20 (m, 2H), 4.65 (d, 1H), 4.32 (d, 1H), 4.06-3.97 (m, 4H), 2.52-2.49 (m, 3H), 1.45-1.39 (t, 3H),1.19-1.10 (m, 6H).Step-5: A stirred solution of ethyl / V-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-N-(N-(tert-butoxycarbonyl) sulfamoyl) glycinate (5.70 g, 10.1 mmol, 1 eq.) in DCM (60 mL), at 0°C, was treated with TFA (7.76 mL, 101 mmol, 10 eq) and then stirred at same temperature. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with a sat. NaHCOs aqueous solution (50 mL), diluted with water (50 mL) and extracted with DCM (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated. The crude residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc (25-28%) in PE to yield 3.3 g of ethyl / V-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-N-sulfamoylglycinate.1H NMR (400 MHz, CDCI3) 6 ppm 7.52-7.49 (t, 2H), 7.42-7.38 (m, 2H), 7.35 (t, 1H), 7.21-7.18 (m, 2H), 7.04 (s, 2H), 5.20 (s, 2H), 4.38 (d, 1H), 4.21 (d, 1H), 4.00-3.80 (m, 3H), 1.98 (s, 1H), 1.19-1.12 (m, 4H)Step-6: A stirred solution of ethyl / V-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-N-sulfamoylglycinate (3.2 g, 6.94 mmol, 1 eq.) in THF (50 mL), at 0°C, was treated with sodium methoxide (30% solution in methanol) (1.87 mL, 10.41 mmol, 1.5 eq.) and resulting reaction mixture was then stirred at O °C. After completion of the reaction (TLC monitoring), the reaction mixture was acidified with AcOH (2 mL), evaporated under reduced pressure to obtain the crude residue which was triturated with n-pentane (50 mL). Obtained solid was filtered and thoroughly dried to afford 3.0 g of 5-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide lnt-01 which was used as such in the next step.1H NMR (400 MHz, CDCI3) 6 ppm 7.50-7.48 (d, 2H), 7.37-7.30 (m, 3H), 7.17-7.16 (m, 2H), 5.19 (s, 2H), 3.94 (s, 2H), 1.83 (s, 4H).Synthesis of lnt-02:int-02A stirred solution of 2,2,6, 6-tetramethylpiperidine CAS# 768-66-1 (22.88 g, 161.9 mmol, 1.2 eq.) in THF (300 mL) was treated with a 2.5 M solution of n-BuLi in hexanes (64.8 mL, 161.9 mmol, 1.2 eq.) at -30 °C and stirred for 30 min at this temperature. The reaction mixture was then cooled to -78 °C and treated with a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) methane CAS# 78782-17-9 (36.17 g, 134.9 mmol, 1 eq.) in THF (300 mL) and stirred for another 30 minSPC6349at -78°C. Later, tert-butyl 3-oxopyrrolidine-1 -carboxylate CAS# 101385-93-7 (25 g, 134.9 mmol, 1 eq.) in THF (300 mL) was added at the same temperature. The resulting reaction mixture was then allowed to RT and stirred for 16 h. After reaction completion, the reaction mixture was cooled to 0 °C and quenched with sat. aq. NH4CI solution (150 mL). The solids were filtered off and the filtrate was evaporated under reduced pressure. The obtained residue was diluted with water (500 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine solution (300 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc (6-7%) in PE to yield 20 g of a E / Z mixture of tert-butyl -3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl) methylene) pyrrolidine-1 -carboxylate lnt-02.1H NMR (400 MHz, CDCI3) 6 ppm 5.34-5.30 (m, 1H), 4.20-4.14 (m, 1H), 4.08-3.96 (m, 1H), 3.56- 3.40 (m, 2H), 2.84 (t, 1H), 2.67 (t, 1H), 1.48 (s, 9H), 1.24 (s, 12H).Synthesis of lnt-03:Os / OX o Cl NCOFOa's-NHBoc NIS, ln(OTf)3(BuOH, Et3N DCM, 0 °C-RT,16 h DCM, 0 °C-RT, 2 hStep-1 Step-2FO=s-NH1 yTFA NaOMe BrDCM, 0 °C-RT, 6 h THF, 0 °C, 30 minStep-3Step-4OBnlnt-03Step-1: To a stirred solution of ethyl (6-(benzyloxy)-3-bromo-2-fluorophenyl)glycinate (CAS 3070099-37-2, 15 g, 39.243 mmol, 1.0 equiv.) and indium(lll) trifluoromethanesulfonate (2.21 g, 3.924 mmol, 0.1 equiv.) in DCM (200 mL), was added / V-iodosuccinimide (11.48 g, 51.017 mmol, 1.3 equiv.) portion-wise at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. The progression of the reaction was monitored by TLC (TLC system: 5% EtOAc in PE, TLC detection: UV active, compound RA 0.42). After completion, the reaction mixture was poured in ice-cold water (150 mL) and extracted with DCM (2 x 250 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the crude product (19 g) as a pale-yellow gummy. The crude compound was purified by flash column chromatography using a 120 g cartridge filled with 230-400 silica gel and the compound was eluted using 20-30% of EtOAc in PE as a gradient. The pure fractions were collected and concentrated under reduced pressure to afford ethyl (6-(benzyloxy)-3-bromo-2-fluoro-4-iodophenyl)glycinate (12 g) as a pale-yellow gummy.SPC6349-85-1H NMR (400 MHz, CDCl3) 5 ppm: 7.43-7.33 (m, 5H), 7.12 (d, 1H), 5.05 (s, 2H), 4.66 (brs, 1H), 4.19 (q, 2H), 4.08 (s, 2H), 1.25 (t, 3H).Step-2: To a stirred solution of chlorosulfonyl isocyanate (4.10 mL, 47.232 mmol, 2.0 equiv.) in DCM (200 mL), was added tert-butanol (4.49 mL, 47.232 mmol, 2.0 equiv.) drop-wise at 0 °C and the reaction mixture was stirred at the same temperature for 30 min under nitrogen atmosphere. This pre-reagent mixture was added to a stirred solution of ethyl (6-(benzyloxy)-3-bromo-2-fluoro-4-iodophenyl)glycinate (12 g, 23.616 mmol, 1.0 equiv.) and triethylamine (9.89 mL, 70.849 mmol, 3.0 equiv.) in DCM (200 mL) at 0 °C and the resulting reaction mixture was allowed to warm to RT and was stirred for 2 h. The progression of the reaction was monitored by TLC (TLC mobile phase: 30% EtOAc in PE, TLC detection: UV active, RA 0.63). After completion, the reaction mixture was diluted with water (150 mL) and extracted with DCM (3 x 250 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the crude ethyl / V-(6-(benzyloxy)-3-bromo-2-fluoro-4-iodophenyl)- / V-( / \ / -(tert-butoxycarbonyl)sulfamoyl)glycinate (15 g) as a pale-brown solid. Step-3: To a stirred solution of ethyl / V-(6-(benzyloxy)-3-bromo-2-fluoro-4-iodophenyl)- / \ / -( / \ / -(tert-butoxycarbonyl)sulfamoyl)glycinate (14.5 g, 21.097 mmol, 1.0 equiv.) in DCM (200 mL), was added trifluoroacetic acid (8.07 mL, 105.483 mmol, 5.0 equiv.) at 0 °C. The resulting reaction mixture was allowed to warm to RT and was stirred for 6 h. The progression of the reaction was monitored by TLC (TLC mobile phase: 30% EtOAc in PE, TLC detection: UV active, Rf: 0.40.). After completion, the reaction mixture was poured in water (100 mL), basified with sat. sodium bicarbonate solution (100 mL) and extracted with DCM (150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the crude product (12 g) as a brown gummy. The crude compound was purified by flash column chromatography over silica gel and the compound was eluted using 15-20% EtOAc in PE as a gradient. The collected pure fractions were concentrated under reduced pressure to provide ethyl / V-(6-(benzyloxy)-3-bromo-2-fluoro-4-iodophenyl)- / \ / -sulfamoylglycinate (9 g) as an off-white solid.1H NMR (400 MHz, CDCI3) 5 ppm: 7.58 (d, 1H), 7.50 (d, 2H), 7.40 (t, 2H), 7.35-7.32 (m, 1H), 7.13 (s, 2H), 5.19 (s, 2H), 4.28 (dd, 2H), 4.05-3.98 (m, 2H), 1.11 (t, 3H).Step-4: To a stirred solution of ethyl / V-(6-(benzyloxy)-3-bromo-2-fluoro-4-iodophenyl)- / \ / -sulfamoylglycinate (9 g, 15.327 mmol, 1.0 equiv.) in THF (100 mL), was added sodium methoxide solution (25% w / w in MeOH, 4.97 mL, 22.991 mmol, 1.5 equiv.) drop-wise at 0 °C and the resulting reaction mixture was stirred at the same temperature for 30 min under nitrogen atmosphere. The progression of the reaction was monitored by TLC (TLC mobile phase: 50% EtOAc in PE, TLC detection: UV active, RA 0.06). After completion, the reaction mixture was acidified with acetic acid (2.65 mL) at 0 °C, stirred for 10 min at RT and concentrated under reduced pressure toSPC6349provide the crude compound (8 g) as brown gummy. The resulting residue was dissolved in a mixture of THF: EtOAc (1:1, 150 mL) and was washed with water (100 mL). The aqueous layer was again extracted with a mixture of THF: EtOAc (1:1, 2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get semi pure compound, which was triturated with diethyl ether (3 x 50 mL) and dried under high vacuum to afford 5-(6-(benzyloxy)-3-bromo-2-fluoro-4-iodophenyl)-1,2,5-thiadiazolidin-3-one 1, 1 -dioxide (lnt-03, 5.50 g) as an off-white solid.1H NMR (400 MHz, DMSO-6) 5 ppm: 7.56 (d, 1H), 7.48 (d, 2H), 7.38-7.31 (m, 3H), 5.19 (s, 2H), 4.00 (s, 2H).19F NMR (376.49 MHz, DMSO-6) 5 ppm: -99.92 (s).Synthesis of lnt-04:lnt-04 Step-1: A solution of 4-bromo-5-fluoro-2-methylaniline [52723-82-7] (200 g, 980 mmol, 1Eq) and Acetic anhydride (200 g, 1960 mmol, 2 Eq), AcOK (144 g, 1470 mmol, 1.5 Eq) in CHCh (2000 mL) was stirred at room temperature for 10 min under nitrogen atmosphere. To the above mixture was added 2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16-benzohexaoxacyclooctadecine (61.2 g, 196 mmol, 0.2 Eq) and tert-butyl nitrite (222.3 g, 2156 mmol, 2.2 Eq) in portions over 30 min at room temperature. The resulting mixture was stirred at 60°C for additional overnight. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (3000 mL) at 0°C. The resulting mixture was extracted with CH2CI2 (3x2000 mL). The combined organic layers were washed with brine (2x2000 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product mixture was used in the next step directly without further purification. This resulted in 1-(5-bromo-6-fluoroindazol-1-yl)ethanone (254 g, crude) as a yellow oil.Step-2: A solution of 1-(5-bromo-6-fluoroindazol-1-yl)ethanone (254 g, 988 mmol, 1.0 Eq) and LiOH (47.3 g, 1976 mmol, 2 Eq) in methanol (2540 mL) was stirred at 60°C for 3 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with CH2CI2 (2x4000 mL). The combined organic layers were washed with brine (2x4000 mL), dried overSPC6349-87-anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 5-bromo-6-fluoro-1 / - / -indazole (91 g, 42.8%) as a white solid.Step-3: A solution of 5-bromo-6-fluoro-1 / - / -indazole (91 g, 423 mmol, 1 equiv) in H2SO4 (910 mL) was stirred at 0°C for 5 min under nitrogen atmosphere. To the above mixture was added KNO3 (42.79 g, 423 mmol, 1.0 Eq) in H2SO4 (200 mL) dropwise over 30 min at 0°C. The resulting mixture was stirred at 10°C for additional overnight. The reaction was quenched by the addition of ice water (6000 mL) at 0°C. The product was precipitated by the addition of ice water. The crude product was purified by silica gel column chromatography, eluted with PE I EA (3:1) to afford 5-bromo-6-fluoro-7-nitro-1 / - / -indazole (72 g, 65.4%) as a yellow solid.Step-4: Into a 2 L 4-necked round-bottom flask were added 5-bromo-6-fluoro-7-nitro-1 / - / -indazole (72 g, 277 mmol, 1 Eq), (4-methoxyphenyl)methyl 2,2,2-trichloroethanimidate [89238-99-3] (97.80 g, 346 mmol, 1.25 Eq) and TsOH (9.54 g, 55.4 mmol, 0.2 Eq) in DCM (720 mL) was stirred at room temperature for overnight under nitrogen atmosphere. The resulting mixture was extracted with CH2CI2 (2x1500 mL). The combined organic layers were washed with NaHCO3(2x2000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (3:1) to afford 5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]-7-nitroindazole (80 g, 76.0%) as a yellow solid. LC-MS: exact m / z (calcd): 379; m / z (obsd): 380 [M+H]+Step-5: A solution of 5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]-7-nitroindazole (80 g, 210.4 mmol, 1 Eq) and Acetic acid (25.27 g, 421 mmol, 2.0 Eq), Fe (58.76 g, 1052 mmol, 5.0 Eq) in EtOH (800 mL) and H2O (80 mL) was stirred at 80°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOH (2x500 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2x1000 mL). The combined organic layers were washed with brine (1x1000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1:1) to afford 5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]indazol-7-amine (65 g, 88.21%) as a yellow solid. LC-MS: exact m / z (calcd): 349; m / z (obsd): 350 [M+H]+Step-6: A solution of 5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]indazol-7-amine (65 g, 185.6 mmol, 1 Eq) and ethyl glyoxylate [924-44-7] (28.42 g, 278 mmol, 1.5 Eq) in DMF (650 mL) was stirred at room temperature. To the above mixture was added chlorotrimethylsilane (22.18 g, 204 mmol, 1.1 Eq) dropwise over 20 min at 0°C. The resulting mixture was stirred at room temperature for additional 1 h. To the above mixture was added Sodium cyanoborohydride (29.16 g, 464 mmol, 2.5 Eq) in portions over 20 min at 0°C. The resulting mixture was stirred at room temperature for additional 3 h. The reaction was quenched with sat. NaHCO3(aq.) at 0°C. The resulting mixtureSPC6349-88-was extracted with EtOAc (2x600 mL). The combined organic layers were washed with brine (4x300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product mixture was used in the next step directly without further purification. This resulted in ethyl 2-({5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]indazol-7- yl}amino)acetate (70 g, crude) as a white solid.Step-7: A solution of ethyl 2-({5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]indazol-7- yl}amino)acetate (70 g, 160.4 mmol, 1 Eq) in / V, / V-dimethylacetamide (700 mL) was stirred at room temperature for 5 min under nitrogen atmosphere. To the above mixture was added sulfamoyl chloride [7778-42-9] (44.49 g, 385 mmol, 2.4 Eq) in portions over 30 min at -5°C. The resulting mixture was stirred at room temperature for additional overnight. The resulting mixture was extracted with EtOAc (2x600 mL). The combined organic layers were washed with brine (2x500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1:1) to afford ethyl 2-({5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]indazol-7- yl}(sulfamoyl)amino)acetate (39 g, 47.17%) as a white solid. LC-MS: exact m / z (calcd): 514; m / z (obsd): 515 [M+H]+Step-8: A solution of ethyl 2-({5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]indazol-7- yl}(sulfamoyl)amino)acetate (39 g, 75.7 mmol, 1 Eq) and sodium methoxide (30% in methanol) (20.44 g, 113.5 mmol, 1.5 Eq) in THF (390 mL) and methanol (390 mL) was stirred at room temperature for overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was acidified to pH 3 with HCI (1 M). The resulting mixture was extracted with EtOAc (2x500 mL). The combined organic layers were washed with brine (2x500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1:3) to afford 5-(5-bromo-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-7-yl)-1,2,5- thiadiazolidin-3-one 1,1 -dioxide lnt-04 (25.6121 g, 75.1%) as a light grey solid. LC-MS: exact m / z (calcd): 467; m / z (obsd): 468 [M+H]+1H NMR (400 MHz, DMSO-6) 6 ppm 8.52 (s, 1H), 8.15 (d, J = 6.2 Hz, 1H), 7.45-7.24 (m, 2H), 7.02-6.86 (m, 2H), 5.57 (s, 2H), 4.86 (s, 2H), 3.74 (s, 3H)19F NMR (282 MHz, DMSO-d6) 5 ppm -114.92Examples of compounds of the invention and their preparationExample 1: Synthesis of Cpd001 and Cpd002SPC6349-89-Step-1: Pd(dppf)Cl2. CH2Cl2 CAS# 95464-05-4 (1.31 g, 1.61 mmol, 0.1 eq.) was added to a degassed solution of (3-bromo-2-fluoro-6-methoxyphenyl) boronic acid CAS# 1309980-91-3 (4.0 g, 16.08 mmol, 1.0 eq.), 2-(tert-butyl)-5-chloroisothiazol-3(2 / 7)-one 1,1-dioxide CAS# 850314-47-5 (3.96 g, 17.68 mmol, 1.1 eq.) and triethylamine (7 mL, 48.22 mmol, 3.0 eq.) in toluene (50 mL). The resulting reaction mixture was stirred at 80 °C. After completion of the reaction (TLC monitoring), the reaction mixture was concentrated and the residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc (20-40%) in PE to yield 1.7 g of 5-(3-bromo-2-fluoro-6-methoxyphenyl)-2-(tert-butyl) isothiazol-3(2 / 7)-one 1, 1 -dioxide.LC-MS: exact m / z (calcd): 391; m / z (obsd): 392 [M+H]+1H NMR (400 MHz, CDCI3) d ppm: 7.66-7.62 (m, 1H), 6.75-6.72 (m, 2H), 3.89 (s, 3H), 1.72 (s, 9H).Step-2: A stirred solution of 5-(3-bromo-2-fluoro-6-methoxyphenyl)-2-(tert-butyl)isothiazol-3(2 / 7)-one 1,1-dioxide (1.3 g, 3.31 mmol, 1.0 eq.), tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1 -carboxylate lnt-02 (1.33 g, 4.31 mmol, 1.3 eq.), K3PO4 (1.41 g, 6.63 mmol, 2.0 eq.) and Pd(dtbpf)Ch CAS# 95408-45-0 (107.80 mg, 0.17 mmol, 0.05 eq.) in a 8:2 dioxane:water mix (200 mL) was degassed at RT and stirred in a sealed tube at 70 °C. After completion of the reaction (TLC monitoring), the reaction mixture was cooled down to RT and then was filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc ( 4-8%) in PE to yield 930 mg of a E / Z mixture of tert-butyl 3-(3-(2-(tert-butyl)-1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)-2-fluoro-4-methoxybenzylidene) pyrrolidine-1 -carboxylate.LC-MS: exact m / z (calcd): 494; m / z (obsd): 495 [M+H]+Step-3: To a stirred solution of a E / Z mixture of tert-butyl 3-(3-(2-(tert-butyl)-1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)-2-fluoro-4-methoxybenzylidene) pyrrolidine-1 -carboxylate (0.80 g, 1.62 mmol, 1.0 eq.) in DCM (10 mL), cooled at -78 °C was added a 1M DCM solution of BBrs (16.2 mL, 16.2 mmol, 10 eq.). After addition, the resulting reaction mixture was stirred and allowed to reach gradually RT. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with a 7N solution of NH3 in MeOH (20 mL) and concentrated under reduced pressure. The residue was purified by Prep-HPLC [Prep-HPLC method: Mobile phase A: 10 mM Ammonium bicarbonate in water, Mobile phase B: Acetonitrile, Column: YMC Triart Actus C18 (20x150 mm, 5pm), Flow: 14.0 mL / min, Method: (T / %ofB): 0 / 5, 3 / 5, 10 / 15, 14.20 / 15, 14.30 / 98, 18 / 98, 18.1 / 5, 21 / 5; Temperature: Ambient.] to yield48 mg of first eluting (E)-5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3-ylidenemethyl)phenyl)isothiazol-3(2 / - / )-one 1,1-dioxide Cpd001LC-MS (Method A): r.t 0.83 min.; m / z 325 [M+H]+; m / z 323 [M-H]’1H NMR (400 MHz, DMSO-6) d ppm: 9.23 (br. s., 2H), 7.19 (t, 1H), 6.78 (d, 1H), 6.54 (s, 1H), 6.38 (s, 1H), 3.92 (s, 2H), 3.27 (t, 2H), 2.77 (t, 2H).SPC634919F NMR (376 MHz, DMSO-6) d ppm: -110.0 (d).and 56 mg of second eluting (Z)-5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3-ylidenemethyl)phenyl)isothiazol-3(2 / - / )-one 1,1 -dioxide Cpd002LC-MS (Method A): r.t 1.37 min.; m / z 325 [M+H]+; m / z 323 [M-H]’1H NMR (400 MHz, DMSO-6) d ppm: 9.08 (br. s., 2H), 7.34 (t, 1H), 6.78 (d, 1H), 6.54 (s, 1H), 6.38 (s, 1H), 3.93 (s, 2H), 3.32 (t, 2H), 2.72 (t, 2H).19F NMR (376 MHz, DMSO-6) d ppm: -110.9 (d).Example 2: Synthesis of Cpd003PdCI2(CH3CN)2, XPhos, Cs2CO^ CH3CN, RT Step-2Pd(dtbpf)CI2, Cs2CO3Dioxane: H2O, 90 °CStep-3Step-1: To a stirred solution of 5-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide lnt-01 (4.0 g, 9.63 mmol, 1.0 eq.) in trifluoroacetic acid (40 mL), was added / V-iodosuccinimide (1.63 g, 7.225 mmol, 1.0 eq.) at 0 °C. The resulting reaction mixture was allowed to warm to RT and stirred for 3 h. After reaction completion, the reaction mixture was concentrated and the residue was purified by reverse phase column chromatography over C18 modified silica gel column eluting with a gradient of acetonitrile (35-45%) in water to yield 2.20 g of 5-(6-(benzyloxy)-4-bromo-2-fluoro-3-iodophenyl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide.1H NMR (400 MHz, DMSO-6) d ppm: 7.51 (s, 1H), 7.45 (d, 2H), 7.39-7.27 (m, 3H), 5.22 (s, 2H), 4.28 (s, 2H).Step-2: To a stirred solution of 5-(6-(benzyloxy)-4-bromo-2-fluoro-3-iodophenyl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide (2.20 g, 4.07 mmol, 1.0 eq.) in acetonitrile (30 mL) was added Cs2CO3(1.99 g, 6.098 mmol, 1.5 eq.) at RT and the solution was degassed with argon for 10 min. The reaction mixture was then treated with cyclopropylacetylene CAS# 6746-94-7 (0.69 mL, 8.13 mmol, 2.0 eq.), bis(acetonitrile)dichloropalladium(ll) (52.7 mg, 0.203 mmol, 0.05 eq.) and XPhos (194 mg, 0.407 mmol, 0.1 eq.) at RT. The resulting reaction mixture was stirred at RT for 16 h in a sealed tube. After reaction completion, the reaction mixture was filtered through the celite bed and the bed was rinced with 20% MeOH in DCM (50 mL). The filtrate was concentrated and theSPC6349-91-residue was purified by reverse phase column chromatography over C18 modified silica gel column eluting with a gradient of acetonitrile (35-50%) in water to yield 1.2 g of 5-(6-(benzyloxy)-4-bromo-3-(cyclopropylethynyl)-2-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide.LC-MS: exact m / z (calcd): 478; m / z (obsd): 479 [M+H]+, 477 [M-H]’Step-3: To a stirred solution of 5-(6-(benzyloxy)-4-bromo-3-(cyclopropylethynyl)-2-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (500 mg, 1.04 mmol, 1.0 eq.) and potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate CAS# 1314538-55-0 (371 mg, 1.57 mmol, 1.5 eq.) in a 10:1 dioxane:water mix (16.50 mL) was added Cs2CO3(1.02 g, 3.13 mmol, 3.0 eq.) at RT and the solution was degassed with argon gas for 10 min. Later, bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) (67.9 mg, 0.104 mmol, 0.1 eq.) was added at RT and the resulting reaction mixture was stirred at 90 °C for 6 h in a sealed tube. After reaction completion, the reaction mixture was cooled to RT, filtered through a celite bed and the bed was rinced with 20% MeOH in DCM (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography over C18 modified silica gel column eluting with a gradient of acetonitrile (35-50%) in water to yield 310 mg of tert-butyl (5-(benzyloxy)-2-(cyclopropylethynyl)-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluorobenzyl)carbamate.LC-MS: exact m / z (calcd): 529; m / z (obsd): 528 [M-H]’Step-4: To a stirred solution of tert-butyl (5-(benzyloxy)-2-(cyclopropylethynyl)-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluorobenzyl)carbamate (300 mg, 0.566 mmol, 1.0 eq.) in DCM (10 mL), was added a 1M DCM solution of BBr3(2.83 mL, 2.832 mmol, 5.0 eq.) at -78 °C and the resulting reaction mixture was stirred at -78 °C. After reaction completion (LC-MS monitoring), the reaction mixture was quenched with a sat. NaHCO3aq solution (10 mL) and stirred for 10 min. The reaction mixture was filtered through a celite bed, the filtrate was concentrated and the residue was purified by Prep-HPLC (Prep-HPLC conditions: Mobile phase A 10 mM Ammonium bicarbonate in water, Mobile phase B: Acetonitrile, Column: LUNA C18 (25x150 mm, 10pm, Flow: 18.0 mL / min, Gradient (Time / % of B): 0 / 05, 2 / 05, 10 / 25, 11.4 / 25, 11.5 / 99, 14 / 99,14.1 / 05,17 / 05; Temperature: Ambient.) to yield 44 mg of 5-(4-(aminomethyl)-3-(cyclopropylethynyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide Cpd003.LC-MS (Method B): r.t 1.59 min.; m / z 340 [M+H]+; m / z 338 [M-H]’1H NMR (400 MHz, DMSO-6) d ppm: 8.17 (br. s., 3H), 6.79 (s, 1H), 3.99 (s, 2H), 3.93 (s, 2H), 1.63-1.57 (m, 1H), 0.95-0.90 (m, 2H), 0.79-0.75 (m, 2H)19F NMR (376 MHz, DMSO-6) d ppm: -112.8 (s)The following compound was synthesized using a similar procedure to that of Step-3 and Step-4 of the above Example 2, by selection of reagents, conditions and purification methods known by the skilled in the art.SPC6349-92-Reagent Step-3 Final CpdK®_z-xFOCpd004Potassium triflu 0 ro[(py rrol id i n- 1 -yl)methyl]borateCAS# 888711-53-3Example 3: Synthesis of Cpd005, Cpd006 and Cpd007Pd(dppf)CI2, Et3N LiBH4Pd(dtbpf)CI2, K3PO4 Toluene, 80 °C THF, -78 °C-RT Dioxane: H2O, 70 °C Step-1 Step-2 Step-3Cpd006 Cpd007Step-1: Pd(dppf)Cl2. CH2Cl2 CAS# 95464-05-4 (1.57 g, 1.93 mmol, 0.1 eq.) was added to a degassed solution of (3-bromo-2-fluoro-6-methoxyphenyl) boronic acid CAS# 1309980-91-3 (4.8 g, 19.3 mmol, 1.0 eq.), 2-(ferf-butyl)-5-chloroisothiazol-3(2 / 7)-one 1,1-dioxide CAS# 850314-47-5 (4.32 g, 19.29 mmol, 1.1 eq.) and triethylamine (8.1 mL, 57.87 mmol, 3.0 eq.) in toluene (70 mL). The resulting reaction mixture was stirred at 80 °C. After completion of the reaction (TLC monitoring), the reaction mixture was concentrated and the residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc (20-40%) in PE to yield 2.0 g of 5- (3-bromo-2-fluoro-6-methoxyphenyl)-2-(ferf-butyl) isothiazol-3(2 / 7)-one 1, 1 -dioxide.1H NMR (400 MHz, CDCh) d ppm: 7.66-7.62 (m, 1H), 6.75-6.72 (m, 2H), 3.89 (s, 3H), 1.72 (s, 9H).Step-2 To a stirred solution of 5-(3-bromo-2-fluoro-6-methoxyphenyl)-2-(tert-butyl) isothiazol- 3(2H)-one 1,1-dioxide (1.3 g, 3.31 mmol, 1.0 eq.) in MeOH (20 mL), was added lithium borohydride (2M in THF, 1.99 mL, 3.98 mmol, 1.2 eq.) at -78 °C and the resulting reaction mixture was then stirred at RT. After reaction completion, the reaction mixture was quenched with ice- cold water (20 mL) and extracted with EtOAc (3 X50 mL). The organic layer was separated, dried over Na2SO4 and concentrated. The crude residue was purified by column chromatography onSPC6349-93-silica gel eluting with a gradient of EtOAc (20-30%) in PE to yield 1.0 g of 5-(3-bromo-2-fluoro-6-methoxyphenyl)-2-(tert-butyl) isothiazolidin-3-one 1,1 -dioxide.1H NMR (400 MHz, CDCI3) d ppm: 7.53 (t, 1H), 6.67 (m, 1H), 5.31-5.29 (m, 1H), 3.84 (s, 3H), 3.41-3.28 (m, 1H), 3.12-3.07 (m, 1H), 1.66 (t, 9H).Step-3: A stirred solution of 5-(3-bromo-2-fluoro-6-methoxyphenyl)-2-(tert-butyl) isothiazolidin-3-one 1,1 -dioxide (1.0 g, 2.536 mmol, 1.0 eq.) and of a E / Z mixture of tert-butyl -3-((4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl) methylene) pyrrolidine-1 -carboxylate lnt-02 (1.02 g, 3.30 mmol, 1.3 eq.) and K3PO4 (1.077 g, 5.07 mmol, 2.0 eq.) in a 8:2 dioxane:water mix (20 mL) was degassed with argon for 10 min and then treated with bis(di-tert-butylphosphino) ferrocene]dichloropalladium(ll) CAS# 95408-45-0 (82.6 mg, 0.127 mmol, 0.05 equiv.). The resulting reaction mixture was then stirred at 70 °C in a sealed tube. After reaction completion, the reaction mixture was cooled to RT, filtered and the filtrate was concentrated. The crude residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc (20-30%) in PE to yield 1.0 g of a E / Z mixture of tert-butyl 3-(3-(2-(tert-butyl)-1,1-dioxido-3-oxoisothiazolidin-5-yl)-2-fluoro-4-methoxybenzylidene) pyrrolidine-1 -carboxylate.LC-MS: exact m / z (calcd): 496; m / z (obsd): 497 [M+H]+Step-4 (Chiral SFC): 1.0 g of a E / Z mixture of tert-butyl 3-(3-(2-(tert-butyl)-1,1-dioxido-3-oxoisothiazolidin-5-yl)-2-fluoro-4-methoxybenzylidene) pyrrolidine-1 -carboxylate were subjected to Chiral SFC purification [Preparative SFC conditions: Column / Dimensions: Chiralcel OX-H PACKED (250x30mm, 5pm), % CO2: 85%, % Co solvent: 15% (MeOH), Total Flow: 80 g / min, Back Pressure: 100 bar, Temperature: 30 °C, Wavelength: 255 nm, Stack time: 5 mins / injection, Load ability: 32.27 mg / injection, Solubility: 30 mL of MeOH, no of injections: 40] to yield 200 mg of first eluting (Peak 1)LC-MS: exact m / z (calcd): 496; m / z (obsd): 497 [M+H]+400 mg of second eluting (Peak 2)LC-MS: exact m / z (calcd): 496; m / z (obsd): 497 [M+H]+200 mg of third eluting (Peak 3)LC-MS: exact m / z (calcd): 496; m / z (obsd): 497 [M+H]+Step-5A: To a stirred solution of tert-butyl 3-(3-(2-(tert-butyl)-1,1-dioxido-3-oxoisothiazolidin-5-yl)-2-fluoro-4-methoxybenzylidene) pyrrolidine-1 -carboxylate (Peak-1 from Step4-SFC, 180 mg, 0.362 mmol, 1.0 eq.) in DCM (10 mL), was added a 1M of BBrs in DCM (3.63 mL, 3.63 mmol, 10 eq.) at -78 °C and the resulting reaction mixture was then stirred at RT. After reaction completion, the reaction mixture was quenched with a sat. aq. NaHCO3solution (10 mL) and then concentrated under reduced pressure. The residue was purified by reverse phase Prep-HPLC [Prep-HPLC method: Mobile phase A: 10mM Ammonium bicarbonate in water, Mobile Phase B: Acetonitrile, Column: Luna C18 (25x150 mm, 10pm), Flow: 16.0 mL / min, Gradient (Time / % of B): 0 / 05,3 / 05,10 / 25,11.50 / 25,11.60 / 98,15 / 98,15.1 / 05,18 / 05, Temperature: Ambient.] to yield 8 mg ofSPC6349-94-(Z)-5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3-ylidenemethyl) phenyl) isothiazolidin-3-one 1, 1 -dioxide Cpd005.LC-MS (Method C): r.t 7.74 min.; m / z 327 [M+H]+1H NMR (400 MHz, DMSO-6) d ppm: 6.70 (t, 1H), 6.66 (d, 1H), 6.42 (s, 1H), 4.83-4.79 (m, 1H), 3.69 (s, 2H), 3.05 (t, 2H), 2.94-2.88 (m, 1H), 2.84-2.78 (m, 1H), 2.68-2.61 (m, 2H)19F NMR (376 MHz, DMSO-6) d ppm: -114.6 (s)Step-5B: To a stirred solution of tert-butyl 3-(3-(2-(tert-butyl)-1,1-dioxido-3-oxoisothiazolidin-5-yl)-2-fluoro-4-methoxybenzylidene) pyrrolidine-1 -carboxylate (Peak-2 from Step4-SFC, 380 mg, 0.765 mmol, 1.0 eq.) in DCM (10 mL), was added a 1M of BBr3in DCM (7.65 mL, 7.65 mmol, 10 eq.) at -78 °C and the resulting reaction mixture was then stirred at RT. After reaction completion, the reaction mixture was quenched with a sat. aq. NaHCO3solution (10 mL) and then concentrated under reduced pressure. The residue was purified by reverse phase Prep-HPLC [Prep-HPLC method: Mobile phase A: 10mM Ammonium bicarbonate in water, Mobile phase B: Acetonitrile, Column: X-Select C18 (19x250mm, 5pm), Flow: 13 mL / min, Method: 0 / 4,4 / 4,10 / 15,12 / 15,12.2 / 98,17 / 98,17.2 / 4,21 / 4, Solubility: ACN+ THF + Water, Temperature: Ambient.] to yield15 mg of first eluting (E)-5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3-ylidenemethyl) phenyl) isothiazolidin-3-one 1,1 -dioxide Cpd007.LC-MS (Method C): r.t 6.85 min.; m / z 327 [M+H]+1H NMR (400 MHz, DMSO-6) d ppm: 7.17 (t, 1H), 6.68 (d, 1H), 6.48 (s, 1H), 4.84-4.79 (m, 1H), 3.87 (s, 2H), 3.26 (t, 2H), 2.92-2.88 (m, 1H), 2.84-2.78 (m, 1H), 2.70-2.64 (m, 2H)19F NMR (376 MHz, DMSO-6) d ppm: -114.4 (s)and15 mg of first eluting (Z)-5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3-ylidenemethyl) phenyl) isothiazolidin-3-one 1,1 -dioxide Cpd006.LC-MS (Method C): r.t 7.75 min.; m / z 327 [M+H]+1H NMR (400 MHz, DMSO-6) d ppm: 8.92 (br. s., 2H), 7.01 (t, 1H), 6.68 (d, 1H), 6.49 (s, 1H), 4.84-4.80 (m, 1H), 3.86 (s, 2H), 3.25 (t, 2H), 2.95-2.89 (m, 1H), 2.84-2.78 (m, 1H), 2.76-2.72 (m, 2H)19F NMR (376 MHz, DMSO-6) d ppm: -113.8 (s)SPC6349-95-Example 4: Synthesis of Cpd010OFO=s-NHOlnt-03 2,2,6,6-tetramethylpiperidine Pd(dtbpf)CI2, Na2CO3THF, -78 °C, 16 h DME: H2O, 70 °C, 16 h Step-1 Step-2> PdCI2(CH3CN)2, XPhos, Cs2CO3ACN, 70 °C, 16 h Step-4Cpd010 Step-1: To a stirred solution of 2,2,6, 6-tetramethylpiperidine (11.93 mL, 70.096 mmol, 1.2 equiv.) in THF (200 mL) was added n-BuLi (1.6M in hexane, 43.81 mL, 70.096 mmol, 1.2 equiv.) at -30 °C and the mixture was stirred for 30 min and then bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methane (17.22 g, 64.255 mmol, 1.1 equiv.) in THF (100 mL) was added at -30 °C and stirred for 30 min. Later, tert-butyl 3-oxoazetidine-1 -carboxylate (10 g, 58.413 mmol, 1.0 equiv.) dissolved in THF (100 mL) was added dropwise at -78 °C. The resulting reaction mixture was allowed to warm to RT and was stirred for 16 h. The progression of the reaction was monitored by TLC (Mobile phase: 20% EtOAc in PE, TLC detection: KMnO4active, compound Rr:0.55). After completion, the reaction mixture was cooled to 0 °C, quenched with sat. NH4CI solution (50 mL), added water (200 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the crude product (12 g) as a brown liquid. The crude product was purified by flash column chromatography using 100-200 mesh silica gel and the compound was eluted using 10-15% EtOAc in PE as a gradient. The pure fractions were collected and concentrated under reduced pressure to provide tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)methylene)azetidine-1 -carboxylate (7 g) as a pale-brown liquid.1H NMR (400 MHz, CDCI3) 6 ppm: 5.34-5.32 (m, 1H), 4.64-4.62 (m, 2H), 4.52-4.50 (m, 2H), 1.46 (s, 9H), 1.24 (s, 12H).Step-2: To a stirred solution of 5-(6-(benzyloxy)-3-bromo-2-fluoro-4-iodophenyl)-1,2,5- thiadiazolidin-3-one 1,1 -dioxide (lnt-03, 2 g, 3.696 mmol, 1.0 equiv.) and tert-butyl 3-((4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) methylene) azetidine-1 -carboxylate (872.8 mg, 2.957 mmol, 0.8 equiv.) in DME (40 mL) and water (5 mL) was added sodium carbonate (1.18 g, 11.088 mmol, 3.0 equiv.) at RT and the mixture was degassed with argon gas for 10 min. Pd(dtbpf)Cl2(120.3 mg, 0.185 mmol, 0.05 equiv.) was added at RT and the mixture was again degassed with argon gas for 5 min. The resulting reaction mixture was stirred at 70 °C for 16 h in a sealed tube. The progression of the reaction was monitored by LC-MS. The reaction mixture was cooled to RT,SPC6349-96-filtered through the celite bed and the bed was washed with 20% MeOH in DCM (100 mL). The filtrate was concentrated under reduced pressure to provide the crude product (2 g) as a brown gummy. The crude compound was purified by reverse phase flash column chromatography using an 80 g C18 column and the compound was eluted with a gradient of 30-50% acetonitrile in water. The pure fractions were collected and concentrated under reduced pressure to afford tert-butyl 3-(5-(benzyloxy)-2-bromo-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluorobenzyl)azetidine-1 -carboxylate (600 mg) as a brown solid.Step-3: To a stirred solution of tert-butyl 3-(5-(benzyloxy)-2-bromo-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluorobenzylidene)azetidine-1 -carboxylate (600 mg, 1.030 mmol, 1.0 equiv.) in MeOH (15 mL), was added Raney Nickel (600 mg, 3.090 mmol, 3.0 equiv.) at RT under nitrogen atmosphere. The resulting reaction mixture was stirred at RT for 4 h under hydrogen balloon atmosphere. The progression of the reaction was monitored by LC-MS. The reaction mixture was filtered through the celite bed, and the bed was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to provide the crude product (500 mg) as a brown gummy. The crude compound was purified by reverse phase flash column chromatography using an 80 g C18 column and the compound was eluted with a gradient of 20-40% acetonitrile in water. The pure fractions were collected and concentrated under reduced pressure to furnish tert-butyl 3-(2-bromo-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)azetidine-1-carboxylate (260 mg) as a brown solid.Step-4: A stirred solution of tert-butyl 3-(2-bromo-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)azetidine-1-carboxylate (200 mg, 0.405 mmol, 1.0 equiv.) and cesium carbonate (197.2 mg, 0.607 mmol, 1.5 equiv.) in acetonitrile (5 mL) was degassed with argon gas for 10 min. PdCl2(CH3CN)2 (10.5 mg, 0.040 mmol, 0.1 equiv.), X-Phos (38.6 mg, 0.081 mmol, 0.2 equiv.) and ethynyl cyclopropane (133.7 mg, 2.023 mmol, 5 equiv.) were added at RT. The resulting reaction mixture was stirred at 70 °C for 16 h in a sealed tube. The progression of the reaction was monitored by LC-MS. The reaction mixture was cooled to RT, filtered through the celite bed and the bed was washed with 20% MeOH in DCM (50 mL). The filtrate was concentrated under reduced pressure to provide the crude product (500 mg) as a brown gummy. The crude compound was purified by reverse phase flash column chromatography using an 80 g C18 column and the compound was eluted with a gradient of 10-30% acetonitrile in water. The pure fractions were collected and concentrated under reduced pressure to provide tert-butyl 3-(2-(cyclopropylethynyl)-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)azetidine-1 -carboxylate (180 mg,) as a brown solid.Step-5: To a stirred solution of tert-butyl 3-(2-(cyclopropylethynyl)-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)azetidine-1-carboxylate (170 mg, 0.355 mmol, 1.0 equiv.) in DCM (6 mL), was added 2,2,2-trifluoroacetic acid (404.1 mg, 3.545 mmol, 10 equiv.) at 0 °C. The resulting reaction mixture was stirred at RT for 2 h. The progression of the reaction wasSPC6349-97-monitored by LC-MS. The reaction mixture was concentrated under reduced pressure and basified with ammonium bicarbonate solution (up to pH~7-8). This aqueous mixture was purified by reverse phase Prep HPLC [Prep-HPLC method: Mobile phase A: 10mM Ammonium bicarbonate in water, Mobile phase B: Acetonitrile, Column: Luna Omega C18 ( 21.2x250 mm), 5pm; Flow: 14 mL / min, Gradient (Time / % of B): 0 / 10, 2 / 10, 10 / 45, 10.9 / 45, 11 / 98, 14 / 98, 14.1 / 10, 17 / 10, Temperature: Ambient], The fractions were collected and lyophilized to afford 5-(4- (azetidin-3-ylmethyl)-3-(cyclopropylethynyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1, 1 -dioxide Cpd010 (78 mg) as a white solid.LC-MS (Method-E): r.t.= 2.67 min (97.52%), m / z= 380.26 [M+H]+.UPLC (Method-F): r.t.= 2.14 min (98.39%).1H NMR (400 MHz, DMSO-6) 5 ppm: 8.77 (brs, 3H), 6.53 (s, 1H), 3.96 (t, 2H), 3.91 (s, 2H), 3.73 (t, 2H), 3.14-3.07 (m, 1H), 2.91 (d, 2H), 1.61-1.56 (m, 1H), 0.94-0.89 (m, 2H), 0.76-0.74 (m, 2H).19F NMR (376.5 MHz, DMSO-6) 5 ppm: -112.94 (s).Example 5: Synthesis of Cpd031HCI 4M in 1,4-dioxane, DCM, 0° to RT Step-4Step-1: A stirred suspension of tert-butyl (1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3- carboxylate [2414574-91-5] (0.88 g, 2 Eq, 4.3 mmol), 5-(5-bromo-6-fluoro-2-(4-methoxybenzyl)- 2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide lnt-04 (1.0 g, 1 Eq, 2.1 mmol) and cesium carbonate (1.4 g, 2 Eq, 4.3 mmol) in anhydrous acetonitrile (30 mL) was flushed through with nitrogen gas for 10 minutes. Then acetonitrile - dichloropalladium (2:1) (55 mg, 0.1 Eq, 0.21 mmol) and 2-(dicyclohexylphosphanyl)-2',4',6'-tris(isopropyl)biphenyl (0.15 g, 0.15 Eq, 0.32 mmol) wereSPC6349-98-added. The vial was sealed, and the reaction mixture was stirred and heated at 90°C for 3 hours. The reaction mixture was allowed to cool down to room temperature, diluted with ethyl acetate and then washed with water. The organic layer was separated, washed with brine, dried with MgSO4, filtered and the solvents of the filtrate evaporated under reduced pressure at 45°C. The residue was purified by flash column chromatography (silica gel, 0-10% MeOH in DCM) to give tert-butyl (1R,5S,6s)-6-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-5-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.44 g, 2.0 mmol, 94 %, 83% purity) as an orange / brown solid. LC-MS: exact m / z (calcd): 595; m / z (obsd): 596 [M+H]+Step-2: HCI (4M in dioxane) (3.0 mL, 4.0 molar, 6 Eq, 12.0 mmol) was added to a stirred solution of tert-butyl (1 R,5S,6s)-6-((7-(1, 1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-5-yl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.44 g, 83% Wt, 1 Eq, 2.01 mmol) in DCM (40.1 mL) at 0°C. After addition the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness to give 5-(5-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1.52 g, 2.8 mmol, 140 %, 91% purity) as an orange / brown solid. LC-MS: exact m / z (calcd): 495; m / z (obsd): 496 [M+H]+Step-3: 1-Boc-4-piperidinesulfonyl chloride [782501-25-1] (469 mg, 1.5 Eq, 1.65 mmol) was added to a stirred mixture of 5-(5-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (600 mg, 91% Wt, 1 Eq, 1.10 mmol) and triethylamine (1.54 mL, 10 Eq, 11.0 mmol) in DCE (36 mL) at room temperature. After addition the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and then washed with a saturated aqueous NaHCO3solution. The organic layer was separated, washed with brine, dried with MgSO4, filtered and the solvents of the filtrate were evaporated under reduced pressure at 40°C. The residue was purified by flash column chromatography (silica gel, 0-15% MeOH in DCM) to give tert-butyl 4-(((1 R,5S,6s)-6-((7-(1, 1 -dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-5-yl)ethynyl)-3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)piperidine-1-carboxylate (0.16 g, 0.20 mmol, 18 %, 93% purity) as a light yellow oil. LC-MS: exact m / z (calcd): 742; m / z (obsd): 743 [M+H]+1H NMR (400 MHz, DMSO-6) 6 ppm 8.42 (s, 1 H) 7.72 - 7.76 (m, 1 H) 7.28 - 7.37 (m, 2 H) 6.92 (d, J=8.67 Hz, 2 H) 5.53 (s, 2 H) 4.50 (s, 2 H) 3.73 (s, 3 H) 3.55 (d, J=9.93 Hz, 2 H) 2.95 - 3.49 (m, 9 H) 1.97 - 2.15 (m, 3 H) 1.92 (br d, J=10.03 Hz, 2 H) 1.38 - 1.43 (m, 9 H)Step-4: HCI (4M in dioxane) ( 0.30 mL, 4.0 molar, 6 Eq, 1.2 mmol) was added to a stirred solution of tert-butyl 4-(((1 R,5S,6s)-6-((7-(1, 1 -dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-5-yl)ethynyl)-3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)piperidine-1-carboxylate (0.16 g, 93% Wt, 1 Eq, 0.20 mmol) in DCM (4.0 mL) at 0°C. After addition the reactionSPC6349-99-mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness to give 5-(6-fluoro-2-(4-methoxybenzyl)-5-(((1R,5S,6s)-3-(piperidin-4-ylsulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide (0.18 g, 0.21 mmol, 100 %, 74% purity) as an orange / brown solid. LC-MS: exact m / z (calcd): 642; m / z (obsd): 643 [M+H]+Step-5: Trifluoroacetic acid (2.5 mL, 33 mmol) was added to a stirred solution of 5-(6-fluoro-2-(4-methoxybenzyl)-5-(((1R,5S,6s)-3-(piperidin-4-ylsulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.18 g, 74% Wt, 1 Eq, 0.21 mmol) in DCE (2.5 mL) at room temperature. The reaction mixture was stirred at 60°C for 4 hours. The solvents were evaporated under reduced pressure at 40°C. The residue was purified with Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-5pm, 50x150mm, Mobile phase: 0.1% NH4HCO3 solution in water + 5% CH3CN, CH3CN). The organic solvent was evaporated under reduced pressure at 30°C. The remaining water layer was lyophilized to give 5-(6-fluoro-5-(((1R,5S,6s)-3-(piperidin-4-ylsulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl)ethynyl)-2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide Cpd031 (33 mg, 59 pmol, 29 %, 94% purity) as a white solid. LC-MS: exact m / z (calcd): 522; m / z (obsd): 523 [M+H]+1H NMR (400 MHz, DMSO-6) 6 ppm 13.24 (brs, 1 H) 8.37 (brs, 1 H) 8.07 (s, 1 H) 7.82 (d, J=6.06 Hz, 1 H) 4.09 (s, 2 H) 3.51 - 3.57 (m, 2 H) 3.44 - 3.49 (m, 1 H) 3.33 - 3.43 (m, 4 H) 2.85 - 2.95 (m, 2 H) 2.11 (br s, 4 H) 1.76 (qd, J=12.87, 4.02 Hz, 2 H) 1.64 (t, J=3.34 Hz, 1 H)The following compounds were synthesized using a similar procedure to that of Step-3, Step-4 and Step-5 of the above Example 5 for Cpd033 and that of Step-3 and Step-5 of the above Example 5 for Cpd-032 and Cpd-034, by selection of reagents, conditions and purification methods known by the skilled in the art.SPC6349-100-Table 2Reagent Step-3 Final Cpd°\S Cl[ N 'Q HCICpd0324-Methylpiperazine-1 -sulfonylchloride hydrochlorideCAS# 33581-96-30I_,sCl'b Cpd033tert-butyl 4-(chlorosulfonyl)-1 -piperazinecarboxylateCAS# 162046-65-3O ii— s II-ci0Cpd034 Methanesulfonyl chlorideCAS# 124-63-0Example 6: Synthesis of Cpd035OFO='e-NH TFA, DCE, 60°C PdCI2(CH3CN)2, Step-1 XPhos, Cs2CO3, CH3CN, 90°CPMB Step-2 lnt-04Step-1: Trifluoroacetic acid (30 g, 20 mL, 1.2e+2 Eq, 0.26 mol) was added to a stirred solution of 5-(5-bromo-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide lnt-04 (1.0 g, 1 Eq, 2.1 mmol) in DCE (20 mL). The reaction mixture was stirred at 60°C for 5 hours. The reaction mixture was concentrated to dryness and then co-evaporated with toluene. The residue was dissolved in dichloromethane and purified by flash column chromatography (silica gel, 0-15% [7N NH3 in MeOH] in DCM) to give 5-(5-bromo-6-fluoro-2 / 7-indazol-7-yl)-1,2,5- thiadiazolidin-3-one 1,1 -dioxide (0.63 g, 1.8 mmol, 85 %, 100% purity) as a white solid. LC-MS: exact m / z (calcd): 348; m / z (obsd): 349 [M+H]+Step-2: The atmosphere of a stirred suspension of 5-(5-bromo-6-fluoro-2 / 7-indazol-7-yl)-1,2,5- thiadiazolidin-3-one 1,1 -dioxide (100 mg, 100% Wt, 1 Eq, 286 pmol), cesium carbonate (187 mg, 45.8 pL, 2 Eq, 573 pmol), acetonitrile - dichloropalladium (2:1) (7.43 mg, 0.1 Eq, 28.6 pmol) and 2-(dicyclohexylphosphanyl)-2',4',6'-tris(isopropyl)biphenyl (27.3 mg, 0.2 Eq, 57.3 pmol) in ACN (8.0 mL) in a sealed vial, was replaced three times with nitrogen gas. Then ethynylcyclopropane,SPC6349-101-- [6746-94-7] (56.8 mg, 72.5 pL, 3 Eq, 859 pmol) was added drop-wise and the mixture was flushed through with nitrogen gas for 5 minutes. The reaction mixture was then stirred and heated at 90°C for 3 hours. The mixture was allowed to cool down to room temperature. The mixture was diluted with ethyl acetate and washed with water. The water layer was extracted two more times with ethyl acetate. The combined organic layers were dried with MgSO₄, filtered, and the solvents evaporated under reduced pressure at 40°C. The residue was purified with Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-5µm, 50x150mm, Mobile phase: 0.1% NH4HCO3 solution in water + 5% CH3CN, CH3CN) to give 5-(5-(cyclopropylethynyl)-6-fluoro-2 / 7-indazol-7- yl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide Cpd035 (8.3 mg, 25 pmol, 8.7 %, 100% purity) as an off-white solid. LC-MS: exact m / z (calcd): 334; m / z (obsd): 335 [M+H]+1H NMR (400 MHz, DMSO-6) 6 ppm 8.05 (s, 1 H) 7.80 (d, J=6.06 Hz, 1 H) 4.09 (s, 2 H) 1.55 - 1.62 (m, 1 H) 0.88 - 0.93 (m, 2 H) 0.71 - 0.80 (m, 2 H)Example 7: Synthesis of Cpd036Pd(dtbf)Cl₂, K₃PO₄ 1,4-dioxane, H₂O, 90°C Step-1PMB lnt-04Step-1: A mixture of 1,4-dioxane (16.1 mL) and water (3.2 mL) was added to a vial containing tertbutyl (Z)-3-cyclopropyl-4-((4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1- carboxylate [3070099-68-9] (298 mg, 1 Eq, 852 pmol), 5-(5-bromo-6-fluoro-2-(4-methoxybenzyl)- 2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide lnt-04 (400 mg, 1 Eq, 852 pmol), 1,1'- bis(di-tert-butylphosphino)ferrocene-palladium dichloride (55.6 mg, 0.1 Eq, 85.2 pmol) and potassium phosphate (543 mg, 3 Eq, 2.56 mmol). The atmosphere was evacuated and replaced with nitrogen gas for three times. The mixture was then flushed through with nitrogen gas for 10 minutes. The reaction mixture was stirred and heated at 90°C for 3 hours. The reaction mixture was allowed to cool down to room temperature. The mixture was diluted with ethyl acetate. Water was added and the product was extracted two times with ethyl acetate to the organic layer. The organic layer was separated, dried with MgSO₄, filtered and the solvents of the filtrate evaporated under reduced pressure at 45°C to give tert-butyl (Z)-3-cyclopropyl-4-((7-(1,1-dioxido-4-oxo- 1,2,5-thiadiazolidin-2-yl)-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-5-yl)methylene)pyrrolidine-1- carboxylate (0.68 g, 1.1 mmol, 120 %, 95% purity) as an orange solid. LC-MS: exact m / z (calcd): 611; m / z (obsd): 612 [M+H]+1H NMR (400 MHz, DMSO-6) 6 ppm 8.08- 8.15 (m, 1 H) 7.16 (d, J=6.58 Hz, 1 H) 7.10 (d, J=8.67SPC6349-102-Hz, 2 H) 6.68 (d, J=7.48 Hz, 2 H) 6.42 - 6.48 (m, 1 H) 5.29 (s, 2 H) 4.26 (s, 2 H) 3.91 (s, 2 H) 3.47 - 3.55 (m, 3 H) 3.34 (s, 1 H) 2.89 (br dd, J=10.50, 7.16 Hz, 1 H) 2.01 - 2.15 (m, 1 H) 1.18 (s, 9 H) 0.57 - 0.73 (m, 1 H) 0.35 - 0.47 (m, 1 H) 0.17 - 0.30 (m, 1 H) 0.06 - 0.16 (m, 1 H) -0.06 - 0.04 (m, 1 H).Step-2: Trifluoroacetic acid (11 mL, 0.14 mol) was added to a stirred solution of tert-butyl (Z)-3- cyclopropyl-4-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-6-fluoro-2-(4-methoxybenzyl)-2 / 7- indazol-5-yl)methylene)pyrrolidine-1-carboxylate (0.68 g, 95% Wt, 1 Eq, 1.1 mmol) in DCE (11 mL). The reaction mixture was stirred at 60°C for 4 hours. The solvents were evaporated under reduced pressure at 40°C. The residue was purified with Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-5µm, 50x150mm, Mobile phase: 0.1% NH₄HCO₃ solution in water + 5% CH₃CN, CH₃CN). The organic solvents of the purified fraction were evaporated under reduced pressure at 30°C. The remaining water layer was lyophilized to give (Z)-5-(5-((4- cyclopropylpyrrolidin-3-ylidene)methyl)-6-fluoro-2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1- dioxide Cpd036 (61.1 mg, 156 pmol, 15 %, 100% purity) as a white solid. LC-MS: exact m / z (calcd): 391; m / z (obsd): 392 [M+H]+1H NMR (400 MHz, DMSO-6) 6 ppm 13.19 (br s, 1 H) 8.11 (s, 1 H) 7.66 (d, J=6.48 Hz, 1 H) 6.82 - 6.87 (m, 1 H) 4.05 - 4.19 (m, 4 H) 3.48 - 3.54 (m, 1 H) 3.01 - 3.08 (m, 1 H) 2.31 (q, J=8.19 Hz, 1 H) 0.89 - 0.99 (m, 1 H) 0.66 - 0.75 (m, 1 H) 0.43 - 0.54 (m, 2 H) 0.23 - 0.32 (m, 1 H)Example 8: Synthesis of Cpd037 and Cpd038NBocPd(dtbf)Cl₂, K₃PO₄ 1,4-dioxane, H₂O, 90°C Step-1— Peakl (first eluting) SFCStep-3L-- Peak2 (second eluting)Cpd038SPC6349-103-Step-1: A mixture of 1,4-dioxane (12 mL) and water (2.4 mL) was flushed through with nitrogen gas for 10 minutes. The solution was added to a vial containing tert-butyl 3-((4,4,5,5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)methylene)pyrrolidine-1 -carboxylate [2376764-71-3] (297 mg, 1.5 Eq, 959 pmol), 5-(5-bromo-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide lnt-04 (300 mg, 1 Eq, 639 pmol) and potassium phosphate (407 mg, 3 Eq, 1.92 mmol). The mixture was flushed through with nitrogen gas for 10 minutes. Then 1,1 '-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (41.7 mg, 0.1 Eq, 63.9 pmol) was added. The vial was sealed and the reaction mixture was stirred and heated at 90°C for 4 hours. The reaction mixture was allowed to cool down to room temperature. The mixture was diluted with ethyl acetate. Water was added and the product was extracted two times with ethyl acetate to the organic layer. The organic layer was separated, dried with MgSO₄, filtered and the solvents of the filtrate evaporated under reduced pressure at 45°C. The residue was purified by flash column chromatography (silica gel, 0-15% MeOH in DCM) to give tert-butyl 3-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-5-yl)methylene)pyrrolidine-1-carboxylate (0.35 g, 0.61 mmol, 95 %, 99% purity) as an orange solid. LC-MS: exact m / z (calcd): 571; m / z (obsd): 572 [M+H]+1H NMR (400 MHz, DMSO-6) 6 ppm 8.36 - 8.48 (m, 1 H) 7.39 - 7.59 (m, 1 H) 7.37 - 7.48 (m, 1 H) 7.30 - 7.35 (m, 2 H) 6.92 (d, J=8.36 Hz, 2 H) 6.52 (br s, 1 H) 5.54 (s, 2 H) 4.50 (d, J=1.25 Hz, 2 H) 4.08 (br s, 2 H) 3.73 (s, 3 H) 3.35 - 3.46 (m, 2 H) 2.78 (br s, 2 H) 2.42 - 2.46 (m, 1 H) 1.38 -1.46 (m, 9 H)Step-2: Trifluoroacetic acid (5.0 mL, 150 Eq, 66 mmol) was added to a stirred solution of tert-butyl 3-((7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-6-fluoro-2-(4-methoxybenzyl)-2 / 7-indazol-5-yl)methylene)pyrrolidine-1 -carboxylate (0.25 g, 1 Eq, 0.44 mmol) in DCE (10 mL). The reaction mixture was stirred at 60°C for 2 hours. The solvents were evaporated under reduced pressure at 40°C. The residue was triturated in DIPE. The precipitate was filtered off and washed with DIPE and then dried on the air to give 5-(6-fluoro-5-(pyrrolidin-3-ylidenemethyl)-2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide, trifluoroacetate (203 mg, 436 pmol, 100 %). LC-MS: exact m / z (calcd): 351; m / z (obsd): 352 [M+H]+Step-3: The EZZ-mixture of 5-(6-fluoro-5-(pyrrolidin-3-ylidenemethyl)-2H-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide, trifluoroacetate (203 mg, 578 pmol) was purified and separated into its stereoisomers by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-5µm, 50x150mm, Mobile phase: 0.1% NH₄HCO₃ solution in water + 5% CH₃CN, CH₃CN). The organic solvents of the purified fractions were evaporated under reduced pressure at 30°C. The remaining water layers were lyophilized to give (E)-5-(6-fluoro-5-(pyrrolidin-3-ylidenemethyl)-2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide Cpd037 (29 mg, 83 pmol, 100% purity) as a white solid. LC-MS: exact m / z (calcd): 351; m / z (obsd): 352 [M+H]+1H NMR (400 MHz, DMSO-6) 6 ppm 13.12 (br s, 1 H) 8.10 (s, 1 H) 7.77 (d, J=6.38 Hz, 1 H) 6.68SPC6349-104-(br s, 1 H) 4.11 (s, 2 H) 3.99 (s, 2 H) 3.22 - 3.45 (m, 2 H) 2.82 (br t, J=6.74 Hz, 2 H)and (Z)-5-(6-fluoro-5-(pyrrolidin-3-ylidenemethyl)-2 / 7-indazol-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide Cpd038 (20 mg, 48 pmol, 85% purity) as a white solid. LC-MS: exact m / z (calcd): 351; m / z (obsd): 352 [M+H]+1H NMR (400 MHz, DMSO-6) 6 ppm 13.10 (br s, 1 H) 8.10 (s, 1 H) 7.63 (d, J=6.48 Hz, 1 H) 6.63 - 6.73 (m, 1 H) 4.11 (s, 2 H) 4.01 (br s, 2 H) 3.20 - 3.41 (m, 2 H) 2.82 (brt, J=6.58 Hz, 2 H).Table 3: Analytical LC-MS and NMR data for example compounds of the inventionLC- Calcd Observed ObservedLC-MS r.t MS1H NMR 400 MHz 5 ppmCode Exact [M+H]+[M-H]- Method (min.) purity (DMSO-d6, unless otherwise stated) mass (m / z) (m / z)(%)9.23 (br. s„ 2H), 7.19 (t, 1H), 6.78 (d, 1H), 6.54 (s, 1H), 6.38 (s, 1H), Cpd001 A 0.83 97.9 324 325 3233.92 (s, 2H), 3.27 (t, 2H), 2.77 (t,2H)9.08 (br. s., 2H), 7.34 (t, 1H), 6.78 (d, 1H), 6.54 (s, 1H), 6.38 (s, 1H), Cpd002 A 1.37 97.2 324 325 3233.93 (s, 2H), 3.32 (t, 2H), 2.72 (t,2H)8.17 (br. s„ 3H), 6.79 (s, 1H), 3.99 (s, 2H), 3.93 (s, 2H), 1.63-1.57 (m, Cpd003 B 1.59 98.9 339 340 3381H), 0.95-0.90 (m, 2H), 0.79-0.75 (m, 2H)10.21 (br. s., 1H), 9.68 (br. s„ 1H), 6.89 (s, 1H), 4.34 (br. s„ 2H), 3.94 (s, 2H), 3.48-3.42 (m, 2H), 3.18- Cpd004 D 1.22 98.7 393 394 - 3.12 (m, 2H), 2.07-1.86 (m, 4H), 1.62-1.58 (m, 1H), 0.93-0.77 (m,4H)6.70 (t, 1H), 6.66 (d, 1H), 6.42 (s, 1H), 4.83-4.79 (m, 1H), 3.69 (s, Cpd005 C 7.74 97.8 326 327 - 2H), 3.05 (t, 2H), 2.94-2.88 (m,1H), 2.84-2.78 (m, 1H), 2.68-2.61(m, 2H)SPC6349-105-LC- Calcd Observed ObservedLC-MS r.t MS1H NMR 400 MHz 5 ppm Code Exact [M+H]+[M-H]- Method (min.) purity (DMSO-d6, unless otherwise stated) mass (m / z) (m / z)(%)8.92 (br. s„ 2H), 7.01 (t, 1H), 6.68 (d, 1H), 6.49 (s, 1H), 4.84-4.80 (m, Cpd006 C 7.75 95.1 326 327 - 1H), 3.86 (s, 2H), 3.25 (t, 2H),2.95-2.89 (m, 1H), 2.84-2.78 (m, 1H), 2.76-2.72 (m, 2H) 7.17 (t, 1H), 6.68 (d, 1H), 6.48 (s, 1H), 4.84-4.79 (m, 1H), 3.87 (s, Cpd007 C 6.85 95.6 326 327 - 2H), 3.26 (t, 2H), 2.92-2.88 (m,1H), 2.84-2.78 (m, 1H), 2.70-2.64(m, 2H)8.77 (brs, 3H), 6.53 (s, 1H), 3.96 (t, 2H), 3.91 (s, 2H), 3.73 (t, 2H), Cpd010 E 2.67 97.5 379 380 3.14-3.07 (m, 1H), 2.91 (d, 2H),1.61-1.56 (m, 1H), 0.94-0.89 (m, 2H), 0.76-0.74 (m, 2H) 13.24 (br s, 1 H) 8.37 (br s, 1 H) 8.07 (s, 1 H) 7.82 (d, J=6.06 Hz, 1 H) 4.09 (s, 2 H) 3.51 - 3.57 (m, 2 H) 3.44 - 3.49 Cpd031 G 1.07 93.8 522 523 521 (m, 1 H) 3.33 - 3.43 (m, 4 H) 2.85 - 2.95 (m, 2 H) 2.11 (br s, 4 H) 1.76 (qd, J=12.87, 4.02 Hz, 2 H) 1.64 (t, J=3.34Hz, 1 H)13.24 (br s, 1 H) 9.56 (br s, 1 H) 8.07 (s, 1 H) 7.82 (d, J=6.06 Hz, 1 H) 4.09 (s, 2 H) 3.50 (d, J=9.72 Hz, 2 H) 3.41 Cpd032 G 1.24 100 537 538 536(br d, J=9.30 Hz, 2 H) 2.90 - 3.26 (m, 8 H) 2.76 (br s, 3 H) 2.08 - 2.15 (m, 2 H)1.67 (t, J=3.34 Hz, 1 H)SPC6349-106-LC- Calcd Observed ObservedLC-MS r.t MS1H NMR 400 MHz 5 ppm Code Exact [M+H]+[M-H]- Method (min.) purity (DMSO-d6, unless otherwise stated) mass (m / z) (m / z)(%)13.24 (br s, 1 H) 8.47 (br s, 1 H) 8.07 (s, 1 H) 7.82 (d, J=6.06 Hz, 1 H) 4.09 (s, 2 H) 3.50 (d, J=9.82 Hz, 2 H) 3.41 Cpd033 G 1.12 100 523 524 522(br d, J=9.30 Hz, 2 H) 3.27 - 3.31 (m, 4 H) 3.12 - 3.19 (m, 4 H) 2.11 (br s, 2 H) 1.67 (t, J=3.45 Hz, 1 H) 13.22 (s, 1 H) 8.07 (s, 1 H) 7.84 (d, J=5.96 Hz, 1 H) 4.10 (s, 2 H) 3.48 (d, Cpd034 G 1.20 98.4 453 454 452 J=9.82 Hz, 2 H) 3.40 (br d, J=9.72 Hz,2 H) 2.94 (s, 3 H) 2.07 - 2.12 (m, 2 H) 1.63 (t, J=3.45 Hz, 1 H) 13.19 (s, 1 H) 8.05 (s, 1 H) 7.80 (d, J=6.06 Hz, 1 H) 4.09 (s, 2 H) 1.59 (tt, Cpd035 G 1.35 100 334 335 333J=8.24, 4.98 Hz, 1 H) 0.85 - 0.96 (m, 2 H) 0.72 - 0.80 (m, 2 H) 13.19 (br s, 1 H) 8.11 (s, 1 H) 7.66 (d, J=6.48 Hz, 1 H) 6.82 - 6.87 (m, 1 H) 4.05 - 4.19 (m, 4 H) 3.48 - 3.54 (m, 1 Cpd036 G 1.11 100 391 392 390 H) 3.01 - 3.08 (m, 1 H) 2.31 (q, J=8.19Hz, 1 H) 0.89 - 0.99 (m, 1 H) 0.66 - 0.75 (m, 1 H) 0.43 - 0.54 (m, 2 H) 0.23- 0.32 (m, 1 H) 13.12 (br s, 1 H) 8.10 (s, 1 H) 7.77 (d, J=6.38 Hz, 1 H) 6.68 (br s, 1 H) 4.11 Cpd037 G 0.77 100 351 352 350(s, 2 H) 3.99 (s, 2 H) 3.22 - 3.45 (m, 2 H) 2.82 (brt, J=6.74 Hz, 2 H) 13.10 (br s, 1 H) 8.10 (s, 1 H) 7.63 (d, J=6.48 Hz, 1 H) 6.63 - 6.73 (m, 1 H) Cpd038 G 0.87 85.4 351 352 350 4.11 (s, 2 H) 4.01 (br s, 2 H) 3.20 - 3.41 (m, 2 H) 2.82 (br t, J=6.58 Hz, 2_ H) _SPC6349-107-Part B: Experimental pharmacology procedures / procedures for determining biological activity of the compounds of the inventionExample 9: 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 quench 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 the 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 IC50values 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 (PTP1B, 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 ofSPC6349-108-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 IC50values 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.Table 4: PTPN2 and PTPN1 inhibitory activity of compounds of the invention. “A” represents IC50<200 nM; “B” represents an IC50of 200nM < IC50s 2 pM and “C” represents IC50> 2 pM.PTPN2 PTPN1IC50Compounds IC50Compoundsvalue valueCpd001, Cpd002, Cpd003, Cpd004, A Cpd002, Cpd003, Cpd004, ACpd006B Cpd001, Cpd006 BC Cpd005, Cpd007 C Cpd007Alternative Phosphatase activity assay to determine potency against PTPN1Compound activity was determined using a His-tagged catalytic domain PTPN1 protein (1-321 a. a from Uniprot ID: P18031) in an in vitro enzymatic reaction. Protein expression and purification were conducted internally. The enzymatic assay used to determine potency was the phosphatase (PTP) activity inhibition assay. The assay is performed using a buffer comprising 20mM HEPES pH7.4, 1mM EDTA, 2mM DTT and 150mM NaCI, 0.01% BSA, 0.005% Tween 20 and as phosphated substrate 25 pM 6,8-Difluoro-4-Methylumbelliferyl Phosphate (DiFMUP) (ThermoFisher, Cat# D6567) was used.The assay is carried out at room temperature in 1536-well plate. 5nL of compounds dissolved in DMSO and serially diluted 3-fold in 11 -point format were dispensed to a 1536-well Cyclic Olefin Copolymer Corning plate (Cat# 4371) using Echo 655 (LabCyte) and the plates were spun down at 1000 rpm for 1 minute at room temperature. Next, a buffer solution containing 0.2 nM of PTPN1 enzyme (2.5 nL) was added and the plates were spun down at 1000 rpm for 1 minute atSPC6349-109-room temperature, and then, the plates were incubated for 30 minutes at room temperature. The reaction is initiated by addition of a buffer solution containing 50 µM DIFMUP substrate (2.5 nL) and spinning down the plates at 1000 rpm for 1 minute at room temperature, followed by incubation at room temperature for 60 minutes. Finally, a 0.3% formic acid solution in water (2.5 nL) was added to the reaction plates and the plates were spun down at 1000 rpm for 1 minute at room temperature. The phosphatase activity of the PTPN2 ...

Claims

SPC6349-118-CLAIMS1. 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:represents a double bond ( ) or a triple bond ();- X1is N or C;X2is CR6or N; X3is CR8or N; X4is CR3or N; wherein maximum two groups selected from X2, X3and X4are nitrogen;- isanoptional double bond when valencies allow;R1is selected from cycloalkyl; heterocycle; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; cycloalkylheteroalkyl; cycloalkenylheteroalkyl; cycloalkynylheteroalkyl; aryl; heteroaryl; arylalkyl; arylalkenyl; arylalkynyl, heteroarylalkyl; heteroarylalkynyl; heteroarylalkenyl; heterocyclylalkyl; heterocyclylalkenyl; heterocyclylalkynyl 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;- when - uTj r is a triple bond, then R2is not present;- when - uTj r is a double bond, then 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, -NZ5Z6, -N(Z5)-S(=O)2-Z6, -N(Z5)-S(=O)(=NZ5)-Z6, -S(=O)2-NZ5Z6,SPC6349-119--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 -S(=O)-Z2, cycloalkyl, halogen, alkyl, 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)(=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, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, cycloalkyl-heteroalkyl, cycloalkyl-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, cycloalkyl- 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 is unsubstituted or is substituted with one or more R41;or two R4, optionally two R4on the same atom or on two adjacent atoms, 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 alkyl, heterocycle, hydrogen, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl,SPC6349-120-arylheteroalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylheteroalkyl, heterocyclylheteroalkenyl, and heterocyclylheteroalkynyl;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;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;each R41is independently selected from alkyl, hydrogen, halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, 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 R41attached to the same atom together form a cycloalkyl or 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,SPC6349-121-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 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, -NZ5Z6, -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 cycloalkyl or heterocyclyl;wherein each 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 optionally substituted by one or more halogen, alkyl, cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ5Z6, -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, 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;SPC6349-122-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 optionally substituted with halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, - OCF3, -CHF2, -OCHF2, cyano, nitro, alkyl, cycloalkyl, -O- alkyl, -O- cycloalkyl, -NH-alkyl, - N(alkyl)2, and -NH-cycloalkyl;R3, R6, R7,R8, R9and R10are independently selected from hydrogen, halogen, -OR12, -OR15, alkyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -O-(C1-6 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 heteroaryl cycloalkyl, or heterocyclyl, 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, heterocyclylalkyl, heterocyclyl-heteroalkyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, -C(=O)-OR12, -C(=O)-O-(C1-6-alkyl)-OR15, -(C1-6-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, heterocyclylalkyl, 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 a heterocycle optionally substituted with one, two, or three R20;R15is independently selected at each occurrence from hydrogen, alkyl, (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), alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl are optionallySPC6349-123-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 heterocyclyl, -N(R22)(R23), -O-P(=O)(OH)2, halogen, oxo, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl heteroalkyl, heterocyclyl-alkyl, heterocyclyl-heteroalkyl, -OR22, -SR22, =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;SPC6349-124-or R22and R23attached to the same nitrogen atom form heterocycle.

2. A compound according to claim 1, wherein:when X1is N; X2is C(F); X3is C(H); R7is -OH and X4is C(R3) wherein R3is hydrogen or alkyl; R9, R10and R11are hydrogen; and - is a single bond; 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; and, 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,then:R1is substituted by at least one R4, or, when R1and R2taken together form a cycloalkyl, cycloalkenyl, cycloalkynyl or heterocycle, said cycloalkyl, cycloalkenyl, cycloalkynyl or heterocycle is substituted with at least one R4;and;- said at least one R4is selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl-alkenyl, cycloalkyl-alkynyl, cycloalkylheteroalkyl, cycloalkyl-heteroalkenyl, cycloalkyl-heteroalkynyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, aryl-alkyl, aryl-alkenyl, aryl-alkynyl, aryl-heteroalkyl, arylheteroalkenyl, 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, cycloalkyl- 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 is substituted by at least one R41that is not selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, -SPC6349-125-CF3, -O-alkyl, -OCF3, -CHF2; -OCHF2, cyano, nitro, -C(O)OH, -NH2, -NHalkyl, -N(alkyl)2, - S(O)2alkyl, and -NHS(O)2alkyl;OR,said at least one R4is selected from -OZ1, -SZ1, -NZ1Z2, -N(Z1)-S(=O)2-Z2, -S(=O)2-NZ1Z2, - S(=NZ1)(=NZ1)-Z2, -N(Z1)-S(=O)2-NZ1Z2, -S(=O)2-Z2, -S(=O)-Z2, -S(=O)(=NZ1)-Z2, -C(=O)-O- Z2, -C(=O)-Z2, -NZ1-C(=O)-O-Z2, -C(=O)-NZ1Z2, -NZ1-C(=O)-Z2, -NZ3C(O)NZ3Z4, -P(O)Z1Z2, wherein Z1and / or Z2are substituted by at least one R41that is not selected from alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, =0, halogen, -SH, =S, -CF3, -O-alkyl, -OCF3, -CHF2; - OCHF2, cyano, nitro, -C(O)OH, -NH2, -NHalkyl, -N(alkyl)2, OR,said at least one R4is selected from -N(Z1)-S(=O)(=NZ1)-Z2, -S(=O)(=NZ1)-NZ1Z2, - N=S(=O)Z1Z2, -O-C(=O)-Z2and -O-C(=O)-NZ1Z2.

3. A compound according to claim 1 or 2, wherein when X1is N; X2is C(F); X3is C(H); R7is -OH and X4is C(R3); R9, R10and R11are hydrogen; and - is a single bond; then R3is not hydrogen or unsubstituted alkyl.

4. A compound according any preceding claim, whereineach R4 is independently selected from halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, C4-12-heterocyclyl, C4-12-heterocyclyl-C1-6-alkyl, C4-12-heterocyclyl-C2-6-alkenyl, C4-12-heterocyclyl-C2-6-alkynyl, C5-12-heteroaryl, C5-12-heteroaryl-C1-6-alkyl, C5-12-heteroaryl-C2-6-alkenyl, C5-12-heteroaryl-C2-6-alkynyl, aryl, aryl-C1-6-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 C3-8-cycloalkyl or C4-8-heterocyclyl;wherein each C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, C4-12-heterocyclyl, C4-12-heterocyclyl-C1-6-alkyl, C4-12-heterocyclyl-C2-6-alkenyl, C4-12-heterocyclyl-C2-6-alkynyl, C5-12-heteroaryl, C5-12-heteroaryl-C1-6-alkyl, C5-12-heteroaryl-C2-6-alkenyl, C5-12-heteroaryl-C2-6-alkynyl, aryl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6-alkynyl is optionally further substituted with one, two, three or four R41;SPC6349-126-- Z1and Z2are independently selected from hydrogen, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3- 8-cycloalkyl, C4-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-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-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 C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, C4-12-heterocyclyl, C4-12-heterocyclyl-C1-6-alkyl, C4-12-heterocyclyl-C2-6-alkenyl, C4-12-heterocyclyl-C2-6-alkynyl, C5-12-heteroaryl, C5-12-heteroaryl-C1-6-alkyl, C5-12-heteroaryl-C2-6-alkenyl, C5-12-heteroaryl-C2-6-alkynyl, aryl, aryl-C1-6-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, C3-8-cycloalkyl-C1-6-alkyl, Cs-s-cycloalkyl-Cs-e-alkenyl, Cs-s-cycloalkyl-Cs-e- alkynyl, C4-8-cycloalkenyl-C1-6-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 C3-8-cycloalkyl or C4-8-heterocyclylwherein each C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C3-8-alkenyl, C3-8-cycloalkyl-C3-8-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, C4-12-heterocyclyl, C4-12-heterocyclyl-C1-6-alkyl, C4-12-heterocyclyl-C2-6-alkenyl, C4-12-heterocyclyl-C2-6-alkynyl, C5-12-heteroaryl, C5-12-heteroaryl-C1-6-alkyl, C5-12-heteroaryl-C2-6-alkenyl, C5-12-heteroaryl-C2-6-alkynyl, aryl, aryl-C1-6-alkyl, aryl-C2-6-alkenyl and aryl-C2-6-alkynyl is optionally further substituted with one, two, three or four R42;Z3 and Z4 are independently selected from hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C3-8-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-SPC6349-127-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, C4-8-cycloalkenyl, C3-8- 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 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, C3-8-cycloalkyl-C1-6-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-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, -NZ5Z6, -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 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, C1-6-alkyl, Cs-s-cycloalkyl, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, -CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, -OZ5, -NZ5Z6, -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, C3-8-cycloalkyl, C4-8-cycloalkenyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C3-8-SPC6349-128-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, C4-12- 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, 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 with halogen, hydroxyl, sulfhydryl, =0, =S, -SCF3, -SF5, - CF3, -OCF3, -CHF2, -OCHF2, cyano, nitro, Ci-4-alkyl, C3-7-cycloalkyl, -O-C1-4-alkyl, -O-C3-7-cycloalkyl, -NH-C1-4-alkyl, -N(C1-4-alkyl)2, and -NH-C3-7-cycloalkyl.

5. A compound according to any of the preceding claims, wherein the compound is according to formula (II),(II) whereinB 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 any of claims 1 or 5.

6. A compound according to claim 5 wherein the compound is of formula (Ila) or (lib)SPC6349-129-(Ha) (Hb).

7. A compound according to any of the preceding claims wherein the compound is of formula (He)(He)wherein each Q7and Q8are as R4as defined for any of claims 1 to 4.

8. A compound according to claim 7, wherein each Q8is independently selected from halogen (fluor), Ci-6-alkyl, C2-6-alkenyl, Cs-s-cycloalkyl, C4-8-heterocyclyl-OZ5, -NZ5Z6, -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 Ca-s-cycloalkyl or C4-8-heterocyclyl;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, -NZ5Z6, -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-7-cycloalkyl, mono- or di-Ci-4-alkylamino and -NH-Cs-7-cycloalkyl.

10. A compound according to any of claims 1 to 4 wherein the compound is according to formula (HI),SPC6349-130-R1is C3-12-cycloalkyl, C3-12-heterocycle, C4-12-cycloalkenyl, C4-12-cycloalkynyl, C6-12-aryl or C5-12-heteroaryl, wherein said cycloalkyl, heterocycle, cycloalkenyl, cycloalkynyl, aryl or heteroaryl is optionally substituted by one or more R4;- X1, X2, X3, X4, R4, R7, R9, R10, R11and dotted line are as defined for any of claim 1 to 4.

11. A compound according to claim 10 wherein R1is selected from12. A compound according to claim 10 wherein R1is selected from13. A compound according to claim 10, 11 or 12 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; - C(=O)-O-Z2; -C(=O)-Z2; -C(=O)-NZ1Z2; and,Ci-6-alkyl, Cs-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;andeach Z1, Z2, Z3and Z4is independently selected from alkyl, alkenyl, alkynyl, heterocyclyl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heterocyclyl and heteroaryl is optionally furtherSPC6349-131-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.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient, an effective amount of a compound according to any one of claims 1-13.

15. The compound according to any one of claims 1-13, or a pharmaceutical composition according to claim 14, for use as a medicine.

16. The compound or pharmaceutical composition according to claim 15, for use in the prevention or treatment of a PTPN2 and / or PTPN1 mediated disorder in an animal, mammal or human.

17. The compound or pharmaceutical composition for use according to claim 16, wherein the PTPN2 and / or PTPN1 mediated disorders is selected from the group comprising cancer and metabolic diseases.

18. The compound or pharmaceutical composition for use according to claim 16, 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.

19. 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 1-13.

20. A method of treatment or prevention of PTPN2 and / or PTPN1 activation mediated disorder according to claim 19 comprising administering to a patient in need thereof an effective dose of a compound according to any one of claims 1-13, in combination with one or more other anti-cancer agents, more specifically immunotherapeutic agents.

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