Substituted 3,7-dihydro-1 h-purine-2,6-diones and use thereof

Abstract

The present invention relates to 3,7,8-trisubstituted 3,7-dihydro-1H-purine-2,6-dione compounds also named as 3,7,8-trisubstituted xanthine compounds of general formula (I) or pharmaceutically acceptable salts thereof.The invention further relates to pharmaceutical compositions comprising such compounds as well as the use of the compounds or pharmaceutical compositions as medicaments, especially in methods for the treatment or prophylaxis of a neoplastic and / or infectious disease and in vitro methods. These compounds activate immune cells, in particular T-cells such as CD4+ and CD8+ cells.

Description

[0001] Substituted 3, 7-dihydro-1H-purine-2, 6-diones and use thereof

[0002] Field of the Invention

[0003] The present invention relates to 3,7,8-trisubstituted 3, 7-dihydro-1 / - / -purine-2, 6-dione compounds also named as 3,7,8-trisubstituted xanthine compounds of general formula (I) or pharmaceutically acceptable salts thereof.

[0004] The invention further relates to pharmaceutical compositions comprising such compounds as well as their use as medicaments, especially in methods for the treatment or prophylaxis of a neoplastic and / or infectious disease and in vitro methods. These compounds activate immune cells, including NK cells or T-cells such as CD4+ and CD8+ cells.

[0005] Background of the Invention

[0006] Malignant neoplasia (cancer) and infectious diseases are two of the main causes of death all over the world. In an increasing number of cases, it is known that there is often interdependency between neoplastic and infectious diseases, such as, e.g., between cervix neoplasia and herpes simplex virus infections. Although a large variety of compounds for treating and preventing these diseases has been found, it is well-known that such compounds bear significant drawbacks such as provoking severe side effects. Therefore, there is still an unmet need for new compounds for treating and preventing neoplastic and / or infectious diseases.

[0007] In order to overcome these drawbacks, therapeutic and prophylactic approaches based on modulating the immune response of the patient gain increasing importance in today's medicine. The immunological activity of the patient is hereby often supported by a medicinal treatment. In practice, in this context, immunologic treatments against neoplastic and infectious diseases are of particular interest. In this regard, it is well-known that in a body several types of immune cells such as, e.g., natural killer (NK) cells, T cells, B cells, dendritic cells, monocytes and macrophages, are often involved in the inactivation and removal of pathogens. With respect to neoplasia for instance, it is known that each matured neoplasm (tumor) bears specific antigens and / or neo-antigens (e.g., Sensi and Anichini, 2006, Clin Cancer Res. 12:5023-5032). This may in general trigger the adaptive immune system (e.g., T cells and / or B cells) as well as the innate immune system (e.g., natural killer (NK) cells). The immune system in a healthy body is mostly effective enough to prevent or cure said body from neoplastic and infectious diseases.

[0008] CD4+T cells along with CD8+T cells make up the majority of T-lymphocytes. CD4+T cells after being activated and differentiated into distinct effector subtypes play a major role in mediating immune response through the secretion of specific cytokines. The CD4+T cells carry out multiple functions, ranging from activation of the cells of the innate immune system, B-lymphocytes, cytotoxic T cells, as well as nonimmune cells, and also play critical role in the suppression of immune reaction.

[0009] Cytotoxic CD8+T cells also play a key role in the elimination of intracellular infections and malignant cells and can provide long-term protective immunity. In the response to infection, CD8+T cell metabolism is coupled to transcriptional, translational and epigenetic changes that are driven by extracellular metabolites and immunological signals. These programs facilitate the adaptation of CD8+T cells to the diverse and dynamic metabolic environments encountered in the circulation and in the tissues.

[0010] In some cases, the immune system however fails to eliminate such neoplastic or infectious disease and such disease becomes chronic. In these cases, in particular when the patient suffers from malignant neoplasia (cancer), the immune system is often downregulated. Whereas in a healthy body (i.e., in a non-suppressed immune environment) a suitable expression of major histocompatibility complex I (MHC I) presenting antigens to immune cells, e.g. cytotoxic CD8 T cells is found, the expression of MHC I is down-regulated in tumor cells. This can be countered by NK cells, specifically recognizing and destroying cells with decreased MHC-I surface expression. However, during the maturation of neoplasms (in particular tumor progression), due to a multitude of immunosuppressive mechanisms leading to immune tolerance, maturating neoplasms can increasingly escape the immune system, i.e., the neoplastic antigen is not recognized as non-self, and the immune system is not activated. This mechanism is a general principle of maturating neoplasm and is neither restricted to specific neoplasms nor dependent on specific neoplastic antigens. Notably, it has been found that in most cancer patients, tumor- associated T cells and NK cells exist, but do not produce sufficient amounts of a number of cytokines (such as e.g., IL-2 and IFN-y) or exert cytotoxic activity towards the tumor since suppression by various mechanisms hinders efficient anti-tumor immune responses (De Paola et al., 2003, British Journal of Cancer 88:320-326; Ahmadzadeh et al., 2009, Blood 114:1537-1544, in particular pages 1541-1542, section “PD-1+ TILs display an impaired effector function”). This is evidently also one of the reasons why tumor vaccination often fails.

[0011] Likewise, numerous infections are known to down-regulate the patient's immune system, in particular viral infections such as, e.g., human immunodeficiency virus (HIV) infections or herpes simplex virus (HSV) infections. Also in this context, the production of cytokines by T cells and other anti-viral immune cells is disordered.

[0012] There is still an unmet need for such compounds enabling to increase immunogenic activity and thereby enable the treatment and / or prophylaxis of neoplastic and / or infectious diseases.

[0013] It is the objective of the present invention to provide compounds and pharmaceutic compositions which activate immune cells, in particular T-cells. These compounds can be used as pharmaceutically active agents, especially for prophylaxis and / or treatment of neoplastic and infectious disease.

[0014] The present invention provides novel 3,7,8-trisubstituted xanthine compounds of general formula (I), activating immune cells.

[0015] Thus, the objective of the present invention is solved by the teachings of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.

[0016] Description of the invention

[0017] Thus, the present invention is directed to a compound of the formula (I): wherein A represents

[0018] B is -O-R3, -O-CHR3R3*, -O-CH2-CH2-R3, or -O-CH2-CH2-CH2-R3;

[0019] R1represents

[0020] R2aand R2brepresent independently of each other -H, -F, -CH3, -C2Hs,

[0021] -CH2F, -CHF2I-CF3I-CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CF2-CH3, -CHF-CHF2I-CHF-CF3, -CF2-CF3; wherein R2ais not -H;

[0022] R3represents

[0023] R3* represents -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2-CF3;

[0024] R4and R4* represent indepenently of each other -H, -F, -Cl, — Br, -CH3, -C2H5, -CH2F, -CHF2I-CF3, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OCH2F, -OCHF2I-OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2I-CHF-CF3,

[0025] R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other

[0026] -H, -cyclo-CsHs, -cyclo-C4H7, -cyclo-CsHg, -cyclo-CeHn, -cyclo-C7Hi3,

[0027] -cycloC3H5O, -OH, -OCH3, — OC2HS,

[0028] -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3,

[0029] -OC4H9, -OPh, -OCH2-Ph, -OCPh3, -CH^OCH3, -C2H4-OCH3,

[0030] -C3H6-OCH3, -CH^OC2H5, -C2H4-OC2H5, -C3H6-OC2H5, -CH^OC3H7, -C2H4— OC3H7, -C3H6— OC3H7, -CH2— 0— cyclo-CsHs, -C2H4— 0— cyclo-CsHs, -C3H6-O-cyclo-C3H5, -CH^OCH(CH3)2, -C2H4-OCH(CH3)2, -C3H^OCH(CH3)2, -CH^OC(CH3)3, -C2H4-OC(CH3)3, -C3H6-OC(CH3)3, -CH^OC4H9,

[0031] -C2H4-OC4H9, -C3H6-OC4H9, -CH^OPh, -C2H4-OPh, -C3H6-OPh,

[0032] -CH^OCH2-Ph, -C2H4-OCH2-Ph, -C3H6-OCH2-Ph, -SH, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H5, -SCH(CH3)2, -SC(CH3)3, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-CsHs, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2,

[0033] -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2,

[0034] -NHCOCH3, -NHCOC2H5, -NHCOC3H7, -NHCO-cyclo-CsHs, -NHCO-CH(CH3)2, -NHCO-C(CH3)3, -NHCO-OCH3, -NHCO-OC2H5, -NHCO-OC3H7, -NHCO-O-cyclo-C3H5, -NHCO-OCH(CH3)2, -NHCO-OC(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3, -SO2CH3, -SO2C2H5, -SO2C3H7,

[0035] -SO^cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3,

[0036] -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3,

[0037] -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NH-cyclo-C3H5, -SO2NHCH(CH3)2, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2,

[0038] -SO2N(C3H7)2, -SO2N(cyclo-C3H5)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2,

[0039] -O-S(=O)CH3, -O-S(=O)C2H5, -O-S(=O)C3H7, -O-S(=O)-cyclo-C3H5,

[0040] -O-S(=O)CH(CH3)2, -O-S(=O)C(CH3)3, -S(=O)(=NH)CH3, -S(=O)(=NH)C2H5I-S(=O)(=NH)C3H7I-S(=O)(=NH)-cyclo-C3H5, -S(=O)(=NH)CH(CH3)2,

[0041] -S(=O)(=NH)C(CH3)3, -NH-SO2-CH3, -NH-SO2-C2H5, -NH-SO2-C3H7,

[0042] -NH-SO2-cyclo-C3H5, -NH-SO2-CH(CH3)2, -NH-SO2-C(CH3)3, -O-SO2-CH3, -O-SO2-C2H5, -O-SO2-C3H7, -O-SO2-cyclo-C3H5, -O-SO2-CH(CH3)2,

[0043] -O-SO2-C(CH3)3, -OCH2F, -OCHF2, -OCF3, -CH^OCF3, -C2H4-OCF3, -C3H6-OCF3, -CH^OCHF2, -C2H4-OCHF2, -C3H6-OCHF2,

[0044] -OC2F5, -CH^OC2F5, -C2H4-OC2F5, -C3H6-OC2F5, -O-COOCH3,

[0045] -O-COOC2H5, -O-COOC3H7, -O-COO-cyclo-C3H5,

[0046] -O-COOCH(CH3)2, -O-COOC(CH3)3, -NH-CO-NH2, -NH-CO-NHCH3, -NH-CO-NHC2H5, -NH-CO-NHC3H7, -NH-C(=NH)-NH2, -NH-CO-N(C3H7)2, -NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2,

[0047] -NH-CO-N(C2H5)2, -NH-CO-NH-cyclo-C3H5, -NH-CO-N(cyclo-C3H5)2, -NH-CO-N[CH(CH3)2]2, -NH-C(=NH)-NHCH3I-NH-C(=NH)-NHC2H5, -NH-C(=NH)-NHC3H7I-O-CO-NH-cyclo-C3H5, -NH-C(=NH)-NH-cyclo-C3H5, -NH-C(=NH)-NH[CH(CH3)2], -O-CO-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH3)3], -NH-C(=NH)-N(CH3)2I-NH-C(=NH)-N(C2H5)2I-NH-C(=NH)-N(C3H7)2I

[0048] -NH-C(=NH)-N(cyclo-C3H5)2, -O-CO-NHC3H7, -NH-C(=NH)-N[CH(CH3)2]2, -NH-C(=NH)-N[C(CH3)3]2, -O-CO-NH2, -O-CO-NHCH3,

[0049] -O-CO-NHC2H5I-O-CO-NH[C(CH3)3], -O-CO-N(CH3)2I-O-CO-N(C2H5)2, -O-CO-N(C3H7)2I-O-CO-N(cyclo-C3H5)2, -O-CO-N[CH(CH3)2]2,

[0050] -O-CO-N[C(CH3)3]2, -O-CO-OCH3, -O-CO-OC2H5, -O-CO-OC3H7, -O-CO-O-cyclo-C3H5, -O-CO-OCH(CH3)2, -O-CO-OC(CH3)3, -CH2F, -CHF2, -CF3I-CH2-CH2F, -CH2-CHF2I-CH2-CF3Icyclo-CsHis, -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH=CH-Ph, -CPh3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3I-C5H11, -CH(CH3)-C3H7,

[0051] -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2I-C(CH3)2-C2H5, -CH2-C(CH3)3I-CH(C2H5)2I-C2H4-CH(CH3)2I-C6HI3, -C7Hi5, -C8HI7, -C3H6-CH(CH3)2, -C2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9I-CH2-CH(CH3)-C3H7, -CH(CH3)-CH2- CH(CH3)2I-CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2I

[0052] -CH2-C(CH3)2-C2H5, -C(CH3)2-C3H7I-C(CH3)2-CH(CH3)2I-C2H4-C(CH3)3I

[0053] -CH(CH3)-C(CH3)3, -CH=CH2I-CH2-CH=CH2I-C(CH3)=CH2I-CH=CH-CH3I-C2H4-CH=CH2I-CH2-CH=CH-CH3I-CH=CH-C2H5, -CH2-C(CH3)=CH2I-CH(CH3)-CH=CH, -CH=C(CH3)2I-C(CH3)=CH-CH3I-CH=CH-CH=CH2, -C3H6-CH=CH2, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CH=CH-C3H7,

[0054] -CH=CH-CH=CH-CH3, -C2H4-C(CH3)=CH2, -CH2-CH(CH3)-CH=CH2I-CH(CH3)-CH2-CH=CH2I-CH2-CH=C(CH3)2I-CH2-C(CH3)=CH-CH3I

[0055] -CH(CH3)-CH=CH-CH3I-CH=CH-CH(CH3)2I-CH=C(CH3)-C2H5, -C(CH3)=CH-C2H5, -C(CH3)=C(CH3)2I-C(CH3)2-CH=CH2I

[0056] -CH(CH3)-C(CH3)=CH2, -C4H8-CH=CH2, -C3H6-CH=CH-CH3, -C2H4-CH=CH- C2H5I-CH2-CH=CH-C3H7I-CH=CH-C4H9I-C3H6-C(CH3)=CH2, -C2H4-CH(CH3)-CH=CH2I-CH2-CH(CH3)-CH2-CH=CH2I-C2H4-CH=C(CH3)2I-CH(CH3)-C2H4-CH=CH2I-C2H4-C(CH3)=CH-CH3I

[0057] -CH2-CH(CH3)-CH=CH-CH3I-CH(CH3)-CH2-CH=CH-CH3I-CH2-CH=CH- CH(CH3)2I-CH2-CH=C(CH3)-C2H5, -CH2-C(CH3)=CH-C2H5,

[0058] -CH(CH3)-CH=CH-C2H5, -CH=CH-CH2-CH(CH3)2I-CH=CH-CH(CH3)-C2H5, -CH=C(CH3)-C3H7, -C(CH3)=CH-C3H7, -CH2-CH(CH3)-C(CH3)=CH2I

[0059] -C[C(CH3)3]=CH2I-CH(CH3)-CH2-C(CH3)=CH2I-CH(CH3)-CH(CH3)-CH=CH2I-CH=CH-C2H4-CH=CH2I-C(CH3)2-CH2-CH=CH2I-CH2-C(CH3)=C(CH3)2I-CH(CH3)-CH=C(CH3)2I-C(CH3)2-CH=CH-CH3I

[0060] -CH=CH-CH2-CH=CH-CH3I-CH(CH3)-C(CH3)=CH-CH3, -CH=C(CH3)-CH(CH3)2I-C(CH3)=CH-CH(CH3)2I-C(CH3)=C(CH3)-C2H5, -CH=CH-C(CH3)3I C(CH3)2-C(CH3)=CH2, -CH(C2H5)-C(CH3)=CH2, -C(CH3)(C2H5)-CH=CH2

[0061] CH(CH3)-C(C2H5)=CH2, -CH2-C(C3H7)=CH2, -CH2-C(C2H5)=CH-CH3

[0062] CH(C2H5)-CH=CH-CH3, -C(C4H9)=CH2, -C(C3H7)=CH-CH3

[0063] C(C2H5)=CH-C2H5, -C(C2H5)=C(CH3)2, -C[CH(CH3)(C2H5)]=CH2

[0064] C[CH2-CH(CH3)2]=CH2, -C2H4-CH=CH-CH=CH2, -CH2-CH=CH-CH2-CH=CH2

[0065] C3H6-CEC-CH3, -CH2-CH=CH-CH=CH-CH3, -CH=CH-CH=CH-C2H5

[0066] -CH(CH3)-CH2-CECH, -CH(CH3)-CEC-CH3, -C2H4-CH(CH3)-CECH, -CH=CH- CH=C(CH3)2I-CH2-CH(CH3)-CH2-CECH,

[0067] -CH=CH-C(CH3)=CH-CH3I-CH=C(CH3)-CH=CH-CH3I-CH2-CH(CH3)-CECH, -C(CH3)=CH-CH=CH-CH3I-CECH, -CEC-CH3, -CH2-CECH, -C2H4-CECH, -CH2-CEC-CH3, -CEC-C2H5, -C3H6-CECH, -C2H4-CEC-CH3,

[0068] -CH2-CEC-C2H5, -C=C-C3H7, -CH(CH3)-CECH, -C4H8-C=CH,

[0069] -C2H4-CEC-C2H5, -CH2-CEC-C3H7, -C=C-C4H9I-CEC-CH2-CH(CH3)2,

[0070] -CH(CH3)-C2H4-CECH, -CH2-CH(CH3)-CEC-CH3, -C(CH3)(C2H5)-CECH,

[0071] -CH(CH3)-CH2-CEC-CH3, -CH(CH3)-CEC-C2H5, -CH2-CEC-CH(CH3)2,

[0072] -CEC-CH(CH3)-C2H5, -CH2-C=C-C=C-CH3I-CH(C2H5)-CEC-CH3,

[0073] -C(CH3)2-CEC-CH3, -CH(C2H5)-CH2-CECH, -CH2-CH(C2H5)-CECH,

[0074] -C(CH3)2-CH2-CECH, -CH2-C(CH3)2-CECH, -CH(CH3)-CH(CH3)-CECH,

[0075] -CH(C3H7)-CECH, -CH2-CH(CECH)2, -C=C-C=CH, -CH2-C=C-C=CH,

[0076] -C=C-C=C-CH3I-CH(C=CH)2I-C2H4-C=C-C=CH, -CH2-C=C-CH2-C=CH,

[0077] -CEC-C2H4-CECH, -CEC-C(CH3)3, -C=C-CH2-C=C-CH3,

[0078] -CEC-CEC-C2H5, or

[0079] R5and R6or R6and R7may form together with the two carbon atoms of the phenyl ring to which they are attached a 4 to 8-membered ring system, which is optionally substituted with one or more substituents selected from R10, R11, R12, and R13; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt of the above-mentioned compound.

[0080] Preferably, the present invention is directed to a compound of the formula (I): wherein

[0081] A represents B represents -0-R3, -O-CH2-R3, -O-CH2-CH2-R3, -O-CH2-CH2-CH2-R3;

[0082] R1represents

[0083] R2aand R2brepresent independently of each other -H, or C1-3 alkyl, and the C1-3 alkyl is optionally substituted with 1 to 6 fluoro atoms or -OH;

[0084] R3represents ;

[0085] R4represents -H, halogen, C1-4 alkyl, -O-C1-4 alkyl, C3-4 cycloalkyl, -O-C3-4 cycloalkyl, and the Ci -4 alkyl, -O-Ci-4alkyl, -O-C3-4 cycloalkyl, and C3-4 cycloalkyl may optionally be substituted with 1 to 6 fluoro atoms;

[0086] R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other

[0087] -H, -cyclo-CsHs, -cyclo-C4H7, -cyclo-CsHg, -cyclo-CeHn, -cyclo-CyHn, -cycloC3H5O, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OPh, -OCH2-Ph, -OCPh3, -CH^OCH3, -C2H4-OCH3, -C3H6-OCH3, -CH^OC2H5, -C2H4-OC2H5, -C3H6-OC2H5, -CH^OC3H7,

[0088] -C2H4— OC3H7, -C3H6— OC3H7, -CH2— 0— cyclo-CsHs, -C2H4— 0— cyclo-CsHs, -CsHe-O-cyclo-CsHs, -CH^OCH(CH3)2, -C2H4-OCH(CH3)2, -C3H^OCH(CH3)2, -CH^OC(CH3)3, -C2H4-OC(CH3)3, -C3H6-OC(CH3)3, -CH^OC4H9,

[0089] -C2H4-OC4H9, -C3H6-OC4H9, -CH^OPh, -C2H4-OPh, -C3H6-OPh,

[0090] -CH^OCH2-Ph, -C2H4-OCH2-Ph, -C3H^OCH2-Ph, -SH, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H5, -SCH(CH3)2, -SC(CH3)3, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5,

[0091] -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2,

[0092] -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -NHCOCH3, -NHCOC2H5, -NHCOC3H7, -NHCO-cyclo-C3H5,

[0093] -NHCO-CH(CH3)2, -NHCO-C(CH3)3, -NHCO-OCH3, -NHCO-OC2H5, -NHCO-OC3H7, -NHCO-O-cyclo-C3H5, -NHCO-OCH(CH3)2, -NHCO-OC(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2,

[0094] -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3I-SOC2H5I-SOC3H7I-SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3I-SO2CH3, -SO2C2H5, -SO2C3H7,

[0095] -SO^cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3I-SO3H, -SO3CH3I-SO3C2H5I-SO3C3H7I-SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3,

[0096] -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NH-cyclo-C3H5, -SO2NHCH(CH3)2, -SO2NHC(CH3)3, -SO2N(CH3)2I-SO2N(C2H5)2, -SO2N(C3H7)2I-SO2N(cyclo-C3H5)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2,

[0097] -O-S(=O)CH3, -O-S(=O)C2H5I-O-S(=O)C3H7I-O-S(=O)-cyclo-C3H5,

[0098] -O-S(=O)CH(CH3)2, -O-S(=O)C(CH3)3I-S(=O)(=NH)CH3, -S(=O)(=NH)C2H5, -S(=O)(=NH)C3H7, -S(=O)(=NH)-cyclo-C3H5, -S(=O)(=NH)CH(CH3)2,

[0099] -S(=O)(=NH)C(CH3)3, -NH-SO2-CH3, -NH-SO2-C2H5, -NH-SO2-C3H7,

[0100] -NH-SO2-cyclo-C3H5, -NH-SO2-CH(CH3)2, -NH-SO2-C(CH3)3, -O-SO2-CH3, -O-SO2-C2H5, -O-SO2-C3H7I-O-SO2-cyclo-C3H5, -O-SO2-CH(CH3)2, -O-SO2-C(CH3)3, -OCH2F, -OCHF2I-OCF3I-CH^OCF3I-C2H4-OCF3, -C3H6-OCF3, -CH^OCHF2I-C2H4-OCHF2, -C3H6-OCHF2, -OC2F5, -CH^OC2F5, -C2H4-OC2F5, -C3H6-OC2F5, -O-COOCH3,

[0101] -O-COOC2H5I-O-COOC3H7I-O-COO-cyclo-C3H5,

[0102] -O-COOCH(CH3)2, -O-COOC(CH3)3I-NH-CO-NH2, -NH-CO-NHCH3, -NH-CO-NHC2H5I-NH-CO-NHC3H7I-NH-C(=NH)-NH2I-NH-CO-N(C3H7)2I-NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2I-NH-CO-N(C2H5)2I-NH-CO-NH-cyclo-C3H5, -NH-CO-N(cyclo-C3H5)2, -NH-CO-N[CH(CH3)2]2, -NH-C(=NH)-NHCH3I-NH-C(=NH)-NHC2H5I-NH-C(=NH)-NHC3H7I-O-CO-NH-cyclo-C3H5, -NH-C(=NH)-NH-cyclo-C3H5, -NH-C(=NH)-NH[CH(CH3)2], -O-CO-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH3)3], -NH-C(=NH)-N(CH3)2I-NH-C(=NH)-N(C2H5)2I-NH-C(=NH)-N(C3H7)2I

[0103] -NH-C(=NH)-N(cyclo-C3H5)2, -O-CO-NHC3H7, -NH-C(=NH)-N[CH(CH3)2]2, -NH-C(=NH)-N[C(CH3)3]2, -O-CO-NH2, -O-CO-NHCH3, -O-CO-NHC2H5, -O-CO-NH[C(CH3)3], -O-CO-N(CH3)2I-O-CO-N(C2H5)2, -O-CO-N(C3H7)2I-O-CO-N(cyclo-C3H5)2, -O-CO-N[CH(CH3)2]2, -O-CO-N[C(CH3)3]2, -O-CO- OCH3, -O-CO-OC2H5I-O-CO-OC3H7I-O-CO-O-cyclo-C3H5, -O-CO- OCH(CH3)2, -O-CO-OC(CH3)3I-CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-CHF2I-CH2-CF3Icyclo-CsHis, -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH=CH-Ph, -CPh3, -CH3, -C2H5I-C3H7I-CH(CH3)2I-C4H9I-CH2-CH(CH3)2I-CH(CH3)-C2H5, -C(CH3)3I-C5H11, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2I-C(CH3)2-C2H5, -CH2-C(CH3)3I-CH(C2H5)2I

[0104] -C2H4-CH(CH3)2I-C6HI3, -C7Hi5, -C8HI7, -C3H6-CH(CH3)2, -C2H4-CH(CH3)- C2H5I-CH(CH3)-C4H9I-CH2-CH(CH3)-C3H7I-CH(CH3)-CH2-CH(CH3)2I-CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2I-CH2-C(CH3)2-C2H5, -C(CH3)2-C3H7I-C(CH3)2-CH(CH3)2I-C2H4-C(CH3)3I-CH(CH3)-C(CH3)3I-CH=CH2I-CH2-CH=CH2I-C(CH3)=CH2I-CH=CH-CH3, -C2H4-CH=CH2, -CH2-CH=CH-CH3I-CH=CH-C2H5, -CH2-C(CH3)=CH2I-CH(CH3)-CH=CH, -CH=C(CH3)2I-C(CH3)=CH-CH3I-CH=CH-CH=CH2, -C3H6-CH=CH2, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CH=CH-C3H7, -CH=CH-CH=CH-CH3, -C2H4-C(CH3)=CH2I-CH2-CH(CH3)-CH=CH2I-CH(CH3)-CH2-CH=CH2I-CH2-CH=C(CH3)2I-CH2-C(CH3)=CH-CH3I-CH(CH3)-CH=CH-CH3I-CH=CH-CH(CH3)2I-CH=C(CH3)-C2H5, -C(CH3)=CH-C2H5, -C(CH3)=C(CH3)2I-C(CH3)2-CH=CH2I-CH(CH3)-C(CH3)=CH2I-C4H8-CH=CH2, -C3H6-CH=CH-CH3,

[0105] -C2H4-CH=CH-C2H5, -CH2-CH=CH-C3H7I-CH=CH-C4H9I-C3H6-C(CH3)=CH2, -C2H4-CH(CH3)-CH=CH2I-CH2-CH(CH3)-CH2-CH=CH2I-C2H4-CH=C(CH3)2I-CH(CH3)-C2H4-CH=CH2I-C2H4-C(CH3)=CH-CH3I-CH2-CH(CH3)-CH=CH- CH3I-CH(CH3)-CH2-CH=CH-CH3I-CH2-CH=CH-CH(CH3)2I

[0106] -CH2-CH=C(CH3)-C2H5, -CH2-C(CH3)=CH-C2H5, -CH(CH3)-CH=CH-C2H5, -CH=CH-CH2-CH(CH3)2I-CH=CH-CH(CH3)-C2H5, -CH=C(CH3)-C3H7I-C(CH3)=CH-C3H7I-CH2-CH(CH3)-C(CH3)=CH2I-C[C(CH3)3]=CH2I

[0107] -CH(CH3)-CH2-C(CH3)=CH2I-CH(CH3)-CH(CH3)-CH=CH2I

[0108] -CH=CH-C2H4-CH=CH2I-C(CH3)2-CH2-CH=CH2I-CH2-C(CH3)=C(CH3)2I

[0109] -CH(CH3)-CH=C(CH3)2I-C(CH3)2-CH=CH-CH3I-CH=CH-CH2-CH=CH-CH3,

[0110] -CH(CH3)-C(CH3)=CH-CH3I-CH=C(CH3)-CH(CH3)2I-C(CH3)=CH-CH(CH3)2,

[0111] -C(CH3)=C(CH3)-C2H5, -CH=CH-C(CH3)3I-C(CH3)2-C(CH3)=CH2I

[0112] -CH(C2H5)-C(CH3)=CH2, -C(CH3)(C2H5)-CH=CH2, -CH(CH3)-C(C2H5)=CH2,

[0113] -CH2-C(C3H7)=CH2I-CH2-C(C2H5)=CH-CH3, -CH(C2H5)-CH=CH-CH3,

[0114] -C(C4H9)=CH2I-C(C3H7)=CH-CH3I-C(C2H5)=CH-C2H5, -C(C2H5)=C(CH3)2,

[0115] -C[CH(CH3)(C2H5)]=CH2, -C[CH2-CH(CH3)2]=CH2I-C2H4-CH=CH-CH=CH2,

[0116] -CH2-CH=CH-CH2-CH=CH2, -C3H6-CEC-CH3, -CH2-CH=CH-CH=CH-CH3,

[0117] -CH=CH-CH=CH-C2H5, -CH(CH3)-CH2-CECH, -CH(CH3)-CEC-CH3, -C2H4-CH(CH3)-CECH, -CH=CH-CH=C(CH3)2I-CH2-CH(CH3)-CH2-CECH, -CH=CH-C(CH3)=CH-CH3I-CH=C(CH3)-CH=CH-CH3I-CH2-CH(CH3)- C=CH, -C(CH3)=CH-CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -C2H4-CECH, -CH2-CEC-CH3, -CEC-C2H5, -C3H6-CECH, -C2H4-CEC-CH3,

[0118] -CH2-CEC-C2H5, -C=C-C3H7I-CH(CH3)-CECH, -C4H8-CECH,

[0119] -C2H4-CEC-C2H5, -CH2-CEC-C3H7, -C=C-C4H9I-CEC-CH2-CH(CH3)2,

[0120] -CH(CH3)-C2H4-CECH, -CH2-CH(CH3)-CEC-CH3, -C(CH3)(C2H5)-CECH,

[0121] -CH(CH3)-CH2-CEC-CH3, -CH(CH3)-CEC-C2H5, -CH2-CEC-CH(CH3)2,

[0122] -CEC-CH(CH3)-C2H5, -CH2-CEC-CEC-CH3, -CH(C2H5)-CEC-CH3,

[0123] -C(CH3)2-CEC-CH3, -CH(C2H5)-CH2-CECH, -CH2-CH(C2H5)-CECH,

[0124] -C(CH3)2-CH2-CECH, -CH2-C(CH3)2-CECH, -CH(CH3)-CH(CH3)-CECH, -CH(C3H7)-CECH, -CH2-CH(CECH)2, -C=C-C=CH, -CH2-C=C-C=CH, -C=C-C=C-CH3, -CH(C=CH)2, -C2H4-C=C-C=CH, -CH2-C=C-CH2-C=CH, -C=C-C2H4-C=CH, -CEC-C(CH3)3, -C=C-CH2-C=C-CH3, -C=C-C=C-C2H5I or

[0125] R5and R6or R6and R7may form together with the two carbon atoms of the phenyl ring to which they are attached a 4 to 8-membered ring system, which is optionally substituted with one or more substituents selected from R10, R11, R12, and R13; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt of the above-mentioned compound.

[0126] These compounds are suitable for enhancing the cytokine level secreted by stimulated immune cells and thereby increase the local activity of immune cells in proximity to said stimulated immune cells. These findings make that compounds of the invention useful for the treatment and / or prophylaxis of neoplastic and / or infectious diseases.

[0127] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. The compounds of the present invention may form salts with organic or inorganic acids or bases. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, D-o- tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, trifluoroacetic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form of the compounds of formula (I) with a sufficient amount of the desired acid to produce a salt in the conventional manner well known to those skilled in the art.

[0128] In the case the inventive compounds bear acidic groups, salts could also be formed with inorganic or organic bases. Examples for suitable inorganic or organic bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.

[0129] As used herein, the term „4 to 8-membered ring system" refers to 4 to 8-membered aromatic ring, or 4 to 8-membered heteroaromatic ring, 4 to 8-membered carbohyclyl, or 4 to 8-membered heterocyclyl group. R5and R6or R6and R7form said 4 to 8- membered ring system and in said 4 to 8-membered ring system, two carbon atoms of the phenyl ring, at which R5and R6or R6and R7are substituted, are inculded.

[0130] Preferably, 4 to 8-membered aromatic ring refers to phenyl and naphthyl, wherein these phenyl and naphthyl residues can be substituted with 1 to 4 substituents selected from R10to R13. However it is clear to a skilled person that the term “can be substituted” refers to the replacement of a hydrogen atom by one of the substituents R10to R13.

[0131] Preferably, 4- to 8-membered heteroaromatic ring” includes at least one heteroatom such as 0, S, SO, SO2, N, NO, and one double bond, wherein these monounsaturated 4-membered heterocyclic residues can be substituted with 1 to 4 substituents selected from R10to R13. It is clear to a skilled person that the term “can be substituted” refers to the replacement of a hydrogen atom by one of the substituents R10to R13.

[0132] Preferably, 4- to 8-membered heterocyclyl group” includes at least one heteroatom such as 0, S, SO, SO2, and N, and optionally one carbonyl (CO) bond, one or more double bond, wherein this 4 to 8-membered heterocyclyl group can be substituted with 1 to 4 substituents selected from R10to R13. it is clear to a skilled person that the term “can be substituted” refers to the replacement of a hydrogen atom by one of the substituents R10to R13.

[0133] Preferably, 4- to 8-membered carbocyclyl group” can include optionally one or more double bond and can be substituted with 1 to 4 substituents selected from R10to R13. it is clear to a skilled person that the term “can be substituted” refers to the replacement of a hydrogen atom by one of the substituents R10to R13. Preferably, in the formula (I), R5and R6, or R6and R7may form the following 4- to 6- membered ring systems, wherein the 4- to 6-membered ring system can be optionally substituted with 1 to 4 substituents selected from R10to R13:

[0134] Thus, in the formula (I), R3represents preferably the following bicyclic ring, in which R5and R6, or R6and R7form the 4- to 6-membered ring system fused to a phenyl ring, wherein the 4- to 6-membered ring system can be optionally substituted with 1 to 4 substituents selected from R10to R13.

[0135] More preferably, in the formula (I), R5and R6, or R6and R7may form the following 4- to 6-membered ring system, wherein the 4- to 6-membered ring system can be optionally substituted with 1 to 4 substituents selected from R10to R13:

[0136] Thus, in the formula (I), R3represents preferably the following bicyclic ring, in which R5and R6, or R6and R7form the 4- to 6-membered ring system fused to a phenyl ring, wherein the 4- to 6-membered ring system can be optionally substituted with 1 to 4 substituents selected from R10to R13:

[0137] Still more preferably, in the formula (I), R5and R6, or R6and R7may form the following

[0138] 6-membered ring system, wherein the 6-membered ring system can be optionally substituted with 1 to 4 substituents selected from R10to R13:

[0139] More preferably, the present invention is directed to a compound of the formula (I): wherein

[0140] A represents

[0141] B is -O-R3, -O-CHR3R3*, -O-CH2-CH2-R3, or -O-CH2-CH2-CH2-R3;

[0142] H<X

[0143] R1representsR2aR2b or

[0144] R2aand R2brepresent independently of each other -H, -F, -CH3, -C2Hs,

[0145] -CH2F, -CHF2I-CF3I-CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CF2-CH3, -CHF-CHF2I-CHF-CF3, -CF2-CF3; wherein R2ais not -H;

[0146] R3represents or preferably

[0147] R3* represents -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2-CF3;

[0148] R4and R4* represent indepenently of each other -H, -F, -Cl, — Br, -CH3, -C2H5, -CH2F, -CHF2I-CF3, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OCH2F, -OCHF2I-OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2I-CHF-CF3,

[0149] R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other -H, -cyclo-CsHs, -cyclo-C4H7, -cyclo-CsHg, -cyclo-CeHn, -cyclo-C7Hi3, -cycloC3H5O, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3,

[0150] -OC4H9, -OPh, -OCH2-Ph, -OCPh3, -CH^OCH3, -C2H4-OCH3, -C3H6-OCH3, -CH^OC2H5I-C2H4-OC2H5, -C3H6-OC2H5, -CH^OC3H7, -C2H4— OC3H7, -C3He— OC3H7, -CH^- 0— cyclo-C3Hs, -C2H4— 0— cyclo-C3Hs, -C3H6-O-cyclo-C3H5, -CH^OCH(CH3)2, -C2H4-OCH(CH3)2, -C3H6-OCH(CH3)2, -CH^OC(CH3)3, -C2H4-OC(CH3)3I-C3H6-OC(CH3)3, -CH^OC4H9,

[0151] -C2H4-OC4H9I-C3H6-OC4H9, -CH^OPh, -C2H4-OPh, -C3H6-OPh, -CH^OCH2-Ph, -C2H4-OCH2-Ph, -C3H6-OCH2-Ph, -SH, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H5, -SCH(CH3)2, -SC(CH3)3, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5I-COC3H7I-CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3I-COOC2H5I-COOC3H7I-COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3I-OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7I-CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2I-CON(C2H5)2, -CON(C3H7)2I-CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2,

[0152] -NHCOCH3, -NHCOC2H5, -NHCOC3H7, -NHCO-cyclo-C3H5, -NHCO-CH(CH3)2, -NHCO-C(CH3)3I-NHCO-OCH3I-NHCO-OC2H5, -NHCO-OC3H7, -NHCO-O-cyclo-C3H5, -NHCO-OCH(CH3)2, -NHCO-OC(CH3)3, -NH2, -NHCH3I-NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3I-N(CH3)2, -N(C2H5)2, -N(C3H7)2I-N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3I-SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3I-SO2CH3, -SO2C2H5, -SO2C3H7,

[0153] -SO^cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3I

[0154] -SO3C2H5, -SO3C3H7I-SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3,

[0155] -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NH-cyclo-C3H5, -SO2NHCH(CH3)2, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2,

[0156] -SO2N(C3H7)2, -SO2N(cyclo-C3H5)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2,

[0157] -O-S(=O)CH3, -O-S(=O)C2H5, -O-S(=O)C3H7I-O-S(=O)-cyclo-C3H5,

[0158] -O-S(=O)CH(CH3)2, -O-S(=O)C(CH3)3, -S(=O)(=NH)CH3, -S(=O)(=NH)C2H5I-S(=O)(=NH)C3H7, -S(=O)(=NH)-cyclo-C3H5, -S(=O)(=NH)CH(CH3)2,

[0159] -S(=O)(=NH)C(CH3)3, -NH-SO2-CH3, -NH-SO2-C2H5, -NH-SO2-C3H7,

[0160] -NH-SO2-cyclo-C3H5, -NH-SO2-CH(CH3)2, -NH-SO2-C(CH3)3, -O-SO2-CH3, -O-SO2-C2H5, -O-SO2-C3H7, -O-SO2-cyclo-C3H5, -O-SO2-CH(CH3)2,

[0161] -O-SO2-C(CH3)3, -OCH2F, -OCHF2I-OCF3I-CH^OCF3, -C2H4-OCF3, -C3H6-OCF3, -CH^OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -OC2F5, -CH^OC2F5, -C2H4-OC2F5, -C3H6-OC2F5, -CH2F,

[0162] -CHF2I-CF3, -CH2-CH2F, -CH2-CHF2I-CH2-CF3Icyclo-CsHis, -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH=CH-Ph, -CPh3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H11, -CH=CH2,

[0163] -CH2-CH=CH2I-C(CH3)=CH2I-CH=CH-CH3I-CECH, -CEC-CH3, -CH2-CECH, / ''' z°\ z°\ /

[0164] / X \z / , ’ \ \z X \ or / Xv;o; preferably R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other -H, -cyclo-C3H5, -cyclo-C4H7, -cyclo-CsHg, -cyclo-CeHn, -cyclo-C7Hi3, -cycloC3H5O, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OPh, -OCH2-Ph, -OCPh3, -CH^OCH3, -C2H4-OCH3, -C3H6-OCH3, -CH^OC2H5, -C2H4-OC2H5, -C3H6-OC2H5, -CH^OC3H7,

[0165] -C2H4— OC3H7, -C3He— OC3H7, -CH^- 0— cyclo-C3H5, -C2H4— 0— cyclo-C3H5,

[0166] -C3H6-O-cyclo-C3H5, -CH^OCH(CH3)2, -C2H4-OCH(CH3)2, -C3H6-OCH(CH3)2, -CH^OC(CH3)3, -C2H4-OC(CH3)3, -C3H6-OC(CH3)3, -CH^OC4H9,

[0167] -C2H4-OC4H9, -C3H6-OC4H9, -CH^OPh, -C2H4-OPh, -C3H6-OPh,

[0168] -CH^OCH2-Ph, -C2H4-OCH2-Ph, -C3H6-OCH2-Ph, -F, -Cl, -Br, -I, -CN,

[0169] -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3I-COOC2H5, -COOC3H7, -COO-cyclo-C3H5,

[0170] -COOCH(CH3)2, -COOC(CH3)3I-OOC-CH3, -OOC-C2H5, -OOC-C3H7,

[0171] -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2I-CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2,

[0172] -NHCOCH3, -NHCOC2H5, -NHCOC3H7, -NHCO-cyclo-C3H5, -NHCO-CH(CH3)2, -NHCO-C(CH3)3I-NHCO-OCH3I-NHCO-OC2H5, -NHCO-OC3H7, -NHCO-O-cyclo-C3H5, -NHCO-OCH(CH3)2, -NHCO-OC(CH3)3, -NH2, -NHCH3I-NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3I-N(CH3)2I-N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3I-SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3I-SO2CH3, -SO2C2H5, -SO2C3H7,

[0173] -SO^cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3,

[0174] -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3,

[0175] -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NH-cyclo-C3H5, -SO2NHCH(CH3)2, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2,

[0176] -SO2N(C3H7)2, -SO2N(cyclo-C3H5)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2,

[0177] -O-S(=O)CH3, -O-S(=O)C2H5, -O-S(=O)C3H7, -O-S(=O)-cyclo-C3H5,

[0178] -O-S(=O)CH(CH3)2, -O-S(=O)C(CH3)3I-O-SO2-CH3,

[0179] -O-SO2-C2H5, -O-SO2-C3H7, -O-SO2-cyclo-C3H5, -O-SO2-CH(CH3)2,

[0180] -O-SO2-C(CH3)3, -OCH2F, -OCHF2, -OCF3, -CH^OCF3, -C2H4-OCF3, -C3H6-OCF3, -CH^OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -OC2F5, -CH^OC2F5, -C2H4-OC2F5, -C3H6-OC2F5, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-CHF2I-CH2-CF3I-CH3, -C2H5I-C3H7I-CH(CH3)2I-C4H9,

[0181] -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H11, -CH=CH2,

[0182] -CH2-CH=CH2I-C(CH3)=CH2I-CH=CH-CH3I-CECH, -CEC-CH3, -CH2-CECH, or

[0183] R5and R6or R6and R7may form together with the two carbon atoms of the phenyl ring to which they are attached a 4 to 8-membered ring system, which is optionally substituted with one or more substituents selected from R10, R11, R12, and R13; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt of the above-mentioned compound.

[0184] In all general formulae disclosed herein B represents preverably -O-R3, -O-CHR3R3* or -O-CH2-CH2-R3.

[0185] Moreover, it was found that the compounds of formula (I), wherein B represents -O-R3are well able to pass the blood brain barrier. Consequently, in regard to indications where the ability to pass the blood brain barrier is important, these compopunds of formula (I) are especially preferred, wherein B represents -O-R3.

[0186] Therefore, as disclosed herein, the group of compounds of formula (I) is claimed, wherein B represents only -O-R3in order to have a claim on the group of compounds which are able to easily pass the blood brain barrier.

[0187] Consequently, the remaining compounds for formula (I) are claimed, wherein B represents -O-CHR3R3* or -O-CH2-CH2-R3or -O-CH2-CH2-CH2-R3.

[0188] Moreover, the inventors found that the R1residue is especially important for the inhibitory activity. The R1residue has to have a hydroxy group (-OH) and in addition has to have at least the substituent R2awhich is different from hydrogen (-H) and optionally a second substituent R2b.

[0189] In regard to all general formulae disclosed herein the substituents R2aand R2bare defined as follows:

[0190] R2aand R2brepresent independently of each other -H, -F, -CH3, -C2Hs,

[0191] -CH2F, -CHF2I-CF3I-CH2-CF3I-CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CF2-CH3I-CHF-CHF2I-CHF-CF3I-CF2-CF3; wherein R2ais not -H; or in other words:

[0192] R2arepresents -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3,

[0193] -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3I-CH2CH2OCH3I-CF2-CH3I-CHF-CHF2I-CHF-CF3I-CF2-CF3; and

[0194] R2brepresents -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3I-CH2CH2OCH3I-CF2-CH3I-CHF-CHF2I-CHF-CF3, -CF2-CF3.

[0195] Thus, under the proviso that R2ais different from hydrogen (-H), it is preferred that R2aand R2brepresent independently of each other -H, -F, -CH3, -C2Hs,

[0196] -CH2F, -CHF2I-CF3, -CH2-CF3I-CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3I-CF2-CH3I-CHF-CHF2I-CHF-CF3I-CF2-CF3; more preferably, R2aand R2brepresent independently of each other -H, -F, -CH3, -C2H5, -CH2F, -CHF2I-CF3I-CH2-CF3I-CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CF2-CH3I-CHF-CHF2; more preferably, R2aand R2brepresent independently of each other -H, -F, -CH3, -C2H5, -CH2F, -CHF2I-CF3I-CH2-CF3I-CHF-CH2F, -CH2OH, -CH2CH2OH, -CF2-CH3I-CHF-CHF2I-CHF-CF3I-CF2-CF3; more preferably, R2aand R2brepresent independently of each other -H, -F, -CH3, -C2H5, -CH2F, -CHF2I-CF3I-CH2-CF3I-CHF-CH2F, -CH2OH, -CF2-CH3I-CHF-CHF2I-CHF-CF3I-CF2-CF3; more preferably, R2aand R2brepresent independently of each other -H, -F, -CH3, -C2H5, -CH2F, -CHF2I-CF3I-CH2-CF3I-CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CF2-CH3I-CHF-CHF2; more preferably, R2aand R2brepresent independently of each other -H, -F, -CH3, -C2H5, -CH2F, -CHF2I-CF3I-CH2-CF3I-CHF-CH2F, -CH2OH, -CH2CH2OH, -CF2-CH3I-CHF-CHF2; more preferably, R2aand R2brepresent independently of each other -H, -F, -CH3, -C2H5, -CH2F, -CHF2I-CF3I-CH2-CF3I-CHF-CH2F, -CH2OH, -CF2-CH3I-CHF-CHF2; more preferably, R2aand R2brepresent independently of each other -H, -F, -CH3, -C2H5, -CH2F, -CHF2I-CF3I-CH2-CF3I-CHF-CH2F, -CH2OH, -CF2-CH3I-CHF-CHF2; more preferably, R2aand R2brepresent independently of each other -H, -F, -CH3, -C2H5, -CH2F, -CHF2I-CF3I-CH2-CF3I-CHF-CH2F, -CH2OH (always under the proviso that R2ais different rom hydrogen).

[0197] Also preferred are compounds, wherein R2aand R2brepresent both -CH3or -C2Hs, and more preferably -CH3. Moreover, also preferred are compounds, wherein R2brepresents -H and R2arepresents -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CF2-CH3, -CHF-CHF2I-CHF-CF3, -CF2-CF3 ; and more preferably -CH3, -C2Hs, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CF2-CH3, -CHF-CHF2I-CHF-CF3, -CF2-CF3 ; and more preferably -CH3, -C2Hs, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CF2-CH3, -CHF-CHF2I-CHF-CF3, -CF2-CF3 ; and more preferably -CH3, -C2Hs, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CF2-CH3,

[0198] -CHF-CHF2; and more preferably -CH3, -C2H5, -CH2F, -CHF2, -CF3,

[0199] -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CF2-CH3,

[0200] -CHF-CHF2; and more preferably -CH3, -C2H5, -CH2F, -CHF2, -CF3,

[0201] -CH2-CF3, -CHF-CH2F, -CH2OH, -CF2-CH3, -CHF-CHF2; and more preferably -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F,

[0202] -CH2OH, -CF2-CH3, -CHF-CHF2; and more preferably -CH3, -C2H5, -CH2F,

[0203] -CHF2I-CF3I-CH2-CF3, -CHF-CH2F, -CH2OH; and more preferably -CH3, -CH2F, -CHF2I-CF3I-CH2-CF3, -CHF-CH2F, -CH2OH; and more preferably -CH3, -CH2F, -CHF2I-CF3I-CHF-CH2F, -CH2OH; and more preferably -CH3, -CH2F, -CHF2I-CF3I-CH2OH.

[0204] R2brepresents preferably -H or -CH3; and more preferably R2brepresents -CH3 if R2arepresents -CH3, and R2brepresents -H if R2ais different from -CH3.

[0205] More preferably, in the formula (I), R3represents still more preferably R3represents

[0206] Moreover, in all general formulae disclosed herein it is preferred that R10, R11, R12, and R13Represent hydrogen (-H).

[0207] Also preferred are compounds of the general formula (I), wherein

[0208] R2arepresents -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3,

[0209] -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3; and

[0210] R2brepresents -H or -CH3; and preferably R2brepresents -CH3if R2arepresents -CH3, and R2brepresents -H if R2ais different from -CH3.

[0211] B represents -O-R3or -O-CHR3R3*;

[0212] R3represents

[0213] R3* represents -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2,

[0214] -CF3, -CH2-CF3 ;

[0215] R4and R4* represent indepenently of each other -H, -F, -Cl, — Br, -CH3, -C2H5, -CH2F, -CHF2I-CF3, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, and A, R1, R5, R6, R7, R8, R9, R10, R11, R12and R13have the same meanings as defined in claim 1 or as defined herein.

[0216] In all general formulae disclosed herein and especially in residue A the substituent R4represents preferably -H, -F, -Cl, -Br, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-CF3,

[0217] -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, or -CF2-CF3 ; more preferably -H, -F, -Cl, -Br, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, or -CF2-CF3 ; more preferably -H, -F, -Cl, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -OCH2F, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, or -CF2-CF3 ; more preferably -H, -F, -Cl, -CHF2, -CF3I-OCH3, -OC2H5, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, or -CF2-CF3 ; still more preferably -H, -F, -Cl, -CHF2, -CF3, -OCH3, -OC2H5, -OCHF2, -OCF3I-CHF-CHF2I-CHF-CF3I-CF2-CH3I-CF2-CH2F, -CF2-CHF2Ior -CF2-CF3; still more preferably -H, -F, -Cl, -CHF2, -CF3, -OCH3, -OC2H5, -OCHF2I-OCF3I-CHF-CHF2I-CHF-CF3I-CF2-CHF2Ior -CF2-CF3; still more preferably -H, -F, -Cl, -CHF2, -CF3, -OCH3, -OC2H5, -OCHF2, -OCF3, -CF2-CHF2, or -CF2-CF3; still more preferably -H, -F, -Cl, -CHF2, -CF3, -OCH3, -OC2H5, -OCHF2, or -OCF3; still more preferably -H, -F, -Cl, -CHF2, -CF3I-OCH3I-OCHF2Ior -OCF3.

[0218] In combination with the preferred definitons of R4, the substituent R4* represents preferably -H, -F, -Cl, -CH2F, -CHF2, -CF3, -OCHF2, or -OCF3, more preferably R4* represents preferably -H, -F, -Cl, -CHF2, -CF3, -OCHF2, or -OCF3, still more preferably -H, -F, -Cl, -CHF2, -OCHF2, or -OCF3, still more preferably -H, -F, -Cl, -OCHF2, or -OCF3, still more preferably -H, -F, -Cl, or -OCF3, still more preferably still more preferably -H, -F, or -OCF3, still more preferably -H or -F, still more preferably -H.

[0219] In all general formula dosclosed herein the substituents R5, R6, R7, R8, R9, R10, R11, R12and R13or the substituents R5, R6, R7, R8and R9, preferably represent independently of each other -H, -cyclo-C3Hs, -cyclo-C4H7, -cyclo-CsHg, -cyclo- C6HH, -OH, -OCH3I-OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2,

[0220] -OC(CH3)3, -OC4H9, -CH^OCH3, -C2H4-OCH3, -CH^OC2H5, -CH^O-cyclo- C3H5, -CH^OCH(CH3)2I-F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3I-COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3I-OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2I-CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2,

[0221] -NHCOCH3, -NHCOC2H5, -NHCOC3H7, -NHCO-cyclo-C3H5, -NHCO-CH(CH3)2, -NHCO-C(CH3)3I-NH2I-NHCH3I-NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO^cyclo-C3H5, -SO2CH(CH3)2, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2,

[0222] -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NH-cyclo-C3H5, -SO2NHCH(CH3)2, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2,

[0223] -O-S(=O)CH3I-O-S(=O)C2H5, -O-S(=O)C3H7, -O-S(=O)-cyclo-C3H5, -O-S(=O)CH(CH3)2, -O-SO2-CH3, -O-SO2-C2H5, -O-SO2-C3H7,

[0224] -O-SO2-cyclo-C3H5, -O-SO2-CH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH^OCF3, -C2H4-OCF3, -CH^OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -OC2F5, -CH^OC2F5, -CH2F, -CHF2I-CF3I-CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9,

[0225] -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H11, -CH=CH2,

[0226] -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3I-CECH, -CEC-CH3, -CH2-CECH; or

[0227] R5and R6or R6and R7may form together with the two carbon atoms of the phenyl ring to which they are attached a 6-membered aromatic or 6-membered N- heteroaromatic ring system, which is optionally substituted with one or more substituents selected from R10, R11, R12, and R13; and which is preferably not substituted (R10= R11= R12= R13= -H).

[0228] Still more preferably, in all general formula dosclosed herein the substituents R5, R6, R7, R8, R9, R10, R11, R12and R13or the substituents R5, R6, R7, R8and R9, preferably represent independently of each other -H, -cyclo-CsHs, -cyclo-C4H7, -cyclo-CsHg, -cyclo-C6Hn, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -CH^OCH3, -C2H4-OCH3, -CH^OC2H5, -CH^O-cyclo- C3H5, -CH^OCH(CH3)2, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CON(CH3)2, -CON(C2H5)2,

[0229] -NHCOCH3, -NHCOC2H5, -NHCOC3H7, -NHCO-cyclo-C3H5, -NHCO-CH(CH3)2, -NH2I-NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO^cyclo-C3H5, -SO2CH(CH3)2, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2,

[0230] -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NH-cyclo-C3H5, -SO2N(CH3)2, -SO2N(C2H5)2, -O-S(=O)CH3I-O-S(=O)C2H5, -O-S(=O)C3H7, -O-S(=O)-cyclo-C3H5, -O-S(=O)CH(CH3)2, -O-SO2-CH3, -O-SO2-C2H5,

[0231] -O-SO2-C3H7, -O-SO2-cyclo-C3H5, -O-SO2-CH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH^OCF3, -C2H4-OCF3, -CH^OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -OC2F5, -CH^OC2F5, -CH2F, -CHF2I-CF3I-CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH3, -C2H5, -C3H7, -CH(CH3)2; or

[0232] R5and R6or R6and R7may form together with the two carbon atoms of the phenyl ring to which they are attached a 6-membered aromatic or 6-membered N- heteroaromatic ring system containing one or two nitrogen atoms, which is optionally substituted with one or more substituents selected from R10, R11, R12, and R13; and which is preferably not substituted (R10= R11= R12= R13= -H).

[0233] Still more preferably, in all general formula dosclosed herein the substituents R5, R6, R7, R8, R9, R10, R11, R12and R13or the substituents R5, R6, R7, R8and R9, preferably represent independently of each other -H, -cyclo-CsHs, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -CH^OCH3, -CH^OC2H5, -F, -Cl, -Br, -CN, -COCH3, -COC2H5, -CONH2, -CONHCH3, -CONHC2H5, -CON(CH3)2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO^cyclo-C3H5, -SO2CH(CH3)2, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2,

[0234] -O-S(=O)CH3I-O-S(=O)C2H5, -O-S(=O)C3H7, -O-S(=O)-cyclo-C3H5,

[0235] -O-S(=O)CH(CH3)2, -O-SO2-CH3, -O-SO2-C2H5, -O-SO2-C3H7,

[0236] -O-SO2-cyclo-C3H5, -O-SO2-CH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH^OCF3, -C2H4-OCF3, -CH^OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -OC2F5, -CH^OC2F5, -CH2F, -CHF2I-CF3I-CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH3, -C2H5, -C3H7, -CH(CH3)2; or

[0237] R5and R6or R6and R7may form together with the two carbon atoms of the phenyl ring to which they are attached a 6-membered aromatic or 6-membered N- heteroaromatic ring system containing one nitrogen atom, which is optionally substituted with one or more substituents selected from R10, R11, R12, and R13; and which is preferably not substituted (R10= R11= R12= R13= -H).

[0238] Preferably R3represents wherein the substituents R5- R7have the meanings as disclosed above on the two previous pages and still more preferably R5- R7are independently of each other selected from -H, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -F, -Cl, -Br, -CN, -SO2CH3, -SO2C2H5, -OCH2F, -OCHF2, -OCF3, -CH^OCF3, -CH^- OCHF2, -OC2F5, -CH2F, -CHF2I-CF3, -CH2-CHF2, -CH2-CF3, -CH3, -C2H5, -C3H7, -CH(CH3)2; more preferably from -H, -OCH3, -OC2H5, -F, -Cl, -CN, -SO2CH3, -SO2C2H5, -OCH2F, -OCHF2, -OCF3, -CH2F, -CHF2I-CF3I

[0239] -CH3, -C2H5 ; still more preferably from -H, -OCH3, -OC2H5, -F, -Cl, -CN, -SO2CH3, -SO2C2H5, -OCH2F, -OCHF2, -OCF3, -CH2F, -CHF2I-CF3I-CH3 ; still more preferably from -H, -OCH3, -F, -Cl, -OCHF2, -OCF3, -CHF2, -CF3I-CH3. Moreover it is preferred that only one of the substituents R5- R7represents hydrogen and the other two are different from hydrogen. More preferably, R5is different from hydrogen and R6represents hydrogen or R7represents hydrogen or R6and R7represent hydrogen. Consequently, the para-substitution of residue R3is preferred.

[0240] In all general formula dosclosed herein the substituent R3represents preferably

[0241] In some embodiments, the present invention refers to a compound of the formula (I):

[0242] R1wherein

[0243] R2aand R2brepresent independently of each other -H, -F, -CH3, -C2H5,

[0244] -CH2F, -CHF2I-CF3, -CH2-CF3I-CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3I-CH2CH2OCH3, -CF2-CH3I-CHF-CHF2I-CHF-CF3I-CF2-CF3; wherein R2ais not -H;

[0245] R3represents

[0246] R3* represents -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2-CF3;

[0247] R4and R4* represent indepenently of each other -H, -F, -Cl, — Br, -CH3, -C2H5, -CH2F, -CHF2I-CF3, -OCH3, -OC2H5, -OCH(CH3)2I-OCH2F, -OCHF2I-OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2I-CHF-CF3,

[0248] Preferably, R4represents -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, --0— < > -0CH3, -OCH(CH3)2, -OCHF2I-0CF3, -CF2-CHF2, XZ , or

[0249] --O— ( ?

[0250] V-Z ; and more preferably -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3,

[0251] Preferably, R4* represents -H, -F, -Cl, -CH2F, -CHF2, -CF3, -OCHF2, or -OCF3, more preferably, R4* represents -H, or -F; and R5, R6, R7, R8, R9, R10, R11, R12and R13have the same meanings as defined herein and R10, R11, R12, and R13preferably represent hydrogen.

[0252] Preferably, the present invention refers to the compounds of the formula (I), wherein A represents

[0253] B is -O-R3, -O-CHR3R3*, -O-CH2-CH2-R3, or -O-CH2-CH2-CH2-R3; and preferably B represents -0-R3or -O-CHR3R3*;

[0254] R1represents or

[0255] R2arepresents -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3; and R2brepresents -H or -CH3; and preferably R2brepresents -CH3if R2arepresents -CH3, and R2brepresents -H if R2ais different from -CH3.

[0256] R3represents

[0257] or ; R3* represents –H, –F, ^CH3, ^C2H5, ^C3H7, ^CH(CH3)2, ^CH2F, ^CHF2, ^CF3 , ^CH2 ^CF3 ; R4 and R4* represent indepenently of each other –H, –F, –Cl, –Br, ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OC2H5, ^OCH(CH3)2, ^OCH2F, ^OCHF2, ^OCF3, ^CH2 ^CF3, ^CHF ^CH2F, ^CHF ^CHF2, ^CHF ^CF3, O OO^CF2 ^CH3, ^CF2 ^CH2F, ^CF2 ^CHF2, ^CF2 ^CF3, , , O O O or ; preferably, R4 represents –H, –F, –Cl, ^CH3, ^CH2F, ^CHF2, ^CF3, ^OCH3, O O O ^OCH(CH3)2, ^OCHF2, ^OCF3, ^CF2 ^CHF2, , or ; preferably, R4* represents –H, –F, –Cl, ^CH2F, ^CHF2, ^CF3, ^OCHF2, or ^OCF, mor 4* 3 e preferably, R represents –H, or –F; and R5, R6, R7, R8, R9, R10, R11, R12 and R13 have the same meanings as defined herein and R10, R11, R12, and R13 preferably represent hydrogen. Preferably, in the compounds of the formula (I) as defined herein R1 represents , , , , , , , , , , , , , , , , , , , , , or . More preferably, R1 represents , , , , , , , , In some embodiments, the present invention relates to the compound of formula (la) or (lb):

[0258] R7R6

[0259] (la) wherein n is 0, 1 , 2, or 3; preferably n is 0, 1 , or 2, more preferably n is 0 or 1 ;

[0260] R1, R2a, R2b, R4, R5, R6, R7, R8, and R9have the same meanings as defined above. Preferred are the compounds of the formula (la),

[0261] R7R6HO / ^N-X^NN^ °^XR8R5

[0262] ,CH2R4

[0263] R1(la) wherein n is 0, 1 , or 2, more preferably n is 0 or 1 ;

[0264] R1represents

[0265] R4represents -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3,

[0266] -OCH(CH3)2, -0CH2F, -0CHF2, -0CF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2,

[0267] -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, -CF2-CF3,

[0268] Preferably, R4represents -H, -F, -Cl, -CH3, -CH2F, -CHF2I-CF3I-OCH3,

[0269] -OCH(CH3)2, -OCHF2, -OCF3, -CF2-CHF2, more preferably, R4represents -H, -F, -Cl, -CH2F, -CHF2, -CF3, -OCHF2,

[0270] -OCF3, -CF2-CHF2, still more preferably preferably, R4represents -H, -F,

[0271] -CH2F, -CHF2, -CF3, -0CHF2, -0CF3, -CF2-CHF2 ; and R5to R8have the same meanings as defined herein.

[0272] More preferably, in the formula (I), (la) or (lb),

[0273] HO HCX ,' HOz,

[0274] R1represents or

[0275] HOz, more preferably R1represents or

[0276] In some embodiments, the present invention relates to the compound of any one of the following formulae (11-1) to (II-5), (111-1) to (HI-6), (IV-1) to (IV-8), (V-1) to (V-5), (VI-1) to (VI-2) and (VII-1) to (VII-3):

[0277] (II-3) (II-4)

[0278] (VI-2) (VII-1) (VI I -3) wherein R1, R3*, R4, R4*, R5, R6, R7, R8, R10, R11, R12, and R13have the same meanings as defined in the same meanings as defined above. In some embodiments, the present invention relates to the compound of any one of the following formulae (11-1 ) to (II-5), (111-1 ) to (HI-6), (IV-1 ) to (IV-6), (V-1 ) to (V-3):

[0279] (111-1) (HI-2) wherein R1, R4, R5, R6, R7, R8, R10, R11, R12, and R13have the same meanings as defined above.

[0280] Preferably, in the compound of any one of the following formulae (11-1) to (H-5), (111-1) to (HI-6), (IV-1) to (IV-6), (V-1) to (V-3), (11-1) to (II-5), (111-1) to (HI-6), (IV-1) to (IV-8), (V-1) to (V-5), (VI-1) to (VI-2) and (VII-1) to (VII-3):

[0281] R1represents

[0282] Preferably, R1represents

[0283] Preferably, in the compound of any one of the following formulae (11-1) to (H-5), (HI-1) to (HI-6), (IV-1) to (IV-8), (V-1) to (V-5), (VI-1) to (VI-2) and (VII-1) to (VII-3),

[0284] R4represents -H, -F, -Cl, -Br, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -OCH(CH3)2I-OCH2F, -OCHF2I-OCF3I-CH2-CF3I -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2,

[0285] -CF2-CF3, preferably, R4represents -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, -CF2-CF3, or more preferably, R4represents -H, -F, -Cl, -CH3, -CH2F, -CHF2I-CF3,

[0286] — 0— <y

[0287] -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -CF2-CHF2, and still more preferably -H, -F, -Cl, -CH3, -CH2F, -CHF2,

[0288] -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -CF2-CHF2.

[0289] Still more preferably, R4represents -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3 or -CF2-CHF2 ; and still more preferably -H, -F, -Cl, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3; and most preferably R4is -OCF3.

[0290] In a preferred embodiment, the present invention is directed to the compound of the formula (I),

[0291] XCH2wherein

[0292] A represents

[0293] R4

[0294] B represents -0-R3or -O-CH2-R3;

[0295] HCX HO.

[0296] R1represents

[0297] HO. HO^ HO,,

[0298] HO

[0299] HO' preferably R1represents

[0300] F ; more preferably R1represents

[0301] R3represents

[0302] R4represents -H, -F, -Cl, -CH3, -CF3, -OCH3, -OCHF2, or -OCF3; and

[0303] R5, R6, R7, and R8represent independently of each other -H, -F, -Cl, -CN, -CH3, -CHF2I-CF3, -OCHF2, -OCF3, or -SO2CH3; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt of the above-mentioned compound.

[0304] More preferred are the compounds of any one of the following formulae (111-1) to (III- 2), (HI-4) to (HI-6), (IV-1) to (IV-2), and (IV-4) to (IV-6):

[0305] (111-1) (HI-2) HO - HO^ ,- HO,,

[0306] „ F^F F"T"F F"T"F more preferably R1represents F , F , F ;

[0307] R4represents -F, -Cl, -Br, -CH3, -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3,

[0308] -OCH3, -OCH2F, -OCHF2I-OCF3I-OCH2CH2F, -OCH2CF3, or -OCF2CF3; preferably, R4represents -H, -F, -Cl, -CH3, -CF3, -OCH3, -OCHF2, or

[0309] -OCF3; and

[0310] R5, R6, R7, and R8represent independently of each other -H, -F, -Cl, -CN, -CH3, -CHF2I-CF3, -OCHF2, -OCF3, or -SO2CH3; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt of the above-mentioned compound.

[0311] In some embodiment, the present invention relates to the compound of any one of the following formulae (I), (11-1) to (II-5), (111-1) to (HI-6), (IV-1) to (IV-8), (V-1) to (V-5), (VI-1) to (VI-2) and (VII-1) to (VII-3): , wherein R3represents

[0312] F F

[0313] Preferably, R3represents

[0314] In a preferred embodiment, the present invention is directed to the compound of the formula (I), wherein

[0315] A represents

[0316] B represents -O-R3, -O-CH2-R3or -O-CHR3R3*;

[0317] R3* represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, or -CH2-CF3;

[0318] R4and R4* represent indepenently of each other -H, -F, -Cl, -CH3,

[0319] -CH2F, -CHF2I-CF3I-OCH3, -OCH(CH3)2, -0CH2F, -0CHF2,

[0320] -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3,

[0321] -CF2-CH2F, -CF2-CHF2, -CF2-CF3,

[0322] Preferably, R4represents -H, -F, -Cl, -CH3, -CH2F -CHF2, -CF3,

[0323] -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -CF2-CHF2,

[0324] --Q— ( |

[0325] ; more preferably, R4represents -H, -F, -ci, -CH2F,

[0326] -CHF2, -CF3, -OCHF2, -OCF3, -CF2-CHF2, , still more preferably preferably, R4represents -H, -F, -CH2F, -CHF2, -CF3, -OCHF2, -OCF3, -CF2-CHF2 ; preferably, R4* represents -H, -F, -Cl, -CH2F, -CHF2, -CF3, -OCHF2, or -OCFs, more preferably, R4* represents -H, or -F; and

[0327] R5, R6, R7, and R8represent independently of each other -H, -F, -Cl, -CN, -CH3, -CHF2I-CF3I-OCH3, -OCHF2, -OCF3, or -SO2CH3; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt of the above-mentioned compound. In a preferred embodiment, the present invention is directed to the compound of the formula (I),

[0328] B represents -0-R3or -O-CH2-R3;

[0329] HO

[0330] HO

[0331] HO preferably R1represents F

[0332] HO,, HO. HO«. HO,,

[0333] F' H'F „ F^F F^F F ^F

[0334] F ; more preferably R1represents F , F , F

[0335] R3represents

[0336] R4represents -H, -F, -Cl, -CH3, -CF3, -OCH3, -OCHF2, or -OCF3; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt of the above-mentioned compound.

[0337] Especially preferred compounds according to the present invention include compounds presented by Table 1.

[0338]

[0339] or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt thereof.

[0340] Most preferred compounds according to the present invention include compounds 142, 156, 248, and 329, or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt thereof.

[0341] Syntheses of the compounds

[0342] The compound of formula (I) can be prepared by reference to the methods illustrated by the following reaction protocols. The compound of formula (I) can be produced as outlined below by the suitable selection of reagents with appropriate substitution. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. Other synthetic routes to prepare the compound of formula (I) can be applied in analogy to methods disclosed in the literature by one of ordinary skill in the art. Scheme 1

[0343] (1-3*)

[0344] The present invention is also directed to a method for producing the compounds of formula (lb), comprising the following steps:

[0345] Step A) providing a compound (1-1*)

[0346] Step B1 )

[0347] B1a) performing a C-C coupling reaction between the compound (1-1*) and (A1*) in a presence of a Pd-catalyst and a base to obtain a compound (1-4*);

[0348] B1 b) removing a protecting group P1from the compound (1-4*) to obtain the compound (lb); wherein

[0349] X represent a leaving group, preferably halogen;

[0350] P1represents a hydroxy protecting group;

[0351] R' represents hydrogen, or C1-3 alkyl; or two R' form together a pinacol moiety; n, R2a, R2b, R4, and R5to R9have the same meanings as defined in the formula (lb).

[0352] Alternatively, a method for producing the compounds of formula (lb) comprising the following steps:

[0353] Step A) providing a compound (1-1*)

[0354] Step B2)

[0355] B2a) performing a C-C coupling reaction between the compounds (1-1*) and (A2*) in a presence of a Pd-catalyst and a base (R'O)2B to obtain a compound (1-2*)

[0356] B2b) performing a coupling reaction between the compounds (1-2*) and (B*)

[0357] R6

[0358] (B*);to obtain the compound (lb) wherein

[0359] X represent a leaving group, preferably halogen;

[0360] P1represents a hydroxy protecting group;

[0361] R' represents hydrogen, or C1-3 alkyl; or two R' form together a pinacol moiety; n, R2a, R2b, R4, and R5to R9have the same meanings as defined in the formula (lb).

[0362] Alternatively, a method for producing the compounds of formula (lb) comprising the following steps:

[0363] Step A2) providing a compound (1-3*)

[0364] Step B3) B2a) performing a coupling reaction between the compounds (1-3*) and (R1*) o2a I

[0365] OH(R1*) . to obtain a compound (lb) wherein

[0366] X represent a leaving group, preferably halogen; n, R2a, R2b, R4, and R5to R9have the same meanings as defined in the formula (lb).

[0367] In the step B1a), Suzuki coupling reaction of brominated compound (1-1*) with a compound A1* as a boronic acid derivative, or in the step B2a), Suzuki coupling reaction of brominated compound (1-1*) with a compound A2* as a boronic acid derivative

[0368] (A2*) is performed in the presence of the palladium catalyst and the base, wherein R' represents hydrogen, or C1-3 alkyl; or two R' form together a pinacol moiety; preferred, the boronic acid derivative (A1*) or (A2*) may be a boronic acid (R' = - H) or an ester of the boronic acid, e.g. its isopropyl ester (R' = -CH(CH3)2), a pinacol moiety (R'-R' = -C(CH3)2-C(CH3)2-).

[0369] The palladium catalyst is Pd(0) or Pd(ll) catalyst. The Pd(0) catalyst may be tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4], tris(dibenzylideneacetone)di- palladium(O) [Pd2(dba)s]. Pd(ll) catalyst may be dichlorobis(triphenylphosphine)- palladium(ll) [Pd(PPh3)2Cl2], palladium^ I) acetate and triphenylphosphine or more preferred [1 ,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2). The reaction is preferably carried out in a mixture of a solvent like dioxane, DMF, DME, THF, or isopropanol with water and in the presence of the base like aqueous sodium bicarbonate or K3PO4.

[0370] P1is hydroxy protecting group and preferred is silicon based protecting group selected from trimethylsilyl (TMS), triethylsilyl (TES), isopropyldimethylsilyl (IPMDS), diethylisopropylsilyl (DEIPS), te / Y-butyldimethylsilyl (TBS), te / Y-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), [2-(trimethylsilyl)ethoxy]methyl (SEM), 2- (trimethylsilyl)ethxy carbonate (Teoc), more preferred, te / Y-butyldimethylsilyl (TBS), or te / Y-butyldiphenylsilyl (TBDPS).

[0371] Medical Use

[0372] Surprisingly, it was found that the compounds of the present invention effectively activate immune cells, in particular, CD4+ and / or CD8+ cells as demonstrated in Table B-1 and natural killer (NK) cells in the context of T cell receptor (TCR) as well as NK cell receptor signalling, respectively. This allows highly selective TCR- or NK cell receptor-mediated activation of the immune system against mutated tissue or tissue infected with foreign pathogens. Hence, by applying the present invention in a clinical set up highly effective treatment can be achieved by minimizing the risk of severe side effects. This is further evident due to the possibility of administering highly potent compounds based on EC50 below nanomolar concentrations. This present invention therefore opens a broad dosing window in order to tip the balance between effective treatment and toxic off target effects for sustained tolerability in the course of multiple treatments.

[0373] As indicated above, the present invention also refers to the use of the compound of the present invention in a pharmaceutical context. Herein, a pharmaceutical context may be understood in the broadest sense as any means for improving a patient's health status and / or wellness. The terms "pharmaceutical" and "medicinal" may be understood interchangeably.

[0374] A further aspect of the present invention refers to a pharmaceutical composition comprising at least one compound of the present invention and at least one pharmaceutically acceptable carrier.

[0375] Preferably, a pharmaceutical composition comprising at least one compound of the present invention and at least one pharmaceutically acceptable carrier, excipient and / or diluent. More preferably, said pharmaceutical composition further compries at least one stimulating agent for activating immune cells. In this aspect relating to a pharmaceutical composition, the definitions as laid out in detail above also apply mutatis mutandis.

[0376] A pharmaceutically acceptable carrier according to the present invention may be any additive that is pharmaceutically acceptable, therefore, any additive that is non-toxic to the patient. Exemplarily, a pharmaceutically acceptable carrier may comprise a solvent such as, e.g., water, dimethyl sulfoxide (DMSO), ethanol, vegetable oil, paraffin oil or combinations thereof. Furthermore, a carrier may contain one or more detergent(s), one or more foaming agent(s) (e.g., sodium lauryl sulfate (SLS) / sodium dodecyl sulfate (SDS)), one or more coloring agent(s) (e.g., TiCh , food coloring), one or more vitamin(s), one or more salt(s) (e.g., sodium, potassium, calcium, zinc salts), one or more humectant(s) (e.g., sorbitol, glycerol, mannitol, propylene glycol, polydextrose), one or more enzyme(s), one or more preserving agent(s) (e.g., benzoic acid, methylparabene), one or more texturing agent(s) (e.g., carboxymethyl cellulose (CMC), polyethylene glycol (PEG), sorbitol), one or more emulsifier(s), one or more bulking agent(s), one or more glacing agent(s), one or more separating agent(s), one or more antioxidant(s), one or more herbal and plant extract(s), one or more stabilizing agent(s), one or more polymer(s) (e.g., hydroxypropyl methacrylamide (HPMA), polyethylene imine (PEI), carboxymethyl cellulose (CMC), polyethylene glycol (PEG)), one or more uptake mediator(s) (e.g., polyethylene imine (PEI), dimethyl sulfoxide (DMSO), a cell-penetrating peptide (CPP), a protein transduction domain (PTD), an antimicrobial peptide, etc.) one or more antibody / antibodies, one or more sweetener(s) (e.g., sucrose, acesulfame K, saccharin Na, stevia), one or more counterstain dye(s) (e.g., fluorescein, fluorescein derivatives, Cy dyes, an Alexa Fluor dye(s), S dye(s), rhodamine, quantum dot(s), etc.), one or more homeopathic ingredient(s) one or more gustatory substance(s) and / or one or more fragrance(s).

[0377] Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn, rice, and potato, and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 5 to about 95 % by weight of the total composition, preferably from about 25 to about 75 weight %, and more preferably from about 30 to about 60 weight %.

[0378] Suitable excipients are binders, disintegrants, lubricants, glidents and / or coloring agents. The term disintegrants refers to materials added to the composition to support break apart (disintegrate) and release the pharmaceutically active ingredients of a medicament. Suitable disintegrants include starches, “cold water soluble” modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures. The amount of disintegrant in the composition may range from about 2 to about 20 weight % of the composition, more preferably from about 5 to 10 weight %.

[0379] Binders are substances which bind or “glue” together powder particles and make them cohesive by forming granules, thus serving as the “adhesive” in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat, com, rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminium silicate. The amount of binder in the composition may range from about 2 to about 20 weight % of the composition, preferably from about 3 to about 10 weight %, and more preferably from about 3 to about 6 weight %.

[0380] Lubricants refer to a class of substances which are added to the dosage form to enable the tablet granules etc. after being compressed to release from the mould by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L- leucine. Lubricants are usually added at the very last step before compression, since they must be present at the surface of the granules. The amount of lubricant in the composition may range from about 0.2 to about 5 weight % of the composition, preferably from about 0.5 to about 2 weight %, and more preferably from about 0.3 to about 1 .5 weight % of the composition.

[0381] Glidents are materials that prevent caking of the components of the pharmaceutical composition and improve the flow characteristics of granulate so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition may range from about 0.1 to about 5 weight % of the final composition, preferably from about 0.5 to about 2 weight %. Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminium oxide. The amount of the coloring agent may vary from about 0.1 to about 5 weight % of the composition, preferably from about 0.1 to about 1 weight %.

[0382] A pharmaceutical composition of the present invention comprises at least one compound of the present invention. Optionally, the pharmaceutical composition may also comprise more than one compound of the present invention such as the combination of two, three, four, five or even more compounds of the present invention.

[0383] Optionally, the pharmaceutical composition may also comprise one or more other pharmaceutically active agent(s), such as, e.g., one or more further stimulating agent(s) activating immune cells which may be other pharmaceutically active ingredients of the pharmaceutical composition other than the compounds of the present invention. Examples for such further stimulating agent(s) activating immune cells are provided below.

[0384] The compound as well as a pharmaceutically acceptable salt thereof and a pharmaceutical composition of the present invention may be used as a medicament.

[0385] Therefore, another aspect of the present invention relates to the compound or the pharmaceutical composition of the present invention for use as a medicament.

[0386] In this aspect relating to the use as medicament, the definitions as laid out in detail above also apply mutatis mutandis.

[0387] In the context of the present invention, the terms "medicament", "therapeutic", "medicine", "drug", "therapeutic agent", "pharmaceutic", "pharmaceutical agent", "prophylactic agent" etc. may be understood in the broadest sense as any kind of compound suitable for being used in a medicinal context, i.e., for treating and / or preventing a pathological condition.

[0388] A compound or a pharmaceutical composition comprising such may be administered to the patient by any means known in the art such as, e.g, orally, via injection, nasally, transdermally / percutaneously, etc. Administration may be local administration (e.g., intratumorally, intranodally (i.e., into lymph nodes), intrathecally, intracerebroventricularly (icv), topically or intravitreally) or systemic administration (e.g., intravenously (i.v.), intraarterially (i.a.), intraperitoneally (i.p.), intramusculary (i.m.), subcutaneously (s.c.), orally, nasally). Preferably, administration is oral, intraveneous, subcutaneous, intratumoral or intranodal administration, in particular oral or intraveneous administration.

[0389] Administration may be administration once ((acute) single administration) or may be a repeated administration such as, e.g., administration of repeated pulse doses or chronic administration. Repeated administration may exemplarily be administration two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, more than ten times or even permanently. Between two administrations, there may be a time interval of less than one hour, one hour or more, six hours or more, twelve hours or more, 24 hours or more. Administration may be daily, may be twice daily, three times daily, four times daily, every second day, every three days, weekly, biweekly, monthly, twice a year or yearly. Clinically viable administration schemes may be determined by the person skilled in the art based on balancing efficacy and toxicity.

[0390] Preferably, the medicament is suitable for treating or preventing pathologic conditions associated with an insufficient immune response. In other words, the present invention also relates to a medicament suitable for increasing an immune response. As used in the context of the activity of an immune response, the terms "activating", "enhancing", "strengthening", "increasing", "triggering", "stimulating" and the like may be understood interchangeably in the broadest sense as the provision of an increased activity of an immune response.

[0391] In the context of the present invention, an increase of the immune response is preferably a local increase of the immune response, i.e. , an increase of the immune response in proximity of the antigen recognized by the immune cells responsible for the respective immune response.

[0392] More specifically, the antigen-stimulated, TCR-ligated immune cells subjected to a compound of the present invention show a significantly increased secretion of several cytokines such as, e.g., IL-2, IFN-y and / or TNF-a as well as increased proliferation and cytotoxicity shown by increased expression of cytotoxic factors, e.g. granzyme B, whereas corresponding un-stimulated immune cells do not. This leads to a local secretion of cytokines and effective antigen-specific cytotoxicity in the proximity of the neoplasm and / or infectious pathogen improving the local immune response to said neoplasm and / or infectious pathogen. More preferably, the compounds of the present invention provide a therapeutic or prophylactic intervention that increases the local effector efficiency of anti-tumor or anti-viral T cells, B cells and NK cells. The undesired significant increase of the systemic level of cytokines may however be widely avoided in the absence of tumor- or pathogen-associated antigens. When the antigen is exemplarily localized on the surface of neoplastic cells (e.g. cancer cells) and / or antigen presenting cells (e.g., maturated dendritic cells), the activity of immune cells, in particular T cells, contacted with such antigen may be increased. It has been found that upon administration of the compounds of the present invention, stimulated immune cells, in particular activated T cells contacted with their cognate antigen (e.g., a tumor and / or pathogen antigen), show increased local activation of the immune system in the tumor microenvironment and draining lymph nodes. Therefore, the enhanced immune response in the proximity to the neoplasm can be the driving force of increased physiological immune reactions supporting cytotoxicity against neoplasms. This further triggers antigen spreading and neo antigen presentation by APCs inducing a broader spectrum of T cell specific immunity. When the antigen is exemplarily localized on the surface of virus-infected cells (e.g., human papilloma (HPV)- or hepatitis C- infected cells), the activity of immune cells contacted with such antigen may be increased.

[0393] Notably, in contrast to vaccination-based strategies (e.g., tumor vaccination), for their activity, the compounds of the present invention do not necessarily require that the immune cells have been contacted with a specific tumor antigen, but stimulation of the cells can also be achieved by other means, e.g. stimulating the TCR I CD3 pathway and / or a costimulatory pathway such as CD28. In the context of the present invention, an increased immune response is preferably characterized by an increase in the secretion of at least one cytokine, more preferably by an increase in the secretion of at least one cytokine selected from the group consisting of IL-2, IFN-y, TNF-a, IL-1 and IL-6, even more preferably in the secretion of at least one cytokine selected from the group consisting of IL-2, IFN-y and TNF-a. Particularly preferably, an increased immune response is preferably characterized by an increase in the secretion of at least two cytokines such as, particularly preferred, IL-2 and IFN-y, IL-2 and TNF-a, or IFN-y and TNF-a. Also highly preferred is an increase in at least three cytokines such as of IL-2, IFN-y and TNF-a. Additionally or alternatively, also other markers associated with immunologic activity may be increased in expression such as, e.g., CD40 ligand (CD40L, also known as CD154), granzyme / perforine, CD69, CD25 and / or CD71 . Preferably such marker is CD40L.

[0394] As laid out above, enhanced IL-2 and IFN-gamma production by tumor infiltrating lymphocytes (TILs), in particular T cells specific for neoplastic and / or infectious antigens, is known to be linked to improved immunity against the neoplastic and / or infectious lesion(s). TNF-alpha has such effects as well. IL-2 may directly activate CD8 cells and natural killer (NK) cells. Therefore, its release may be beneficial at a neoplastic and / or infectious lesion, but also may have a general role for fostering T cell survival. Therefore, its release during antigen-presenting cell (APC) stimulation of T cells (e.g., in the lymph nodes) may also enhance an immune response. Granzyme / perforine is considered as an effector molecule and consequently a marker for direct killing of neoplastic cells, in particular tumor cells, and may be released specifically proximal to or even in a neoplasm. Likewise, also IFN-gamma and TNF-alpha may activate immune cells (such as, e.g., NK cells and myeolid cells) but also directly upregulate apoptosis pathways in neoplastic cells.

[0395] IL-6 is a pleiotropic cytokine, which is particularly known to support B cell survival and its release in the lymph node, therefore, may also support B cell survival.

[0396] Release of IL-1 and IL-6 may enhance the development of T helper cells (e.g. Th17 cells), which are known to play a considerably role in immunity against neoplastic and infectious diseases. Therefore, the presence of enhanced levels of II-6 and IL-1 both at a neoplastic and / or infectious lesion and a lymph node may have beneficial effects on the immune response.

[0397] CD25, CD69, CD71 and CD40L are well-known surface markers for T cell activation and are known to demonstrate effects of the compounds on the level of individual T cell activation. CD69 is particularly an early marker of T cell activation. CD25 is the IL-2 receptor and high(er) expression typically supports (more) rapid expansion of activated T cells. CD71 is the receptor for transferrin and typically supports T cells to supply with Fe for proliferation. CD40L is a receptor on T helper cells which is known to support both APC and B cell activation and survival and proliferation.

[0398] In particular, an increase of IL-2, IFN-y and / or TNF-a secretion, and / or CD40L expression is also exemplified in the Example section below. All these markers are well-known factors in anti-neoplastic immune response evidencing the anti-neoplastic (in particular, anti-tumor) activity of the compounds of the present invention.

[0399] Such increase of the secretion of cytokines by immune cells may be an increase of at least 10%, of at least 20%, of at least 30%, of at least 40%, of at least 50%, of at least 75%, of at least 2fold, of at least 3fold, of at least 4fold, or of at least 5fold compared to the secretion of the corresponding cytokine by immune cells subjected to the same stimulating agent and cultivated under comparable conditions but without being subjected to the compound of the present invention. The person skilled in the art will notice that the rate of an increase will typically also depend on the amount of the compound of the present invention subjected to the respective immune cells in a dose-dependent manner. Accordingly, it will, in many cases also depend on the dose of the compound of the present invention subjected to a patient in a dose-dependent manner. Within a suitable dose range, a higher dose will typically also lead to a higher increase. The person skilled in the art will further know that the dosedependency also relates to the patient's body weight, the patient's fat and body water content, the patient's individual metabolism rate of deactivating and / or eliminating the compound, the patient's individual immunologic condition etc. Therefore, the person skilled in the art may adjust the dose accordingly. Additionally or alternatively, also the proliferation rates of immune cells such as T cells, NK cells, B cells and / or monocytes may be increased. Exemplarily, the proliferation of CD4+ and / or CD8+ cells may be increased. Additionally or alternatively, also the maintenance (i.e, the survival rates, activity time or live time) of immune cells such as, e.g., T cells, NK cells, B cells and / or monocytes (e.g., CD4+ and / or CD8+ cells) may be increased.

[0400] Notably, the compounds of the present invention may also increase T cell reactivity to tumor antigens presented by MHC I to CD8 T cells or by MHC II to CD4 T cells independently of the tumor type and independently of the tumor antigens. Furthermore, the compounds of the present invention may increase the immunologic activity of the patient's NK cells to aid destruction of tumor cells that have decreased the MHC-I mediated display of tumor antigens. Moreover, strong antigen-specific T cell responses may be further increased by B cells and other immune cells, which may be also targeted by the compounds of the present invention. Thus, the compounds of the present invention may also abolish immunological ignorance towards neoplasia and / or infectious pathogens, so that the patient's specific tumor antigens are recognized as non-self and thus, the patient's own immune system may be re-activated to attack those tumor cells present in the patient, independently of the respective type of neoplastic and / or infectious disease.

[0401] In the view of the above, in a further aspect, the present invention relates to the compound, the pharmaceutically acceptable salt thereof, or pharmaceutical composition of the present invention for use in the treatment or prevention of a neoplastic and / or infectious disease.

[0402] Disclosed herein is a method of treating or preventing a neoplastic and / or infectious disease in a patient, comprising administering to said patient an amount of a compound or pharmaceutical composition of the present invention sufficient for treating or preventing said neoplastic and / or infectious disease in said patient.

[0403] In this aspect relating to such medical use and method of treatment or prevention, respectively, the definitions as laid out in detail above (in particular, in the context of the compound, the pharmaceutical composition and the use thereof as a medicament) also apply mutatis mutandis.

[0404] As used throughout the present invention, the term "patient" may be understood in the broadest sense as any subject or individual to be prevented or treated by means of a compound or pharmaceutical composition of the present invention, in particular having or being at risk of developing a neoplastic and / or infectious disease, irrespective whether clinical symptoms occur or do not occur. The patient may be any animal, including humans. Preferably, the patient is a mammal (e.g., a human, a mouse, a rat, a cow, a pig, a dog, a cat, a horse, a donkey, a goat, etc.), most preferably a human.

[0405] In the context of the present invention, the term "disease" may be understood in the broadest sense as any pathologic condition, irrespective whether clinical symptoms occur or do not occur. Therefore, the disease may be associated with a phenotype or may be latent. Preferably, a disease is a pathologic condition accompanied by one or more clinical symptom(s).

[0406] A disease in the context of the present invention may be a chronic and / or an acute disease. Preferably, it is a chronic disease. A chronic disease is persistent or otherwise long-lasting in its effects. In the context of the present invention, a chronic disease also includes a disease with a recurrent course, i.e., a recurrent disease relapsing repeatedly, with periods of remission in between. Accordingly, as used herein, a chronic disease may be understood in the broadest sense as any disease that lasts for at least a week, at least a month, at least three months, at least six month, at least a year or even several years (with or without clinical symptoms). When the patient is a human, a chronic disease is usually understood as lasting for at least one month or preferably at least three months. This understanding may also be applied to the present invention. In this context, it may be understood that, for instance, a neoplasm may typically but not necessarily grow for several months or even years until the first clinical symptoms occur. Nevertheless, the neoplastic disease already exists from the occasion of the first neoplastic cells, typically not associated with any clinical symptoms. Therefore, a recognized neoplastic disease is typically but not necessarily a chronic disease per se. Likewise, an infectious disease like a human immunodeficiency virus (HIV) infection is typically a chronic disease when it starts to provoke clinical symptoms and is first recognized.

[0407] As used herein, a neoplastic disease may be understood in the broadest sense as any tissue resulting from miss-controlled cell growth. In many cases a neoplasm leads to at least bulky tissue mass optionally innervated by blood vessels. It may or may not comprise the formation of one or more metastasis / metastases. A neoplastic disease of the present invention may be any neoplasm as classified by the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) classes C00-D48.

[0408] Exemplarily, a neoplastic disease according to the present invention may be the presence of one or more malignant neoplasm(s) (tumors) (ICD-10 classes C00-C97), may be the presence of one or more in situ neoplasm(s) (ICD-10 classes D00-D09), may be the presence of one or more benign neoplasm(s) (ICD-10 classes D10-D36), or may be the presence of one or more neoplasm(s) of uncertain or unknown behavior (ICD-10 classes D37-D48). Preferably, a neoplastic disease according to the present invention refers to the presence of one or more malignant neoplasm(s), i.e. , is malignant neoplasia (ICD-10 classes C00-C97).

[0409] In a more preferred embodiment, the neoplastic disease is cancer.

[0410] Cancer may be understood in the broadest sense as any malignant neoplastic disease, i.e., the presence of one or more malignant neoplasm(s) in the patient. Cancer may be solid or hematologic malignancy. Preferably, the cancer is such accessible to at least one kind of immunotherapy (including, e.g., therapeutic antibodies targeted against tumor antigens and / or experimental approaches such as, e.g., cancer vaccination).

[0411] Subtypes of cancer may be classified in different ways such as by the location in the body the main or only tumor bulk is found or by the tissue of origin the tumor(s) is / are derived from.

[0412] Exemplarily, such malignant neoplasm according to the present invention may be located on or in the lip, oral cavity and pharynx (ICD-10 classes C00-C14), on or in the digestive organs (ICD-10 classes C15-C26), on or in the respiratory system and intrathoracic organs (ICD-10 classes C30-C39), on or in the bone and articular cartilage (ICD-10 classes C40-C41 ), on or in the skin (ICD-10 classes C43-C44), on or in the connective and soft tissue (ICD-10 classes C45-C49), on or in the breast and female genital organs (ICD-10 classes C50-C58), on or in the male genital organs (ICD-10 classes C60-C63), on or in the urinary organs (ICD-10 classes C64- C68), on or in the eye, brain and central nervous system (ICD-10 classes C69-C72), on or in the endocrine glands and related structures (ICD-10 classes C73-C75), may be secondary and ill-defined neoplasms (ICD-10 classes C76-C80), may be stated or presumed to be primary, of lymphoid, haematopoetic and related tissue neoplasms (ICD-10 classes C81-C96), and / or may be neoplasms of independent (primary) multiple sites (ICD-10 class C97).

[0413] Exemplarily, cancers in the context of the present invention may be selected from the group consisting of carcinoma (i.e., cancers derived from epithelial cells; e.g., adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, and small cell carcinoma), sarcoma (i.e, cancers derived from connective tissue; e.g., Askin's tumor, sarcoma botryoides, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant Schwannoma, osteosarcoma, and soft tissue sarcomas), hematologic cancer such as lymphoma, a leukemia or a myeloma. A hematologic cancer contemplated herein includes, but is not limited to lymphoma and leukemia (i.e., cancers derived from hematopoietic (blood-forming) cells; e.g., mature B-cell neoplasms, mature T cell and natural killer (NK) cell neoplasms, Hodgkin lymphoma, immunodeficiency-associated lymphoproliferative disorders, lymphocytic leukemia, myelogenous leukemia), germ cell tumor (i.e., cancers derived from pluripotent cells in the sexual organs; e.g., germinoma (including dysgerminoma and seminoma), dysgerminoma, seminoma), blastoma (i.e., cancers derived from immature "precursor" cells or embryonic tissue; e.g., hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuropulmonary blastoma, retinoblastoma, glioblastoma), and melanoma and preforms thereof (i.e., cancers derived from melanocytes; e.g., Lentigo maligna , superficial spreading melanoma, acral lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma, amelanotic melanoma, soft-tissue melanoma), and nonmelanoma skin cancer (i.e., non-melanoma cancers derived from skin, e.g. basal cell carcinoma, squamous cell carcinoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, keratoacanthoma, spindle cell tumors, sebaceous carcinomas, microcystic adnexal carcinoma, Paget's disease of the breast, atypical fibroxanthoma, leiomyosarcoma, angiosarcoma) and glioma (i.e., cancers derived from brain or spine cells., e.g., ependymoma, astrocytoma, oligodendrogliomas, brainstem glioma, optic nerve glioma, mixed glioma).

[0414] In some embodiments of the invention herein, the cancer is a non-hematologic cancer such as a sarcoma, a carcinoma, or a melanoma. Preferably, non- hematologic cancer may be the formation of one or more solid tumor(s) such as, e.g., those selected from the group consisting of melanoma, neuroblastoma, lung cancer, non-small-cell lung cancer, small cell lung cancer, renal cell carcinoma, epithelial squamous cell cancer, in addition breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, testicular cancer, colon cancer, colorectal cancer, hepato-cellular carcinoma, bladder cancer, stomach cancer, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, mesothelioma, thyroid cancer, adrenal cancer, brain cancer, and head-and-neck cancer.

[0415] More preferably, the compounds of the invention, or the pharmaceutical composition of the present invention is useful for the prophylaxis and / or the treatment of the cancer, wherein the cancer is interstitial fibrosis, prostate cancer, colon cancer, melanomas, lung cancer, rectal cancer, breast cancer, multiple myeloma, gastrointestinal cancer, non-small cell lung cancer (NSCLC).

[0416] Alternatively, cancer may be the formation of one or more hematopoietic tumor(s) such as, e.g., those selected from the group consisting of multiple myeloma, NonHodgkin lymphoma, AML (Acute Myeloid leukemia, DLBCL (Diffuse Large B-cell Lymphoma), and B-CLL (B-cell chronic lymphocytic lymphoma).

[0417] In an alternative preferred embodiment, the disease may be an infectious disease. As used in the context of the present invention, the term "infectious disease" may be understood in the broadest sense as any pathologic condition caused by the invasion of a patient's body by one or more biological agent(s) foreign to the body able to provoke an immune reaction in the patient's body. An infectious disease may or may not be accompanied by an inflammatory response (inflammation). Preferably, an infectious disease in the context of the present invention is accompanied by an inflammatory response. Exemplarily, such immune reaction in the patient's body may be in more detail caused by a biological agent itself (e.g., by the presence of surface antigens thereof), by antigens originating from a biological agent provided on a major histocompatibility complex I or II (MHC I or MHC II), by the multiplication of a biological agent, by the reaction of host tissues to such biological agent, by compounds produced or caused by such biological agent (e.g., toxins, sem iochemicals, cytokines, etc.), or by the formation of an antigen from a haptene originating from such biological agent. Such biological agents may be non-living or living agents. Exemplarily, an infectious disease may be caused by biological agents selected from the group consisting of viruses, viroids, prions, microorganisms such as bacteria, nematodes such as roundworms and pinworms, arthropods (e.g., ticks, mites, fleas, and lice), fungi, ringworms, and tapeworms. Preferably, an infectious disease according to the present invention is caused by viruses or bacteria, in particular is a virus infection.

[0418] A viral infection in the context of the present invention may be an infection by any virus. The viral infection may be an acute viral infection or a chronic viral infection. Preferably, it is a chronic viral infection. Nonrestrictive examples of clinically important virus families and species in the context of the present invention include Adenovirus, Herpes simplex, type 1 , Herpes simplex, type 2, Varicellazoster virus, Epstein-barr virus, Human cytomegalovirus, Human herpesvirus, type 8, Human papillomavirus, BK virus, JC virus, Smallpox, Hepatitis B virus, Human bocavirus, Parvovirus B19, Human astrovirus, Norwalk virus, coxsackievirus, hepatitis A virus, poliovirus, rhinovirus, Severe acute respiratory syndrome virus, Hepatitis C virus, yellow fever virus, dengue virus, West Nile virus, Rubella virus, Hepatitis E virus, Human immunodeficiency virus, Influenza virus, Guanarito virus, Junin virus, Lassa virus, Machupo virus, Sabia virus, Crimean-Congo hemorrhagic fever virus, Ebola virus, Marburg virus, Measles virus, Mumps virus, Parainfluenza virus, Respiratory syncytial virus, Human metapneumovirus, Hendra virus, Nipah virus, Rabies virus, Hepatitis D, Rotavirus, Orbivirus, Coltivirus, and Banna virus.

[0419] In the context of the present invention, those virus infections associated with a downregulation of the immune response are of particular interest, such as, e.g., a Human immunodeficiency virus (HIV) infection, without symptoms or associated with symptoms (Acquired Immune Deficiency Syndrome (AIDS)). Further, also such virus infections associated with neoplasia such as, e.g., Herpes simplex virus (HSV), type 1 or 2, are also of particular interest. Here, the compounds or pharmaceutical composition of the present invention may concomitantly be pharmaceutically active against the virus infection as well as the neoplasm resulting from said virus infection.

[0420] Further, also such virus infections being latent for a longer time and, thus, hiding from the immune system, such as, e.g., HSV 1 or HSV2, are also of particular interest.

[0421] Optionally but not necessarily, an infectious disease, in particular a chronic infectious disease (e.g., a chronic virus infection), may be associated with inflammation. In this context, inflammation may be characterized by an increase in the NF-KB activity, C- reactive protein (CRP) level, interferon-gamma (IFN-gamma) level, interleukin 1 (IL- 1 ) level and / or interleukin 8 (IL-8) level.

[0422] In the context of a treatment or prevention of a neoplastic and / or infectious disease, the compound(s) of the present invention may be administered as the sole pharmaceutically active agent or may be administered in combination with one or more other pharmaceutically active agent(s). Exemplarily, such other pharmaceutically active agent may be a stimulating agent activating immune cells, may be an anti-proliferative agent (e.g., an anti-cancer agent such as a chemotherapeutic, an antimetabolite, a hormone, an antibody (Ab)), an antiviral agent, and / or an antibiotic.

[0423] Preferably, such other pharmaceutically active agent is a biological compound such as a therapeutic monoclonal antibody which has been shown to be efficacious in treating neoplasms. Exemplarily, such therapeutic monoclonal antibody is directed against the PD-1 molecule, the PD-L1 molecule or another ligand of the PD-1 molecule, the CTLA-4 molecule, the TIM3 molecule, the LAG3 molecule, the VISTA molecule or the BTLA-4 molecule.

[0424] The application of such combination therapy will depend on the pharmacokinetic and pharmacodynamics properties of the chosen compounds and agents used in such combination therapy (adjunction).

[0425] Optionally, the further agent may be administered concomitantly, previously, or subsequently with one or more compound(s) of the present invention. As used herein, a concomitant administration may be an administration in a single composition (e.g., combined in the pharmaceutical composition of the present invention) or in two separate compositions that may also, optionally, be administered via the same or different routes of administration (e.g., via injection, orally, nasally, percutaneously, etc.). As used herein, when administering the compound of the present invention previously or subsequently, there may be a time interval between the administration of said compound(s) and the further agent(s) of less than one hour, one hour or more, three hours or more, six hours or more, twelve hours or more, 24 hours or more, two days or more or a week or more.

[0426] As mentioned in the context of the compound of the present invention above, also the one or more further agent(s) may be administered once (single administration) or may be a repeated administration such as, e.g., two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, more than ten times or even permanently. Between two administrations, there may be a time interval of less than one hour, one hour or more, six hours or more, twelve hours or more, 24 hours or more. Administration may be daily, may be twice daily, three times daily, four times daily, every second day, every three days, weekly, biweekly, monthly, twice a year or yearly.

[0427] In a preferred embodiment, the compound or pharmaceutical composition of the present invention is administered in combination with one or more further stimulating agent(s) activating immune cells.

[0428] Immune cells as used in the context of the present invention may be any immune cells known in the art. Immune cells may be cells of the adaptive immune system (e.g., T cells or B cells, cells of the innate immune system (natural killer (NK) cells, macrophages, monocytes), and / or cells subsumable under both groups (e.g., dendritic cells (DCs); antigen-presenting cells (APCs))) and / or cells known for phagocytic activity such as basophilic, neutrophilic or eosinophilic granulocytes.

[0429] In a preferred embodiment, the immune cells are peripheral blood mononuclear cells (PBMCs).

[0430] In a preferred embodiment, the immune cells are selected from those bearing T cell antigen receptor (TCR) and a CD4 and / or CD8 co-receptor on their cellular surface. Those immune cells bearing a CD4 co-receptor on their cellular surface may be selected from the group consisting of T helper cells (Th cells), macrophages, and dendritic cells (DCs). Those immune cells bearing a CD8 co-receptor on their cellular surface may be selected from the group consisting of cytotoxic T cells, natural killer (NK) cells, cortical thymocytes, and dendritic cells (DCs).

[0431] In another preferred embodiment, the immune cells are selected from the group consisting of T cells, NK cells, monocytes and B cells.

[0432] In a particularly preferred embodiment, the immune cells are T cells and / or NK cells.

[0433] T cells and NK cells are well-known to bear particular efficiency against neoplasia (particularly anti-tumor immunity) and infectious diseases. NK cells are preferably lymphocytes which can be stimulated via the Fc receptor (FcR). In particular in the context of antibody dependent cellular cytotoxicity (ADCC), this may be of some benefit in the context of the present invention (e.g., as single application or when coadministering a therapeutic antibody against neoplastic and / or infectious antigens).

[0434] B cells are well-known to play a considerable role in humoral response to infectious pathogens. It has been further known in the art that also B cells may also play a role in developing humoral immunity against neoplastic cells.

[0435] Monocytes may be understood as the transient phenotype of myeloid cells present in large numbers in PBMCs. Moreover, myeloid cells include dendritic cells (DCs). Macrophages may bear both positive and suppressive effects on immunity, in particular anti-neoplastic therapies. Macrophages of particular interest include M1- type macrophages. Myeloid cells may also include myeloid-derived suppressor cells (MDSCs) bearing a negative effect in anti-neoplastic immune response. Myeloid cells can be stimulated via the FC receptor (FcR). In particular in the context of antibody dependent cellular cytotoxicity (ADCC), this may be of some benefit in the context of the present invention (e.g., as single application or when co-administering a therapeutic antibody against neoplastic and / or infectious antigens). It may also be enhancing the effect of naturally developed humoral immunity against tumor antigens in the patient.

[0436] An activation of immune cells may be understood in the broadest sense as the increase of immunologic activity of such cell and / or the increase of cell proliferation of such cells.

[0437] In a more preferred embodiment, the further stimulating agent(s) activating immune cells is / are selected from the group consisting of one or more antigen(s) of the neoplasm and / or infectious pathogen to be treated, one or more TCR or CD3 agonist(s), one or more CD28 agonist(s), one or more agonist(s) to other costimulatory T cell surface receptors such as CD40L, CD69, 0X40, GITR, CD137, CD27 and / or HVEM, and a combination of two or more thereof.

[0438] A TCR I CD3 agonist may be any agent triggering CD3. It may be a peptide or nonpeptide agonist binding to the extracellular side of TCR I CD3 in the context or absence of MHC-dependent antigen presentation, may be an agonist binding to the intracellular side of TCR I CD3, or may be an agent activating the intracellular signal transduction pathway triggered by TCR I CD3 engagement. Preferably, a CD3 agonist may be an anti-CD3 antibody, a peptide antigen presented by MHC I or MHC II, an anti-CD3 antibody fragment or an anti-CD3 antibody mimic. Highly preferably, a CD3 agonist is a tumor antigen presented by MHC I or MHC II.

[0439] A CD28 agonist may be any agent triggering CD28. It may be an agonist binding to the extracellular side of CD28, may be an agonist binding to the intracellular side of CD28, or may be an agent activating the intracellular signal transduction pathway triggered by CD28. Preferably, a CD28 agonist may be an anti-CD28 antibody, an anti-CD28 antibody fragment, an anti-CD28 antibody mimetic or a protein containing a natural ligand for CD28 such as B7.1 or B7.2. Highly preferably, a CD28 agonist is an (agonistic) anti-CD28 antibody or an Ig fusion protein containing a natural ligand for CD28 such as B7.1 or B7.2.

[0440] An antibody in the context of the present invention may be a monoclonal or a polyclonal antibody of any species or origin. It may bind to any epitope(s) comprised in the polypeptide bearing the respective cognate antigen (e.g, CD3 or CD28, respectively) including its posttranslational modifications. The cognate antigen may exemplarily be a linear epitope, a structural epitope, a primary epitope, and / or a secondary epitope. An antibody may be of natural origin, of gene technologic origin and / or of synthetic origin.

[0441] An antibody fragment may be understood in the broadest sense as any fragment of an antibody that still bears binding affinity to its target polypeptide. Exemplarily, the antibody fragment may be a fragment antigen binding (Fab fragment), a truncated antibody comprising one or both complementarity determining region(s) (CDR(s)) or the variable fragment (Fv) of an antibody. The antibody fragments may be of natural origin, of gene technologic origin and / or of synthetic origin.

[0442] An antibody mimetic may be understood in the broadest sense as organic compounds that, like antibodies, can specifically bind antigens and that typically have a molecular mass in a range of from approximately 3 kDa to approximately 25 kDa. Antibody mimetics may be, e.g., Affibody molecules (Affibodies), Affilins, Affitins, Anticalins, Avimers, DARPins, Fynomers, Kunitz domain peptides, single-domain antibodies (e.g., VHH antibodies or VNAR antibodies) Monobodies, Diabodies, Triabodies, flexibodies and tandabs. The antibody mimetics may be of natural origin, of gene technologic origin and / or of synthetical origin.

[0443] Peptide antigens may be understood in the broadest sense as organic compounds that specifically bind to MHC I or MHC II molecules and that typically consist of 8-30 amino acids and preferably consist of 9-25 amino acids. The peptides may be of natural origin, of gene technologic origin and / or of synthetical origin.

[0444] Preferably, the further stimulating agents activating immune cells are a combination of one or more CD3 agonist(s) and one or more CD28 agonist(s). Particularly preferably, the further stimulating agents activating immune cells are a combination of at least one (agonistic) anti-CD3 antibody and at least one (agonistic) anti-CD28 antibody. As it is evident from the Examples shown below, a stimulation of the immune cells by means of contacting these with (agonistic) anti-CD3 antibodies and / or (agonistic) anti-CD28 antibodies mechanistically simulates T cells, irrespective of the individual TCR-recognized specific antigen. A stimulation with (agonistic) anti- CD3 antibodies and (agonistic) anti-CD28 antibodies very well mimics activation of T cells in a patient's body in vivo.

[0445] Additionally or alternatively, the immune cells may also be triggered by an antigen of the neoplasm and / or infectious pathogen (e.g., by means of vaccinating the patient with one or more antigen(s)). Then, the antigen is considered as a stimulating agent. An antigen of the neoplasm and / or infectious pathogen may be, exemplarily, a vaccine comprising one or more antigen(s) of the neoplasm and / or infectious pathogen, such as e.g, a polypeptide-based vaccine, a polynucleotide vaccine, an oligosaccharide vaccine, or a vaccine based on fragments of neoplasms of the same type or on fragments of infectious pathogens of the same type. The person skilled in the art knows numerous methods for providing such vaccines. Several anti-tumor and antiviral vaccines are also commercially available.

[0446] Additionally or alternatively, the immune cells may also be triggered by antigen- loaded antigen-presenting cells (APCs). Then, the antigen-loaded APCs are considered as a further stimulating agent. In this context, the antigens are also antigens of the neoplasm and / or infectious pathogen as mentioned before.

[0447] Additionally or alternatively, the one or more further stimulating agent(s) may be selected from the group consisting of checkpoint blockade therapeutics (in particular T cell surface receptor-binding agents such as, e.g., those binding one or more selected from the group consisting of CTLA4, PD-1 , PDL-1 , TIM3, LAG3, BTLA, VISTA and / or a ligand thereof (e.g., anti-CTLA4, anti-PD-1 and / or anti-PDL-1 antibodies)), cytokines (e.g., IL-2, IL-15 and / or IL-7), activating agents of APCs (e.g., CD40 agonists), adoptive cellular agents (in particular adoptive T cells (e.g., chimeric immune receptor T cell therapy such as, e.g., CAR T cell therapy), dendritic cell therapy (e.g., sipuleucel-T) and / or natural killer cell therapies), enhancers of T cell functions (e.g., lenalidomide and related agents), enhancers of natural killer cell functions (e.g., anti-KIR antibodies), and therapeutic antibodies directed against tumor antigens.

[0448] Optionally, in particular when the patient is suffering from a neoplastic disease, the patient may be further administered with one or more chemotherapeutic(s), cytokine(s) and / or other anti-neoplastic agent(s) in addition to one or more compound(s) of the present invention. Exemplarily, such chemotherapeutics, cytokines and anti-cancer agents may be selected from the group consisting of polyclonal or monoclonal antibodies (e.g., rituximab, trastuzumab, cetuximab, bevacizumab, basiliximab, daclizumab), anti-metabolites (e.g., 5-fluorouracil, azathioprine, 6-mercaptopurine, mercaptopurine, pyrimidines, thioguanine, fludarabine, floxuridine, cytosine arabinoside (cytarabine), pemetrexed, raltitrexed, pralatrexate, methotrexate), alkylating agents (e.g., mechlorethamine, cyclophosphamide, chlorambucil, Ifosfamide), platins (e.g., cisplatin, carboplatin, oxaliplatin), plant alkaloids and terpenoids (e.g., vinca alkaloids (vincristine, vinblastine, vinorelbine, vindesine), taxanes (e.g., paclitaxel), cytoxan), topoisomerase inhibitors (e.g., camptothecins: irinotecan, topotecan, etoposide, etoposide phosphate, teniposide), melphalan, antineoplastica (e.g., doxorubicin (adriamycin), doxorubicin lipo, epirubicin, bleomycin)), actinomycin D, aminoglutethimide, amsacrine, anastrozole, antagonists of purine and pyrimidine bases, anthracyclines, aromatase inhibitors, asparaginase, antiestrogens, bexarotene, buserelin, busulfan, camptothecin derivatives, capecitabine, carmustine, cladribine, cytarabine, cytosine arabinoside, alkylating cytostatics, dacarbazine, daunorubicin, docetaxel, epirubicin, estramustine, etoposide, exemestane, fludarabine, fluorouracil, folic acid antagonists, formestane, gemcitabine, glucocorticoids, goserelin, hormones and hormone antagonists, hycamtin, hydroxyurea, idarubicin, irinotecan, letrozole, leuprorelin, lomustine, mercaptopurine, miltefosine, mitomycins, mitosis inhibitors, mitoxantrone, nimustine, procarbazine, tamoxifen, temozolomide, teniposide, testolactone, thiotepa, topoisomerase inhibitors, treosulfan, tretinoin, triptorelin, trofosfamide, cytostatically active antibiotics, everolimus, pimecrolimus, tacrolimus, azithromycin, spiramycin, sirolimus (rapamycin), roxithromycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concancamycin, clarithromycin, troleandomycin, folimycin, tobramycin, mutamycin, dactinomycin, dactinomycin, rebeccamycin, a statin (e.g., cerivastatin, simvastatin, lovastatin, somatostatin, fluvastatin, nystatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, pentostatin,), 4-hydroxyoxycyclophosphamide, bendamustine, thymosin a-1, aclarubicin, fludarabine-5' -dihydrogen phosphate, hydroxycarbamide, aldesleukin, pegaspargase, cepharanthine, epothilone A and B, azathioprine, mycophenolate mofetil, c-myc antisense, b-myc antisense, betulinic acid, camptothecin, melanocyte stimulating hormone (a-MSH), activated protein C, IL-1 [3 inhibitor, fumaric acid and esters thereof, dermicidin, calcipotriol, taclacitol, lapachol, [3-lapachone, podophyllotoxin, betulin, podophyllic acid 2-ethyl hydrazide, sagramostim, (rhuGM-CSF), peginterferon a-2b, lenograstim (r-HuG-CSF), filgrastim, macrogol, cephalomannine, selectin (cytokine antagonist), CETP inhibitor, cadherins, cytokinin inhibitors, COX inhibitor (COX-2 or COX-3 inhibitor), angiopeptin, ciprofloxacin, fluroblastin, bFGF antagonists, probucol, prostaglandins, 1 ,11- dimethoxyeanthin-6-one, 1 -hydroxy-11-methoxycanthin-6-one, scopoletin, colchicine, NO donors, pentaerythrityl tetranitrate, sydnonimines, S-nitroso derivatives, staurosporine, [3-estradiol, a-estradiol, estriol, estrone, ethinyl estradiol, fosfestrol, medroxyprogesterone, estradiol cypionates, estradiot benzoates, tranilast, kamebakaurin, verapamil, ciclosporin A, paclitaxel and derivatives thereof such as 6- a-hydroxy paclitaxel, baccatin, taxotere, mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamoyl-phenoxy-acetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, [3- sitosterol, ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, elipticine, Calbiochem D-24851 , colcemid, cytochalasin A-E, indanocine, nocodazole, bacitracin, vitronectin receptor antagonists, azelastine, free nucleic acids, nucleic acids incorporated into virus transmitters, DNA and RNA fragments, plasminogen activator inhibitor-1 , plasminogen activator inhibitor-2, antisense oligonucleotide, VEGF inhibitors, IGF-1 , active agents from the group of antibiotics such as cefadroxil, cefazolin, cefaclor, cefoxitin, gentamicin, penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotics, argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, enoxaparin, Gpllb / llla platelet membrane receptor, antibodies to factor Xa inhibitor, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidole, trapidil, nitroprussides, PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin,, vapiprost, interferon a, [3 and y, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, NF-kB or Bcl-xL antisense oligonucleotides, halofuginone, nifedipine, tocopherol, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, boswellic acids and derivatives thereof, leflunomide, anakinra, etanercept, sulfasalazine, tetracycline, triamcinolone, procainimide, retinoic acid, quinidine, disopyramide, flecainide, propafenone, sotalol, amiodarone, natural and synthetically obtained steroids such as bryophyllin A, inotodiol, maquiroside A, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, acyclovir, ganciclovir, zidovudine, antimycotics, clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, terbinafine, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, bamngtogenol-021-angelate 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelic acid, baccharinoids B1 , B2, B3 and B7, tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hyptatic acid A, zeorin, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-alpha-senecioyloxychapamne, taxamairin A and B, regenilol, triptolide, cymarin, apocymarin, aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburin chloride, cicutoxin, sinococuline, combrestatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-beta-hydroxypregnadiene-3, 20-dione bilobol, ginkgol, ginkgolic acid, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, glycoside 1a, justicidin A and B, larreatin, malloterin, mallotochromanol, isobutyrylmallotochromanol, marchantin A, maytansine, lycoridicin, margetine, pancratistatin, liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-AII, periplocoside A, ghalakinoside, deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, chromones of spathelia, stizophyllin, akagerine, dihydrousambaraensine, hydroxyusambarine, strychnopentamine, strychnophylline, usambarine, usambarensine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferone, afromoson, acetylvismione B, desacetylvismione A, vismione A and B), radiation therapy (e.g, Intensity-Modulated Radiation Therapy (IMRT), 3-Dimensional Conformal Radiotherapy (3DCRT), Stereotactic body radiation therapy (SBRT), Stereotactic radiosurgery (SRS), image-guided radiation therapy (IGRT), Particle Therapy (e.g, proton therapy), Brachytherapy, Radioisotope Therapy (RIT) (e.g., with iodine-131 , lutetium-177, strontium-89 and samarium (153Sm) lexidronam and / or yttrium-90)), antiangiogenic therapy (e.g., carboxyamidotriazole, TNP-470, CM101 , , Suramin, SU5416, Thrombospondin, VEGFR antagonists, angiostatic steroids + heparin, Cartilage-Derived Angiogenesis Inhibitory Factor, matrix metalloproteinase inhibitors, 2-methoxyestradiol, Tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, soluble VEGFR-1 and NRP-1 , Angiopoietin 2, angiostatin (e.g., TSP-1 and TSP-2 angiostatin), endostatin, vasostatin, canstatin, calreticulin, platelet factor-4, TIMP and CDAI, Meth-1 and Meth-2, CXCLIOprothrombin (kringle domain-2), antithrombin III fragment prolactin, VEGI, SPARC, osteopontin, maspin, proliferin-related protein, restin), kinase inhibitors (e.g., imatinib, imatinib mesylate, gefitinib, erlotinib, pazopanib, apatinib), proteasome inhibitors (e.g., bortezomib), PARP inhibitors (e.g., iniparib, olaparib), and combinations of two or more thereof.

[0449] Alternatively or additionally, the patient is suffering from or being at risk of developing a neoplastic and / or infectious disease, may be further administered with one or more cytokines, hormones or analogues thereof (e.g., selective estrogen receptor modulator tamoxifen, IL-2, IFN-a, IFN-|3, IFN-y, IL-4, IL-12, IL-18, platelet factor-4, TNF-a). These cytokines, hormones or analogues thereof may further trigger the patient's immune system. As mentioned before, high doses of many of such agents may provoke severe side effects. However, lower doses may optionally be used to support the treatment or prevention of the present invention.

[0450] Optionally, in particular when the patient is suffering from a viral infection, the patient may be further administered with one or more antiviral compound(s) in addition to one or more compound(s) of the present invention. Such antiviral compound may exemplarily be selected from the group consisting of an entry or fusion inhibitor, a nucleoside / nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a protease inhibitor. Optionally, in particular when the patient is suffering from a bacterial infection, the patient may be further administered with one or more antibacterial antibiotic(s) in addition to one or more compound(s) of the present invention. Such antibacterial antibiotic may exemplarily be selected from the group consisting of antibiotics targeting the bacterial cell wall (e.g., penicillins and cephalosporins) or the cell membrane (e.g., polymyxins), interfering with essential bacterial enzymes (e.g., rifamycins, lipiarmycins, quinolones, and sulfonamides), and / or targeting polypeptide synthesis (e.g., macrolides, lincosamides and tetracyclines).

[0451] Further, a treatment or prevention according to the present invention may also be combined with other means of treatment such as, e.g., radiation therapy (exemplarily based on x-ray radiation, ultraviolet (UV) radiation (e.g., IIV-A, IIV-B, and / or IIV-C radiation), alpha radiation, beta radiation, gamma radiation, or cosmic radiation), and / or surgery.

[0452] As laid out above, it will be understood that the compounds of the present invention may be very well used for the treatment and / or prevention of neoplastic and / or infectious diseases in a patient in vivo. However, a compound of the present invention may not merely be used for in vivo application, but likewise also for any kind of ex vivo and / or in vitro use. Exemplarily, it may also be used for activating immune cells in vivo, ex vivo and in vitro.

[0453] Exemplarily, the compounds of the present invention may be used in any method supporting the generation and / or amplification of immune cells ex vivo and / or in vitro, in particular but not necessarily for further use in an adoptive cell therapy (ACT). For ACT preferably antigen-specific T cells may be used. Such methods may also provide activated DCs which may optionally be useful for DC vaccination approaches.

[0454] In another aspect, the present invention refers to an in vitro or ex vivo method for the production of activated immune cells comprising the steps of:

[0455] (i) providing immune cells;

[0456] (ii) contacting the cells of step (i) with:

[0457] (a) at least one compound or pharmaceutically acceptable salt thereof as defined in any of claims 1 to 9, and optionally

[0458] (b) one or more further stimulating agents activating said immune cells; and

[0459] (iii) cultivating the cells of step (ii) under conditions suitable for maintaining the viability of said cells.

[0460] In this aspect relating to such method, the definitions as laid out in detail above also apply mutatis mutandis. The method is conducted ex vivo and / or in vitro, i.e., is an ex vivo and / or in vitro method. Therefore, in the context of this aspect relating to such method, the immune cells are preferably activated outside of a living being, in particular outside a patient.

[0461] Preferably, the immune cells (e.g., T cells and / or natural killer cells) are mature immune cells. Such cells (in particular the T cells) may be CD4+ and / or CD8+ cells. The immune cells may be obtained from any source suitable for this purpose. Alternatively or additionally, the cells may also be B cells such as, e.g., CD19+ B cells. The person skilled in the art knows various ways of obtaining such immune cells. Exemplarily, mature immune cells may be obtained from a blood sample (e.g., a stored blood preservation or fresh blood). Then, peripheral blood mononuclear cells (PBMCs) may exemplarily be obtained from the buffy coat after centrifugation of a blood sample and optionally further isolated / purified, exemplarily, by means of labeling cell type-specific surface markers with fluorescence-labeled antibodies followed by fluorescence activated cell sorting (flow cytometry) or by labeling cell type-specific surface markers with metal bead-labelled antibodies followed by magnetic extraction of the desired cells.

[0462] Alternatively, mature immune cells may also be obtained from cell culture. The ways of obtaining a buffy coat and isolating and purifying the cells further is exemplified in the example section below. (Mature) immune cells are also commercially available. Alternatively, immature immune cells or precursors thereof may be used and matured in an intermediate step by well-known means of supplementation with the respective cytokines and growth factors.

[0463] The immune cells are subsequently contacted with at least one compound of the present invention and optionally one or more further stimulating agent(s) activating immune cells. The person skilled in the art will immediately notice that these compound(s) and agent(s) may be added to the cells in any kind of solution or medium suitable for the cells. Exemplarily, such solution or medium may also comprise ingredients defined in the context of a pharmaceutical composition above. A further stimulating agent activating immune killer cells may be understood in the broadest sense as defined above. Optionally, the further agent may be administered concomitantly, previously or subsequently with one or more compound(s) of the present invention. The cells may be contacted with the compound(s) and / or agent(s) for less than 30 min, at least 30 min, at least 1 h, for at least 2 h, for at least 5 h, for at least 12 h, for at least 1 day or longer.

[0464] Subsequent to or concomitant with contacting the cells with the compound(s) and optional agent(s) (step (ii)), the cells are cultivated under conditions suitable for maintaining the viability of said cells (step (iii)). Therefore, steps (ii) and (iii) may be conducted as one step (simultaneously) or two separate steps (subsequently) or with a partly temporal overlap. Typically, the cells are cultivated in a suitable cell culture medium (e.g., X-Vivo 15) optimized to allow cell culture in the absence of FCS RPMI 1640) optionally supplemented with fetal calf serum (FCS) at 5% CO 2 and a temperature of 30°C-39°C, preferably (approximately) 37°C. Preferably, the cells are cultivated for at least 1 h, for at least 2 h, for at least 5 h, for at least 12 h, for at least 1 day or for at least 3 days.

[0465] As a result from the method of the present invention, activated immune cells (e.g., T cells and / or natural killer cells) may be obtained.

[0466] These activated immune cells may be optionally isolated by any means known in the art (optional step (iv)). Optionally, as a further step (v), the activated immune cells may subsequently be administered to a patient in need thereof. Alternatively, the isolated activated immune cells obtained from step (iv) or the cells of step (iii) may also be stored and / or preserved (e.g., dispersed in a DMSO-containing medium and stored at -80°C). Alternatively, the isolated activated immune cells of step (iv) or the cells of step (iii) may be used for any other in vitro and / or in vivo purposes. Exemplarily, such activated immune cells may be used for research purposes intended to further investigate activated immune cells (in particular activated T cells and / or natural killer cells).

[0467] Exemplarily, the activated immune cells (in particular activated T cells and / or natural killer cells) may be used for the production of cytokines secreted by the cells. Then, a further step (iv) is the cultivating of the cells until the level(s) of the desired cytokine(s) secreted into the medium reach(es) the desired level, followed by step (v) of isolating and, optionally purifying the desired cytokine(s). The isolation and optional purification of cytokines may be performed by any means known in the art such as, e.g., chromatographic means. Optionally, such cytokine(s) may subsequently be stored and / or preserved (e.g., frozen, dried or freeze-dried).

[0468] Furthermore, a compound of the present invention may be further used as a research tool for investigating immune cell activation in more detail.

[0469] In a further aspect, the present invention refers to the compound for use, or the pharmaceutically acceptable salt thereof for use, or the pharmaceutical composition thereof for use as a medicament in the prophylaxis or treatment of a neoplastic and / or infectious disease, a heart disease, wherein the heart disease is myocardial infraction, acute coronary syndrome, myocardial ischemia, ischemic cardiomyopathy, myocardial reperfusion injury, non-ischemic cardiomyopathy, or acute or chronic heart failure. Description of Figures

[0470] Fig 1. Treatment schedules for compound 142 in vivo efficacy experiments with p.o. compound administration. Efficacy experiment 1 treatment schedule for POC study monitoring tumor volume and survival rate of mice treated p.o. Arrows indicate p.o. compound 142 administration.

[0471] Fig 2. Compound 142 impact on in vivo tumor growth rate. Average tumor volumes ± SEM of mice receiving p.o. treatment with compound 142 d3: 30 mg / kg + QD: 10 mg / kg or d3: 9 mg / kg + QD: 3 mg / kg. Statistically significant difference (p < 0.05) between treatment groups and vehicle control group was calculated using 2- way ANOVA analysis.

[0472] Fig. 3A-B. M21 cell growth upon stimulated PBMC co-culture. M21 melanoma cells were incubated with isolated PBMCs and stimulated with anti-CD3 / 28 and Compound 142 at 5 different concentrations.

[0473] Fig 4A-B. M21 cell growth upon stimulated T cell co-culture. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti- CD3 / 28 and Compound 142 at different concentrations. EC50 was calculated at 32 hours post anti-CD3 / 28 and compound 142 addition using GraphPad Prism.

[0474] Fig 5A-C. M21 cell growth upon stimulated T cell co-culture. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti- CD3 / 28 and Compound 142, Compound 156 or Compound 119 at different concentrations.

[0475] Fig 6. M21 cell growth upon unstimulated PBMC and T cell co-culture. M21 melanoma cells were incubated with unstimulated PBMCs or T cells and 10 pM Compound 142.

[0476] Fig 7. Treatment schedules for Compound 142 in vivo efficacy experiments with p.o. compound administration. Efficacy experiment 2 treatment schedule for POC study monitoring tumor volume and survival rate of mice treated p.o. Arrows indicate p.o. Compound 142 administration. Asterisk indicates 40 mg / kg Compound 142 treatment every 48 hours except for day 7 (30 mg / kg) and day 9 (60 mg / kg).

[0477] Fig 8. Treatment schedules for Compound 142 in vivo efficacy experiments with p.o. compound administration. Efficacy experiment 3 treatment schedule for POC study monitoring tumor volume and survival rate of mice treated p.o. Arrows indicate p.o. Compound 142 administration. Ill

[0478] Fig 9. Treatment schedules for Compound 142 or Compound 120 in vivo efficacy experiments with p.o. compound administration. Efficacy experiment 4 treatment schedule for POC study monitoring tumor volume and survival rate of mice treated p.o. Black arrows indicate daily p.o. Compound 142 or Compound 120 administration, grey arrows depict p.o. Compound 142 treatment every third day.

[0479] Fig 10. Treatment schedules for Compound 142, Compound 156 or Compound 119 in vivo efficacy experiments with p.o. compound administration. Efficacy experiment 5 treatment schedule for POC study monitoring tumor volume and survival rate of mice treated p.o. Arrows indicate daily Compound 142, Compound 156 or Compound 119 administration.

[0480] Fig 11. Treatment schedules for Compound 142, Compound 156 or Compound 119 in vivo efficacy experiments with p.o. compound administration. Efficacy experiment 6 treatment schedule for POC study monitoring tumor volume and survival rate of mice treated p.o. Arrows indicate daily p.o. Compound 142, Compound 156 or Compound 119 administration.

[0481] Fig 12. Compound 142 impact on in vivo tumor growth rate. Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound142 60 mg / kg D3 + 40 mg / kg Q2D* or vehicle. Asterisk indicates 40 mg / kg Compound 142 treatment every 48 hours except for day 7 (30 mg / kg) and day 9 (60 mg / kg). Statistically significant difference (p < 0.05) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis.

[0482] Fig 13. Compound 142 impact on in vivo tumor growth rate. Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 142 30 mg / kg D4 + 10 mg / kg QD, 9 mg / kg D4 + 3 mg / kg QD or vehicle. Statistically significant difference (p < 0.05) between treatment groups and vehicle control group was calculated using 2 -way ANOVA analysis.

[0483] Fig 14. Compound 142 and Compound 120 impact on in vivo tumor growth rate. Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 142 30 mg / kg D4 + 10 mg / kg QD or 30mg / kg Q3D, Compound 120 25mg / kg QD or vehicle. Statistically significant difference (** p < 0.01 ) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis.

[0484] Fig 15A, B and C1-C4. Compound 142, Compound 156 and Compound 119 impact on in vivo tumor growth rate and survival. A: Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 142 30 mg / kg D4 + 10 mg / kg QD, Compound 156 20 mg / kg D4 + 10mg / kg QD, Compound 119 10mg / kg QD or vehicle. Statistically significant difference (** p < 0.01 , **** p < 0.0001 ) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis. B: Survival of mice receiving p.o. treatment with Compound 142 30 mg / kg D4 + 10 mg / kg QD, Compound 156 20 mg / kg D4 + 10mg / kg QD, Compound 119 10mg / kg QD or vehicle. C: Average tumor volumes ± SEM and tumor volumes of individual mice with primary B16-SIY challenge or secondary B16-SIY rechallenge.

[0485] Fig 16A-B. Compound 142, Compound 156 and Compound 119 impact on in vivo tumor growth rate. A: Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 142, Compound 156 or Compound 119 7 to 21 days post B16-SIY inoculation. Statistically significant difference (** p < 0.01 , *** p < 0.001 ) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis. B: Survival of mice receiving p.o. treatment with Compound 142, Compound 156 or Compound 119 7 to 21 days post B16-SIY inoculation.

[0486] Fig 17. Treatment schedules for Compound 142, Compound 156 and Compound 119 in vivo efficacy experiments with p.o. compound administration Efficacy experiment treatment schedule for POC study monitoring tumor volume and survival rate of mice treated p.o. Arrows indicate p.o. drug treatment.

[0487] Fig 18A-B. Compound 142, Compound 156 and Compound 119 impact on in vivo tumor growth rate. A: Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 142, Compound 156 or Compound 119 7 to 21 days post EO771 inoculation. Statistically significant difference (p < 0,01) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis. B: Survival of mice receiving p.o. treatment Compound 142, Compound 156 or Compound 119 7 to 21 days post EO771 inoculation.

[0488] Fig 19. Treatment schedules for Compound 142 in vivo efficacy experiments with p.o. compound administration. Efficacy experiment treatment schedule for POC study monitoring tumor growth of mice treated p.o. Arrows indicate p.o. drug treatment.

[0489] Fig 20. Compound 142 impact on in vivo tumor growth rate. Average tumor volumes ± SEM of mice receiving p.o. treatment 7 to 28 days post GL261-LUC2- iRFP inoculation. Statistically significant difference (p < 0,0001 ) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis.

[0490] Fig 21A-B. In vitro CD4+ or CD8+ T-cell stimulation. Purified T-cells were stimulated with anti-CD3, anti-CD3 / CD28 or CEFx viral peptide and Compound 142 at 8 different concentrations. Preparative Examples

[0491] General Information:

[0492] All reactions involving air- or moisture-sensitive reagents or intermediates were carried out in flame-dried glassware under an argon atmosphere. Dry solvents (THF, toluene, MeOH, DMF, DCM) were used as commercially available.1H-NMR and13C- NMR were recorded on a Broker DRX400 (400 MHz). Multiplicities are indicated as: br s (broadened singlet), s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m (multiplet); and coupling constants (J) are given in Hertz (Hz). HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using Waters Acquity Performance Liquid Chromatography (UPLC) equipped SQ 3100 Mass detector spectrometer. Column: Acquity UPLC BEH C18 1.7um, 2.1x50mm. Flow: 0.5ml / min. Eluents: A: H2O with 0.05% formic acid and B: ACN with 0.05% TFA. All chemicals and solvents were purchased from commercial sources like Sigma-Aldrich, Fluka, TCI, Acros Organics, ABCR, Alfa Aesar, Enamine, VWR, Combi-Blocks, Apollo Scientific, Aquilla Pharmatech, Ark Pharm, D-L Chiral Chemicals, ChemBridge, Renno Tech, Accela, KeyOrganics, Pharmablock and Chem Impex. Unless otherwise noted, all commercially available compounds were used as received without further purifications.

[0493] Abbreviations used in the description and in the Examples that follow are: mCPBA (mefa-chloroperoxybenzoic acid), chx (cyclohexane), DAST (diethylaminosulfur trifluloride), DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene), DCM (dichloromethane), DIPEA ( / V, / V-diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethylsulfoxide), LCMS (liquid chromatography mass spectroscopy), Ms (mesyl, methanesulfonyl), p-TSA (PTSA, p-toluenesulfonic acid),

[0494] Pd(dppf)Cl2 ([1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride),

[0495] SEM ([2-(trimethylsilyl)ethoxy]methyl), TBDMS (tert-Butyldimethysilyl), TFA (trifluoroacetic acid), THF (tetrahydrofuran),

[0496] TMAD ( / V, / V, / V( / V'-tetramethylazodicarboxamide), TMB (1 ,3,5-trimethoxybenzene), TLC (thin layer chromatography), TPP (triphenyl phosphine), Tos (tosyl, p- toluenesulfonyl);

[0497] ACK (Ammonium-Chloride-Potassium), CD (Cluster of differentiation), CCR (C-C motif receptor), DMEM (Dulbecco's Modified Eagle's Medium), FBS (Fetal Bovine Serum), EDTA (Ethylene-Diamine-Tetra-Acetic acid), FACS (Fluorescence activated cell sorting), HPbCD (2-Hydroxypropyl-l3>-cyclodextrin), HPMC (Hydroxypropylmethylcellulose), PEG400 (polyethylene glycol), Pen-Strep (Penicillin-Streptomycin), PBMCs (Peripheral blood mononuclear cells), PBS (Phosphate Buffered Saline). General Information

[0498] General procedures and synthetic routes to disclosed compounds

[0499] In the following section some general procedures are described enabling persons skilled in the art to synthesize many key intermediates and final compounds disclosed in this patent. The synthetic approach is not limited to the outlined synthetic routes and reactions. Substances described herein can also be obtained by other conditions or reaction sequences as published in the literature. Synthetic routes Route 2

[0500] 2) i)HCl, ii) NH3

[0501] Route 3 General procedures

[0502] General Procedure A: Mitsunobu reaction

[0503] 1 ) TPP, o°c

[0504] 2) TMAD, THF, 55°C

[0505] Dissolve a phenol (1.0 eq.) and the alcohol (1.5 eq.) in dry THF (0.1 M). Dry the solution with molecular sieve 4 A. Remove the molecular sieve, cool down to 0°C, add TPP (2.2 eq.) and seal the reaction vessel. Stir at 0°C for 30 min, then add TMAD (2.6 eq.) and stir for additional 30 min at 0°C. Heat to 55°C and stir overnight. After completion of the reaction add Celite and evaporate solvent. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[0506] General Procedure B: nucleophilic substitution

[0507] K2CO3

[0508] MeCN, 60°C

[0509] Dissolve a phenol (1.0 eq.), halide (1.5 eq.) and K2CO3 (3.0 eq.) in dry acetonitrile (0.1 M). Stir the mixture in a sealed reaction vessel at 60°C overnight. After reaction is completed add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). An alternative suitable base is CS2CO3, and acetonitrile can be replaced by THF, DMF or acetone. Depending on the availability of the starting materials the equivalents of phenol and halide can be inverted.

[0510] General Procedure C: aryl-trimethoxyphenyl iodonium salts i) pTSA, mCPBA, MeCN, 80 °C ii) TMB, MeCN, 80°C

[0511] OCF3

[0512] Dissolve an iodoarene (1.0 eq.) in dry acetonitrile (0.15 M). Acidify the solution with pTSA (1.1 eq.). Then add mCPBA (1.1 eq.) and stir at 80 °C for 1-2 h. Upon completion of the oxidation step add 1 ,3,5-trimethoxybenzene (TMB) and stir for additional 30 min at 80 °C. After completion add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, DCM / methanol gradient). General Procedure D: O-arylation with aryl-trimethoxyphenyl iodonium salts

[0513] Suspend a phenol (1 .2 eq.) and K2CO3 (3.0 eq.) in dry acetonitrile (0.25 M). Heat the mixture to 55°C and add the iodonium salt to the stirred solution. Continue stirring at 55°C overnight. Add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). To extend the scope of the reaction, the phenol and K2CO3 can be replaced by an aliphatic alcohol and NaH.

[0514] General Procedure E: Miyaura borylation

[0515] OCF3

[0516] Dissolve an aryl halide (1.0 eq.), bis(pinacolato)diboron (1.2 eq.), Pd(dppf)Cl2*DCM (0.1 eq.) and KOAc (3.0 eq.) in dry 1 ,4-dioxane (0.1 M). Seal the reaction vessel and stir at 90°C overnight. After completion add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[0517] General Procedure F: Suzuki cross coupling

[0518] O -TBDMS OCF3

[0519] Dissolve a 8-bromoxanthine derivative (1.0 eq.), boronic ester (1.2 eq.), Pd(dppf)Cl2*DCM (0.1 eq.) and K3PO4 (3.0 eq.) in a 4:1 mixture of 1 ,4-dioxane and water (0.1 M). Seal the reaction vessel and stir at 90°C overnight. After complete reaction add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient). The boronic ester can be replaced by a boronic acid. General-Procedure G: TBDMS deprotection of an alcohol

[0520] Dissolve a TBDMS-protected alcohol (1.0 eq.) in THF (0.1 M). Add concentrated hydrochloric acid (15 eq.) and stir at room temperature overnight. After complete deprotection remove volatiles under reduced pressure. Dissolve the residue in DMSO and purify via reversed-phase HPLC (C18 column, water (0.1 %TFA) and ACN (0.1 %TFA) gradient). Desired fractions were lyophilized to give the final compound.

[0521] General Procedure H: SEM protection

[0522] SEM-CI, DIPEA

[0523] THF, RT

[0524] O-TBDMS O-TBDMS

[0525] Dissolve xanthine derivative (1.0 eq.) in dry THF (0.2 M) and DIPEA (6.0 eq.). Add SEM-CI (4.0 eq.) and continue stirring at room temperature overnight. Add more DIPEA and SEM-CI in case incomplete reaction. After completion add saturated NaHCOs solution, concentrate the mixture under reduced pressure, add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[0526] General Procedure I: TBDMS and SEM-deprotection

[0527] OH

[0528] Dissolve a SEM and TBDMS protected compound (1.0 eq.) in THF (0.1 M). Add concentrated hydrochloric acid (15.0 eq.) and stir at room temperature overnight. Remove volatiles under reduced pressure and add ammonia in methanol (25.0 eq, 7 M). Stir at room temperature for 30min. Aagain remove volatiles under reduced pressure and dissolve the residue in DMSO and purify by reversed-phase HPLC (C18 column, water (0.1 %TFA) I acetonitrile (0.1 %TFA) gradient). The desired fractions were lyophilized to give the final compound.

[0529] General Procedure J: Deoxofluorination of alcohols R= Alkyl / H

[0530] Dissolve an alcohol (1.0 eq.) in dry DCM (0.1 M) and cool to 0°C. Add Deoxofluor (1.1 meq.) and seal the reaction vessel. Stir at 20°C for 2h. After completion of the reaction add Celite and evaporate the solvent. Purification can be achieved via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). An alternative suitable reagent is DAST.

[0531] General Procedure K: Deoxofluorination of aldehydes and ketones

[0532] R=Alkyl / H

[0533] Dissolve an aldehyde or ketone (1.0 eq.) in dry DCM (0.1 M) and cool down to 0°C. Add Deoxofluor (2.1 eq.) and seal the reaction vessel. Stir at room temperature. After completion of the reaction add Celite and evaporate volatiles. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). DAST can be used instead of Deoxofluor.

[0534] General Procedure L: Dess-Martin oxidation

[0535] HO O

[0536] Dess-Martin-Periodan

[0537] DCM, 60°C

[0538] R=Alkyl / H

[0539] Dissolve an alcohol (1.0 eq.) in dry DCM (0.1 M). Add Dess-Martin-Periodan (2.0 eq.) and seal the reaction vessel. Stir at 60°C. After completion of the reaction add Celite and evaporate the volatiles. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[0540] General Procedure M: Nucleophilic aromatic substitution

[0541] K2CO3

[0542] DMSO, 110°C

[0543] F Dissolve an aryl-fluoride (1 .0 eq.), phenol (1 .5 eq.) and K2CO3 (3.0 eq.) in dry DMSO (0.1 M). Stir the mixture in a sealed reaction vessel at 110°C for 3h. After reaction is completed add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). An alternative suitable base is Cs2CO3. Depending on the availability of the starting materials equivalents of phenol and halide can be inverted. The reaction can be performed under microwave irradiation instead of normal heating.

[0544] General Procedure N: Nucleophilic aromatic substitution (pyridine)

[0545] R= Alkyl, OAlkyl, H

[0546] Dissolve an aryl fluoride (1.0 eq.), phenol (1.5 eq.) and K2CO3 (3.0 eq.) in dry DMF (0.1 M). Stir the mixture in a sealed reaction vessel at 110°C. After reaction is completed add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Alternative suitable bases are CS2CO3 or K3PO4. Depending on the availability of the starting materials equivalents of phenol and halide can be inverted. Instead of a phenol, an alcohol may be used as well. The reaction can be performed under microwave irradiation instead of normal heating.

[0547] General Procedure O: Telescoped SNArZ Suzuki reaction ci

[0548] K3PO4,

[0549] 1 ,4-dioxan, 100°C

[0550] Ar-Br, water, Pd(dppf)CI2* DCM

[0551] 1 ,4-dioxan, 100°C

[0552] Dissolve an aryl fluoride (1.5 eq.), alcohol (1.5 eq.) and K3PO4 (4.0 eq.) in dry 1 ,4- dioxan (0.1 M). Stir the mixture in a sealed reaction vessel at 100°C. After the first step is completed add the (hetero)aryl bromide (1.0 eq.), Pd(dppf)Cl2*DCM (0.1 eq.) and water to get to a 4:1 ratio of 1 ,4-dioxane: water. Stir at 100°C. After the second reaction is completed add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Depending on the availability of the starting materials the equivalents of the components of the boronic acid and the halide can be inverted. Instead of a phenol, an alcohol may be used as well.

[0553] General Procedure P: N-3 alkylation of 7-methylxanthine derivatives

[0554] MgO, TBAB

[0555] DMSO, 100°C

[0556] F

[0557] Dissolve a 7-methylxanthine derivative (1 .0 eq.), MgO (1 .0 eq.) and TBAB (1 .0 eq.) in dry DMSO (0.1 M) and heat to 100°C. Add the epoxide (1.1 eq.) and seal the reaction vessel. Stir at 100°C. After completion of the reaction add Celite and evaporate volatiles. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate methanol gradient).

[0558] General Procedure Q: TBDMS deprotection

[0559] Dissolve TBDMS protected xanthine derivative (1.0 eq.) and CsF (5.0 eq.) in dry EtOH / DMSO 5 / 1 (0.1 M). Seal the reaction vessel and stir at 60°C. After completion of the reaction add Celite and evaporate volatiles. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient). The reaction can be performed under microwave irradiation instead of normal heating.

[0560] EXAMPLES

[0561] Preparation of 8-bromo-3-(2-hydroxypropyl)-7-methyl-3,7-dihydro-1 H-purine-2,6- dione (1)

[0562] 1 To a stirred solution of 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione (5 g, 20.49 mmol) in DMF (50 mL) at room temperature were added 1-bromo-2-propanol (4.24 g, 30.73 mmol) and DBU (3.1 g, 20.49 mmol). The resultant reaction mixture was stirred for 16 h at 90 °C. After completion of reaction the reaction mass was cooled to room temperature. The reaction mixture was concentrated under reduced pressure to get crude reaction mass. This mass was diluted with DCM (100 mL) and precipitated solid was collected. The crude was dried under vacuum to afford compound 1 (3.66 g, 59%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ: 11.16 (brs, 1H), 4.80 (d, J = 5.2 Hz, 1H), 4.06-4.00 (m, 1H), 3.88-3.78 (m, 4H), 3.69 (dd, J= 13.4, 5.6 Hz,1H), 1.05 (d, J = 6.0 Hz, 3H). LCMS (ESI+): found 303.1 [M+H]+, calculated 302.00 for C9H11BrN4O3. Preparation of (R)-8-bromo-3-(3,3-difluoro-2-hydroxypropyl)-7-methyl-3,7-dihydro-1H- purine-2,6-dione (3b) To a mixture of 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione (3.13 g, 12.8 mmol), MgO (429 mg, 10.6 mmol) and tetrabutylammoniumbromid (3.77g, 11.7 mmol) in 60 ml DMSO at 60°C were added 1.0 g (10.6 mmol) (R)-2- (difluoromethyl)oxirane. The reaction was stirred overnight and filtered over Celite. The filtrate was concentrated under reduced pressure and purified by reversed phase column chromatography (RP18, water / acetonitrile gradient) to give (R)-8-bromo-3- (3,3-difluoro-2-hydroxypropyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 3b. LCMS (ESI+): found 339 / 341 (1:1) [M+H]+, calculated 338.0 / 340.0 for C9H9BrF2N4O3. Preparation of 5-(difluoromethyl)-2,2-dimethyl-1,3-dioxane 69 To a stirred solution of 2,2-dimethyl-1,3-dioxane-5-carbaldehyde (300 mg, 2.08 mmol), in DCM (6 mL) were added DAST (0.55 mL, 4.16 mmol) at room temperature, LDC-P04374WO31 PCT Application (final).docx the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The crude was purified by column chromatography, compound eluted in 10% EtOAc in petroleum ether. Fractions containing the compound were combined and evaporated to get 69 (0.2 g, 58%) as brown liquid.1H NMR (400 MHz, CDCl3) δ ppm: 6.09 (td, J = 56.0, 7.2 Hz, 1H), 4.04-4.08 (m, 2H), 3.99-3.90 (m, 2H), 1.89-1.98 (m, 1H), 1.46 (s, 3H), 1.40 (s, 3H). Preparation of 2-(difluoromethyl)propane-1,3-diol 70 To a stirred solution of compound 69 (1.3 g, 7.82 mmol, 1.0 eq.) in MeOH:H2O (3:1 26 mL) was added p-TSA (1.61 g 9.38 mmol, 1.2 eq.) at 0 ℃, the reaction mixture was stirred at RT for 2 h. Reaction mixture was evaporated to remove excess volatiles, diluted in EtOAc and washed with water. The separated organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound 70 (400 mg, 41%) as a thick pale yellow syrup. 1H NMR (400 MHz, CDCl3) δ ppm: 6.09 (td, J = 56.0, 5.2 Hz, 1H), 4.02-3.95 (m, 4H), 2.05-2.24 (m, 2H). Preparation of 3,3-difluoro-2-(hydroxymethyl)propyl methanesulfonate 111 To a stirred solution of compound 70 (200 mg, 1.58 mmol, 1.0 eq.) in DCM (4 mL) was added triethylamine (0.22 mL, 1.58 mmol, 1.0 eq.), methane sulfonyl chloride (0.12 mL, 1.58 mmol, 1.0 eq.) at 0 ℃. The reaction mixture was stirred at RT for 2 h. Reaction mixture was evaporated under reduced pressure to remove excess volatiles to afford compound 111 (120 mg, 37%). Crude compound was taken to next step without purification as thick pale-yellow syrup. 1H NMR (400 MHz, CDCl3) δ ppm: 6.12-5.82 (m, 1H), 4.49-4.39 (m, 3H), 3.92-3.89 (m, 1H), 3.06-3.08 (m, 3H), 2.73- 2.44 (m, 1H). Preparation of 8-bromo-3-(3,3-difluoro-2-(hydroxymethyl)propyl)-7-methyl-3,7- dihydro-1H-purine-2,6-dione 71 LDC-P04374WO31 PCT Application (final).docx To a stirred solution of compound 111 (100 mg, 0.49 mmol, 1.0 eq.) in DMF (1 mL) was added 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione (179 mg, 0.73 mmol, 1.5 eq.) and DBU (73 mg, 0.49 mmol, 1.0 eq.) The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was allowed to cool to room temperature. It was diluted with water, extracted with EtOAc (2 x 10 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography using 3% methanol in dichloromethane as mobile phase to obtain compound 71 (100 mg, 58%) as a colorless solid.1H NMR (400 MHz, CDCl3) δ ppm: 11.31 (s, 1H), 6.11 (td, J = 56.0, 4 Hz, 1H), 4.84 (t, J = 5.2 Hz, 1H), 4.13 (dd, J = 14 Hz, 1H), 3.98 (dd, J= 14 Hz, 1H), 3.82 (s, 3H), 3.52 (t, J= 5.2 Hz, 2H). LCMS (ESI+): found 355.3 [M+H]+, calculated 354.0 for C10H11BrF2N4O3. Preparation of 8-bromo-7-methyl-3-(3,3,3-trifluoro-2-(hydroxymethyl)propyl)-3,7- dihydro-1H-purine-2,6-dione 71a 2-((8-bromo-7-methyl-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)-3,3,3- trifluoropropanoic acid To a stirred solution of 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione (2.5 g, 10.20 mmol, 1.0 equiv.) and 2-(trifluoromethyl)acrylic acid (1.43 g, 10.20 mmol, 1.0 equiv.) in DMF (50 ml) was added DBU (1.5 ml, 10.20 mmol, 1.0 equiv.) under argon atmosphere at room temperature in air tight microwave vial. Then the reaction mixture was stirred at 80 °C for 30 min under microwave irradiation until LC-MS which showed total consumption of starting material. All volatiles were evaporated under reduce pressure to get crude material (2.8 g) that was used for next step without further purification. LC-MS: found 386.06 [M+H]+, calculated 383.97 for C10H8BrF3N4O4. LDC-P04374WO31 PCT Application (final).docx methyl 2-((8-bromo-7-methyl-2,6-dioxo-1 ,2,6,7-tetrahydro-3H-purin-3-yl)methyl)-

[0563] 3,3,3-trifluoropropanoate r MeOH, H2SO4

[0564] O N 70 °C, 16 h O N

[0565] COOH COOMe

[0566] CF3CF3

[0567] To a stirred solution of 2-((8-bromo-7-methyl-2,6-dioxo-1 ,2,6,7-tetrahydro-3H-purin-3- yl)methyl)-3,3,3-trifluoropropanoic acid (2.8 g, 7.27 mmol, 1.0 equiv.) in MeOH (28 ml) at 0 °C was added sulfuric acid (143 mg, 1.45 mmol, 0.2 equiv.) under argon atmosphere. Then the reaction mixture was stirred at 70 °C for 16 hours until total consumption of starting material. All volatile solvent was evaporated under reduce pressure to get crude product that was purified by column chromatography (230-400 mesh silica) by using 58% Ethyl acetate in petrolether as an eluent. The compound containing fractions were concentrated and dried to afford methyl 2-((8-bromo-7- methyl-2,6-dioxo-1 ,2,6,7-tetrahydro-3H-purin-3-yl)methyl)-3,3,3-trifluoropropanoate as colorless solid. LC-MS: found 399.12 [M+H]+, calculated 397.98 for C11 H10BrF3N4O4.

[0568] 8-bromo-7-methyl-3-(3,3,3-trifluoro-2-(hydroxymethyl)propyl)-3,7-dihydro-1 H-purine-

[0569] 2,6-dione 71a

[0570] LiBFU

[0571] THF, 0 °C-RT, 5 h

[0572] 71a

[0573] To a stirred solution of methyl 2-((8-bromo-7-methyl-2,6-dioxo-1 ,2,6,7-tetrahydro-3H- purin-3-yl)methyl)-3,3,3-trifluoropropanoate (900 mg, 2.25 mmol, 1.0 equiv.) in THF (20 ml) at 0 °C was added UBH4 (2M in THF (2.3 ml, 4.5 mmol, 2 equiv.) under argon atmosphere. Then the reaction mixture was stirred at room temperature for 5 hours. The progress of the reaction was monitored by LC-MS which showed total consumption of starting material. The reaction mixture was quenched with ice-cold water (10 ml) and extracted with ethyl acetate (5 x 50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (230-400 mesh silica) by using 75% Ethyl acetate in petrolether as an eluent. The compound containing fractions were concentrated and dried to afford 8-bromo-7-methyl-3-(3,3,3-trifluoro-2- (hydroxymethyl)propyl)-3,7-dihydro-1 H-purine-2, 6-dione as colorless solid. LC-MS: found 371.19 [M+H]+, calculated 369.99 for C10H10BrF3N403.

[0574] Building blocks disclosed in table A-1 can be made e.g. in analogy to the methods described for derivatives 1, 3b, 71, or 71a.

[0575] Table A-1 :

[0576] LCMS

[0577] Cpd exact structure name formula [M+H]+no mass found

[0578] ? I 8-bromo-3-(2-

[0579] T II Br hydroxypropyl)-7- C9H11 BrN4

[0580] 1 O^A'''^ 302.00 303 methyl-3,7-dihydro- 03

[0581] OH 1 H-purine-2, 6-dione HN' AA-'Az8-bromo-3-(3-fluoro-2-

[0582] A JL X hydroxypropyl)-7- C9H10BrFN4

[0583] 2Bro^AN319.99 321 methyl-3,7-dihydro- 03 F-XXY^

[0584] OH 1 H-purine-2, 6-dione

[0585] 8-bromo-3-(3,3-

[0586] Azdifluoro-2-

[0587] A JLBrC9H9BrF2N4 339

[0588] 3 O^^NNhydroxypropyl)-7- 337.98

[0589] HO^ J 03 methyl-3,7-dihydro-

[0590] F^F 1 H-purine-2, 6-dione

[0591] J / (R)-8-bromo-3-(3,3-

[0592] HN>VN\ difluoro-2-

[0593] JL 1BrC9H9BrF2N4 339

[0594] 3b O^^NNhydroxypropyl)-7- 337.98

[0595] HO,„„ J 03 methyl-3,7-dihydro-

[0596] F^F 1 H-purine-2, 6-dione

[0597] A18-bromo-7-methyl-3-

[0598] A X XBr(3,3,3-trifluoro-2- 0<#A''NC9H8BrF3N4

[0599] 4 hydroxypropyl)-3,7- 355.97 357

[0600] HO^ J 03 dihydro-1 H-purine-

[0601] F4^F 2, 6-dione LCMS

[0602] Cpd exact structure name formula [M+H]+no mass found jf / (R)-8-bromo-7-methyl-

[0603] °H °- 3-(3,3,3-trifluoro-2-

[0604] JLz / —. / 1BrC9H8BrF3N4

[0605] 4bN^ °\= \ hydroxypropyl)-3,7- 355.97 357

[0606] HO,„„ J 03 dihydro-1 H-purine-

[0607] > o 1 F^FTCD - 5 2, 6-dione

[0608] 8-bromo-3-(3- j? / hydroxy-2-

[0609] T II ?— Br C10H13BrN4

[0610] 5 0<^N"'Nmethylpropyl)-7- 316.02 317 03 methyl-3,7-dihydro- 1 H-purine-2, 6-dione

[0611] X78-bromo-3-(2,3-

[0612] H< V Vo

[0613] T JI ABrdihydroxypropyl)-7- C9H11 BrN4

[0614] 7N318.0 319 methyl-3,7-dihydro- 04 HO'A^ HO 1 H-purine-2, 6-dione

[0615] 8-bromo-3-(3,3-

[0616] X / difluoro-2-

[0617] T X ABr(hydroxymethyl)propyl C10H11BrF2

[0618] 71 O^N^N 352.00 353 )-7-methyl-3,7- N4O3 dihydro-1 H-purine-

[0619] F' T 2, 6-dione

[0620] 8-bromo-7-methyl-3- (3,3,3-trifluoro-2-

[0621] C10H10BrF3

[0622] 71a (hydroxymethyl)propyl 369.99 371.19

[0623] N4O3 )-3,7-dihydro-1 H- purine-2, 6-dione

[0624] Preparation of 8-bromo-3-(2-((tert-butyldimethylsilyl)oxy)propyl)-7-methyl-3,7-dihydro- 1 H-purine-2, 6-dione (8) To a stirred solution of compound 1 (3.5 g, 11.55 mmol) in DMF (35 mL) at room temperature were added imidazole (5.2 g, 34.7 mmol) and TBDMSCI (2.36 g, 34.7 mmole). The resultant reaction mixture was stirred for 16 h at room temperature. After completion of reaction (monitored by LC-MS), the reaction mass was cooled to room temperature. The reaction mixture was evaporated under reduced pressure. The crude mass was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to afford 8 (4.22 g, 87.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 11.28 (s, 1H), 4.22-4.19 (m, 1H), 3.95-3.90 (m, 1H), 3.81 (s, 3H), 3.70 (dd, J = 13.2, 4.0 Hz, 1H), 1.12 (d, J = 6 Hz, 3H), 0.70 (s, 9H), - 0.05 (s, 3H), -0.25 (s, 3H). LCMS (ESI+): found 417.3 [M+H]+, calculated 416.1 for C15H25BrN4O3Si. Preparation of 8-bromo-3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoropropyl)- 7-methyl-3,7-dihydro-1H-purine-2,6-dione 13 O O N HN N HN Br Br TBDMSCl, imidazole ONNONNDMF, RT Si OH O F F F F 71 13 To a stirred solution of compound 71 (100 mg, 0.28 mmol, 1.0 equiv.), in dry DMF (2 mL) were added imidazole (39 mg, 0.57 mmol, 2.0 eq.) and TBDMS-Cl (86 mg, 0.57 mmol, 2.0 eq.). Then the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2 x 10 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography using 3% Methanol in dichloromethane to obtain compound 13 (75 mg, 58%) as a colorless solid. LCMS (ESI+): found 467.3 [M+H]+, calculated 466.01 for C16H25BrF2N4O3Si.1H NMR (400 MHz, DMSO-d6) δ ppm: 11.30 (s, 1H), 6.11 (td, J = 56.0, 4.4 Hz, 1H), 4.13-4.04 (m, 2H), 3.81 (s, 3H), 3.72 (d, J = 4.8 Hz, 2H), 2.67-2.51 (m, 1H), 0.81 (s, 9H), -0.010 (s, 3H), -0.018 (s, 3H). Building blocks in the following table A-2 can be synthesized e.g. as exemplified for compound 8 or 13.

[0625] Preparation of 8-(4-(benzyloxy)-3-methoxyphenyl)-7-methyl-3,7-dihydro-1 H-purine- 2, 6-dione 15 500 mg 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione, 790 mg (4-(benzyloxy)- 3-methoxyphenyl)boronic acid, 170 mg Pd(dppf)Cl2*DCM and 423 mg K2CO3were suspended under a nitrogen atmosphere in 20 ml 1,4-dioxane / water (1:1) and heated to 100 °C until reaction was complete. After cooling to room temperature 15 ml water were added to precipitate the product which was collected by filtration. The crude was then triturated with 30 ml acetonitrile overnight. The solid was collected, washed and dried to yield 680 mg of compound 15. LCMS (ESI-): found 377 [M-H]-, calculated 378.13 for C20H18N4O4. Preparation of 8-(4-(benzyloxy)-3-fluorophenyl)-7-methyl-3,7-dihydro-1H-purine-2,6- dione 15a Anhydrous sodium carbonate (216 mg, 2.04 mmol, 2.0 equiv.) was added to a solution of 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione (250 mg, 1.02 mmol, 1.0 equiv.) and (4-(benzyloxy)-3-fluorophenyl)boronic acid (276 mg, 1.12 mmol, 1.1 equiv.) in mixture of solvents (1,4-dioxane (6 ml) and H2O (3 ml)) at room temperature under argon atmosphere. The whole reaction mixture was degassed with argon for 15 minutes, then [1,1′-Bis(diphenylphosphino)ferrocene]dichloro- palladium(II), complex with dichloromethane (41.7 mg, 0.051 mmol, 0.05 equiv.) was added. Then the reaction was stirred at 100 ℃ for 1 h under microwave irradiation. H2O (20 ml) was added and extracted with EtOAc (3 x 150 ml). The combined organic extracts were washed with brine (1 x 30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure afforded crude product. The obtained crude was purified by reverse phase column chromatography over C18 silica gel using 50%-60% ACN in H2O to afforded 8-(4-(benzyloxy)-3-fluorophenyl)-7- methyl-3,7-dihydro-1H-purine-2,6-dione (142 mg) as colorless solid. LC-MS: found 367.14 [M+H]+, calculated 366.1 for C19H15FN4O3. Preparation of 7-methyl-8-(3-(trifluoromethoxy)-4-(4-(trifluoromethoxy)phenoxy)- phenyl)-3,7-dihydro-1H-purine-2,6-dione 15b LDC-P04374WO31 PCT Application (final).docx 15b 7-methyl-8-(3-(trifluoromethoxy)-4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro- 1H-purine-2,6-dione was prepared in analogy to 8-(4-(benzyloxy)-3-fluorophenyl)-7- methyl-3,7-dihydro-1H-purine-2,6-dione. LC-MS: found 503.2 [M+H]+, calculated 502.1 for C20H12F6N4O5. Preparation of 8-(4-(benzyloxy)-3-methoxyphenyl)-3-(2-hydroxypropyl)-7-methyl-3,7- dihydro-1H-purine-2,6-dione 16 150 mg compound 15, 0.051 ml 1-bromo-2-propanol, 46 mg Na2CO3 were suspended under a nitrogen atmosphere in 3.9 ml DMF and stirred at 50 °C for 72 h. After cooling to room temperature some water was added to precipitate the product which was collected, washed and dried. Pure compound 16 was obtained after purification by preparative TLC (DCM / MeOH, 15:1). LCMS (ESI+): found 437 [M+H]+, calculated 436.17 for C23H24N4O5. Preparation of 8-(4-(benzyloxy)-3-fluorophenyl)-3-(3,4-difluoro-2-hydroxybutyl)-7- methyl-3,7-dihydro-1H-purine-2,6-dione 203 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane m-CPBA (26.84 g, 156.04 mmol, 2.0 equiv.) and NaHCO3 (13.1 g, 156.04 mmol, 2.0 equiv.) were added to stirred solution of 2,2-dimethyl-4,7-dihydro-1,3-dioxepine (10 g, 78.02 mmol, 1.0 equiv.) in DCM (250 ml) at 0 ℃ under inert atmosphere. Then it was stirred at room temperature for 16 h. The obtained solid was filtered through filter paper, washed with excess of DCM (3 x 100 mL). The combined filtrates were washed with saturated NaHCO3 (2 x 100 ml), brine (2 x 50 ml), dried over anhydrous Na2SO4, filtered and concentrated to afford the crude which was purified by silica gel (100-200 Mesh) column chromatography using 15-20% EtOAc in petrolether to give LDC-P04374WO31 PCT Application (final).docx 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (7.5 g) as colourless liquid.1H NMR (400 MHz, CDCl3) δ ppm: 4.03 (qd, J = 14.4 Hz, 1.2 Hz, 4H), 3.21-3.20 (m, 4H), 1.37 (s, 3H), 1.32 (s, 3H). 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluoroethan-1-ol Triethylamine trihydrofluoride (97%) (83.86 g, 520.2 mmol, 3.0 equiv.) was added to a teflon vial containing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (25 g, 173.4 mmol, 1.0 equiv.) under the flow of argon at room temperature. Then the vial was tightly closed and stirred at 65 ℃ for 24 h. Reaction mass was cooled down to room temperature and poured into ice cold saturated NaHCO3 solution (300 ml) and stirred for 30 minutes, then extracted with EtOAc (3 x 300 ml). The combined organic layers were washed with saturated NaHCO3 solution (1 x 100 ml), brine (1 x 100 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. This was purified by silica gel (230-400 Mesh) column chromatography using 35% EtOAc in petrolether as eluent to give 2-(2,2-dimethyl- 1,3-dioxolan-4-yl)-2-fluoroethan-1-ol (7.2 g) as colorless liquid.1H NMR (400 MHz, CDCl3) δ ppm: 4.65-4.45 (m, 1H), 4.36-4.27 (m, 1H), 4.13-4.08 (m, 1H), 3.95-3.82 (m, 3H), 2.04 (br s, 1H), 1.44 (s, 3H), 1.38 (s, 3H). 4-(1,2-difluoroethyl)-2,2-dimethyl-1,3-dioxolane DAST (8.84 mL, 67 mmol, 2.5 equiv.) was added to a stirred solution of 2-(2,2- dimethyl-1,3-dioxolan-4-yl)-2-fluoroethan-1-ol (4.4 g, 26.8 mmol, 1.0 equiv.) in toluene (60 ml) at room temperature under argon atmosphere. After 5 minutes pyridine (6.42 mL, 80.4 mmol, 3.0 equiv.) was added to the reaction at room temperature and it was then stirred at room temperature for 8 h. Reaction was quenched with aqueous saturated NaHCO3 (50 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with saturated NaHCO3 (1 x 50 ml), brine (1 x 50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 4-(1,2-difluoroethyl)-2,2-dimethyl-1,3-dioxolane (0.8 g) as LDC-P04374WO31 PCT Application (final).docx light yellow liquid. The obtained crude product was used for next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm: 4.75-4.53 (m, 3H), 4.32-4.22 (m, 1H), 4.13-4.08 (m, 1H), 3.95 (dd, J = 8.4 Hz, 6.4 Hz, 1H), 1.43 (s, 3H), 1.37 (s, 3H). 3,4-difluorobutane-1,2-diol 4-(1,2-difluoroethyl)-2,2-dimethyl-1,3-dioxolane (0.800 g, 4.81 mmol, 1.0 equiv.) was dissolved in methanol (10 ml) under argon atmosphere and cooled to ℃. Then p- toluene sulfonic acid monohydrate (91.58 mg, 0.481 mmol, 0.1 equiv.) was added and the reaction was stirred at room temperature for 5 h. All the volatiles were removed under reduced pressure. The obtained residue was dissolved in EtOAc (100 ml) and organic layer was washed with saturated NaHCO3(3 x 20 ml, brine (2 x 20 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude product was purified by silica gel (230-400 Mesh) column chromatography using 40% EtOAc in pet ether as eluent afforded 3,4-difluorobutane-1,2-diol (170 mg) as colorless liquid.1H NMR (400 MHz, CDCl3) δ ppm: 4.79-4.67 (m, 3H), 4.01-3.92 (m, 1H), 3.84-3.75 (m, 1H), 2.45 (d, J = 5.2 Hz, 1H), 1.94 (t, J = 5.6 Hz, 3H). 3,4-difluoro-2-hydroxybutyl trifluoromethanesulfonate To a stirred solution of 3,4-difluorobutane-1,2-diol (20 mg, 0.159 mmol, 1 equiv.) in dry DCM (2 ml) was added triethylamine, 99% (24.1 mg, 0.238 mmol, 1.5 equiv.) followed by addition of trifluoromethanesulfonic anhydride, 98% (53.697 mg, 0.190 mmol, 1.2 equiv.). Addition of all the reagents has been done at 0 ℃ and under argon atmosphere. Then after reaction was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC which showed total consumption of SM (50% EtOAc in petrolether, Rf = 0.55, H2SO4). The reaction was quenched by addition of ice cold water (5 ml) and extracted with DCM (2 x 30 ml). The combined organic extracts were washed with 1N NaHCO3 (1 x 5 ml), brine (1 x 10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure gave crude product. The obtained crude was used for next step immediately. LDC-P04374WO31 PCT Application (final).docx 8-(4-(benzyloxy)-3-fluorophenyl)-3-(3,4-difluoro-2-hydroxybutyl)-7-methyl-3,7-dihydro- 1H-purine-2,6-dione 203 Cesium carbonate (56.1 mg, 0.172 mmol, 2.0 equiv.) was added to solution of 8-(4- (benzyloxy)phenyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione (30 mg, 0.086 mmol, 1 equiv.) in dry DMF (2 mL) at room temperature under argon atmosphere and stirred for 30 minutes under argon atmosphere. Then 3,4-difluoro-2-hydroxybutyl trifluoromethanesulfonate (28.90 mg, 0.112 mmol, 1.3 equiv.) was added to the reaction flask and reaction was stirred at 60 ℃ for 30 h. The progress of the reaction was monitored by LC-MS. H2O (10 ml) was added and extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with ice-cold water (3 x 20 ml), brine (3 x 20 ml), dried over anhydrous Na2SO4, filtered through cotton and concentrated to afford the crude. The crude was first purified by reverse phase (C18column chromatography) using 30% ACN in (0.01% FA) water to give 8-(4- (benzyloxy)-3-fluorophenyl)-3-(3,4-difluoro-2-hydroxybutyl)-7-methyl-3,7-dihydro-1H- purine-2,6-dione as off white solid after lyophilization.1H NMR (400 MHz, DMSO-d6) δ ppm: 11.11 (s, 1H), 7.71 (dd, J = 12.4 Hz, 2.0 Hz, 1H), 7.60-7.58 (m, 1H), 7.50- 7.34 (m 6H), 5.47 (br s, 1H), 5.28 (s, 2H), 4.84-4.58 (m, 3H), 4.23-4.12 (m, 2H), 4.05- 4.00 (m, 1H), 3.98 (s, 3H). LC-MS: found 475.3 [M+H]+, calculated 474.15 for C23H21F3N4O4. Preparation of 7-methyl-3-(4,4,4-trifluoro-2-hydroxybutyl)-8-(3-(trifluoromethoxy)-4-(4- (trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1H-purine-2,6-dione 216 Dissolve 30 mg 7-methyl-8-(3-(trifluoromethoxy)-4-(4- (trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1H-purine-2,6-dione 15b (1.0 eq.), 2.6 mg MgO (1.0 eq.) and 21.2 mg TBAB (1.0eq.) in 1mL dry DMSO (0.1 M) and heat up LDC-P04374WO31 PCT Application (final).docx to 100°C. Add 6.4uL 2-(2,2,2-trifluoroethyl)oxirane (1.1 eq.) and seal the reaction vessel. Stir at 100°. After completion of the reaction add Celite and evaporate volatiles. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient) to obtain 7-methyl-3-(4,4,4-trifluoro-2-hydroxybutyl)-8-(3- (trifluoromethoxy)-4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1H-purine-2,6- dione 216. LCMS (ESI+): found 629.5 [M+H]+, calculated 628.1 for C24H17F9N4O6 Compounds in the following table A-3 were synthesized e.g. as exemplified by compound 16, 203 or 216.

[0626] Preparation of (4-(trifluoromethoxy)phenyl)(2,4,6-trimethoxyphenyl)iodonium 4- methylbenzenesulfonate 104

[0627] 20.0 g 1-iodo-4-(trifluoromethoxy)benzene were dissolved in 250 ml dry acetonitrile.

[0628] 13.15 g pTSA and 26.0 g mCPBA were added and the reaction was stirred at 80 °C for 2 h. Upon completion of the oxidation 12.8 g 1 ,3,5-trimethoxybenzene were added and stirring was continued for additional 30 min at 80 °C. The mixture was concentrated under reduced pressure and the residue was absorbed on Celite. Volatiles were removed under reduced pressure. Purification was achieved via normal phase column chromatography (silica, DCM / methanol gradient). LCMS (ESI+): found 454.8 [M]+, calculated 455,00 for C16H15F3IO4T

[0629] Preparation of (2-(trifluoromethoxy)phenyl)(2,4,6-trimethoxyphenyl)iodonium 4- methylbenzenesulfonate 108

[0630] 150 mg 1-iodo-2-(trifluoromethoxy)benzene were dissolved in 3 ml dry acetonitrile.

[0631] 117 mg pTSA and 167 mg mCPBA were added and the reaction was stirred at 55 °C for 1 h. Upon completion of the oxidation 96 mg 1 ,3,5-trimethoxybenzene were added and stirring was continued for additional 30 min at 55 °C. The mixture was absorbed on Celite. Volatiles were removed under reduced pressure. Purification was achieved via normal phase column chromatography (silica, DCM / methanol gradient). LCMS (ESI+): found 454.6 [M]+, calculated 455.0 for C16H15F3IO4T Compounds in the following table A-4 were synthesized as exemplified by compound

[0632] 104, 108 or literature. Other iodonium salts also were commercially available. Preparation of 1-bromo-4-(4-(trifluoromethoxy)phenoxy)benzene 105 8.29 g 4-bromophenol, 20.0 g iodonium tosylate 104, 17.65 g K2CO3in 250 ml acetonitrile were heated to 55°C overnight. Some solvent was removed under reduced pressure and the residue was absorbed on Celite. Purification of compound 105 was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). GCMS (EI): m / z found 334.2 [M]+˙, calculated 333.96 for C13H8BrF3O2 Preparation of 4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-1 ,3,2- dioxaborolane 106

[0633] 10 g bromide 105, 11.43 g bis(pinacolato)diborane, 1.22 g [1 ,1'- bis(diphenylphosphino) ferrocene]palladium dichloride dichloromethane and 11.91 g potassium acetate were mixed in 200 ml 1 ,4-dioxane. The reaction was stirred at 100 °C until complete. Some Soolvent was removed under reduced pressure and the residue absorbed on Celite. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). LCMS (ESI+): found 381.2 [M+H]+, calculated 380.14 for C19H20BF3O4.

[0634] Preparation of 4-bromo-2-(difluoromethoxy)-1-((4-methylbenzyl)oxy)benzene 130

[0635] 52 mg p-tolylmethanol and 53 mg KOtBu were added to 2 ml ice cold toluene under a nitrogen atmosphere. The mixture was allowed to warm to room temperature. 388 mg iodonium salt 129 were added and stirring at room temperature was continued for 1.5 h. the reaction mixture was a absorbed on Celite and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). LCMS (ESI+): found 343.4 [M+H]+, calculated 342.01 for C15H13BrF2O2.

[0636] Preparation of 2-(3-(difluoromethoxy)-4-((4-methylbenzyl)oxy)phenyl)-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane 131

[0637] 85 mg bromide 130, 94 mg bis(pinacolato)diborane, 42 mg [1 ,1'- bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane and 49 mg potassium acetate were mixed in 1.5mL 1 ,4-dioxane. The reaction was stirred at 85 °C until complete and then directly absorbed on Celite. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). LCMS (ESI+): found 391.3 [M+H]+, calculated 390.18 for C21H25BF2O4. Preparation of 2-(4-((4-(difluoromethyl)benzyl)oxy)-3-fluorophenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane 17 500 mg 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 603 mg (1.3 equ.) 1-(bromomethyl)-4-(difluoromethyl)benzene and 138 mg K2CO3were heated in 10 ml dry acetonitrile to 60 °C and stirred until reaction was complete. The mixture was absorbed on Celite, dried and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain compound 17. LCMS (ESI+): found 379 [M+H]+, calculated 378.16 for C20H22BF3O3. Preparation of 2-(4-(benzyloxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane 20 324 mg benzyl alcohol and 500 mg 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenol in 5 ml THF were dried over molecular sieve 3 Å and then transferred to 1.15 g triphenylphosphine in 5 ml THF at 0°C under nitrogen.860 mg TMAD were added. After 30 min the reaction mixture was heated to 55°C until reaction was complete. The mixture was absorbed on Celite, dried and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain compound 20. LCMS (ESI+): found 341 [M+H]+, calculated 340.18 for C20H25BO4. Preparation of 1-(benzyloxy)-4-bromo-2-(trifluoromethoxy)benzene 23 Benzyl bromide (4.16 g), 4-bromo-2-(trifluoromethoxy)phenol (2.5 g) and Cs2CO3 (9.5 g) were mixed in 30 ml THF and stirred at 60 °C until the reaction was complete. The mixture was absorbed on Celite, dried and purified by normal phase column LDC-P04374WO31 PCT Application (final).docx chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain compound 23. LCMS (ESI+): found 348.6 [M+H]+, calculated 347.98 for C14H10BrF3O2. Preparation of 2-(4-(benzyloxy)-3-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane 24 3.5 g bromo derivative 23, 0.411 g Pd(dppf)Cl2*DCM, 4.0 g potassium acetate and 3.84 g bis(pinacolato)diboron in 30 ml 1,4-dioxane were heated to 100°C until reaction was complete. Most of the solvent was evaporated, the residue absorbed on Celite and purified via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to afford pure compound 24. LCMS (ESI+): found 395 [M+H]+, calculated 394.16 for C20H22BF3O4. Preparation 4,4,5,5-tetramethyl-2-(3-(trifluoromethoxy)-4-(4- (trifluoromethoxy)phenoxy)phenyl)-1,3,2-dioxaborolane 337c 11.0 g bromo derivative 333f, 2.16 g Pd(dppf)Cl2*DCM, 10.4 g potassium acetate and 10.1 g bis(pinacolato)diboron in 100 ml 1,4-dioxane were heated to 90°C until reaction was complete. Most of the solvent was evaporated, the residue absorbed on Celite and purified via normal phase column chromatography (330 g silica, cyclohexane / ethyl acetate gradient) to afford pure boronic ester 337c . LCMS (ESI+): found 465.3 [M+H]+, calculated 464.12 for C20H19BF6O5. 1-(4-chlorophenyl)-2,2-difluoroethan-1-ol 331a Dissolve 219 mg 4-chlorobenzaldehyde (1.0 eq.) in 12 ml dry DMF (0.1 M) and add 236 mg CsF (1.0 eq.). Heat up to 40°C, add 400 µL TMS-CF2H (2.0 eq.) and seal the LDC-P04374WO31 PCT Application (final).docx reaction vessel. Stir at 40°C for 4h. After completion of the addition add 3.1 mL 1M TBAF solution (2.0 eq.). After completion of the reaction add Celite and evaporate volatiles. Purify via reversed phase column chromatography (C18, acetonitrile / water) to yield 1-(4-chlorophenyl)-2,2-difluoroethan-1-ol. GCMS (EI): found 192.2[M]·+, calculated 192.0 for C8H7ClF2O 1-(3,4-dichlorophenyl)-2,2-difluoroethan-1-ol 331b 1-(3,4-dichlorophenyl)-2,2-difluoroethan-1-ol was prepared as exemplified for 1-(4- chlorophenyl)-2,2-difluoroethan-1-ol 331a. GCMS (EI): found 226.2 [M]+, calculated 226.0 for C8H6Cl2F2O 1-(4-chloro-3-fluorophenyl)-2,2-difluoroethan-1-ol 331c 1-(4-chloro-3-fluorophenyl)-2,2-difluoroethan-1-ol was prepared as exemplified for 1- (4-chlorophenyl)-2,2-difluoroethan-1-ol 331a. GCMS (EI): found 210.2 [M]+, calculated 210.0 for C8H6ClF3O 1-(3-chloro-4-methylphenyl)-2,2-difluoroethan-1-ol 331d 1-(3-chloro-4-methylphenyl)-2,2-difluoroethan-1-ol was prepared as exemplified for 1- (4-chlorophenyl)-2,2-difluoroethan-1-ol 331a. GCMS (EI): found 206.2[M]+, calculated 206.0 for C9H9ClF2O 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-ol 332a Dissolve 1500 mg 2-(benzyloxy)-5-bromobenzaldehyde (1.0 eq.) in 20 ml dry DMF (0.1 M) and add 782 mg CsF (1.1 eq.). Heat to 40°C, add 1.66 ml TMS-CF2H (2.5 eq.) to the reaction and seal the reaction vessel. Stir at 40°C for 4h. After completion of the addition add 10.3 ml 1M TBAF solution (2.0 eq.). After completion of the reaction add Celite and evaporate the solvent. Purify via normal phase column LDC-P04374WO31 PCT Application (final).docx chromatography (silica, cyclohexane / ethyl acetate / methanol gradient) to obtain 1-(2- (benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1 -ol. GCMS (El): found 342.4[M]’+, calculated 342.0 for C15H10BrF5O3

[0638] 1 -(5-bromo-2-(4-(trifluoromethoxy)phenoxy)phenyl)-2,2-difluoroethan-1-ol333a

[0639] F

[0640] Prepared from 5-bromo-2-(4-(trifluoromethoxy)phenoxy)benzaldehyde similar as exemplified for 1 -(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1 -ol. GCMS (El): found 412.2[M] ’+, calculated 412.0 for C15H13BrF2O2

[0641] 1 -(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1 -one 332b

[0642] Dissolve 500 mg 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-ol (1.0 eq.) in 4 ml dry DCM (0.1 M). Add 1235 mg Dess-Martin periodan (2.0 eq.) and seal the reaction vessel. Stir at 60°C for 6h. After completion of the reaction add Celite and evaporate volatiles. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain 1 -(2-(benzyloxy)-5-bromophenyl)-2,2- difluoroethan-1-one. GCMS (El): found 340.0[M]’+, calculated 340.0 for C15H11 BrF2O2.

[0643] 1 -(5-bromo-2-(4-(trifluoromethoxy)phenoxy)phenyl)-2,2-difluoroethan-1 -one 333b

[0644] F

[0645] Prepared from 1 -(5-bromo-2-(4-(trifluoromethoxy)phenoxy)phenyl)-2,2-difluoroethan- 1 -ol similar as exemplified for 1 -(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1- one. GCMS (El): found 410.0[M] ‘+, calculated 410.0 for C15H8BrF5O3 1 -(benzyloxy)-4-bromo-2-(1 , 1 ,2,2-tetrafluoroethyl)benzene 332c

[0646] Deoxofluor

[0647] DCM, 0-40°C Br

[0648] Dissolve 150 mg 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-one (1.0 eq.) in 5 ml dry DCM (0.1 M) and cool down to 0°C. Add 322 pl Deoxofluor (50 wt% in toluene, 2.1 eq.) and seal the reaction vessel. Stir at 20°C for 2h. After completion of the reaction add Celite and evaporate volatiles. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain 1 -(benzyloxy)- 4-bromo-2-(1 ,1 ,2,2-tetrafluoroethyl)benzene. GCMS (El): found 361.9[M]+, calculated 362.0 for C15H11 BrF4O

[0649] 1 -(benzyloxy)-4-bromo-2-(difluoromethyl)benzene 332d

[0650] Prepared from 2-(benzyloxy)-5-bromobenzaldehyde similar as exemplified for 1- (benzyloxy)-4-bromo-2-(1 ,1 ,2,2-tetrafluoroethyl)benzene. GCMS (El): found 312.0[M]+, calculated 312.0 for C14H11 BrF2O

[0651] 4-bromo-2-(difluoromethyl)-1-(4-(trifluoromethoxy)phenoxy)benzene 333d

[0652] F

[0653] F

[0654] Prepared from 5-bromo-2-(4-(trifluoromethoxy)phenoxy)benzaldehyde similar as exemplified for 1-(benzyloxy)-4-bromo-2-(1 ,1 ,2,2-tetrafluoroethyl)benzene. GCMS (El): found 382.2[M]+, calculated 382.0 for C14H8BrF5O2

[0655] 4-bromo-2-(1 ,1 ,2,2-tetrafluoroethyl)-1-(4-(trifluoromethoxy)phenoxy)benzene 333e F F

[0656] F

[0657] F

[0658] F

[0659] Prepared from 1 -(5-bromo-2-(4-(trifluoromethoxy)phenoxy)phenyl)-2,2-difluoroethan- 1-one similar as exemplified for 1-(benzyloxy)-4-bromo-2-(1 ,1 ,2,2- tetrafluoroethyl)benzene. GCMS (El): found 432.4[M]+, calculated 432.0 for C15H8BrF7O2

[0660] 1 -(benzyloxy)-4-bromo-2-(fluoromethyl)-benzene 332e

[0661] Deoxofluor

[0662] DCM, 0-40°C

[0663] Dissolve 250 mg (2-(benzyloxy)-5-bromophenyl)methanol (1.0 eq.) in 5 ml dry DCM (0.1 M) and cool down to 0°C. Add 314 pl Deoxofluor (50wt% in Toluene, 1.1 eq.) and seal the reaction vessel. Stir at 20°C for 2h. After completion of the reaction add Celite and evaporate the solvent. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain 1-(benzyloxy)-4-bromo-2- (fluoromethyl)-benzene. GCMS (El): found 294.0 [M]+, calculated 294.0 for C14H12BrFO

[0664] 4-bromo-2-(trifluoromethoxy)-1-(4-(trifluoromethoxy)phenoxy)benzene 333f

[0665] Dissolve 5 g 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene (1.0 eq.), 4.1 ml 4- (trifluoromethoxy)-phenol (1.5 eq.) and 5.3 g K2CO3 (3.0 eq.) in 20 ml dry DMSO (0.1 M). Stir the mixture in a sealed reaction vessel at 110°C for 3h. After reaction is completed add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain 4-bromo-2-(trifluoromethoxy)-1-(4-(trifluoromethoxy)phenoxy)benzene. GCMS (EI): found 416.3 [M]·+, calculated 415.9 for C14H7BrF6O3. 5-bromo-3-isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine 334a Dissolve 200mg 5-bromo-2-fluoro-3-isopropoxypyridine (1.0 eq.), 259uL 4- (trifluoromethoxy)phenol (1.5 eq.) and 402mg K2CO3 (3.0 eq.) in 2mL dry DMF (0.1 M). Stir the mixture in a sealed reaction vessel at 110°C for 3h. After reaction is completed add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain 5-bromo-3-isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine. LCMS (ESI+): found 392.1 [M+H]+, calculated 391.0 for C15H13BrF3NO3. 5-bromo-3-methyl-2-(4-(trifluoromethoxy)phenoxy)pyridine 334b Prepared from 5-bromo-2-fluoro-3-methylpyridine similar as exemplified for 5-bromo- 3-isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine. LCMS (ESI+): found 348.0 [M+H]+, calculated 347.0 for C13H9BrF3NO2 5-bromo-2-(4-(trifluoromethoxy)phenoxy)pyridine 334c Prepared from 5-bromo-2-fluoropyridine similar as exemplified for 5-bromo-3- isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine. LCMS (ESI+): found 334.1 [M+H]+, calculated 333.0 for C12H7BrF3NO2 LDC-P04374WO31 PCT Application (final).docx 5-bromo-3-(difluoromethyl)-2-(4-(trifluoromethoxy)phenoxy)pyridine 334d F

[0666] Prepared from 5-bromo-3-(difluoromethyl)-2-fluoropyridine similar as exemplified for 5-bromo-3-isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine. LCMS (ESI+): found 383.0 [M+H]+, calculated 383.0 for C13H7BrF5NO2

[0667] 5-bromo-3-methoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine 334e o—

[0668] Prepared from 5-bromo-2-fluoro-3-methoxypyridine similar as exemplified for 5- bromo-3-isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine. LCMS (ESI+): found 363.0 [M+H]+, calculated 363.0 for C13H9BrF3NO3

[0669] 5-bromo-3-chloro-2-((4-methylbenzyl)oxy)pyridine 334f

[0670] K2CO3

[0671] DMSO, 120°C 10min MW

[0672] Dissolve 200 mg 5-bromo-3-ch loro-2 -fluoropyridine (1.0 eq.), 151 mg p-tolylmethanol (1.3 eq.) and 438 mg K2CO3 (2.0 eq.) in 6 ml dry DMSO (0.15 M). Seal the reaction vessel and stir for 10 min at 120°C under microwave irradiation. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to yield 5- bromo-3-chloro-2-((4-methylbenzyl)oxy)pyridine. LCMS (ESI+): found 312.5 [M+H]+, calculated 311 .0 for C13H11 BrCINO

[0673] Similar to 5-bromo-3-chloro-2-((4-methylbenzyl)oxy)pyridine 334f other 5-bromo-2- alkoxypyridine derivates were synthesized, e.g. 5-bromo-3-chloro-2-(1 - phenylethoxy)pyridine (LCMS (ESI+): found 312.1 [M+H]+, calculated 311.0 for C13H11 BrCINO) and 5-bromo-3-chloro-2-((4-(difluoromethyl)benzyl)oxy)pyridine (LCMS (ESI+): found 348.0 [M+H]+, calculated 347.0 for C14H13BrCINO). Preparation of 2-(4-(benzyloxy)-3-cyclobutoxyphenyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane 337i

[0674] Dissolve 150 mg 2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (1.0 eq.) and 47 pl cyclobutanol (1.5 eq.) in 5 ml dry THF (0.1 M). Dry the solution over molecular sieve 4 A. Remove the molecular sieve, cool down to 0°C, add 241 mg TPP (2.2 eq.) and seal the reaction vessel. Stir at 0°C for 30 min, then add 187 mg TMAD (2.6 eq.) and stir for additional 30 min at 0°C. Heat to 55°C and stir overnight. After completion of the reaction add Celite and evaporate the solvent. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain 2-(4-(benzyloxy)-3-cyclobutoxyphenyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane. LCMS (ESI+): found 531.4 [M+H]+, calculated 530.2 for C23H29BO4

[0675] Building blocks in the following table A-5 were synthesized e.g. as exemplified by compound 17, 20, 24, 106, 131, 337c, 337i and others.

[0676]

[0677]

[0678] Preparation of 8-(4-((4-(difluoromethyl)benzyl)oxy)-3-fluorophenyl)-7-methyl-3-(3,3,3- trifluoro-2-hydroxypropyl)-3,7-dihydro-1 H-purine-2, 6-dione 18 To 730 mg bromide 4, 70 mg boronic ester 17, 100 mg K3PO4 and 26.6 mg Pd(dppf)Cl2 under nitrogen 3 ml 1 ,4-dioxane / water (5:1 ) were added and the mixture was heated to 100 °C until starting material was consumed. The mixture was absorbed on Celite, dried and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain compound 18. LCMS (ESI+): found 529.3 [M+H]+, calculated 528.12 for C23H18F6N4O4.

[0679] Preparation of 8-(4-(benzyloxy)-3-methoxyphenyl)-3-(3,3-difluoro-2-hydroxypropyl)-7- methyl-3,7-dihydro-1 H-purine-2, 6-dione 68

[0680] 1) Pd(dppf)Cl2K3PO4

[0681] 1,4-dioxane / water, 100°C

[0682] ) 2 M HC1 (aq.) / THF, 60 °C

[0683] To 50 mg bromide 10, 66 mg boronic ester 20, 70 mg K3PO4 and 18.7 mg Pd(dppf)Cl2 under nitrogen 3 ml 1 ,4-dioxane / water (5:1 ) were added and the mixture was heated to 100 °C until starting material was consumed. The mixture was absorbed on Celite, dried and purified by normal phase column chromatography

[0684] (silica, cyclohexane / ethyl acetate gradient) to obtain the protected intermediate. The protecting group was removed by dissolving the intermediate in 1.5 ml THF / 200 pl 2M aqueous hydrochloric acid and stirring the mixture at 60 °C overnight. The mixture was absorbed on Celite and purified by reversed phase column chromatography (RP18, water / acetonitrile gradient) to give compound 68. LCMS (ESI+): found 473.3 [M+H]+, calculated 472.16 for C23H22F2N4O5.

[0685] Preparation of 8-(4-(benzyloxy)-3-(trifluoromethoxy)phenyl)-3-(2-hydroxypropyl)-7- methyl-3,7-dihydro-1 H-purine-2, 6-dione 120

[0686] CsF

[0687] EtOH / DMSO, 60°C

[0688] Dissolve 150 mg 8-(4-(benzyloxy)-3-(trifluoromethoxy)phenyl)-3-(2-( (tertbutyldimethylsilyl)oxy)-propyl)-7-methyl-3,7-dihydro-1 H-purine-2, 6-dione (1 .0 eq.) and 192 mg CsF (5.0 eq.) in 5 ml dry EtOH / DMSO 9 / 1 (0.1 M). Seal the reaction vessel and stir at 80°C overnight. After completion of the reaction add Celite and evaporate volatiles. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient) to obtain 8-(4-(benzyloxy)-3- (trifluoromethoxy)phenyl)-3-(2-hydroxypropyl)-7-methyl-3,7-dihydro-1 H-purine-2, 6- dione 120 LCMS (ESI+): found 491 ,2[M+H]+, calculated 490.1 for C23H21 F3N4O5.

[0689] Preparation of 8-(5-chloro-6-((4-chloro-3-fluorobenzyl)oxy)pyridin-3-yl)-7-methyl-3-

[0690] (3, 3, 3-trifluoro-2-hydroxypropyl)-3,7-dihydro-1 H-purine-2, 6-dione 299

[0691] Dissolve 150 mg 3-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine (1.5 eq.), (4-chloro-3-fluorophenyl)methanol (1.5 eq.) and 90 mg K3PO4 (4.0 eq.) in 3 ml dry 1 ,4-dioxan (0.1 M). Stir the mixture in a sealed reaction vessel at 100°C for 5h. After the first reaction is completed add 35 mg 8-bromo-7-methyl-3-

[0692] (3,3,3-trifluoro-2-hydroxypropyl)-3,7-dihydro-1 H-purine-2,6-dione (1.0 eq.), 5.9 mg Pd(dppf)Cl2*DCM (0.05 eq.) and 750 pL water. Stir at 100°C for 2h. After the second reaction is completed add Celite and remove volatiles under reduced pressure. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain 8-(5-chloro-6-((4-chloro-3-fluorobenzyl)oxy)pyridin-3-yl)-7-methyl-3-(3,3,3- trifluoro-2-hydroxypropyl)-3,7-dihydro-1 H-purine-2, 6-dione. LCMS (ESI+): found 548.4 [M+H]+, calculated 547.0 for C21 H15CI2F4N5O4

[0693] Compounds in the following table A-6 were synthesized as exemplified by compound 18, 68, 120, 299 or others using 8-bromoxanthine derivatives e.g. disclosed in tables

[0694] A-1 or A-2 and boronic acids or esters e.g. commercially available or disclosed in table A-5 or made in analogy to the herein disclosed or to literature procedures.

[0695] Preparation of 8-bromo-3-(2-((tert-butyldimethylsilyl)oxy)propyl)-7-methyl-1 -((2-

[0696] (trimethylsilyl)ethoxy)methyl)-3,7-dihydro-1 H-purine-2, 6-dione 42 DIPEA

[0697] THF, RT

[0698] 3.0 g compound 8 and 3.74 ml DIPEA were dissolved in 20 ml THF. 2.55 ml SEMCI were added at room temperature und the reaction mixture was stirred overnight. Additional SEMCI (0.5 ml) and DIPEA (1 ml) were added and the reaction was stirred at room temperature overnight again. Ethyl acetate was added and the organic phase was washed with saturated NaHCOs solution, dried over MgSCU and volatiles were removed under reduced pressure. The crude was pure enough to be used in the next reactions without further purification. LCMS (ESI+): found 547.3 [M+H]+, calculated 546.17 for C21 H39BrN4O4Si2.

[0699] Preparation of 3-(2-((tert-butyldimethylsilyl)oxy)propyl)-8-(3-fluoro-4-hydroxyphenyl)-

[0700] 7-methyl-1 -((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-1 H-purine-2, 6-dione 43

[0701] 2.5 g bromide 42, 1.3 g 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenol, 0.39 g Pd(dppf)Cl2*DCM and 2.91 g K3PO4 under an inert atmosphere in 30 ml 1 ,4-dioxane / water (4:1 ) were stirred at 90 °C overnight. The mixture was concentrated under reduced pressure and absorbed on Celite. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to yield phenol 43. LCMS (ESI+): found 579.4 [M+H]+, calculated 578.28 for C27H43FN4O5Si2.

[0702] Preparation of 8-(4-(benzyloxy)-3-fluorophenyl)-3-(2-hydroxypropyl)-7-methyl-3,7- dihydro-1 H-purine-2, 6-dione 44 1 ) PPh3,TMAD, THF, 0°C to

[0703] 2) THF / conc. HCI, 30°C

[0704] 3) NH3 / 1,4-dioxane, RT

[0705] 30 mg phenol 43 and 12 mg benzyl alcohol were dissolved in 1.5 ml THF and dried over 4 A molecular sieves. This solution was then transferred to 30 mg triphenylphosphine in 0.5 ml THF under a nitrogen atmosphere at 0°C. After 30 min TMAD was added and after additional 30 min at 0°c the mixture was heated to 55 °C overnight. The mixture was absorbed on Celite and purified via normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient) to give the protected intermediate. To remove both protecting groups the crude was dissolved in 750 pl THF and 750 pl concentrated aqueous hydrochloric acid were added. After stirring at 30 °C volatiles were removed and the crude was dissolved in 2 ml ammonia (0.5 M solution in dry 1 ,4-dioxane) at room temperature. After 5 min volatiles were removed again, the crude dissolved in some DMSO and directly purified by reversed-phase HPLC (C18 column, water (0.1 %TFA) I acetonitrile (0.1 %TFA) gradient). The desired fractions were lyophilized to yield title compound 44. LCMS (ESI+): found 425.3 [M+H]+, calculated 424.15 for C22H21 FN4O4.

[0706] Preparation of 8-(4-(4-chlorophenoxy)-3-fluorophenyl)-3-(2-hydroxypropyl)-7-methyl-

[0707] 3,7-dihydro-1 H-purine-2, 6-dione 197

[0708] 130 mg phenol 43, 218 mg iodonium salt 159 and 62 mg K2CO3 in 4 ml acetonitrile were stirred at 55 °C until full conversion of the phenol. The mixture was absorbed on Celite and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). The protected intermediate was dissolved in 3 ml DCM and 500 pl TFA and stirred at 40 °C overnight. Volatiles were removed and the crude was dissolved in 3 ml ammonia (7 M solution in methanol) at room temperature. After 5 min volatiles were removed again, the crude dissolved in some DMSO and directly purified by reversed-phase HPLC (C18 column, water (0.1 %TFA) I acetonitrile (0.1 %TFA) gradient). The desired fractions were lyophilized to yield title compound 197. LCMS (ESI+): found 445.4 [M+H]+, calculated 444.1 for C21 H18CIFN4O4.

[0709] Preparation of 3-(2-((tert-butyldimethylsilyl)oxy)propyl)-8-(4-hydroxy-3-

[0710] (trifluoromethyl)phenyl)-7-methyl-3,7-dihydro-1 H-purine-2, 6-dione 154

[0711] 100 mg bromide 8, 104 mg 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)phenol, 30.4 mg Pd(dppf)2CI*DCM and 153 mg K3PO4 under inert atmosphere were mixed with 2.5 ml 1 ,4-dioxane / water (4:1 ) and stirred at 90 °C overnight. The mixture was concentrated under reduced pressure and absorbed on Celite. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to yield phenol 154. LCMS (ESI+): found 499.2 [M+H]+, calculated 498.19 for C22H29F3N4O4Si.

[0712] Preparation of 3-(2-hydroxypropyl)-7-methyl-8-(3-(trifluoromethoxy)-4-(4-

[0713] (trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1 H-purine-2, 6-dione 155 o'-'

[0714] 100 mg phenol 154, 138 mg iodonium salt 104 and 111 mg K2CO3 in 4 ml acetonitrile were stirred at 55 °C until full conversion of the phenol. The mixture was absorbed on Celite and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient). The protected intermediate was dissolved in 2 ml THF and 500 pl concentrated hydrochloric acid and stirred at 28 °C overnight. Purification was achieved by reversed-phase HPLC (C18 column, water (0.1 %TFA) I acetonitrile (0.1 %TFA) gradient). The desired fractions were lyophilized to yield title compound 155. LCMS (ESI+): found 545.2 [M+H]+, calculated 544.12 for C23H18F6N4O5. Preparation of 3-(2-((tert-butyldimethylsilyl)oxy)propyl)-8-(4-hydroxy-3-

[0715] (trifluoromethyl)phenyl)-7-methyl-3,7-dihydro-1 H-purine-2, 6-dione 157

[0716] Pd(dppf)CI2, K3PO4

[0717] 1 ,4-dioxane / water, 90°C

[0718] 100 mg bromide 8, 104 mg 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- (trifluoromethoxy)phenol, 30.4 mg Pd(dppf)Cl2*DCM and 153 mg K3PO4 under inert atmosphere were mixed with 2.5 ml 1 ,4-dioxane / water (4:1 ) and stirred at 90 °C overnight. The mixture was concentrated under reduced pressure and absorbed on Celite. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to yield phenol 157. LCMS (ESI+): found 515.5 [M+H]+, calculated 514.19 for C22H29F3N4OOSi.

[0719] Preparation of 3-(2-hydroxypropyl)-7-methyl-8-(3-(trifluoromethoxy)-4-(4-

[0720] (trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1 H-purine-2, 6-dione 156 ox'

[0721] 100 mg phenol 157, 138 mg iodonium salt 104 and 111 mg K2CO3 in 4 ml acetonitrile were stirred at 55 °C until full conversion of the phenol. The mixture was absorbed on Celite and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient). The protected intermediate was dissolved in 2 ml THF and 500 pl concentrated hydrochloric acid and stirred at 28 °C overnight. Purification was achieved by reversed-phase HPLC (C18 column, water (0.1 %TFA) I acetonitrile (0.1 %TFA) gradient). The desired fractions were lyophilized to yield title compound 156. LCMS (ESI+): found 561.1 [M+H]+, calculated 560.11 for C23H18F6N4O6.

[0722] Compounds in the following table A-7 were synthesized as exemplified by compound 44, 155, 156, 197 or others. Biological Examples

[0723] 1. Example B-1 : Immunostimulation assays with CD4+ and CD8+ T-cells

[0724] In Example B-1 the principle of selection of potent compounds based on structure activity relation (SAR) using human, anti-CD3 / 28 stimulated T-cells is shown. Enhanced activation of stimulated T-cells is measured by CD69 expression by flowcytometry.

[0725] 1 .1 Materials for Bioassay

[0726] 1 .2 Procedure I Description

[0727] 1.2.1 Collection of PBMCs from buffy Coat

[0728] White blood cell enriched buffy coats were ordered from the Austrian red cross, diluted with PBS to a total volume of 480 ml, 30 ml transferred to 50ml falcons and 11 ml lymphoprep added. Cell suspensions were centrifuged for 20 min at 2200 rpm and the PBMC containing layer transferred, three times washed with PBS and counted.

[0729] 1 .2.2 Isolation of CD4+ and CD8+ T-Cells

[0730] 10A7 PBMCs were magnetically labeled with CD4 and CD8 microbeads according to manufacturer’s instructions and separated using autoMACS device. For dose response experiments with purified CD4+CD8+ T-cells 80000 cells were seeded per 96-well flat bottom cell culture dish.

[0731] 1 .2.3 Serial dilution of compounds of the invention

[0732] 10 mM compounds of the invention stocks were further diluted using DMSO and equal amounts transferred to T-cell containing 96-wells. Final concentrations tested were: 30 pM, 10 pM, 3 pM, 1 pM, 0.3 pM, 0.1 pM, 0.03 pM, 0.01 pM, 0.003 pM and 0.001 pM.

[0733] 1 .2.4 Stimulation setup for EC50 testing

[0734] For the stimulation assays 80.000 purified CD4+ and CD8+ T-cells were seeded per 96-well and incubated with 1 pg / ml anti-CD3, 1 pg / ml anti-CD28 and compounds of the invention ranging from 0.001 pM to 30 pM. DMSO only wells served as control to determine minimal T-cell activation upon stimulation and CD3 / 28 coupled Dynabeads were used to determine the maximal activation of T-cells. Cells were cultured for 16 hours in a humidified incubator at 37 °C and 5 % CO2.

[0735] 1 .2.5 Determination of EC50 values for compounds of the invention by surface FACS

[0736] T-cells were stained for surface antigens (anti-CD4 and anti-CD8) and cell activation markers (anti-CD25 and anti-CD69). Additionally, a fixable viability dye was used to stain viable cells. Staining was performed for 15 minutes and cells analyzed using a Fortessa flow cytometer and FlowJo Software. EC50S were calculated using GraphPad Prism® and a variable slope model (agonist vs. response - variable slope).

[0737] The assay results are summarized in Table B-1 .

[0738] Table B-1 shows immunostimulation assay data. Immunostimulation of CD4+ and CD8+ T-cells are indicated as EC50 [nM] = not measured). Compounds having an activity designated as ”A” provided an ECso ^ 100 nM; compounds having an activity designated as ”B” provided an 100 nM < EC50 500 nM; compounds having an activity designated as ”C” provided an 500 nM < ECso ^ 1000 nM; compounds having an activity designated as ”D” provided an 1000 nM < EC50 5000 nM; compounds having an activity designated as ”E” provided an an ECso > 5000 nM. 2 Example B-2: In vitro killing potency

[0739] Compound 119, 142, 156, 120, 288, 248, 240, 238, 213, and 207 are tested for their potential to enhance PBMC or T cell mediated killing of allogeneic M21 melanoma cells using Xcelligence based methodology.

[0740] 2.1 Materials for Bioassay

[0741] 2.2 Procedure I Description

[0742] 2.2.1 Seeding of M21 melanoma cells

[0743] E-plates were coated with 10 pg / ml fibronectin for 1 hour at 37 °C. Sub-confluent M21 melanoma cells were trypsinized, counted and 5000 cells per fibronectin coated 96 well seeded in RPMI containing 10 % FCS and 1 % PenStrep. M21 cells were grown in a humidified incubator at 37 °C and 5 % CO2 and used for purified PBMCs or T cells co-culture 20-24 hours post seeding.

[0744] 2.2.2 Collection of PBMCs from buffy Coat

[0745] White blood cell enriched buffy coats were ordered from the Austrian red cross, diluted with PBS to a total volume of 480 ml, 30 ml transferred to 50 ml falcons and 11 ml lymphoprep added. Cell suspensions were centrifuged for 20 min at 2200 rpm and the PBMC containing layer transferred, three times washed with PBS and counted. For dose response experiments with PBMC co-cultures 25000 cells were seeded per M21 containing E-plate 96-well (PBMC to M21 5:1 ).

[0746] 2.2.3 Isolation of CD4+ and CD8+ T-Cells

[0747] 10A7 PBMCs were magnetically labeled with CD4 and CD8 microbeads according to manufacturer’s instructions and separated using autoMACS device. For dose response experiments with purified T-cell co-sultures 25000 cells were seeded per M21 containing E-plate 96-well (T cell to M21 5:1 ). 2.2.4 Serial dilution of compounds of the invention (LMW compounds)

[0748] 10 mM compound stocks of the invention were further diluted using DMSO and equal amounts transferred to M21 and PBMC or T-cell containing 96-wells. Final concentrations tested were: 10 pM, 3 pM, 1 pM, 0.3 pM, and 0.1 pM or 10 pM, 3 pM, 1 pM, 0.3 pM, and 0.1 pM, 0.03 pM,0.01 pM or 0.003 pM.

[0749] 2.2.5 Xcelligence in vitro killing assay

[0750] E-plates containing M21 cell layers and isolated PBMCs or T cells were incubated with 1 pg / ml anti-CD3, 1 pg / ml anti-CD28 and LMW compounds ranging from 0.1 pM to 10 pM. DMSO only and M21 only (without effector cells) wells and wells containing unstimulated effector cells without anti-CD3 / 28 addition served as control. E-plates were cultured for 40 hours in a humidified incubator at 37 °C and 5 % CO2 and M21 growth was monitored every 15 min using an Xcelligence device.

[0751] 2.2.6 Determination of EC50 values for compounds of the invention using Xcelligene

[0752] Xcelligence data were analysed using GraphPad Prism and EC50s calculated using a variable slope model (agonist vs. response - variable slope).

[0753] 2.3 Results

[0754] 2.3.1 In vitro killing assay using stimulated PBMCs

[0755] Stimulated PBMCs from two different donors were used to assess M21 melanoma cell killing in the presence of Compound 142 at 5 different concentrations over the course of 40 hours. PBMCs from both donors showed efficient M21 killing upon anti- CD3 / CD28 stimulation and + / - Compound 142 addition but no dose dependency upon increasing Compound 142 doses (Fig 3A and 3B).

[0756] Fig. 3A and 3B depict M21 cell growth upon stimulated PBMC co-culture. M21 melanoma cells were incubated with isolated PBMCs and stimulated with anti- CD3 / 28 and Compound 142 at 5 different concentrations.

[0757] 2.3.2 In vitro killing assay using stimulated CD4+ and CD8+ T cells

[0758] Stimulated CD4+ and CD8+ T cells from one donor (Donor 2) were co-cultured with M21 melanoma cells upon Compound 142 addition and cell growth monitored for 40 hours. EC50 was calculated at 32 hours post anti-CD3 / 28 and Compound 142 addition using GraphPad Prism. Purified T cells showed dose-dependent M21 killing upon anti-CD3 / CD28 stimulation and increasing concentrations of Compound 142 with an EC50 of 628 nM at 32 hours (Fig 4A and 4B).

[0759] Fig. 4A and 4B depict M21 cell growth upon stimulated T cell co-culture. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / 28 and Compound 142 at different concentrations. EC50 was calculated at 32 hours post anti-CD3 / 28 and Compound 142 addition using GraphPad Prism.

[0760] Stimulated CD4+ and CD8+ T cells from another donor were co-cultured with M21 melanoma cells upon Compound 142 (Donor 3), Compound 156 (Donor 1 ) or Compound 119 (Donor 1 ) addition at different concentrations and cell growth monitored for 40 hours. Purified T cells showed dose-dependent M21 killing upon anti-CD3 / CD28 stimulation and increasing concentrations of Compounds 142, 156 or 119 (Fig 5A-C).

[0761] Fig. 5A-C depict M21 cell growth upon stimulated T cell co-culture. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti- CD3 / 28 and Compound 142, Compound 156 or Compound 119 at different concentrations.

[0762] Stimulated CD4+ and CD8+ T cells from the same donor as above were co-cultured with M21 melanoma cells upon Compound 142, Compound 120, Compound 156, Compound 288, Compound 119, Compound 248, Compound 240, Compound 238, Compound 213 (active R enantiomer of Compound 238) or Compound 207 (active R enantiomer of Compound 240) addition and cell growth monitored for 40 hours. Purified T cells showed dose-dependent M21 killing upon anti-CD3 / CD28 stimulation and increasing concentrations of Compound 142, Compound 120, Compound 156, Compound 288, Compound 119, Compound 248, Compound 240, Compound 238, Compound 213 or Compound 207 (Fig 5D-M). ECsos were calculated 32 hours post compound addition using GraphPad Prism.

[0763] Fig 5D-M depict M21 cell growth upon stimulated T cell co-culture. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti- CD3 / 28 and Compound 142, Compound 120, Compound 156, Compound 288, Compound 119, Compound 248, Compound 240, Compound 238, Compound 213 or Compound 207 at different concentrations.

[0764] 2.3.3 In vitro killing assay using unstimulated PBMCs and T Cells

[0765] The killing efficiencies of unstimulated PBMCs as well as CD4+ and CD8+ T cells from one donor (Donor 2) co-cultured with M21 melanoma cells were assessed in the presence of 10 pM Compound 142. Unstimulated PBMCs cultured together with M21 cells showed efficient killing upon Compound 142 addition compared to DMSO control, purified T and M21 cell co-culture on the other hand did not show enhanced killing over the course of 40 hours (Fig 6).

[0766] Fig. 6 depicts M21 cell growth upon unstimulated PBMC and T cell co-culture. M21 melanoma cells were incubated with unstimulated PBMCs or T cells and 10pM Compound 142. 3 Example B-3: Efficacy on B16-SIY melanoma

[0767] Compounds 142, 156, 120, 119, 288, 248, 240, 238, 213, 207, 260, 262, and 329 show preclinical efficacy in a murine B16-SIY melanoma model.

[0768] Individual compounds of the invention were selected based on their potency, ADME and PK profile and tested in immune competent C57BL / 6J mice transplanted with B16-SIY melanoma cells.

[0769] 3.2 Procedure I Description

[0770] 3.2.1 Animals and Ethics

[0771] Eight-weeks-old C57BL / 6 mice were purchased from Charles River. All animal experiments were in accordance with institutional guidelines of the Research Institute of Molecular Pathology (Austria) and approved according to the European Community rules of animal care with the permission of the Austrian Ministry of Science. Mice were sacrificed when the tumor volume was > 1000 mm3or humane endpoints were reached. 3.2.2 B16-SIY cell culture

[0772] B16-SIY melanoma cells were cultured in DMEM containing 10 % FCS, 1 % PenStrep and 1 % glutamine and grown in a humidified incubator at 37 °C and 5 % CO2. For tumor inoculations sub-confluent B16-SIYcells were trypsinized, washed, counted and resuspended in PBS or 50 % PBS and 50 % matrigel to a final concentration of 1x107B16-SIY cells / ml.

[0773] 3.2.3 Tumor inoculation and compound treatment

[0774] 3.2.3.1 Efficacy Experiment 1 : Compound 142

[0775] 30 C57BL / 6 mice were inoculated intradermally with 1x106B16-SIY cells and tumor bearing mice randomly assigned to 3 different groups 3 days post transplantation: Compound 142 30 mg / kg 3 days post B16-SIY inoculation and subsequent daily administration of 10 mg / kg (10 mice), Compound 142 9 mg / kg 3 days post B16-SIY inoculation and subsequent daily treatment of 3 mg / kg (10 mice), or vehicle control (10 mice). Compound 142 was diluted in 10 % DMSO, 20 % PEG400, 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O and mice treated p.o. with 2 different treatment schedules: d3: 30 mg / kg + QD: 10 mg / kg or d3: 9 mg / kg + QD: 3 mg / kg (Figure 1 ). 10 % DMSO, 20 % PEG400 and 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O served as vehicle control. Tumors were measured daily and mice sacrificed 21 days post B16-SIY inoculation (Figure 1 ).

[0776] 3.2.3.2 Efficacy Experiment 2: Compound 142

[0777] 30 C57BL / 6 mice were inoculated intradermally with 1x106B16-SIY cells and tumor bearing mice randomly assigned to 3 different groups 3 days post transplantation: Compound 142 treated (10 mice, 60 mg / kg D3 + 40 mg / kg Q2D; 40 mg / kg were administered every 48 hours except for 7 days (30 mg / kg) and 9 days (60 mg / kg) post inoculation), vehicle control (10 mice, 100pl QD) or left untreated (10 mice). Compound 142 was diluted in 10 % DMSO, 20 % PEG400, 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O and mice treated p.o. with different treatment regimes (Fig 7). Mice receiving Compound 142 were treated with 60 mg / kg 3 days post B16-SIY inoculation followed by 40 mg / kg Compound 142 every 48 hours (60 mg / kg D3 + 40 mg / kg Q2D*) except for 7 days (30 mg / kg) and 9 days (60 mg / kg) post inoculation. Tumors were measured daily and mice sacrificed 19 days post B16-SIY inoculation.

[0778] Fig. 7 shows the treatment schedule for POC study monitoring tumor volume and survival rate of mice for Compound 142 in in vivo efficacy experiments with p.o. compound administration. Arrows indicate p.o. drug treatment with Compound 142.

[0779] Asterisk indicates 40 mg / kg Compound 142 treatment every 48 hours except for day 7 (30 mg / kg) and day 9 (60 mg / kg). 3.2.3.3 Efficacy Experiment 3: Compound 142

[0780] 35 C57BL / 6J mice were inoculated intradermally with 1x106B16-SIY cells and tumor bearing mice randomly assigned to 3 different groups 3 days post transplantation: Compound 142 30 mg / kg 4 days post B16-SIY inoculation and subsequent daily administration of 10 mg / kg (10 mice, 30 mg / kg D4 + 10 mg / kg QD), Compound 142 9 mg / kg 4 days post B16-SIY inoculation and subsequent daily treatment of 3 mg / kg (10 mice, 9 mg / kg D4 + 3 mg / kg QD), or vehicle control (10 mice, 100pl QD). Compound 142 was diluted in 10 % DMSO, 20 % PEG400, 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O and mice treated p.o. with 2 different treatment schedules (Fig 8). 10 % DMSO, 20 % PEG400 and 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O served as vehicle control. Tumors were measured daily and mice sacrificed 21 days post B16-SIY inoculation.

[0781] Fig. 8 shows the treatment schedule for POC study monitoring tumor volume and survival rate of mice for Compound 142 in in vivo efficacy experiments with p.o. compound administration. Arrows indicate p.o. Compound 142 administration.

[0782] 3.2.3.4 Efficacy Experiment 4: Compound 142 or 120

[0783] 40 C57BL / 6J mice were inoculated intradermally with 1x106B16-SIY cells and tumor bearing mice randomly assigned to 4 different groups 3 days post transplantation: Compound 142 treated (10 mice, 30 mg / kg D4 + 10 mg / kg QD), Compound 142 treated (10 mice, 30 mg / kg Q3D), Compound 120 (10 mice, 25 mg / kg QD), and vehicle control (10 mice, 10OpI QD). Compound 142 and Compound 120 were diluted in 10 % DMSO, 20 % PEG400, 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O and mice treated p.o. (Fig 9). 10 % DMSO, 20 % PEG400 and 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O served as vehicle control. Tumors were measured daily and mice sacrificed 20 days post B16-SIY inoculation.

[0784] Fig. 9 shows the treatment schedule for POC study monitoring tumor volume and survival rate of mice for Compound 142 or Compound 120 in in vivo efficacy experiments with p.o. compound administration. Black arrows indicate daily p.o. Compound 142 or Compound 120 administration, grey arrows depict p.o. Compound 142 treatment every third day.

[0785] 3.2.3.5 Efficacy Experiment 5: Compound 142, 156 or 119

[0786] 40 C57BL / 6J mice were inoculated intradermally with 1x106B16-SIY cells and tumor bearing mice randomly assigned to 4 different groups 3 days post transplantation: Compound 142 treated (10 mice, 30 mg / kg D4 + 10 mg / kg QD), Compound 156 (10 mice, 20 mg / kg D4 + 10 mg / kg QD), Compound 119 (10 mice, 10 mg / kg QD) and vehicle control (10 mice, 10OpI QD). Compound 142, 155 and 119 were diluted in 10 % DMSO, 20 % PEG400, 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O and mice treated p.o. (Fig 10). 10 % DMSO, 20 % PEG400 and 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O served as vehicle control. Tumors were measured daily and mice treated 4 days to 21 days after B16-SIY inoculation followed by a 40 days treatment free observation period. Mice were sacrificed when the tumor volume was > 1000 mm3or humane endpoints were reached. Mice surviving beyond day 61 were rechallenged on day 62 with an additional intradermal B16-SIY cell inoculation as described above.

[0787] Fig. 10 shows the treatment schedule for POC study monitoring tumor volume and survival rate of mice for Compound 142, 156 or 119 in in vivo efficacy experiments with p.o. compound administration. Arrows indicate daily p.o. Compound 142, 156 or 119 administration.

[0788] 3.2.3.6 Efficacy Experiment 6: Compound 142, 156 and 119

[0789] 55 C57BL / 6J mice were inoculated intradermally with 1x106B16-SIY cells and tumor bearing mice randomly assigned to 5 different groups 6 days post transplantation followed by daily administration on day 7: Compound 142 treated (10 mice, 30 mg / kg D7 + 10 mg / kg QD), Compound 156 treated (10 mice, 20 mg / kg D7 + 10 mg / kg QD), Compound 156 treated (10 mice, 6 mg / kg D7 + 3 mg / kg QD), Compound 119 (10 mice, 10 mg / kg QD) and vehicle control (10 mice, 100 pl QD). Compound 142, 156 and 119 were diluted in 10 % DMSO, 20 % PEG400, 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O and mice treated p.o. (Fig. 11 ). 10 % DMSO, 20 % PEG400 and 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O served as vehicle control. Tumors were measured daily and mice sacrificed when the tumor volume was > 1000 mm3or humane endpoints were reached. Mice surviving beyond day 65 were rechallenged on day 66 with an additional intradermal B16-SIY cell inoculation as described above and terminated on day 82.

[0790] Fig. 11 shows the treatment schedule for POC study monitoring tumor volume and survival rate of mice for Compound 142, 156 or 119 in in vivo efficacy experiments with p.o. compound administration. Arrows indicate daily p.o. Compound 142, 156 or 119 administration.

[0791] 3.2.3.7 Efficacy Experiment 7: Compound 156 and anti-PD1

[0792] 41 C57BL / 6J mice were inoculated intradermally with 1x106B16-SIY cells and tumor bearing mice randomly assigned to 4 different groups (10 mice / group) 3 days post transplantation. Group 1 received Compound 156 (30 mg / kg D3 + 10 mg / kg QD) and rat lgG2a isotype control antibody (BioXcell, clone 2A3; 10 mg / kg BIW), group 2 Compound 156 (30 mg / kg D3 + 10 mg / kg QD) and anti-PD1 antibody (BioXcell, clone RMP1 -14; 10 mg / kg BIW), group 3 vehicle control (1 OOpI QD) and rat lgG2a isotype control antibody (BioXcell, clone 2A3; 10 mg / kg BIW) and group 4 vehicle control (1 OOpI QD) and anti-PD1 antibody (BioXcell, clone RMP1 -14; 10 mg / kg BIW). Compound 156 was diluted in 10 % DMSO, 20 % PEG400, 21 % HPbCD, 0,35 % HPMC and 48,65 % H2O and mice treated p.o. (Fig 23). 10 % DMSO, 20 % PEG400 and 21 % HPbCD, 0,35 % HPMC and 48,65 % H2O served as vehicle control. Anti- PD1 and isotype control antibodies were diluted in PBS and i.p. administered. Tumors were measured 3 times a week and mice treated 3 days to 19 days after B16-SIY inoculation. Mice were sacrificed on D19 or when the tumor volume was > 2000 mm3or humane endpoints were reached.

[0793] Fig. 23 shows the treatment schedule for Compound 156, isotyp control and anti-PD1 in vivo efficacy experiments with p.o. compound and i.p. antibody administration. Black arrows indicate daily p.o. Compound 156 administration, grey arrows depict i.p. antibody treatment twice a week.

[0794] 3.2.3.8 Efficacy Experiment 8: Compound 156, 238, 213, 207, and 248

[0795] 125 C57BL / 6J mice were inoculated intradermally with 1x106B16-SIY cells and tumor bearing mice randomly assigned to 11 different groups 3 days post transplantation: Compound 156 (10 mice, 10 mg / kg QD), 2 groups Compound 248 (20 mice, 20 mg / kg D4 + 10 mg / kg QD), Compound 238 (10 mice, 20 mg / kg D4 + 10 mg / kg QD), Compound 207 (10 mice, 20 mg / kg D4 + 10 mg / kg QD), Compound 213 (10 mice, 20 mg / kg D4 + 10 mg / kg QD), Compound 248 (10 mice, 20 mg / kg QD), Compound 248 (10 mice, 6 mg / kg D4 + 3 mg / kg QD), Compound 248 (10 mice, 2 mg / kg D4 + 1 mg / kg QD) and 2 groups vehicle control (20 mice, 100pl QD). Compound 156, 843, 207 and 213 were diluted in 10 % DMSO, 20 % PEG400, 21 % HPbCD, 0,35 % HPMC and 48,65 % H2O. Compound 248 was diluted in 10 % DMSO, 20 % PEG400, 21 % HPbCD, 0,35 % HPMC and 48,65 % H2O or 20% transcutol, 20% TPGS, 0,6 % HPMC and 59,4 % H2O. 10 % DMSO, 20 % PEG400 and 21 % HPbCD, 0,35 % HPMC and 48,65 % H2O or 20% transcutol, 20% TPGS, 0,6 % HPMC and 59,4 % H2O served as vehicle control. Tumors were measured 3 times a week and mice treated 4 days to 21 days after B16-SIY inoculation followed by a 40 days treatment free observation period (Fig 25). Mice were sacrificed when the tumor volume was > 1000 mm3or humane endpoints were reached. Mice surviving beyond day 61 were rechallenged on day 62 with an additional intradermal B16-SIY cell inoculation as described above and terminated on day tbd (experiment ongoing).

[0796] Fig. 25 shows the treatment schedule for Compound 156, 238, 213, 207, and 248 of experiment 8 in vivo efficacy experiments with p.o. compound administration monitoring tumor volume and survival rate of mice. Arrows indicate p.o. drug treatment.

[0797] 3.2.3.9 Efficacy Experiment 9: Compound 156, 329, 213, and 262

[0798] C57BL / 6J mice were inoculated intradermally with 1x106B16-SIY cells and tumor bearing mice randomly assigned to 10 different groups 3 days post transplantation:

[0799] Compound 156 (8 mice, 10 mg / kg QD), Compound 329 (8 mice, 10 mg / kg QD),

[0800] Compound 213 (8 mice, 10 mg / kg QD), Compound 213 (8 mice, 25 mg / kg QD),

[0801] Compound 213 (8 mice, 60 mg / kg QD), Compound 262 (8 mice, 10 mg / kg QD), Compound 329 (7 mice, 20 mg / kg QD) and vehicle control (8 mice, 100pl QD). Compound 156, 329, 213, or 262 were diluted in 20% transcutol, 20% TPGS, 0,6 % HPMC and 59,4 % H2O. 20% transcutol, 20% TPGS, 0,6 % HPMC and 59,4 % H2O served as vehicle control. Tumors were measured 3 times a week and mice treated 4 days to 21 days after B16-SIY inoculation followed by a treatment free observation period (Fig 27, experiment ongoing). Mice were sacrificed when the tumor volume was > 1000 mm3or humane endpoints were reached.

[0802] Fig. 27 shows the treatment schedule for Compound 156, 329, 213, and 262 in vivo efficacy experiments with p.o. compound administration monitoring tumor volume and survival rate of mice (data not shown - experiment ongoing). Arrows indicate p.o. drug treatment.

[0803] 3.3 Results

[0804] 3.3.1 Efficacy Experiment 1 : Compound 142

[0805] C57BL / 6 mice were inoculated intradermally with B16-SIY cells and treated p.o. with 30 mg / kg compound 142 3 days post B16-SIY injection followed by daily administration of 10 mg / kg (d3: 30 mg / kg + QD: 10 mg / kg) or received 9 mg / kg compound 142 3 days post B16-SIY inoculation followed by 3 mg / kg daily (d3: 9 mg / kg + QD: 3 mg / kg). Vehicle treated mice were used as controls. Tumor volumes in mice upon treatment with both compound 142 regimes were significantly reduced compared to vehicle control over the course of 21 days (Figure 2).

[0806] 3.3.2 Efficacy Experiment 2: Compound 142

[0807] C57BL / 6J mice were inoculated intradermally with B16-SIY cells and treated p.o. with 60 mg / kg Compound 142 3 days post B16-SIY injection and subsequently 40 mg / kg Compound 142 every 48 hours (60 mg / kg D3 + 40 mg / kg Q2D; 40 mg / kg were administered every 48 hours except for 7 days (30 mg / kg) and 9 days (60 mg / kg) post inoculation) except for 7 days (30 mg / kg) and 9 days (60 mg / kg) post inoculation. Mice receiving vehicle (100μl QD) or left untreated served as controls. Compound 142 administered mice showed a pronounced reduction in tumor size over the course of 19 days compared to all other treatment groups (Fig 12).

[0808] Fig. 12 shows the impast on in vivo tumor growth rate of Compound 142. Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 142 60 mg / kg D3 + 40 mg / kg Q2D* or vehicle. Asterisk indicates 40 mg / kg Compound 142 treatment every 48 hours except for day 7 (30 mg / kg) and day 9 (60 mg / kg). Statistically significant difference (p < 0.05) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis.

[0809] 3.3.3 Efficacy Experiment 3: Compound 142

[0810] C57BL / 6J mice were inoculated intradermally with B16-SIY cells and treated p.o. with

[0811] 30 mg / kg Compound 142 4 days post B16-SIY injection followed by daily administration of 10 mg / kg (30 mg / kg D4 + 10 mg / kg QD) or received 9 mg / kg Compound 142 4 days post B16-SIY inoculation followed by 3 mg / kg daily (9 mg / kg D4 + 3 mg / kg QD). Vehicle treated mice (1 OOpI QD) were used as controls. Tumor volumes in mice upon treatment with both Compound 142 regimes were significantly reduced compared to vehicle control over the course of 21 days (Fig 13).

[0812] Fig. 13 shows the impast on inv vivo tumor growth rate. Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 142 30 mg / kg D4 + 10 mg / kg QD, 9 mg / kg D4 + 3 mg / kg QD or vehicle. Statistically significant difference (p < 0.05) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis.

[0813] 3.3.4 Efficacy Experiment 4: Compound 142 or 120

[0814] C57BL / 6J mice were inoculated intradermally with B16-SIY cells and treated p.o. with 30 mg / kg Compound 142 4 days post B16-SIY injection followed by daily administration of 10 mg / kg (30 mg / kg D4 + 10 mg / kg QD) or 30 mg / kg Compound 142 4 days post B16-SIY inoculation followed by 30 mg / kg every third day (30 mg / kg Q3D). Compound 120 (25 mg / kg QD) was administered daily starting 4 days post B16-SIY inoculation, vehicle treated mice (100pl QD) served as controls. Tumor volumes in mice upon treatment with Compound 142 regime was significantly reduced compared to vehicle control over the course of 20 days. Compound 120 application did not affect tumor growth compared to vehicle treated control group (Fig 14).

[0815] Fig. 14 shows the impact of Compound 142 and 120 on in vivo tumor growth rate. Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 142 30 mg / kg D4 + 10 mg / kg QD or 30 mg / kg Q3D, Compound 120 25 mg / kg QD, or vehicle. Statistically significant difference (** p < 0.01 ) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis.

[0816] 3.3.5 Efficacy Experiment 5: Compound 142, 156 or 119

[0817] C57BL / 6J mice were inoculated intradermally with B16-SIY cells and treated p.o. with 30 mg / kg Compound 142 4 days post B16-SIY injection followed by daily administration of 10 mg / kg (30 mg / kg D4 + 10 mg / kg QD) until 21 days or 20 mg / kg Compound 156 4 days post B16-SIY inoculation followed by daily administration of 10 mg / kg (20 mg / kg D4 + 10 mg / kg QD) until 21 days. Compound 119 (10 mg / kg QD) was administered daily starting 4 days post B16-SIY inoculation until 21 days, vehicle treated mice (100μl QD) served as controls. Mice were subsequently observed without treatment for 40 days. Compound 142, 156 and 119 treated mice showed significantly reduced tumor volumes and prolonged survival compared to vehicle control over the course of 61 Days (Fig 15A-C). 3 mice receiving Compound 156 between 4 days and 21 days, survived beyond day 61 and were rechallenged on day 62 with an additional intradermal B16-SIY cell inoculation. 3 previously untreated mice without primary tumor were inoculated intradermally with B16-SIY cells and served as control.

[0818] Fig. 15A-C show the impact of Compound 142, 156 and 119 on in vivo tumor growth rate nd survival. A: Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 142 30 mg / kg D4 + 10 mg / kg QD, Compound 156 20 mg / kg D4 + 10 mg / kg QD, Compound 119 10 mg / kg QD or vehicle. Statistically significant difference (** p < 0.01 , **** p < 0.0001 ) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis. B: Survival of mice receiving p.o. treatment with Compound 142 30 mg / kg D4 + 10 mg / kg QD, Compound 156 20 mg / kg D4 + 10 mg / kg QD, Compound 119 10 mg / kg QD or vehicle. C: Average tumor volumes ± SEM and tumor volumes of individual mice with primary B16-SIY challenge or secondary B16-SIY rechallenge.

[0819] 3.3.6 Efficacy Experiment 6: Compound 142, 156 or 119

[0820] C57BL / 6J mice were inoculated intradermally with B16-SIY cells and treated p.o. with 30 mg / kg Compound 142 7 days post B16-SIY injection followed by daily administration of 10 mg / kg (30 mg / kg D7 + 10 mg / kg QD) until 21 days. 20 mg / kg Compound 156 was administered 7 days post B16-SIY inoculation followed by daily treatment with 10 mg / kg (20 mg / kg D7 + 10 mg / kg QD) until 21 days or 6 mg / kg Compound 156 7 days post B16-SIY inoculation followed by daily administration of 3 mg / kg (6 mg / kg D7 + 3 mg / kg QD) until 21 days. Compound 119 (10 mg / kg QD) was administered daily starting 7 days post B16-SIY inoculation until 21 days, vehicle treated mice (100 μl QD) served as controls. Mice were subsequently observed without treatment for 44 days. Compound 156 and Compound 119 treated mice showed significantly reduced tumor volumes and prolonged survival compared to vehicle control over the course of 65 Days (Fig 16). 1 mouse receiving Compound 156 20 mg / kg D7 + 10 mg / kg QD and 1 mouse receiving 6 mg / kg D7 + 3 mg / kg QD between 7 days and 21 days survived beyond day 65 and were rechallenged on day 66 with an additional intradermal B16-SIY cell inoculation. 3 previously untreated age matched mice without primary tumor were inoculated intradermally with B16-SIY cells and served as control. Rechallenged mice did not show primary or secondary B16- SIY tumor growth compared to control over the course of 16 days and were terminated on day 82.

[0821] Fig 16A and B depict the impact of Compound 142, 156 and 119 on in vivo tumor growth rate. A: Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 142, Compound 156 or Compund 119 7 to 21 days post B16-SIY inoculation. Statistically significant difference (** p < 0.01 , *** p < 0.001 ) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis. B: Survival of mice receiving p.o. treatment with Compound 142, Compound 156 or Compound 119 7 to 21 days post B16-SIY inoculation. 3.3.7 Efficacy Experiment 7: Compound 156 and anti-PD1

[0822] C57BL / 6J mice were inoculated intradermally with B16-SIY cells and treated p.o. with 30 mg / kg Compound 156 3 days post B16-SIY inoculation followed by daily administration of 10 mg / kg (30 mg / kg D3 + 10 mg / kg QD) until 19 days and additionally i.p. injected with anti-PD1 antibody (10 mg / kg BIW) or rat lgG2a isotype control antibody (10 mg / kg BIW) twice a week starting 4 days post tumor cell inoculation until 19 days. Vehicle treated mice (100pL / mouse QD) additionally injected with anti-PD1 antibody (10 mg / kg BIW) or rat lgG2a isotype control antibody (10 mg / kg BIW) twice a week starting 4 days post tumor cell inoculation until 19 days served as controls. Vehicle and anti-PD1 , Compound 156 and isotype control as well as Compound 156 and anti-PD1 treated mice showed significantly reduced tumor volumes compared to the vehicle and isotype control administered group over the course of 19 days. Compound 156 and anti-PD1 combination treatment showed the best response regarding tumor growth control and tumor weight (Fig. 24A-B).

[0823] Fig 24A and B depict Compound 156 and anti-PD1 antibody mono- and combinationtherapy impact on in vivo tumor growth rate. A: Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 156 or vehicle in combination with i.p. administration of anti-PD1 or rat lgG2a isotype control antibody 3 to 19 days post B16-SIY inoculation. Treatment groups were dosed as follows: (gray) vehicle [QD] p.o. + isotype [10mg / kg BIW] i.p.; (yellow) vehicle [QD] p.o. + anti-PD-1 [10mg / kg BIW] i.p.; (purple) Compound 156 [30mg / kg D3 + 10mg / kg QD] p.o. + isotype [10mg / kg BIW] i.p.; (turquoise) Compound 156 [30mg / kg D3 + 10mg / kg QD] p.o. + anti-PD-1 [10mg / kg BIW] i.p. Statistically significant difference (* p < 0.5, **** p < 0.0001 ) between treatment groups and vehicle control group was calculated using 2- way ANOVA analysis. B: Tumor weight of individual mice receiving p.o. and i.p. treatment as in A.

[0824] 3.3.8 Efficacy Experiment 8: Compound 156, 238, 213, 207, and 248

[0825] C57BL / 6J mice were inoculated intradermally with B16-SIY cells and treated p.o. with 10 mg / kg Compound 156 daily (10mg / kg QD) or 20 mg / kg Compound 248, Compound 238, Compound 207 (R enantiomer of Compound 240) or Compound 213 (R enantiomer of Compound 238) 4 days post B16-SIY inoculation followed by daily administration of 10 mg / kg (20 mg / kg D4 + 10 mg / kg QD) until 21 days. Compound 248 was furthermore assessed with the following dosing regimes: 20 mg / kg QD, 6 mg / kg D4 + 3 mg / kg QD, 2 mg / kg D4 + 1 mg / kg QD and the 20 mg / kg D4 + 10 mg / kg QD treatment schedule compared in two different formulations. Vehicle administered mice (100pL / mouse QD) treated from 4 days post B16-SIY inoculation until 21 days served as controls. Mice were subsequently observed without treatment for 40 days. Compound 156, Compound 248, Compound 238, Compound 207 and Compound 213 treated mice showed significantly reduced tumor volumes and prolonged survival compared to vehicle control over the course of 61 Days (Fig 26A-D). 4 mice receiving Compound 156, 6 mice receiving Compound 248 20 mg / kg QD, 6 mice receiving Compound 248 20 mg / kg D4 + 10 mg / kg QD, 3 mice receiving Compound 248 6 mg / kg D4 + 3 mg / kg QD, 5 mice receiving Compound 238, 1 mouse receiving Compound 207, 2 mice receiving Compound 213 and 2 mice receiving Compound 248 20 mg / kg D4 + 10 mg / kg QD in a different formulation between 4 days and 21 days survived beyond day 61 and were rechallenged on day 62 with an additional intradermal B16-SIY cell inoculation. 5 previously untreated mice without primary tumor were inoculated intradermally with B16-SIY cells and served as control (experiment ongoing).

[0826] Fig 26A to D depict Compound 156, 238, 213, 207, and 248 impact on in vivo tumor growth rate and survival. A: Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 156, Compound 248 or vehicle 4 to 21 days post B16-SIY inoculation. B: Survival of mice receiving p.o. treatment as in A. C: Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 156, 238, 213, 207, and 248 or vehicle 4 to 21 days post B16-SIY inoculation. D: Survival of mice receiving p.o. treatment as in C.

[0827] 3.3.9 Efficacy Experiment 9: Compound 156, 329, 213, and 262

[0828] C57BL / 6J mice were inoculated intradermally with B16-SIY cells and treated p.o. with 10 mg / kg Compound 156, Compound 329 (R enantiomer of Compound 248), Compound 213 (R enantiomer of Compound 238), and Compound 262, Compound 213 was furthermore assessed with the following dosing regimes: 25 mg / kg QD and 60 mg / kg QD and Compound 329 also at 20 mg / kg QD starting 4 days post inoculation until 21 days. Vehicle treated mice (100pL / mouse) served as controls. Mice were subsequently observed without treatment (experiment ongoing).

[0829] All compounds and treatment regimes resulted in significantly reduced tumor volumes and prolonged survival compared to vehicle control over the course of several days (Fig 28, experiment ongoing).

[0830] Fig. 28 depicts Compound 156, 329, 213, and 262 impact on in vivo tumor growth rate. Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 156, 329, 213, and 262 or vehicle 4 to 18 days post B16-SIY inoculation.

[0831] 4 Example B-4: Efficacy on EO771 breast cancer

[0832] Compounds 156 and 119 were selected based on their potency, ADME and PK profile and tested in immune competent C57BL / 6J mice transplanted with EO771 breast cancer cells. Compound formulation and dosing for proof of concept (POC) studies were based on PK testing at LDC (Lead Discovery Center, Dortmund).

[0833] Compounds 156 and 119 show preclinical efficacy in a murine EO771 breast cancer model. 4.1 Materials for Bioassay

[0834] 4.2 Procedure I Description

[0835] 4.2.1 Animals and Ethics

[0836] Eight-weeks-old C57BL / 6J mice were purchased from Charles River. All animal experiments were in accordance with institutional guidelines of the Research Institute of Molecular Pathology (Austria) and approved according to the European Community rules of animal care with the permission of the Austrian Ministry of Science.

[0837] 4.2.2 EO771 cell culture

[0838] EO771 breast cancer cells were cultured in DMEM containing 10 % FCS, 1 % PenStrep, 1 % sodium pyruvate, 1 % non-essential amino acid solution and 1 % L- glutamine and grown in a humidified incubator at 37 °C and 5 % CO2. For tumor inoculations sub-confluent EO771 cells were trypsinized, washed, counted, resuspended in 50 % PBS and 50 % matrigel to a final concentration of 20x106EO771 cells / ml. 4.2.3 Efficacy Experiment

[0839] 4.2.3.1 Tumor inoculation and compound treatment

[0840] Efficacy experiment 1 with treatment schedule for POC study monitors tumor volume and survival rate of mice treated p.o. drug treatment.

[0841] 46 C57BL / 6J mice were inoculated into the 4thmammary fat pad with 0,5x106EO771 cells and tumor bearing mice randomly assigned to 4 different groups 6 days post transplantation: Compound 142 treated (10 mice, 30 mg / kg D7 + 10 mg / kg QD), Compound 156 (10 mice, 20 mg / kg D7 + 10 mg / kg QD), Compound 119 (10 mice, 10 mg / kg QD) and vehicle control (10 mice, QD). Compounds 142, 156 and 119 were diluted in 10 % DMSO, 20 % PEG400, 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O and mice treated p.o from Day 7 to Day 21. 100 pL 10 % DMSO, 20 % PEG400 and 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O served as vehicle control. Tumors were measured daily and mice sacrificed when the tumor volume was > 700 mm3or humane endpoints were reached.

[0842] Fig. 17 depicts the treatment schedules for Compounds 142, 156 and 119 in in vivo efficacy experiments with p.o. compound administration. Arrows indicate p.o. drug treatment.

[0843] 4.3 Results

[0844] EO771 tumor bearing C57BL / 6J mice received 30 mg / kg Compound 142 7 days post EO771 injection followed by daily administration of 10 mg / kg (30 mg / kg D7 + 10 mg / kg QD) until 21 days or 20 mg / kg Compound 156 7 days post EO771 inoculation followed by daily administration of 10 mg / kg (20 mg / kg D7 + 10 mg / kg QD) until 21 days. Compound 119 (10 mg / kg QD) was administered daily starting 7 days post EO771 inoculation until 21 days, vehicle treated mice (100pL / mouse QD) served as controls. Mice were sacrificed when the tumor volume was > 700 mm3or humane endpoints were reached. Mice were subsequently observed without treatment for 40 days. Compound 156 administration resulted in complete tumor rejection in 8 out of 10 mice, Compound 119 treated mice showed a reduced tumor growth rate compared to vehicle control beyond the end of treatment. Compound 156 and Compound 119 treated mice showed prolonged survival beyond the end of treatment and compared to the vehicle control group. Compound 142 administration did not affect tumor growth or survival rate compared to the vehicle control group. 3 mice receiving Compound 142, 8 mice receiving Compound 156, 4 mice receiving Compound 119 and 2 mice receiving no treatment between 7 days and 21 days, survived beyond day 61 and were rechallenged on day 62 with an additional EO771 cell inoculation. 8 previously untreated age-matched mice without primary tumor were inoculated with EO771 cells and served as control. Rechallenged mice did not show primary or secondary EO771 tumor growth compared to control over the course of 20 and were terminated on day 82 (Fig 18). Fig. 18A and B depict the impact of Compound 142, 156 or 119 on in vivo tumor growth rate. A: Average tumor volumes ± SEM of mice receiving p.o. treatment with Compound 142, 156 or 119 7 to 21 days post EO771 inoculation. Statistically significant difference (p < 0.01) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis. B: Survival of mice receiving p.o. treatment with Compound 142, 156 or 119 7 to 21 days post EO771 inoculation.

[0845] 5 Example B-5: Efficacy on GL261-LUC2-iRFP glioma

[0846] Compound 142 shows preclinical efficacy in a murine GL261-LUC2-iRFP glioma model.

[0847] 5.1 Materials for Bioassay

[0848] 5.2 Procedure I Description

[0849] 5.2.1 Animals and Ethics

[0850] Eight-weeks-old C57BL / 6J mice were purchased from Charles River. All animal experiments were in accordance with institutional guidelines of the Research Institute of Molecular Pathology (Austria) and approved according to the European Community rules of animal care with the permission of the Austrian Ministry of Science. 5.2.2 GL261-LUC24RFP cell culture

[0851] GL261-LUC2-iRFP glioma cells were cultured in DMEM containing 10 % FCS, 1 % PenStrep, and 1 % L-glutamine and grown in a humidified incubator at 37 °C and 5 % CO2. For tumor inoculations sub-confluent GL261-LUC2-iRFP cells were trypsinized, washed, counted and resuspended in PBS to a final concentration of 50x106GL261- LUC2-iRFP cells / ml.

[0852] 5.2.3 Efficacy Experiment

[0853] 5.2.3.1 Tumor inoculation and compound treatment

[0854] 20 C57BL / 6J mice were inoculated into the left hemisphere with 0,1x106GL261- LUC2-iRFP cells and tumor bearing mice randomly assigned to 2 different groups 7 days post transplantation: Compound 142 treated (10 mice, 30 mg / kg D7 + 10 mg / kg QD) and vehicle control (10 mice, QD). Compound 142 was diluted in 10 % DMSO, 20 % PEG400, 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O and mice treated p.o from Day 7 to Day 28. 100 pL 10 % DMSO, 20 % PEG400 and 21 % HPbCD, 0.35 % HPMC and 48.65 % H2O served as vehicle control. Tumor growth was monitored on day 4, 10, 14, 17, 21 , 24, 28, 31 post GL261-LUC2-iRFP inoculation using MS® Spectrum in vivo imaging system. Mice were sacrificed 31 days post GL261-LUC2- iRFP inoculation or when humane endpoints were reached.

[0855] Fig. 19 depicts the treatment schedules for Compound 142 in in vivo efficacy experiments with p.o. compound administration. Arrows indicate p.o. drug treatment.

[0856] 5.3 Results

[0857] GL261-LUC2-iRFP tumor bearing C57BL / 6J mice received 30 mg / kg Compound 142 7 days post GL261-LUC2-iRFP injection followed by daily administration of 10 mg / kg (30 mg / kg D7 + 10 mg / kg QD) until 28 days, vehicle treated mice (100 pl / mouse QD) served as controls. Compound 142 treated mice showed reduced tumor volumes compared to vehicle control over the course of 31 Days (Fig 20).

[0858] Fig. 20 depicts the impact of Compound 142 on in vivo tumor growth rate. Average tumor volumes ± SEM of mice receiving p.o. treatment 7 to 28 days post GL261- LUC2-iRFP inoculation. Statistically significant difference (p < 0.0001 ) between treatment groups and vehicle control group was calculated using 2-way ANOVA analysis.

[0859] 6 Example B-6: T cell stimulation potency against viral antigens in vitro

[0860] Compond 142 is tested for its potential to enhance PBMC or T cell mediated immunity against a viral peptide mix (CEFX) by measuring CD69 expression by flowcytometry. 6.1 Materials for Bioassay

[0861] 6.2 Procedure I Description

[0862] 6.2.1 Collection of PBMCs from buffy coat

[0863] White blood cell enriched buffy coats were ordered from the Austrian red cross, diluted with PBS to a total volume of 480 ml, 30 ml transferred to 50 ml falcons and 11 ml lymphoprep added. Cell suspensions were centrifuged for 20 min at 2200 rpm and the PBMC containing layer transferred, three times washed with PBS and counted.

[0864] 6.2.2 Isolation of CD4+ and CD8+ T-Cells

[0865] 10A7 PBMCs were magnetically labeled with CD4 and CD8 microbeads according to manufacturer’s instructions and separated using autoMACS device.

[0866] 6.2.3 Serial dilution of LMW compounds

[0867] 10 mM LMW compound stocks were further diluted using DMSO and equal amounts transferred to T-cell containing 96-wells. Final concentrations tested were: 30 pM, 10 pM, 3 pM, 1 pM, 0.3 pM, 0.1 pM, 0.03 pM and 0.01 pM.

[0868] 6.2.4 Stimulation setup for EC50 testing

[0869] For the stimulation assays 80,000 purified CD4+ and CD8+ T-cells were seeded per 96-well and incubated with 1 pg / ml anti-CD3, 1 pg / ml anti-CD3 and 1 pg / ml anti- CD28 or 0,5 pg / mL CEFx viral peptide and LMW compounds ranging from 0.01 pM to 30 pM. DMSO only wells and wells without anti-CD3, anti-CD28 or CEFx addition served as controls. Stimulated and unstimulated cells were cultured for up to 3 days in a humidified incubator at 37 °C and 5 % CO2.

[0870] 6.2.5 Determination of EC50 values for LMW compounds by surface FACS

[0871] T-cells were stained for surface antigens (anti-CD4 and anti-CD8) and cell activation markers (anti-CD25 and anti-CD69). Additionally, a fixable viability dye was used to stain viable cells. Staining was performed for 15 minutes and cells analyzed using a Fortessa flow cytometer and FlowJo Software. EC50s were calculated using GraphPad Prism and a variable slope model (agonist vs. response - variable slope). 6.3 Results

[0872] 6.3.1 In vitro CD4+ and CD8+ T-Cell stimulation assays

[0873] Purified CD4+ and CD8+ T-cells were incubated with anti-CD3, anti-CD3 / CD28 or CEFx viral peptide as well as Compound 142 and T cell activation monitored 24 hours and 72 hours post stimulation. Purified T-cells showed a dose-dependent increased expression of CD25 and CD69 upon anti-CD3, anti-CD3 / CD28 or CEFx stimulation and increasing concentrations of Compound 142.

[0874] Compound 142 enhances virus-specific T cell activation in cells from healthy individuals (EC50 CD4+: 807nm, EC50 CD8+: 504nm). No antigen-specific independent effects of Compound 142 on T cell activation

[0875] Fig. 21A and B depict in vitro CD4+ and CD8+ T-cell stimulation, respectively. Purified T-cells were stimulated with anti-CD3, anti-CD3 / CD28 or CEFx viral peptide and Compound 142 at 8 different concentrations.

[0876] 7 Example B-7: in vitro phenotyping in human tissue and disease context

[0877] Example B-7 demonstrates the characteristics of Compound 142 in the Eurofins BioMAP Colorectal Cancer (CRC) panel of human primary cell-based systems. These systems are designed to model complex human tissue and disease biology to assess the impact of small molecules in an immune-suppressed tumor microenvironment (TME) as well as cell-based model systems of human vasculature, skin, lung and inflammatory tissues. Quantitative measurements of biomarker activities across this broad panel, along with comparative analysis of the biological activities of known bioactive agents in the BioMAP Reference Database are used to predict the safety, efficacy and function of the investigated agent.

[0878] Compound 142 induces lymphocyte activating biomarker pattern in in vitro cultures mimicking immune responses in human tissue and diseases. Compond 142 elicits an inflammatory biomarker signature in human in vitro cell cultures that mimic immune responses in human tissue and diseases, especially a suppressive Tumor microenvironment. Biomarker expression of Compound 142 treated cancer cell line, primary immune and tissue cell co-cultures compared to vehicle control is measured using BioMAP assay. Compound 142 is active with 17 annotated readouts and is not cytotoxic at the concentrations tested (10 pM and 3.3 pM). Compound 142 impacts inflammation-related activities (increased sTNFa, IP-10, MCP-1 ), matrix remodeling activities (decreased Collagen I, Collagen III), angiogenesis-related activities (decreased uPA, sVEGF) and immune-related activities (decreased slL-10, SIL-17A; increased sIFNy, slL-2, slL-6). 8 Example B-8: EC50testing comparison with prior art compounds

[0879] Example B-8 is directed to the comparison of compounds of the invention to xanthine derivatives from prior art. Xanthine derivatives from prior art, Example 103 and Example 104 of patent application W02000 / 09507A1 , show no or minimal T cell activation compared to compounds of the invention, ie Compound 119, in vitro.

[0880] Compound 119 and 2 xanthine derivatives from patent application W02000 / 09507A1 are tested for their potential to enhance CD3 / 28 stimulated T cell activation. Activation of stimulated human CD4+ and CD8+ T cells is measured by CD69 expression via flowcytometry. Compound 119 induces increased T cell activation at concentrations below 1 pM, xanthine derivatives Example 103 and Example 104 from patent application W02000 / 09507A1 show no or marginal T cell activation at 10 pM.

[0881] 1 .1 Materials for Bioassay

[0882] 1 .2 Procedure I Description

[0883] 1 .2.1 Collection of PBMCs from buffy coat

[0884] White blood cell enriched buffy coats were ordered from the Austrian red cross, diluted with PBS to a total volume of 480 ml, 30 ml transferred to 50 ml falcons and 11 ml lymphoprep added. Cell suspensions were centrifuged for 20 min at 2200 rpm and the PBMC containing layer transferred, three times washed with PBS and counted.

[0885] 1 .2.2 Isolation of CD4+ and CD8+ T-Cells

[0886] 10A7 PBMCs were magnetically labeled with CD4 and CD8 microbeads according to manufacturer’s instructions and separated using autoMACS device. For dose response experiments with purified CD4+CD8+ T-cells 80000 cells were seeded per 96-well flat bottom cell culture dish.

[0887] 1 .2.3 Serial dilution of LMW compounds

[0888] 10 mM LMW compound stocks were further diluted using DMSO and equal amounts transferred to T-cell containing 96-wells. Final concentrations tested were: 30 pM, 10 pM, 3 pM, 1 pM, 0.3 pM, 0.1 pM, 0.03 pM, 0.01 pM, 0.003 pM and 0.001 pM. 1 .2.4 Stimulation setup for ECso testing

[0889] For the stimulation assays 80.000 purified CD4+ and CD8+ T-cells were seeded per 96-well and incubated with 1 pg / ml anti-CD3, 1 pg / ml anti-CD28 and LMW compounds ranging from 0,001 pM to 30 pM. DMSO only wells served as control to determine minimal T-cell activation upon stimulation and CD3 / 28 coupled Dynabeads were used to determine the maximal activation of T-cells. Cells were cultured for 16 hours in a humidified incubator at 37 °C and 5 % CO2.

[0890] 1 .2.5 Determination of EC50 values for LMW compounds by surface FACS

[0891] T-cells were stained for surface antigens (anti-CD4 and anti-CD8) and cell activation markers (anti-CD69). Additionally, a fixable viability dye was used to stain viable cells. Staining was performed for 15 minutes and cells analyzed using a Fortessa flow cytometer and FlowJo Software. ECsos were calculated using GraphPad Prism and a variable slope model (agonist vs. response - variable slope).

[0892] 1.3 Results

[0893] 1.3.1 EC50 determination

[0894] Stimulated CD4+ and CD8+ T cells from two donors were incubated with increasing concentrations of Compound 142, Example 103 and Example 104 from patent application W02000 / 09507A1 and T cell activation measured 16h post stimulation. Compound 142 showed dose-dependent increased activation of human T cells upon anti-CD3 / CD28 stimulation with an EC50 below 1 pM. Xanthine derivatives, Example 103 and Example 104 from patent application W02000 / 09507A1 showed limited T cell activation at 10 pM and an EC50 for CD4+ T cells above 1 pM (donor 1) (Fig. 22A-B, Table B-2).

[0895] Table B-2: EC50 values CD4+ and CD8+ human T cell Donor 1 (μm] (μm]

[0896] CD4+ and CD8+ T cells from another donor (donor 2) show no or dose-dependent decreased T cell activation upon Example 103 and Example 104 of patent application W02000 / 09507A1 (Fig. 22C-D, Table B-3). Table B-3: EC50 values CD4+ and CD8+ human T cell Donor 2

Claims

Claims1. A compound of the formula (I) whereinA represents orB is -O-R3, -O-CHR3R3*, -O-CH2-CH2-R3, or -O-CH2-CH2-CH2-R3;R1representsR2aand R2brepresent independently of each other -H, -F, -CH3, -C2H5, -CH2F, -CHF2I-CF3I-CH2-CF3I-CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CF2-CH3I-CHF-CHF2I-CHF-CF3I-CF2-CF3; wherein R2ais not -H;R7R6R3representsR3* represents -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2-CF3;R4and R4* represent indepenently of each other -H, -F, -Cl, — Br, -CH3,-C2H5, -CH2F, -CHF2I-CF3, -OCH3I-OC2H5, -OC3H7, -OCH(CH3)2,-OCH2F, -OCHF2I-0CF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2I-CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2I-CF2-CF3,R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other -H, -cyclo-CsHs, -cyclo-C4H7, -cyclo-CsHg, -cyclo-CeHn, -cyclo-C7Hi3, -cycloC3H5O, -OH, -OCH3, -OC2H5,-OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3,-OC4H9, -OPh, -OCH2-Ph, -OCPh3, -CH^OCH3, -C2H4-OCH3, -C3H6-OCH3, -CH^OC2H5, -C2H4-OC2H5, -C3H6-OC2H5, -CH^OC3H7, -C2H4— OC3H7, -C3H6— OC3H7, -CH^- 0— cyclo-CsHs, -C2H4— 0— cyclo-CsHs, -C3H6-O-cyclo-C3H5, -CH^OCH(CH3)2, -C2H4-OCH(CH3)2, -C3H6-OCH(CH3)2, -CH^OC(CH3)3, -C2H4-OC(CH3)3, -C3H6-OC(CH3)3, -CH^OC4H9, -C2H4-OC4H9, -C3H6-OC4H9, -CH^OPh, -C2H4-OPh, -C3H6-OPh,-CH^OCH2-Ph, -C2H4-OCH2-Ph, -C3H6-OCH2-Ph, -SH, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H5, -SCH(CH3)2, -SC(CH3)3, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2I-CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2,-NHCOCH3, -NHCOC2H5, -NHCOC3H7, -NHCO-cyclo-C3H5, -NHCO-CH(CH3)2, -NHCO-C(CH3)3, -NHCO-OCH3, -NHCO-OC2H5, -NHCO-OC3H7, -NHCO-O-cyclo-C3H5, -NHCO-OCH(CH3)2, -NHCO- OC(CH3)3, -NH2I-NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2I-N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3, -SO2CH3, -SO2C2H5, -SO2C3H7,-SO^cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3,-SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NH-cyclo-C3H5, -SO2NHCH(CH3)2, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2,-SO2N(C3H7)2, -SO2N(cyclo-C3H5)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -O-S(=O)CH3, -O-S(=O)C2H5I-O-S(=O)C3H7, -O-S(=O)-cyclo-C3H5, -O-S(=O)CH(CH3)2, -O-S(=O)C(CH3)3, -S(=O)(=NH)CH3, -S(=O)(=NH)C2H5, -S(=O)(=NH)C3H7, -S(=O)(=NH)-cyclo-C3H5, -S(=O)(=NH)CH(CH3)2,-S(=O)(=NH)C(CH3)3, -NH-SO2-CH3, -NH-SO2-C2H5, -NH-SO2-C3H7, -NH-SO2-cyclo-C3H5, -NH-SO2-CH(CH3)2, -NH-SO2-C(CH3)3, -O-SO2-CH3, -O-SO2-C2H5, -O-SO2-C3H7I-O-SO2-cyclo-C3H5, -O-SO2-CH(CH3)2, -O-SO2-C(CH3)3, -OCH2F, -OCHF2I-OCF3I-CH^OCF3I-C2H4-OCF3, -C3H6-OCF3, -CH^OCHF2I-C2H4-OCHF2, -C3H6-OCHF2, -OC2F5, -CH^OC2F5, -C2H4-OC2F5, -C3H6-OC2F5, -O-COOCH3, -O-COOC2H5I-O-COOC3H7I-O-COO-cyclo-C3H5,-O-COOCH(CH3)2, -O-COOC(CH3)3I-NH-CO-NH2, -NH-CO-NHCH3, -NH-CO-NHC2H5I-NH-CO-NHC3H7I-NH-C(=NH)-NH2I-NH-CO-N(C3H7)2I-NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2I-NH-CO-N(C2H5)2I-NH-CO-NH-cyclo-C3H5, -NH-CO-N(cyclo-C3H5)2, -NH-CO-N[CH(CH3)2]2, -NH-C(=NH)-NHCH3I-NH-C(=NH)-NHC2H5I-NH-C(=NH)-NHC3H7I-O-CO-NH-cyclo-C3H5, -NH-C(=NH)-NH-cyclo-C3H5, -NH-C(=NH)-NH[CH(CH3)2], -O-CO-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH3)3], -NH-C(=NH)-N(CH3)2I-NH-C(=NH)-N(C2H5)2I-NH-C(=NH)- N(C3H7)2I-NH-C(=NH)-N(cyclo-C3H5)2, -O-CO-NHC3H7, -NH-C(=NH)- N[CH(CH3)2]2, -NH-C(=NH)-N[C(CH3)3]2I-O-CO-NH2, -O-CO-NHCH3, -O-CO-NHC2H5I-O-CO-NH[C(CH3)3], -O-CO-N(CH3)2I-O-CO- N(C2H5)2I-O-CO-N(C3H7)2I-O-CO-N(cyclo-C3H5)2, -O-CO-N[CH(CH3)2]2, -O-CO-N[C(CH3)3]2, -O-CO-OCH3, -O-CO-OC2H5, -O-CO-OC3H7, -O-CO-O-cyclo-C3H5, -O-CO-OCH(CH3)2, -O-CO-OC(CH3)3, -CH2F, -CHF2, -CF3I-CH2-CH2F, -CH2-CHF2I-CH2-CF3Icyclo-CsHis, -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH=CH-Ph, -CPh3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3I-C5H11, -CH(CH3)-C3H7,-CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2I-C(CH3)2-C2H5, -CH2-C(CH3)3I-CH(C2H5)2I-C2H4-CH(CH3)2I-C6HI3, -C7Hi5, -C8HI7, -C3H6-CH(CH3)2, -C2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9I-CH2-CH(CH3)-C3H7, -CH(CH3)- CH2-CH(CH3)2I-CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2I-CH2-C(CH3)2-C2H5, -C(CH3)2-C3H7I-C(CH3)2-CH(CH3)2I-C2H4-C(CH3)3I-CH(CH3)-C(CH3)3, -CH=CH2I-CH2-CH=CH2I-C(CH3)=CH2I-CH=CH-CH3I-C2H4-CH=CH2I-CH2-CH=CH-CH3I-CH=CH-C2H5, -CH2-C(CH3)=CH2I-CH(CH3)-CH=CH, -CH=C(CH3)2I-C(CH3)=CH-CH3I-CH=CH-CH=CH2, -C3H6-CH=CH2, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CH=CH-C3H7, -CH=CH-CH=CH-CH3I-C2H4-C(CH3)=CH2I-CH2-CH(CH3)-CH=CH2I-CH(CH3)-CH2-CH=CH2I-CH2-CH=C(CH3)2I-CH2-C(CH3)=CH-CH3I-CH(CH3)-CH=CH-CH3I-CH=CH-CH(CH3)2, -CH=C(CH3)-C2H5,-C(CH3)=CH-C2H5, -C(CH3)=C(CH3)2I-C(CH3)2-CH=CH2,-CH(CH3)-C(CH3)=CH2I-C4H8-CH=CH2, -C3H6-CH=CH-CH3, -C2H4-CH=CH-C2H5, -CH2-CH=CH-C3H7I-CH=CH-C4H9I-C3H6-C(CH3)=CH2, -C2H4-CH(CH3)-CH=CH2I-CH2-CH(CH3)-CH2-CH=CH2I-C2H4- CH=C(CH3)2I-CH(CH3)-C2H4-CH=CH2I-C2H4-C(CH3)=CH-CH3I-CH2-CH(CH3)-CH=CH-CH3I-CH(CH3)-CH2-CH=CH-CH3I-CH2- CH=CH-CH(CH3)2I-CH2-CH=C(CH3)-C2H5, -CH2-C(CH3)=CH-C2H5,-CH(CH3)-CH=CH-C2H5, -CH=CH-CH2-CH(CH3)2I-CH=CH-CH(CH3)-C2H5, -CH=C(CH3)-C3H7I-C(CH3)=CH-C3H7I-CH2-CH(CH3)-C(CH3)=CH2I-C[C(CH3)3]=CH2I-CH(CH3)-CH2-C(CH3)=CH2I-CH(CH3)-CH(CH3)- CH=CH2, -CH=CH-C2H4-CH=CH2I-C(CH3)2-CH2-CH=CH2I-CH2-C(CH3)=C(CH3)2I-CH(CH3)-CH=C(CH3)2I-C(CH3)2-CH=CH-CH3I-CH=CH-CH2-CH=CH-CH3, -CH(CH3)-C(CH3)=CH-CH3I-CH=C(CH3)-CH(CH3)2I-C(CH3)=CH-CH(CH3)2I-C(CH3)=C(CH3)-C2H5, -CH=CH-C(CH3)3I-C(CH3)2-C(CH3)=CH2I-CH(C2H5)-C(CH3)=CH2, -C(CH3)(C2H5)-CH=CH2, -CH(CH3)-C(C2H5)=CH2, -CH2-C(C3H7)=CH2I-CH2-C(C2H5)=CH-CH3I-CH(C2H5)-CH=CH-CH3, -C(C4H9)=CH2I-C(C3H7)=CH-CH3I-C(C2H5)=CH-C2H5, -C(C2H5)=C(CH3)2, -C[CH(CH3)(C2H5)]=CH2, -C[CH2-CH(CH3)2]=CH2I-C2H4-CH=CH-CH=CH2, -CH2-CH=CH-CH2- CH=CH2, -C3H6-CEC-CH3, -CH2-CH=CH-CH=CH-CH3, -CH=CH-CH=CH-C2H5, -CH(CH3)-CH2-CECH, -CH(CH3)-CEC-CH3, -C2H4- CH(CH3)-CECH, -CH=CH-CH=C(CH3)2I-CH2-CH(CH3)-CH2-CECH, -CH=CH-C(CH3)=CH-CH3I-CH=C(CH3)-CH=CH-CH3I-CH2-CH(CH3)- C=CH, -C(CH3)=CH-CH=CH-CH3, -CECH, -CEC-CH3, -CH2-CECH, -C2H4-CECH, -CH2-CEC-CH3, -CEC-C2H5, -C3H6-CECH, -C2H4-CEC-CH3,-CH2-CEC-C2H5, -C=C-C3H7I-CH(CH3)-CECH, -C4H8-CECH,-C2H4-CEC-C2H5, -CH2-CEC-C3H7, -CEC-C4H9, -CEC-CH2-CH(CH3)2,-CH(CH3)-C2H4-CECH, -CH2-CH(CH3)-CEC-CH3, -C(CH3)(C2H5)-CECH,-CH(CH3)-CH2-CEC-CH3, -CH(CH3)-CEC-C2H5, -CH2-CEC-CH(CH3)2,-CEC-CH(CH3)-C2H5, -CH2-CEC-CEC-CH3, -CH(C2H5)-CEC-CH3,-C(CH3)2-CEC-CH3, -CH(C2H5)-CH2-CECH, -CH2-CH(C2H5)-CECH,-C(CH3)2-CH2-CECH, -CH2-C(CH3)2-CECH, -CH(CH3)-CH(CH3)-CECH,-CH(C3H7)-CECH, -CH2-CH(CECH)2, -C=C-C=CH, -CH2-C=C-C=CH,-C=C-C=C-CH3I-CH(C=CH)2I-C2H4-C=C-C=CH, -CH2-C=C-CH2-C=CH,-C=C-C2H4-C=CH, -CEC-C(CH3)3, -C=C-CH2-C=C-CH3IR5and R6or R6and R7may form together with the two carbon atoms of the phenyl ring to which they are attached a 4 to 8-membered ring system, which is optionally substituted with one or more substituents selected from R10, R11, R12, and R13; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt of the above-mentioned compound.

2. The compound according to claim 1 , wherein R3represents and R5, R6, R7, R8, R9, R10, R11, R12and R13have the same meanings as defined in claim 1 .

3. The compound according to claim 1 or 2, whereinR2arepresents -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3,-CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3; andR2brepresents -H or -CH3;B represents -O-R3or -O-CHR3R3*;R3representsR3* represents -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2,-CF3, -CH2-CF3;R4and R4* represent indepenently of each other -H, -F, -Cl, -Br, -CH3, -C2H5, -CH2F, -CHF2I-CF3, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2I-OCH2F, -OCHF2I-OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2I-CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2I-CF2-CF3, and R5, R6, R7, R8, R9, R10, R11, R12and R13have the same meanings as defined in claim 1 .

4. The compound according to any one of the claims 1 - 2, wherein B represents -O-CHR3R3*, -O-CH2-CH2-R3, or -O-CH2-CH2-CH2-R3; andR3and R3* have the same meanings as defined in claim 1 .

5. The compound according to any one of the claims 1 - 3, wherein B represents -O-R3; and R3has the same meanings as defined in claim 1 .

6. The compound according to any one of the claims 1 - 5, wherein the compound has any one of the following formulae (11-1) to (II-5), (111-1) to (HI-6), (IV-1) to (IV-8), (V-1) to (V-5), (VI-1) to (VI-2) and (VII-1) to (VII-3):(IV-1) (IV-2)(IV-3) (IV-4)(IV-5) (IV-6)(IV-7) (|V-8)(V-1) (V-2)(V-3) (V-4)(V-5)(VI I -2) wherein R1, R3*, R4, R4*, R5, R6, R7, R8, R10, R11, R12, and R13have the same meanings as defined in any one of the claims 1 - 5.

7. The compound according to any one of the claims 1 - 6, wherein whereinR4*A represents orB represents -O-R3, -O-CH2-R3or -O-CHR3R3*;R3* represents -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2-CF3;R4and R4* represent indepenently of each other -H, -F, -Cl, -CH3,-CH2F, -CHF2I-CF3, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OCH2F, -OCHF2I-0CF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2I-CHF-CF3, andR5, R6, R7, and R8represent independently of each other -H, -F, -Cl, -CN, -CH3, -CHF2I-CF3I-OCH3, -OCHF2, -OCF3, or -SO2CH3.

8. The compound according to any one of claims 1 - 7, wherein R3represents9. The compound according to claim 1 selected from the group consisting of:or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising at least one compound according to any one of the claims 1 - 9 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

11. The pharmaceutical composition according to claim 10 further comprising at least one stimulating agent for activating immune cells.

12. A compound according to any one of the claims 1 - 9, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 or 10 for use as a medicament.

13. A compound according to any one of the claims 1 - 9 for use, a pharmaceutically acceptable salt thereof for use, or the pharmaceutical composition according to claim 9 or 10 for use in the prophylaxis or treatment of a neoplastic and / or infectious disease.

14. The compound for use, the pharmaceutically acceptable salt thereof for use, or the pharmaceutical composition for use according to claim 13, wherein the compound, the pharmaceutically acceptable salt thereof or the pharmaceutical composition is administered in combination with one or more further stimulating agents activating immune cells.

15. An in vitro or ex vivo method for the production of activated immune cells comprising the steps of:(i) providing immune cells;(ii) contacting the cells of step (i) with:(a) at least one compound or pharmaceutically acceptable salt thereof as defined in any one of the claims 1 - 9, and optionally(b) one or more further stimulating agents activating said immune cells; and(iii) cultivating the cells of step (ii) under conditions suitable for maintaining the viability of said cells.

Images