Thieno- and thiazolopyrimidine-2,6-diones and use thereof as immunomodulators

Abstract

The present invention relates to substituted thieno- and thiazolopyrimidine-2,6-dione compounds of the general formula (I) or pharmaceutically acceptable salts thereof. (I) 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.

Description

[0001] 1 Thieno- and thiazolopyrimidine-2,6-diones and use thereofField of the Invention The present invention relates to substituted thieno- and thiazolopyrimidine-2,6-dione5 compounds of the general formula (I) or pharmaceutically acceptable salts thereof. 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 10 methods. These compounds activate immune cells, including NK cells or T-cells such as CD4+ and CD8+ cells. Background of the Invention Malignant neoplasia (cancer) and infectious diseases are two of the main causes of 15 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 20 severe side effects. Therefore, there is still an unmet need for new compounds for treating and preventing neoplastic and / or infectious diseases. In order to overcome these drawbacks, therapeutic and prophylactic approaches based on modulating the immune response of the patient gain increasing importance 25 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, 30 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

[0002] APR-P04602WO24 PCT Application (final).docx 2 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. 5 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 10 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. 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 15 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. In some cases, the immune system however fails to eliminate such neoplastic or 20 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 25 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 30 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 35 number of cytokines (such as e.g., IL-2 and IFN-γ) 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,

[0003] APR-P04602WO24 PCT Application (final).docx 3 section “PD-1+ TILs display an impaired effector function”). This is evidently also one of the reasons why tumor vaccination often fails. Likewise, numerous infections are known to down-regulate the patient's immune 5 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. There is still an unmet need for such compounds enabling to increase immunogenic 10 activity and thereby enable the treatment and / or prophylaxis of neoplastic and / or infectious diseases. It is the objective of the present invention to provide compounds and pharmaceutic compositions which activate immune cells, in particular T-cells. These compounds 15 can be used as pharmaceutically active agents, especially for prophylaxis and / or treatment of neoplastic and infectious disease.The present invention provides novel substituted thieno- and thiazolopyrimidine-2,6-dione compounds of general formula (I), activating immune cells.20 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. 25 Description of the invention Thus, the present invention is directed to a compound of the formula (I): 30 wherein

[0004] APR-P04602WO24 PCT Application (final).docx 4 5 10 and optionally R5 and R6, R6 and R7, or R5 and R8 may form together the following 5- or6-membered ring system:

[0005] APR-P04602WO24 PCT Application (final).docx 5 5 10 15 R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other –H, –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OC(CH3)3, –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, ^C2H4–OCH3, 20 ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O–cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6–OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, 25 ^CH2–OCH2^Ph, ^C2H4–OCH2^Ph, ^C3H6–OCH2^Ph, –SH, –SCH3, –SC2H5, –SC3H7, –S–cyclo-C3H5, –SCH(CH3)2, –SC(CH3)3, –SF5, –F, –Cl, –Br, –I, –CN, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH,

[0006] APR-P04602WO24 PCT Application (final).docx 6 ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, –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, 5 –OOC–cyclo-C3H5, –OOC–CH(CH3)2, –OOC–C(CH3)3, –CONH2, 10 15 20 25 30 –O–COOC2H5, –O–COOC3H7, –O–COO–cyclo-C3H5, –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)2,35 –NH–CO–NH[CH(CH3)2], –NH–CO–NH[C(CH3)3], –NH–CO–N(CH3)2, –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)–NHCH3, –NH–C(=NH)–NHC2H5, –NH–C(=NH)–NHC3H7, –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], –

[0007] APR-P04602WO24 PCT Application (final).docx 7 NH–C(=NH)–N(CH3)2, –NH–C(=NH)–N(C2H5)2, –NH–C(=NH)–N(C3H7)2, –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)2, –O–CO–N(C2H5)2, – 5 O–CO–N(C3H7)2, –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, ^CF3, ^CH2^CH2F, ^CH2^CHF2, ^CH2^CF3, cyclo-C8H15, ^Ph, ^CH2^Ph, 10 15 20 25 30 35

[0008] APR-P04602WO24 PCT Application (final).docx 8 5 10 15 20 Z1, Z2, Z3, Z4, Z5, and Z6represent indepenently of each other –H, –F, –Cl, –Br, –CN, –OH, ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OC2H5, ^OCH2F,25 ^OCHF2, ^OCF3, ^CH2^CF3, or ^CF2^CF3; 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. 30 Preferably, the present invention is directed to a compound of the formula (I):

[0009] APR-P04602WO24 PCT Application (final).docx 9 510

[0010] APR-P04602WO24 PCT Application (final).docx 10 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, –Br, ^CH3, 5 10 R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other –H, –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OC(CH3)3, 15 –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, ^C2H4–OCH3, ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O–cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6–OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, 20 ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, ^CH2–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, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, 25 –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, 30 –CONH[CH(CH3)2], –CONH[C(CH3)3], –CON(CH3)2, –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, 35 –NH2, –NHCH3, –NHC2H5, –NHC3H7, –NH–cyclo-C3H5, APR-P04602WO24 PCT Application (final).docx 11 5 10 15 20 –O–COOC2H5, –O–COOC3H7, –O–COO–cyclo-C3H5, –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, –NH–CO–N(C2H5)2, –NH–CO–NH–cyclo-C3H5, –NH–CO–N(cyclo-C3H5)2, 25 –NH–CO–N[CH(CH3)2]2, –NH–C(=NH)–NHCH3, –NH–C(=NH)–NHC2H5, –NH–C(=NH)–NHC3H7, –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)2, –NH–C(=NH)–N(C2H5)2, –NH–C(=NH)–N(C3H7)2, –NH–C(=NH)–N(cyclo-C3H5)2, –O–CO–NHC3H7, –NH–C(=NH)–N[CH(CH3)2]2, 30 –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)2, –O–CO–N(C2H5)2, –O–CO–N(C3H7)2, –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, 35 ^CHF2, ^CF3, ^CH2^CH2F, ^CH2^CHF2, ^CH2^CF3, cyclo-C8H15, ^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(CH3)–C3H7, –CH2–CH(CH3)–C2H5, –CH(CH3)–CH(CH3)2, –C(CH3)2–C2H5, –CH2–C(CH3)3, –CH(C2H5)2, –C2H4–CH(CH3)2, ^C6H13, ^C7H15, ^C8H17, –C3H6–CH(CH3)2, APR-P04602WO24 PCT Application (final).docx 12 5 10 15 20 25 30 35 APR-P04602WO24 PCT Application (final).docx 13 5 R5 and R6, R6 and R7, or R5 and R8 may form together the following 5- or 6-membered10 Z1, Z2, Z3, Z4, Z5, and Z6represent indepenently of each other –H, –F, –Cl, –Br, 15 ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OC2H5, ^OCH2F, ^OCHF2, ^OCF3, ^CH2^CF3, or ^CF2^CF3; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically20 acceptable salt of the above-mentioned compound. 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 25 the invention useful for the treatment and / or prophylaxis of neoplastic and / or infectious diseases. 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 30 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. APR-P04602WO24 PCT Application (final).docx 14 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 5 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,10 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 the15 conventional manner well known to those skilled in the art. 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 20 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. 25 , Brepresents –O–R3, –S–R3, or –O–CHR3R3*; andR3, R3*and R4have the same meanings as defined in the formula (I). Preferably, in the formula (I),30 APR-P04602WO24 PCT Application (final).docx 15 R3, R3*and R4have the same meanings as defined in the formula (I). Preferably, in the formula (I), R1represents O p y R2aR2b. 5 Preferably, R2, R2a, R2b, and R2crepresent independently of each other –H, –F, –Br, –Cl, ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH; and R2a is not –H;or R2aand R2bform together 10 and Z1 and Z2 have the same meanings as defined in the formula (I).Preferably, in the formula (I), R5 and R6, or R6 and R7 may form one of the following 5-or 6-membered ring systems: , 15 More preferably, in the formula (I), R5 and R6, or R6 and R7 may form one of thefollowing 5- or 6-membered ring systems:20 APR-P04602WO24 PCT Application (final).docx 16 and R10, R11, R12and R13have the same meanings as defined in the formula (I). Preferably, in the formula (I), R3represents 5 10 more preferably, in the formula (I), R3represents , APR-P04602WO24 PCT Application (final).docx 17 5 more preferably, in the formula (I), R3represents 10 still more preferably, R3represents APR-P04602WO24 PCT Application (final).docx 18 still more preferably, R3represents 5 still more preferably, R3 represents10 APR-P04602WO24 PCT Application (final).docx 19 even more preferably, R3 represents5 even more preferably, R3represents , ,10 asdefined in the formula (I). Preferably, the present invention is directed to a compound of the formula (I):APR-P04602WO24 PCT Application (final).docx 20 510 APR-P04602WO24 PCT Application (final).docx 21 5 10 still more preferably, R3 representsAPR-P04602WO24 PCT Application (final).docx 22 5 10 15 R5, R6, R7, R8, R9, R10, R11, R12, R13, Z1 and Z2 have the same meanings as definedherein. More preferably, the present invention is directed to a compound of the formula (I): APR-P04602WO24 PCT Application (final).docx 23 wherein ; 5 or –O–CH2–CH2–CH2–R3; R2arepresents –CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3; and R2b, and R2crepresent indepenently of each other –H or ^CH3; or R2a and R2b form together 10 , APR-P04602WO24 PCT Application (final).docx 24 5 10 15 20 APR-P04602WO24 PCT Application (final).docx 25 ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O–cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6–OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, 5 ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, ^CH2–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, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, 10 –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, 15 –CONH[CH(CH3)2], –CONH[C(CH3)3], –CON(CH3)2, –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, 20 –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, –SO2–cyclo-C3H5, –SO2CH(CH3)2, –SO2C(CH3)3, –SO3H, –SO3CH3, 25 –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)C2H5, ^O–S(=O)C3H7, ^O–S(=O)–cyclo-C3H5, 30 ^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, –P(=O)(CH3)2, –P(=O)(C2H5)2, –P(=O)(OH)2, –P(=O)(OH)(OCH3), –P(=O)(OH)(OC2H5), –P(=O)(OCH3)2, –P(=O)(OC2H5)2, ^NH–SO2–CH3, ^NH–SO2–C2H5, ^NH–SO2–C3H7, 35 ^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, ^O–SO2–C(CH3)3, –OCH2F, –OCHF2, –OCF3, ^CH2–OCF3, ^C2H4–OCF3, ^C3H6–OCF3, ^CH2–OCHF2, ^C2H4–OCHF2, ^C3H6–OCHF2, –OC2F5, ^CH2–OC2F5, ^C2H4–OC2F5, ^C3H6–OC2F5, –O–COOCH3, APR-P04602WO24 PCT Application (final).docx 26 –O–COOC2H5, –O–COOC3H7, –O–COO–cyclo-C3H5, –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, 5 –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)–NHCH3, –NH–C(=NH)–NHC2H5, –NH–C(=NH)–NHC3H7, –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)2, –NH–C(=NH)–N(C2H5)2, –NH–C(=NH)–N(C3H7)2, –NH– 10 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)2, –O–CO–N(C2H5)2, –O–CO–N(C3H7)2, –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, 15 –O–CO–O–cyclo-C3H5, –O–CO–OCH(CH3)2, –O–CO–OC(CH3)3, ^CH2F, ^CHF2, ^CF3, ^CH2^CH2F, ^CH2^CHF2, ^CH2^CF3, cyclo-C8H15, ^Ph, ^CH2^Ph, 20 25 30 35 APR-P04602WO24 PCT Application (final).docx 27 5 10 15 20 25 or30 R5 and R6, R6 and R7, or R5 and R8 may form together the following 5- or 6-memberedring system: , Z1, Z2, Z5, and Z6represent indepenently of each other –H, –F, –Cl, –Br, ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OC2H5, ^OCH2F, ^OCHF2, ^OCF3,35 ^CH2^CF3, or ^CF2^CF3; APR-P04602WO24 PCT Application (final).docx 28 preferably R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other –H, –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, 5 –OCH(CH3)2, –OC(CH3)3, –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, ^C2H4–OCH3, ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O– cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6– OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, 10 ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, ^CH2–OCH2^Ph, ^C2H4–OCH2^Ph, ^C3H6–OCH2^Ph, –F, –Cl, –Br, –I, –CN, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, –COCH3, –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, 15 –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)2, –CON(C2H5)2, 20 –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, –NH2, –NHCH3, –NHC2H5, –NHC3H7, –NH–cyclo-C3H5, 25 –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, –SO2–cyclo-C3H5, –SO2CH(CH3)2, –SO2C(CH3)3, –SO3H, –SO3CH3, –SO3C2H5, –SO3C3H7, –SO3–cyclo-C3H5, –SO3CH(CH3)2, –SO3C(CH3)3, 30 –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)C2H5, ^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, 35 –S(=O)(=NH)C3H7, –S(=O)(=NH)–cyclo-C3H5, –S(=O)(=NH)CH(CH3)2, –S(=O)(=NH)C(CH3)3, –P(=O)(CH3)2, –P(=O)(C2H5)2, –P(=O)(OH)2, –P(=O)(OH)(OCH3), –P(=O)(OH)(OC2H5), –P(=O)(OCH3)2, –P(=O)(OC2H5)2, ^O–SO2–CH3, ^O–SO2–C2H5, ^O–SO2–C3H7, ^O–SO2–cyclo-C3H5, ^O–SO2– CH(CH3)2, ^O–SO2–C(CH3)3, –OCH2F, –OCHF2, –OCF3, ^CH2–OCF3, APR-P04602WO24 PCT Application (final).docx 29 5 10 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. Preferably, in the formula (I), ,15 B represents –O–R3, –S–R3, or –O–CHR3R3*; andR3, R3*and R4have the same meanings as defined above. More preferably, in the formula (I), ;B 20 R3, R3*and R4have the same meanings as defined above. More preferably, in the formula (I), APR-P04602WO24 PCT Application (final).docx 30 Brepresents –O–R3, –S–R3, or –O–CHR3R3*; andR3, R3*and R4have the same meanings as defined above. Thus, the present invention is directed to a compound of the formula (I):5 ; preferably 10 B is –O–R3, –S–R3, or –O–CHR3R3*; R2arepresents –CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3 ; and R2band R2crepresent indepenently of each other –H or ^CH3; or R2a and R2b form together APR-P04602WO24 PCT Application (final).docx 31 R3represents 510 APR-P04602WO24 PCT Application (final).docx 32 5 10 R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other –H, –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, 15 –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OC(CH3)3, –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, ^C2H4–OCH3, ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O–cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6–OCH(CH3)2, 20 ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, ^CH2–OCH2^Ph, ^C2H4–OCH2^Ph, ^C3H6–OCH2^Ph, –SH, –SCH3, –SC2H5, –SC3H7, –S–cyclo-C3H5, –SCH(CH3)2, –SC(CH3)3, –SF5, –F, –Cl, –Br, –I, –CN, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, 25 ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, –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, 30 –CONHCH3, –CONHC2H5, –CONHC3H7, –CONH–cyclo-C3H5, –CONH[CH(CH3)2], –CONH[C(CH3)3], –CON(CH3)2, –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, APR-P04602WO24 PCT Application (final).docx 33 5 10 15 20 –O–COOC2H5, –O–COOC3H7, –O–COO–cyclo-C3H5, –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)2,25 –NH–CO–NH[CH(CH3)2], –NH–CO–NH[C(CH3)3], –NH–CO–N(CH3)2, –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)–NHCH3, –NH–C(=NH)–NHC2H5, –NH–C(=NH)–NHC3H7, –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], 30 –NH–C(=NH)–N(CH3)2, –NH–C(=NH)–N(C2H5)2, –NH–C(=NH)–N(C3H7)2, –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)2, –O–CO–N(C2H5)2, –O–CO–N(C3H7)2, –O–CO–N(cyclo-C3H5)2, –O–CO–N[CH(CH3)2]2, 35 –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, ^CF3, ^CH2^CH2F, ^CH2^CHF2, ^CH2^CF3, cyclo-C8H15, ^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, ^C(CH3)2CN, ^CH(CH3)(OH), APR-P04602WO24 PCT Application (final).docx 34 5 1015 20 25 30 35 APR-P04602WO24 PCT Application (final).docx 35 5 10 or R5 and R6, R6 and R7, or R5 and R8 may form together the following 5- or 6-memberedring system: 15 20 preferably R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other –H, –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OC(CH3)3, –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, ^C2H4–OCH3, ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5,25 ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O– cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6– OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, ^CH2–OCH2^Ph, ^C2H4–OCH2^Ph, ^C3H6–OCH2^Ph, –F, –Cl, –Br, –I, –CN, 30 ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, –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, APR-P04602WO24 PCT Application (final).docx 36 –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)2, –CON(C2H5)2, –CON(C3H7)2, –CON(cyclo-C3H5)2, –CON[CH(CH3)2]2, –CON[C(CH3)3]2, 5 –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)3,1015 –SO2N(C3H7)2, –SO2N(cyclo-C3H5)2, –SO2N[CH(CH3)2]2, –SO2N[C(CH3)3]2, ^O–S(=O)CH3, ^O–S(=O)C2H5, ^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, 20 –S(=O)(=NH)C(CH3)3, –P(=O)(CH3)2, –P(=O)(C2H5)2, –P(=O)(OH)2, –P(=O)(OH)(OCH3), –P(=O)(OH)(OC2H5), –P(=O)(OCH3)2, –P(=O)(OC2H5)2, ^O–SO2–CH3, ^O–SO2–C2H5, ^O–SO2–C3H7, ^O–SO2–cyclo-C3H5, ^O–SO2–CH(CH3)2, 25 30 APR-P04602WO24 PCT Application (final).docx 37 or R5 and R6, or R6 and R7 form together one of the following ring systems: , more preferably,5 R5, R6, R7, R8 and R9 represent independently of each other –H, –F, –Cl,–CN, –CH3, ^C2H5, ^C3H7, ^CH(CH3)2, ^C(CH3)2CN, ^CH(CH3)(OH), ^CH(CF3)(OH), ^C(CH3)2(OH), ^C(CH3)(CF3)(OH), –cyclo-C3H5, –cyclo-C4H7, –CH2F, –CHF2, –CF3, –CH2CF3, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –OCH2CF3, –CH2OCH3, –COCH3,10 –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, –CONH2, –CONHCH3, –CONHC2H5, –CONHC3H7, –CONH–cyclo-C3H5, –CON(CH3)2, –CON(C2H5)2, –NHCH3, –NHC2H5, –NHC3H7, –NH–cyclo-C3H5, –NHCH(CH3)2, –N(CH3)2, –N(C2H5)2, –N(C3H7)2, –SF5, –SOCH3, –SOC2H5, –SOC3H7, –SO–cyclo-C3H5,–SOCH(CH3)2, –SOC(CH3)3, –SO2CH3, –SO2C2H5, –SO2C3H7, 15 –SO2CH(CH3)2, –SO2–cyclo-C3H5, –SO2NH2, –SO2NHCH3, –SO2NHC2H5, –SO2NHC3H7, –SO2NH–cyclo-C3H5, –SO2NHCH(CH3)2, –SO2N(CH3)2, 20 25 R11and R12represent independently of each other –H or –F; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically30 acceptable salt of the above-mentioned compound. APR-P04602WO24 PCT Application (final).docx 38 Still more preferably, in the formula (I), Brepresents –O–R3 or –O–CHR3R3*; andR3, R3*and R4have the same meanings as defined herein. 5Preferably, the present invention is directed to a compound of the formula (I):; preferably 10 B is –O–R3or –O–CHR3R3*; APR-P04602WO24 PCT Application (final).docx 39 R2arepresents –CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3 ; and R2band R2crepresent indepenently of each other –H or ^CH3; 5 10 more preferably, R3represents APR-P04602WO24 PCT Application (final).docx 40 R3*represents –H, –F, ^CH3, ^C2H5, ^C3H7, ^CH(CH3)2, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3 ; 5 R4and R4*represent indepenently of each other –H, –F, –Cl, –Br, ^CH3, 10 R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other –H, –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OC(CH3)3, 15 –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, ^C2H4–OCH3, ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O–cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6–OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, 20 ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, ^CH2–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, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, 25 –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, 30 –CONH[CH(CH3)2], –CONH[C(CH3)3], –CON(CH3)2, –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, 35 –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, APR-P04602WO24 PCT Application (final).docx 41 5 10 15 –O–COOC2H5, –O–COOC3H7, –O–COO–cyclo-C3H5, –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)2,20 –NH–CO–NH[CH(CH3)2], –NH–CO–NH[C(CH3)3], –NH–CO–N(CH3)2, –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)–NHCH3, –NH–C(=NH)–NHC2H5, –NH–C(=NH)–NHC3H7, –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], 25 –NH–C(=NH)–N(CH3)2, –NH–C(=NH)–N(C2H5)2, –NH–C(=NH)–N(C3H7)2, –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)2, –O–CO–N(C2H5)2, –O–CO–N(C3H7)2, –O–CO–N(cyclo-C3H5)2, –O–CO–N[CH(CH3)2]2, 30 –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, ^CF3, ^CH2^CH2F, ^CH2^CHF2, ^CH2^CF3, cyclo-C8H15, ^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(CH3)–C3H7, 35 –CH2–CH(CH3)–C2H5, –CH(CH3)–CH(CH3)2, –C(CH3)2–C2H5, –CH2–C(CH3)3, –CH(C2H5)2, –C2H4–CH(CH3)2, ^C6H13, ^C7H15, ^C8H17, –C3H6–CH(CH3)2, –C2H4–CH(CH3)–C2H5, –CH(CH3)–C4H9, –CH2–CH(CH3)–C3H7, –CH(CH3)–CH2– CH(CH3)2, –CH(CH3)–CH(CH3)–C2H5, –CH2–CH(CH3)–CH(CH3)2, –CH2–C(CH3)2–C2H5, –C(CH3)2–C3H7, –C(CH3)2–CH(CH3)2, –C2H4–C(CH3)3, APR-P04602WO24 PCT Application (final).docx 42 5 10 15 20 25 30 35 APR-P04602WO24 PCT Application (final).docx 43 5 6-membered ring system: Z1, Z2, Z5, and Z6represent indepenently of each other –H, –F, –Cl, –Br, ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OC2H5, ^OCH2F, ^OCHF2, ^OCF3,10 ^CH2^CF3, or ^CF2^CF3; preferably R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other –H, –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, 15 –OCH(CH3)2, –OC(CH3)3, –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, ^C2H4–OCH3, ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O– cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6– OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, 20 ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, ^CH2–OCH2^Ph, ^C2H4–OCH2^Ph, ^C3H6–OCH2^Ph, –F, –Cl, –Br, –I, –CN, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, –COCH3, –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, 25 –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)2, –CON(C2H5)2, 30 –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, –NH2, –NHCH3, –NHC2H5, –NHC3H7, –NH–cyclo-C3H5, 35 –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, APR-P04602WO24 PCT Application (final).docx 44 5 –SO2N(C3H7)2, –SO2N(cyclo-C3H5)2, –SO2N[CH(CH3)2]2, –SO2N[C(CH3)3]2, ^O–S(=O)CH3, ^O–S(=O)C2H5, ^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, 10 –S(=O)(=NH)C(CH3)3, –P(=O)(CH3)2, –P(=O)(C2H5)2, –P(=O)(OH)2, –P(=O)(OH)(OCH3), –P(=O)(OH)(OC2H5), –P(=O)(OCH3)2, –P(=O)(OC2H5)2, ^O–SO2–CH3, ^O–SO2–C2H5, ^O–SO2–C3H7, ^O–SO2–cyclo-C3H5, 15 20 or R5 and R6, or R6 and R7 form together or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically25 acceptable salt of the above-mentioned compound. In all general formulae disclosed herein B represents preferably –O–R3,–S–R3, or –O–CHR3R3; more preferably –O–R3 or –O–CHR3R3.30 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 compounds of formula (I) are especially preferred, wherein B represents –O–R3.APR-P04602WO24 PCT Application (final).docx 45 Therefore, as disclosed herein, the group of compounds of formula (I) is claimed, wherein B represents only –O–R3 in order to have a claim on the group ofcompounds which are able to easily pass the blood brain barrier. Consequently, the remaining compounds for formula (I) are claimed, wherein B 5 represents –O–CHR3R3*or –O–CH2–CH2–R3. Moreover, the inventors found that the R1residue is especially important for the inhibitory activity. The R1 residue has to have a hydroxy group (^OH) and in additionhas to have at least the substituent R2awhich is different from hydrogen (–H) and10 optionally a second substituent R2b.In regard to all general formulae disclosed herein the substituents R2aand R2bare defined as follows: R2, R2a, R2b, and R2crepresent independently of each other –H, –F, –Br, –Cl, 15 ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3, ^CH2CH2OCH3, ^CF2^CH3, ^CHF^CHF2, ^CHF^CF3, ^CF2^CF3 ; and R2ais not –H; or R2aand R2bform together 20 or in other words: R2arepresents –F, –Br, –Cl, ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3, ^CH2CH2OCH3, ^CF2^CH3, ^CHF^CHF2, ^CHF^CF3, ^CF2^CF3; and 25 R2brepresents –H, –F, –F, –Br, –Cl, ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, R2crepresents –H, –F, –Br, –Cl, ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, 30 ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3, ^CH2CH2OCH3, ^CF2^CH3, ^CHF^CHF2, ^CHF^CF3, ^CF2^CF3. APR-P04602WO24 PCT Application (final).docx 46 Thus, under the proviso that R2a is different from hydrogen (–H), it is preferred thatR2a and R2b represent independently of each other –H, –F, –Br, –Cl, ^CH3,^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, 5 10 more preferably, R2a and R2b represent independently of each other –H, –F, –Br,–Cl, ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3, ^CF2^CH3, ^CHF^CHF2; 15 more preferably, R2aand R2brepresent independently of each other –H, –F, ^CH3, ^C2H5, , ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CF2^CH3, ^CHF^CHF2,20 ^CHF^CF3, ^CF2^CF3 ; or R2aand R2bform together , , , ; R2crepresents –H, –F, ^CH3, ^CH2F, ^CHF2, ^CF3 ; more preferably, R2aand R2brepresent independently of each other –H, –F, ^CH3, 25 ^C2H5, , ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CF2^CH3, ^CHF^CHF2, ^CHF^CF3, ^CF2^CF3 ; or R2aand R2bform together , , or ; R2crepresents –H, –F, ^CH3, ^CH2F, ^CHF2, ^CF3; 30 more preferably, R2a and R2b represent independently of each other –H, –F, ^CH3,^C2H5, , ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, APR-P04602WO24 PCT Application (final).docx 47 ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3, ^CF2^CH3, ^CHF^CHF2 ; or R2aand R2bform together , , or ; R2crepresents –H, –F, ^CH3, ^CH2F, ^CHF2, ^CF3; 5 more preferably, R2aand R2brepresent independently of each other –H, –F, ^CH3, 10 more preferably, R2a and R2b represent independently of each other –H, –F, ^CH3,^C2H5, , ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, 15 more preferably, R2a and R2b represent independently of each other –H, –F, ^CH3,^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3,20 more preferably, R2a and R2b represent independently of each other –H, –F, ^CH3,25 ^C2H5, , ^CH(CH3)2, ^cyclo- ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2 or R2aand R2bform together R2crepresents –H, –F, ^CH3; 30 Still more preferably, R2aand R2brepresent independently of each other –H, ^CH3, ^CD3, ^CH2F, ^CHF2, ^CF3, (always under the proviso that R2ais different rom hydrogen). Also preferred are compounds, wherein R2a and R2b represent both ^CH3 or ^C2H5,and more preferably ^CH3 ; or R2aand R2bform together , , . 35 APR-P04602WO24 PCT Application (final).docx 48 Moreover, also preferred are compounds, wherein R2b represents –H and R2arepresents ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3, ^CF2^CH3, ^CHF^CHF2, ^CHF^CF3, ^CF2^CF3 ; and more preferably ^CH3, 5 ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CF2^CH3, ^CHF^CHF2, ^CHF^CF3, ^CF2^CF3 ; and more preferably ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo- C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CF2^CH3, ^CHF^CHF2, ^CHF^CF3, ^CF2^CF3 ; and more preferably 10 ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3, ^CF2^CH3, ^CHF^CHF2 ; and more preferably ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3, ^CF2^CH3, ^CHF^CHF2 ; and more preferably ^CH3, 15 ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CF2^CH3, ^CHF^CHF2 ; and more preferably ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CF2^CH3, ^CHF^CHF2 ; and more preferably ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, 20 ^CHF^CH2F, ^CH2OH; and more preferably ^CH3, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH; and more preferably ^CH3, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CHF^CH2F, ^CH2OH; and more preferably ^CH3, ^CH2F, ^CHF2, ^CF3;or R2aand R2bform together , , . 25 R2brepresents preferably –H or ^CH3; and more preferably R2brepresents ^CH3if R2arepresents –CH3, and R2brepresents ^H if R2ais different from –CH3. Moreover, in all general formulae disclosed herein, it is preferred that R10, R11, R12,30 and R13 represent hydrogen (–H) or –F.Also preferred are compounds of the general formula (I), wherein R2arepresents –CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, 35 ^CH2OCH3; and R2brepresents –H or ^CH3; and preferably R2brepresents ^CH3if R2arepresents –CH3, and R2brepresents ^H if R2ais different from –CH3. or R2aand R2bform together , , or ; APR-P04602WO24 PCT Application (final).docx 49 Brepresents –O–R3, –S–R3, or –O–CHR3R3*;R3represents 5 10 APR-P04602WO24 PCT Application (final).docx 50 5 10 APR-P04602WO24 PCT Application (final).docx 51 5 more preferably, R3represents 10 APR-P04602WO24 PCT Application (final).docx 52 5 10 15 and A, R1, R2, R5, R6, R7, R8, R9, R10, R11, R12and R13have the same meanings as defined as defined herein. Also preferred are compounds of the general formula (I), wherein 20 R2arepresents –CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3; and APR-P04602WO24 PCT Application (final).docx 53 R2brepresents –H or ^CH3; and preferably R2brepresents ^CH3 if R2arepresents –CH3, and R2brepresents ^H if R2ais different from –CH3. or R2aand R2bform together , , ; 5B represents –O–R3 or –O–CHR3R3*;R3represents 1015 APR-P04602WO24 PCT Application (final).docx 54 more preferably, R3represents 5 10 still more preferably, R3represents , APR-P04602WO24 PCT Application (final).docx 55 more preferably, R3represents 5 10 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, –Br, ^CH3, 15 ^C2H5, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OCD3, ^OC2H5, ^OC3H7, ^OCH(CH3)2, ^OCH2F, ^OCHF2, ^OCF3, ^CH2^CF3, ^CHF^CH2F, ^CHF^CHF2, ^CHF^CF3, APR-P04602WO24 PCT Application (final).docx 56 , and A, R1, R2, R5, R6, R7, R8, R9, R10, R11, R12and R13have the same meanings as 5defined in claim 1 or as defined herein.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, ^OCD3, ^OC2H5, ^OCH(CH3)2, ^OCH2F, ^OCHF2, ^OCF3, ^CH2^CF3, 10 ^CHF^CH2F, ^CHF^CHF2, ^CHF^CF3, ^CF2^CH3, ^CF2^CH2F, ^CF2^CHF2, OO O^CF2^CF3 , , or ; more preferably –H, –F, –Cl, –Br, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OCD3, ^OC2H5, ^OCH(CH3)2, ^OCH2F, ^OCHF2, ^OCF3, ^CH2^CF3, ^CHF^CH2F, ^CHF^CHF2, ^CHF^CF3, OO O^CF2^CH3, ^CF2^CH2F, ^CF2^CHF2, ^CF2^CF3, , or ; 15 more preferably –H, –F, –Cl, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OCD3, ^OC2H5, ^OCH2F, ^OCHF2, ^OCF3, ^CH2^CF3, ^CHF^CH2F, ^CHF^CHF2, ^CHF^CF3, OO O^CF2^CH3, ^CF2^CH2F, ^CF2^CHF2, ^CF2^CF3, , or ;more preferably –H, –F, –Cl, ^CHF2, ^CF3, ^OCH3, ^OCD3, ^OC2H5, ^OCHF2, ^OCF3, ^CH2^CF3, ^CHF^CH2F, ^CHF^CHF2, ^CHF^CF3, OO20 ^CF2^CH3, ^CF2^CH2F, ^CF2^CHF2, ^CF2^CF3, or ; still more preferably –H, –F, –Cl, ^CHF2, ^CF3, ^OCH3, ^OCD3, ^OC2H5, ^OCHF2, ^OCF3, ^CHF^CHF2, ^CHF^CF3, ^CF2^CH3, ^CF2^CH2F, ^CF2^CHF2, OO^CF2^CF3, or ; still more preferably –H, –F, –Cl, ^CHF2, ^CF3, ^OCH3, ^OCD3, ^OC2H5, ^OCHF2, ^OCF3, ^CHF^CHF2, ^CHF^CF3, 25 ^CF2^CHF2, or ^CF2^CF3; still more preferably –H, –F, –Cl, ^CHF2, ^CF3, ^OCH3, ^OCD3, ^OC2H5, ^OCHF2, ^OCF3, ^CF2^CHF2, ^CF2^CF3, or O O ; still more preferably –H, –F, –Cl, ^CHF2, ^CF3, ^OCH3, ^OCD3, ^OC2H5, ^OCHF2, or ^OCF3; still more preferably –H, –F, –Cl, ^CHF2, ^CF3, ^OCH3, ^OCD3, ^OCHF2, or ^OCF3. 30 In combination with the preferred definitons of R4, the substituent R4*represents preferably –H, –F, –Cl, ^CH2F, ^CHF2, ^CF3, ^OCHF2, or ^OCF3, more APR-P04602WO24 PCT Application (final).docx 57 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 5 more preferably –H or –F, still more preferably –H. In all general formula disclosed 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 10 –H, –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OC(CH3)3, –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, ^C2H4–OCH3, ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O–15 cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6– OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, ^CH2–OCH2^Ph, ^C2H4–OCH2^Ph, ^C3H6–OCH2^Ph, –SF5, –F, –Cl, –Br, –I, –CN, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, 20 ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, –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, 25 –CONHCH3, –CONHC2H5, –CONHC3H7, –CONH–cyclo-C3H5, –CONH[CH(CH3)2], –CONH[C(CH3)3], –CON(CH3)2, –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, 30 –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, 35 –SO2–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, APR-P04602WO24 PCT Application (final).docx 58 ^O–S(=O)CH3, ^O–S(=O)C2H5, ^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, –P(=O)(CH3)2, –P(=O)(C2H5)2, 5 –P(=O)(OH)2, –P(=O)(OH)(OCH3), –P(=O)(OH)(OC2H5), –P(=O)(OCH3)2, –P(=O)(OC2H5)2, ^O–SO2–CH3, ^O–SO2–C2H5, ^O–SO2–C3H7, ^O–SO2–cyclo-C3H5, ^O–SO2–CH(CH3)2, 10 15 or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of 20 diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt of the above-mentioned compound. R5 and R6, or R6 and R7 may form the following 5- or 6-membered ring system,25 preferably R10, R11, R12 and R13 are hydrogen or F.APR-P04602WO24 PCT Application (final).docx 59 Still more preferably, in all general formula disclosed 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-C3H5, –cyclo-C4H7, –cyclo-C5H9, 5 –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, 10 –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, 15 –CONH[CH(CH3)2], –CON(CH3)2, –CON(C2H5)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, –NH2, –NHCH3, –NHC2H5, –NHC3H7, –NH–cyclo-C3H5, 20 –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, –SO2–cyclo-C3H5, –SO2CH(CH3)2, –SO2C(CH3)3, –SO3H, –SO3CH3, –SO3C2H5, –SO3C3H7, –SO3–cyclo-C3H5, –SO3CH(CH3)2, –SO3C(CH3)3, 25 –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, –S(=O)(=NH)CH3, –S(=O)(=NH)C2H5, –S(=O)(=NH)C3H7, –S(=O)(=NH)–cyclo-C3H5, –S(=O)(=NH)CH(CH3)2, 30 –S(=O)(=NH)C(CH3)3, –P(=O)(CH3)2, –P(=O)(C2H5)2, –P(=O)(OH)2, –P(=O)(OH)(OCH3), –P(=O)(OH)(OC2H5), –P(=O)(OCH3)2, –P(=O)(OC2H5)2, ^O–SO2–CH3, –OCH2F, –OCHF2, –OCF3, ^CH2–OCF3, ^C2H4–OCF3, ^C3H6–OCF3, ^CH2–OCHF2, ^C2H4–OCHF2, ^C3H6–OCHF2, 35 –OCH2CF3, –OC2F5, ^CH2–OC2F5, ^C2H4–OC2F5, ^C3H6–OC2F5, ^CH2F, ^CHF2, ^CF3, ^CH2^CH2F, ^CH2^CHF2, ^CH2^CF3, ^CH3, ^C2H5, ^C3H7, ^CH(CH3)2, ^C4H9, ^CH2^CH(CH3)2, ^CH(CH3)^C2H5, ^C(CH3)3, ^C(CH3)2CN, ^CH(CH3)(OH), ^CH(CF3)(OH), ^C(CH3)(CF3)(OH), ^C5H11, ^CH=CH2,APR-P04602WO24 PCT Application (final).docx 60 or 5R5 and R6, or R6 and R7 may form the following 5- or 6-membered ring system, preferably R10, R11, R12 and R13 are hydrogen or F.10 Still more preferably, in all general formula disclosed 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 other –H, –F, –Cl, –CN, –CH3, ^C2H5, ^C3H7, ^CH(CH3)2, –cyclo-C3H5, –cyclo-C4H7, –CH2F, 15 –CHF2, –CF3, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –OCH2CF3, –CH2OCH3, –COCH3, –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, –CONH2, –CONHCH3,–CONHC2H5, –CONHC3H7, –CONH–cyclo-C3H5, –CON(CH3)2, –CON(C2H5)2,–NHCH3, –NHC2H5, –NHC3H7, –NH–cyclo-C3H5, 20 –NHCH(CH3)2, –N(CH3)2, –N(C2H5)2, –N(C3H7)2, ^SF5, –SOCH3, –SOC2H5, –SOC3H7, –SO–cyclo-C3H5, –SOCH(CH3)2, –SOC(CH3)3, –SO2CH3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, –SO2–cyclo-C3H5, –SO2NH2, –SO2NHCH3, –SO2NHC2H5, –SO2NHC3H7, –SO2NH–cyclo-C3H5, –SO2NHCH(CH3)2, –SO2N(CH3)2, –SO2N(C2H5)2, –S(=O)(=NH)CH3, –S(=O)(=NH)C2H5, 25 –S(=O)(=NH)C3H7, –S(=O)(=NH)–cyclo-C3H5, –S(=O)(=NH)CH(CH3)2, , APR-P04602WO24 PCT Application (final).docx 61 5 Still more preferably, in all general formula disclosed 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 other –H, –F, –Cl, –CN, –CH3, ^CH(CH3)2, –cyclo-C3H5, –cyclo-C4H7, –CH2F, –CHF2, –CF3, –SF5, –OCH3, –OCD3, –OC2H5,10 –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –OCH2CF3, –COCH3, –CONH2, –CON(CH3)2, –CON(C2H5)2,–N(CH3)2, –N(C2H5)2, –N(C3H7)2, –SOCH3, –SOC(CH3)3, –SO2CH3, –SO2CH(CH3)2, –SO2–cyclo-C3H5, –SO2N(CH3)2, 15 Preferably R3represents wherein the substituents R5 – R7 have the meanings as disclosed above on the two previous20 pages and still more preferably R5 – R7 are independently of each other selectedfrom –H, –F, –Cl, –CN, –CH3, ^CH(CH3)2, –cyclo-C3H5, –cyclo-C4H7,–CH2F, –CHF2, –CF3, –SF5, –OCH3, –OCD3, –OC2H5, –OC3H7,–O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –OCH2CF3, –COCH3, –CONH2, –CON(CH3)2, –CON(C2H5)2,–N(CH3)2, –N(C2H5)2, –N(C3H7)2, –SOCH3,25 –SOC(CH3)3, –SO2CH3, –SO2CH(CH3)2, –SO2–cyclo-C3H5, –SO2N(CH3)2, APR-P04602WO24 PCT Application (final).docx 62 5 101520 APR-P04602WO24 PCT Application (final).docx 63 5 10 R5 – R7 are independently of each other selected from –H, –F, –Cl,–CN, –CH3, ^CH(CH3)2, –cyclo-C3H5, –cyclo-C4H7, –CH2F, –CHF2, –CF3, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –COCH3, –CONH2, –CON(CH3)2, –CON(C2H5)2,–N(CH3)2, –N(C2H5)2, –N(C3H7)2, –SOCH3,15 –SOC(CH3)3, –SO2CH3, –SO2CH(CH3)2, –SO2–cyclo-C3H5, –SO2N(CH3)2,–S(=O)(=NH)CH3, –P(=O)(CH3)2, –P(=O)(OC2H5)2, ^C≡CH, ^C≡C^CH3, ^CH2-C≡CH; more preferably –H, –OCH3, –OC2H5, –OC3H7, 20 25 ^CH3 ; still more preferably from –H, –OCH3, –F, –Cl, –OCHF2, –OCF3, APR-P04602WO24 PCT Application (final).docx 64 ^CHF2, ^CF3, ^CH3; or R5and R6may form preferably R10, R11, R12 and R13 are hydrogen or –F.In some embodiments, the present invention refers to a compound of the formula (I): 5 ; 10 R2, R2a, R2band R2crepresent independently of each other –H, –F, –Cl, ^CH3, ^C2H5, , ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3, ^CH2CH2OCH3, ^CF2^CH3, ^CHF^CHF2, ^CHF^CF3, ^CF2^CF3 ; and R2a is not –H;or R2a and R2b form together R3represents APR-P04602WO24 PCT Application (final).docx 65 5 10 15 APR-P04602WO24 PCT Application (final).docx 66 Preferably, R4*represents –H, –F, –Cl, ^CH2F, ^CHF2, ^CF3, ^OCHF2, or ^OCF3, more preferably R4* represents –H or –F;and Z1, Z2, R5, R6, R7, R8, R9, R10, R11, R12 and R13 have the same meanings as5 defined herein and R10, R11, R12, and R13preferably represent –H or –F. Preferably, in the compounds of the formula (I) as defined herein R1 represents10 15 . still more preferably R1 represents20 , APR-P04602WO24 PCT Application (final).docx 67 still more preferably R1 represents still more preferably R1 represents5 In some embodiments, the present invention relates to the compound of any one of the following formulae (Ia) to (Id): wherein A and R1, R2 have the same meanings as defined above.10 Preferably, the present invention is directed to the compound of any one of theformulae (Ia) – (Id), wherein , preferably , ,APR-P04602WO24 PCT Application (final).docx 68 5 R2represents –H –Br, –Cl, –cyclo-C3H5, or –CH3; ^CHF^CH2F, 10 R3represents 15 APR-P04602WO24 PCT Application (final).docx 69 5 10 APR-P04602WO24 PCT Application (final).docx 70 5 10 O O 15 ; preferably –H, –F, –Cl, –Br, ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OC2H5, ^OC3H7, ^OCH(CH3)2, ^OCH2F, ^OCHF2, or ^OCF3; more preferably –H, –F, –Cl, –Br, ^CH3, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OCH2F, ^OCHF2, or ^OCF3; APR-P04602WO24 PCT Application (final).docx 71 R4*represents –H, –F, –Cl, –Br, or ^CH3; preferably –H, –F, or –Cl, more preferably –H or –F;R5, R6, R7, R8, R9, R10, R11, R12and R13have the same meanings as defined herein, 5 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.10 More preferably, the present invention is directed to the compound of any one of theformulae (Ia) – (Id),wherein ; 15 preferably ; preferably R1represents ; 20 APR-P04602WO24 PCT Application (final).docx 72 R2crepresents –H or ^CH3; 5 more preferably, R3represents10 still more preferably, R3represents , APR-P04602WO24 PCT Application (final).docx 73 5 R3*represents –H, –F, ^CH3, ^C2H5, ^C3H7, ^CH(CH3)2, ^CH2F, ^CHF2, ^CF3, or ^CH2^CF3 ; preferably –H or ^CH3 ;10 R4represents –H, –F, –Cl, –Br, ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OC2H5, ^OC3H7, ^OCH(CH3)2, ^OCH2F, ^OCHF2, ^OCF3, ^CH2^CF3, ^CHF^CH2F, ^CHF^CHF2, ^CHF^CF3, ^CF2^CH3, ^CF2^CH2F,15 more preferably –H, –F, –Cl, –Br, ^CH3, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OCH2F, ^OCHF2, or ^OCF3; APR-P04602WO24 PCT Application (final).docx 74 R4*represents –H, –F, –Cl, –Br, or ^CH3; preferably –H, –F, or –Cl, more preferably –H or –F; R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other –H, 5 –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OC(CH3)3, –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, ^C2H4–OCH3, ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O–10 cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6– OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, ^CH2–OCH2^Ph, ^C2H4–OCH2^Ph, ^C3H6–OCH2^Ph, –F, –Cl, –Br, –I, –CN, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, 15 ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, –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, 20 –CONHCH3, –CONHC2H5, –CONHC3H7, –CONH–cyclo-C3H5, –CONH[CH(CH3)2], –CONH[C(CH3)3], –CON(CH3)2, –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, 25 –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, 30 –SO2–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, 35 ^O–S(=O)CH3, ^O–S(=O)C2H5, ^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, –P(=O)(CH3)2, –P(=O)(C2H5)2, –P(=O)(OH)2, –P(=O)(OH)(OCH3), –P(=O)(OH)(OC2H5), –P(=O)(OCH3)2, –P(=O)(OC2H5)2, APR-P04602WO24 PCT Application (final).docx 75 ^O–SO2–CH3, ^O–SO2–C2H5, ^O–SO2–C3H7, ^O–SO2–cyclo-C3H5, 5 10 R5 and R6, or R6 and R7 form one of the following 5- or 6-membered ring systems: preferably R10, R11, R12 and R13 are hydrogen or –F;15 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. 20 Still more preferably, in any one of the formulae (Ia) to (Id), 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-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OC(CH3)3, –OC4H9, ^CH2–OCH3, ^CH2–OC2H5, ^CH2–OC3H7, 25 ^CH2–O–cyclo-C3H5, –F, –Cl, –Br, –I, –CN, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, –COCH3, –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, –COC(CH3)3, –COOH, –COOCH3, –COOC2H5, –COOC3H7, –COO–cyclo-C3H5, 30 –COOCH(CH3)2, –COOC(CH3)3, –OOC–CH3, –OOC–C2H5, –OOC–C3H7, –OOC–cyclo-C3H5, –OOC–CH(CH3)2, –OOC–C(CH3)3, –CONH2, APR-P04602WO24 PCT Application (final).docx 76 –CONHCH3, –CONHC2H5, –CONHC3H7, –CONH–cyclo-C3H5, –CONH[CH(CH3)2], –CON(CH3)2, –CON(C2H5)2, –NHCOCH3, –NHCOC2H5, –NHCOC3H7, –NHCO–cyclo-C3H5, –NHCO–CH(CH3)2, –NHCO–C(CH3)3, –NHCO–OCH3, –NHCO–OC2H5, 5 –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, 10 –SO2–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, 15 –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, 2025 30 preferably R10, R11, R12 and R13 are hydrogen or –F.APR-P04602WO24 PCT Application (final).docx 77 more preferably, in any one of the formulae (Ia) to (Id), R5, R6, R7, R8, R9, R10, R11, R12and R13or the substituents R5, R6, R7, R8and R9, preferably represent independently of each other other –H, –F, –Cl, –CN, –CH3, ^C2H5, ^C3H7, ^CH(CH3)2, –cyclo-C3H5, –cyclo-C4H7, –CH2F, –CHF2, –CF3, –OCH3, –OCD3, 5 –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –OCH2CF3, –CH2OCH3, –COCH3, –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, –CONH2, –CONHCH3, –CONHC2H5, –CONHC3H7, –CONH–cyclo-C3H5,–CON(CH3)2, –CON(C2H5)2, –NHCH3, –NHC2H5, –NHC3H7, –NH–cyclo-C3H5,–NHCH(CH3)2, –N(CH3)2, –N(C2H5)2, –N(C3H7)2, ^SF5, –SOCH3, –SOC2H5, 10 –SOC3H7, –SO–cyclo-C3H5, –SOCH(CH3)2, –SOC(CH3)3, –SO2CH3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, –SO2–cyclo-C3H5, –SO2NH2, –SO2NHCH3, –SO2NHC2H5, –SO2NHC3H7, –SO2NH–cyclo-C3H5, –SO2NHCH(CH3)2, –SO2N(CH3)2, –SO2N(C2H5)2, –S(=O)(=NH)CH3, –S(=O)(=NH)C2H5, –S(=O)(=NH)C3H7, –S(=O)(=NH)–cyclo-C3H5, –S(=O)(=NH)CH(CH3)2, 15 20 still more preferably, in any one of the formulae (Ia) to (Id), R5, R6, R7, R8, R9, R10, R11, R12and R13or the substituents R5, R6, R7, R8and R9, preferably represent independently of each other other –H, –F, –Cl, –CN, –CH3, ^CH(CH3)2, –cyclo-C3H5, –cyclo-C4H7, –CH2F,25 –CHF2, –CF3, –SF5, –OCH3, –OCD3, –OC2H5,–OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –OCH2CF3, –COCH3,30 APR-P04602WO24 PCT Application (final).docx 78 or R5and R6form together , , , , or ; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically5 acceptable salt of the above-mentioned compound. In some embodiments, the present invention relates to the compound of any one of the following formulae (Ia-1) to (Ia-4), (Ib-1) to (Ib-4), (Ic-1) to (Ic-4), and (Id-1) to (Id-4): APR-P04602WO24 PCT Application (final).docx 79 wherein R1, R3*, R4, R4*, R5, R6, R7, R8, R10, R11, R12, and R13have the same meanings as defined above. Preferably, the present invention is directed to the compound of any one of the 5fo preferably , ,10 APR-P04602WO24 PCT Application (final).docx 80 preferably, R1 represents ; R2represents –H –Br, –Cl, –cyclo-C3H5, or –CH3, ^CHF^CH2F, 5 R2crepresents –H or ^CH3; R3represents10 preferably, R3represents APR-P04602WO24 PCT Application (final).docx 81 5 10 still more preferably, R3represents APR-P04602WO24 PCT Application (final).docx 82 5 10 O O ; preferably –H, –F, –Cl, –Br, ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OC2H5, ^OC3H7, ^OCH(CH3)2, ^OCH2F, ^OCHF2, or ^OCF3; 15 more preferably –H, –F, –Cl, –Br, ^CH3, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OCH2F, ^OCHF2, or ^OCF3; R4*represents –H, –F, –Cl, –Br, or ^CH3; preferably –H, –F, or –Cl, more preferably –H or –F; 20 R5, R6, R7, R8, R9, R10, R11, R12and R13have the same meanings as defined herein, 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. APR-P04602WO24 PCT Application (final).docx 83 More preferably, the present invention is directed to the compound of any one of the R2represents –H or –CH3; 5 R2arepresents –CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, or ^CH2OCH3; R2brepresents –H or ^CH3; or R2aand R2bform together 10 R2crepresents –H or ^CH3; R3represents15 more preferably, R3represents APR-P04602WO24 PCT Application (final).docx 84 5 10 15 20 APR-P04602WO24 PCT Application (final).docx 85 R8, R9, R10, R11, R12and R13represent independently of each other –H, –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OC(CH3)3, –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, 5 ^C2H4–OCH3, ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O– cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6– OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, 10 ^CH2–OCH2^Ph, ^C2H4–OCH2^Ph, ^C3H6–OCH2^Ph, –F, –Cl, –Br, –I, –CN, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, –COCH3, –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, –COC(CH3)3, –COOH, –COOCH3, –COOC2H5, –COOC3H7, –COO–cyclo-C3H5, 15 –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)2, –CON(C2H5)2, –CON(C3H7)2, –CON(cyclo-C3H5)2, –CON[CH(CH3)2]2, –CON[C(CH3)3]2, 20 –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, –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, 25 –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, –SO2–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, 30 –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)C2H5, ^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, 35 –S(=O)(=NH)C(CH3)3, –P(=O)(CH3)2, –P(=O)(C2H5)2, –P(=O)(OH)2, –P(=O)(OH)(OCH3), –P(=O)(OH)(OC2H5), –P(=O)(OCH3)2, –P(=O)(OC2H5)2, ^O–SO2–CH3, ^O–SO2–C2H5, ^O–SO2–C3H7, ^O–SO2–cyclo-C3H5, ^O–SO2–CH(CH3)2, ^O–SO2–C(CH3)3, –OCH2F, –OCHF2, –OCF3, ^CH2–OCF3, ^C2H4–OCF3, ^C3H6–OCF3, ^CH2–OCHF2, ^C2H4–OCHF2, ^C3H6–OCHF2, APR-P04602WO24 PCT Application (final).docx 86 5 R5 and R6, or R6 and R7 form one of the following 5- or 6-membered ring systems: 10 preferably R10, R11, R12 and R13 are hydrogen or –F;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. 15 Preferably, in any one of the formulae (Ia-1) – (Ia-4), (Ib-1) – (Ib-4), (Ic-1) – (Ic-4),and (Id-1) – (Id-4), the substituents R5, R6, R7, R8, R9, R10, R11, R12 and R13represent independently of each other –H, –F, –Cl, –CN, –CH3, ^C2H5, ^C3H7, ^CH(CH3)2, –cyclo-C3H5, –cyclo-C4H7, –CH2F, –CHF2, –CF3, –OCH3, 20 –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –OCH2CF3, –CH2OCH3, –COCH3, –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, –CONH2, –CONHCH3, –CONHC2H5, –CONHC3H7, –CONH–cyclo-C3H5, –CON(CH3)2, –CON(C2H5)2, –NHCH3, –NHC2H5, –NHC3H7, –NH–cyclo-C3H5, –NHCH(CH3)2, –N(CH3)2, –N(C2H5)2, –N(C3H7)2, ^SF5, –SOCH3,25 –SOC2H5, –SOC3H7, –SO–cyclo-C3H5, –SOCH(CH3)2, –SOC(CH3)3, –SO2CH3,–SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, –SO2–cyclo-C3H5, –SO2NH2, –SO2NHCH3, –SO2NHC2H5, –SO2NHC3H7, –SO2NH–cyclo-C3H5, –SO2NHCH(CH3)2, –SO2N(CH3)2, –SO2N(C2H5)2, –S(=O)(=NH)CH3, –S(=O)(=NH)C2H5, –S(=O)(=NH)C3H7, –S(=O)(=NH)–cyclo-C3H5, –S(=O)(=NH)CH(CH3)2, 30 APR-P04602WO24 PCT Application (final).docx 87 More preferably, in any one of the formulae (Ia-1) – (Ia-4), (Ib-1) – (Ib-4), (Ic-1) – (Ic-5 4), and (Id-1) – (Id-4), R5, R6, R7, R8, R9, R10, R11, R12 and R13 or the substituents R5,R6, R7, R8and R9, preferably represent independently of each other –H, –F, –Cl, –CN, –CH3, ^CH(CH3)2, –cyclo-C3H5, –cyclo-C4H7, –CH2F, –CHF2, –CF3, –SF5, –OCH3, –OCD3, –OC2H5,–OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –OCH2CF3, –COCH3,10 –CONH2, –CON(CH3)2, –CON(C2H5)2,–N(CH3)2, –N(C2H5)2, –N(C3H7)2, –SOCH3, –SOC(CH3)3, –SO2CH3, –SO2CH(CH3)2, –SO2–cyclo-C3H5, –SO2N(CH3)2, 15 In some embodiments, the present invention relates to the compound of any one of the following formulae (II-1) to (II-6), (III-1) to (III-6), (IV-1) to (IV-6), (V-1) to (V-6),20 (VI-1) to (VI-4) and (VII-1) to (VII-6): APR-P04602WO24 PCT Application (final).docx 88 APR-P04602WO24 PCT Application (final).docx 89 APR-P04602WO24 PCT Application (final).docx 90 wherein R1, R3*, R4, R4*, R5, R6, R7, R8, R10, R11, R12, and R13have the same meanings as defined herein. 5Preferably, in the compound of any one of the following formulae (Ia) to (Id), (Ia-1) to(Ia-4), (Ib-1) to (Ib-4), (Ic-1) to (Ic-4), (Id-1) to (Id-4), (II-1) to (II-6), (III-1) to (III-6), (IV-1) to (IV-6), (V-1) to (V-6): R1represents 10 APR-P04602WO24 PCT Application (final).docx 91 , more preferably, R1represents 5 . still more preferably, R1 represents10 still more preferably, R1 represents still more preferably, R1 represents15 Preferably, in the compound of any one of the following formulae (I), (Ia) to (Id), (Ia-1) to (Ia-4), (Ib-1) to (Ib-4), (Ic-1) to (Ic-4), (Id-1) to (Id-4), (II-1) to (II-6), (III-1) to (III- 6), (IV-1) to (IV-6), (V-1) to (V-6), (VI-1) to (VI-4) and (VII-1) to (VII-6), APR-P04602WO24 PCT Application (final).docx 92 R4represents –H, –F, –Cl, –Br, ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, 5 10 ^OCD3, ^OCH2F, ^OCHF2, ^OCF3; 15 still more preferably, R4represents –H, –F, –Cl, –CH3, –CH2F, –CHF2, –CF3, –OCH3, ^OCD3, –OCHF2, –OCF3 or ^CF2^CHF2 ; and still more preferably –H,–F, –Cl, –CHF2, –CF3, –OCH3, ^OCD3, –OCHF2, –OCF3; and most preferablyR4is –OCF3.20 Preferably, the present invention relates to the compound of any one of the followingformulae (I), (Ia) to (Id), (Ia-1) to (Ia-4), (Ib-1) to (Ib-4), (Ic-1) to (Ic-4), (Id-1) to (Id-4), (II-1) to (II-6), (III-1) to (III-6), (IV-1) to (IV-6), (V-1) to (V-6), (VI-1) to (VI-4) and (VII-1) to (VII-6), wherein R7, R8, R9, R10, R11, R12and R13or the substituents R5, R6, R7, R8and R9, preferably represent independently of each other –H, –F, –Cl, 25 –CN, –CH3, ^C2H5, ^C3H7, ^CH(CH3)2, –cyclo-C3H5, –cyclo-C4H7, –CH2F, –CHF2, –CF3, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –OCH2CF3, –CH2OCH3, –COCH3, –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, –CONH2, –CONHCH3,–CONHC2H5, –CONHC3H7, –CONH–cyclo-C3H5, 30 –CON(CH3)2, –CON(C2H5)2,–NHCH3, –NHC2H5, –NHC3H7, –NH–cyclo-C3H5, –NHCH(CH3)2, –N(CH3)2, –N(C2H5)2, –N(C3H7)2, ^SF5, –SOCH3, –SOC2H5, –SOC3H7, –SO–cyclo-C3H5, –SOCH(CH3)2, –SOC(CH3)3, –SO2CH3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, –SO2–cyclo-C3H5, –SO2NH2, –SO2NHCH3, APR-P04602WO24 PCT Application (final).docx 93 –SO2NHC2H5, –SO2NHC3H7, –SO2NH–cyclo-C3H5, –SO2NHCH(CH3)2, –SO2N(CH3)2, –SO2N(C2H5)2, –S(=O)(=NH)CH3, –S(=O)(=NH)C2H5, –S(=O)(=NH)C3H7, –S(=O)(=NH)–cyclo-C3H5, –S(=O)(=NH)CH(CH3)2, 5 101520 25 In some embodiment, the present invention relates to the compound of any one of the following formulae (I), (Ia) to (Id), (Ia-1) to (Ia-4), (Ib-1) to (Ib-4), (Ic-1) to (Ic-4),(Id-1) to (Id-4), (II-1) to (II-6), (III-1) to (III-6), (IV-1) to (IV-6), (V-1) to (V-6), (VI-1) to (VI-4) and (VII-1) to (VII-6), wherein R3 represents , APR-P04602WO24 PCT Application (final).docx 94 5 10 15 , APR-P04602WO24 PCT Application (final).docx 95 5 10 15 APR-P04602WO24 PCT Application (final).docx 96 5 , 10 15 APR-P04602WO24 PCT Application (final).docx 97 5 In a preferred embodiment, the present invention is directed to the compound of the 10 formula (I), ; , , , 15 preferably APR-P04602WO24 PCT Application (final).docx 98 , , 5 , , R2represents –H, –Br, –Cl, ^CH3, ^C2H5, ^C3H7, ^CH(CH3)2, or10 ^cyclo-C3H5; 15 APR-P04602WO24 PCT Application (final).docx 99 R3*represents –H, –F, ^CH3, ^C2H5, ^C3H7, ^CH(CH3)2, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3 ; 5 10 R5, R6, R7, R8 and R9 represent independently of each other –H, –F, –Cl,–CN, –CH3, ^C2H5, ^C3H7, ^CH(CH3)2, ^C(CH3)2CN, ^CH(CH3)(OH), ^CH(CF3)(OH), ^C(CH3)2(OH), ^C(CH3)(CF3)(OH), –cyclo-C3H5, –cyclo-C4H7, –CH2F, –CHF2, –CF3, –CH2CF3, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –OCH2CF3, –CH2OCH3, 15 –COCH3, –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, –CONH2, –CONHCH3, –CONHC2H5, –CONHC3H7, –CONH–cyclo-C3H5, –CON(CH3)2, –CON(C2H5)2, –NHCH3, –NHC2H5, –NHC3H7, –NH–cyclo-C3H5, –NHCH(CH3)2, –N(CH3)2, –N(C2H5)2, –N(C3H7)2, –SF5, –SOCH3, –SOC2H5, –SOC3H7,–SO–cyclo-C3H5, –SOCH(CH3)2, –SOC(CH3)3, –SO2CH3, –SO2C2H5, –SO2C3H7, 20 25 R11 and R12 represent independently of each other –H or –F.30 More preferably, the present invention is directed to the compound of the formula (I), APR-P04602WO24 PCT Application (final).docx 100 ; preferably ; 5 Brepresents –O–R3 or –O–CHR3R3*;R1represents 10 preferably R1 representsAPR-P04602WO24 PCT Application (final).docx 101 5 10 R2 represents –H, –Cl, ^CH3, ^C2H5, ^C3H7, or ^CH(CH3)2;R3represents 15 APR-P04602WO24 PCT Application (final).docx 102 R3*represents –H, –F, ^CH3, ^C2H5, ^C3H7, ^CH(CH3)2, ^CH2F, ^CHF2, ^CF3, or ^CH2^CF3 ; 5 101520 25 30 APR-P04602WO24 PCT Application (final).docx 103 R11and R12represent independently of each other –H or –F; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of 5 diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically acceptable salt of the above-mentioned compound. In a more preferred embodiment, the present invention is directed to the compound of the formula (I), 10 , preferably 15 , , APR-P04602WO24 PCT Application (final).docx 104 5 10 15 , APR-P04602WO24 PCT Application (final).docx 105 5 10 15 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. APR-P04602WO24 PCT Application (final).docx 106 In a more preferred embodiment, the present invention is directed to the compound of the formula (I), ; , 5 preferably, ; , Brepresents –O–R3 or –O–CHR3R3*;10 R2represents –H, –Cl, or ^CH3; R3represents APR-P04602WO24 PCT Application (final).docx 107 5 10 15 , APR-P04602WO24 PCT Application (final).docx 108 5 10 15 APR-P04602WO24 PCT Application (final).docx 109 5 10 15 R4*represents –H or –F; 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. 20 Still more preferred, the present invention relates to the compound of any one of the following formulae (Ia) to (Id): APR-P04602WO24 PCT Application (final).docx 110 wherein 5 10 APR-P04602WO24 PCT Application (final).docx 111 R2represents –H, –Br, –Cl, ^CH3, ^C2H5, or ^cyclo-C3H5; R3represents 5 10 15 APR-P04602WO24 PCT Application (final).docx 112 5 10 15 R4*represents –H or –F; 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. 20 APR-P04602WO24 PCT Application (final).docx 113 Still more preferred, the present invention relates to the compound of any one of the following formulae (Ia) to (Id), 5 10 15 20 , APR-P04602WO24 PCT Application (final).docx 114 51015 , APR-P04602WO24 PCT Application (final).docx 115 5 1015 APR-P04602WO24 PCT Application (final).docx 116 5 10 R4*represents –H or –F; 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. 15 Still more preferred, the present invention relates to the compound of any one of the fo ; , Brepresents –O–R3 or –O–CHR3R3*;R1represents 20 R2represents –H or ^CH3; R3represents , APR-P04602WO24 PCT Application (final).docx 117 5 10 15 more preferably, R3represents APR-P04602WO24 PCT Application (final).docx 118 5 R3*represents –H, –Cl, or ^CH3, R4represents –H, –F, –Cl, ^CH3, ^CF3, ^CF2CHF2, ^OCH3, ^OCD3, ^OCH2F, ^OCHF2, 10 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. Even more preferably, the present invention is directed to a compound of the formula15 ; , APR-P04602WO24 PCT Application (final).docx 119 Brepresents –O–R3;5 10 15 , APR-P04602WO24 PCT Application (final).docx 120 5R4 represents –H;R4*represents –H; or an enantiomer, a diastereomer, a tautomer, a mixture of enantiomers, a mixture of diastereomers, a mixture of tautomers, a hydrate, a solvate, a pharmaceutically10 acceptable salt thereof. Especially preferred compounds according to the present invention include compounds presented by Table 1. 15 Table 1. APR-P04602WO24 PCT Application (final).docx 121 APR-P04602WO24 PCT Application (final).docx 122 APR-P04602WO24 PCT Application (final).docx 123 APR-P04602WO24 PCT Application (final).docx 124 APR-P04602WO24 PCT Application (final).docx 125 APR-P04602WO24 PCT Application (final).docx 126 APR-P04602WO24 PCT Application (final).docx 127 APR-P04602WO24 PCT Application (final).docx 128 APR-P04602WO24 PCT Application (final).docx 129 APR-P04602WO24 PCT Application (final).docx 130 APR-P04602WO24 PCT Application (final).docx 131 APR-P04602WO24 PCT Application (final).docx 132 APR-P04602WO24 PCT Application (final).docx 133 APR-P04602WO24 PCT Application (final).docx 134 APR-P04602WO24 PCT Application (final).docx 135 APR-P04602WO24 PCT Application (final).docx 136 APR-P04602WO24 PCT Application (final).docx 137 APR-P04602WO24 PCT Application (final).docx 138 APR-P04602WO24 PCT Application (final).docx 139 APR-P04602WO24 PCT Application (final).docx 140 APR-P04602WO24 PCT Application (final).docx 141 APR-P04602WO24 PCT Application (final).docx 142 APR-P04602WO24 PCT Application (final).docx 143 APR-P04602WO24 PCT Application (final).docx 144 APR-P04602WO24 PCT Application (final).docx 145 APR-P04602WO24 PCT Application (final).docx 146 APR-P04602WO24 PCT Application (final).docx 147 APR-P04602WO24 PCT Application (final).docx 148 APR-P04602WO24 PCT Application (final).docx 149 APR-P04602WO24 PCT Application (final).docx 150 APR-P04602WO24 PCT Application (final).docx 151 APR-P04602WO24 PCT Application (final).docx 152 APR-P04602WO24 PCT Application (final).docx 153 APR-P04602WO24 PCT Application (final).docx 154 APR-P04602WO24 PCT Application (final).docx 155 APR-P04602WO24 PCT Application (final).docx 156 APR-P04602WO24 PCT Application (final).docx 157 APR-P04602WO24 PCT Application (final).docx 158 APR-P04602WO24 PCT Application (final).docx 159 APR-P04602WO24 PCT Application (final).docx 160 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. APR-P04602WO24 PCT Application (final).docx 161 Most preferred compounds according to the present invention include compounds 49, 55, 56, 60, 95, 248, 294, and 305, 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. 5 Medical Use Surprisingly, it was found that the compounds of the present invention effectively activate immune cells, in particular, CD4+ and / or CD8+ cells as demonstrated in10 Table B-1 and natural killer (NK) cells in the context of T cell receptor (TCR) as wellas NK cell receptor signalling, respectively. This allows highly selective TCR- or NKcell receptor-mediated activation of the immune system against mutated tissue or tissue infected with foreign pathogens. Hence, by applying the present invention in a APR-P04602WO24 PCT Application (final).docx 162 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 5 between effective treatment and toxic off target effects for sustained tolerability in the course of multiple treatments. 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 10 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. A further aspect of the present invention refers to a pharmaceutical composition 15 comprising at least one compound of the present invention and at least one pharmaceutically acceptable carrier. Preferably, a pharmaceutical composition comprising at least one compound of the present invention and at least one pharmaceutically acceptable carrier, excipient 20 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. 25 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, 30 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., TiO2 , 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, 35 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 APR-P04602WO24 PCT Application (final).docx 163 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 5 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)10 and / or one or more fragrance(s). 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, 15 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 %. 20 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 25 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 30 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 %. 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. 35 Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn, 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 APR-P04602WO24 PCT Application (final).docx 164 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 %. 5 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 10 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, 15 preferably from about 0.5 to about 2 weight %, and more preferably from about 0.3 to about 1.5 weight % of the composition. 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 20 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 25 vary from about 0.1 to about 5 weight % of the composition, preferably from about 0.1 to about 1 weight %. A pharmaceutical composition of the present invention comprises at least one compound of the present invention. Optionally, the pharmaceutical composition may 30 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. Optionally, the pharmaceutical composition may also comprise one or more other pharmaceutically active agent(s), such as, e.g., one or more further stimulating 35 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. APR-P04602WO24 PCT Application (final).docx 165 The compound as well as a pharmaceutically acceptable salt thereof and a pharmaceutical composition of the present invention may be used as a medicament. Therefore, another aspect of the present invention relates to the compound or the 5 pharmaceutical composition of the present invention for use as a medicament. In this aspect relating to the use as medicament, the definitions as laid out in detail above also apply mutatis mutandis. In the context of the present invention, the terms "medicament", "therapeutic", 10 "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. 15 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 20 (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. 25 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 30 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 on35 balancing efficacy and toxicity. 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", 40 "enhancing", "strengthening", "increasing", "triggering", "stimulating" and the like may APR-P04602WO24 PCT Application (final).docx 166 be understood interchangeably in the broadest sense as the provision of an increased activity of an immune response. In the context of the present invention, an increase of the immune response is 5 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. More specifically, the antigen-stimulated, TCR-ligated immune cells subjected to a 10 compound of the present invention show a significantly increased secretion of several cytokines such as, e.g., IL-2, IFN-γ and / or TNF-α as well as increasedproliferation 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 15 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 cytokines20 may however be widely avoided in the absence of tumor- or pathogen-associatedantigens. 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 25 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 30 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 ofimmune cells contacted with such antigen may be increased. 35 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 / CD3 40 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 APR-P04602WO24 PCT Application (final).docx 167 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-γ, TNF-α, 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-γ and TNF-α. Particularly preferably,5 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-γ, IL-2 and TNF-α, or IFN-γ and TNF-α. Also highly preferred is an increase in at least threecytokines such as of IL-2, IFN-γ and TNF-α. Additionally or alternatively, also othermarkers associated with immunologic activity may be increased in expression such 10 as, e.g., CD40 ligand (CD40L, also known as CD154), granzyme / perforine, CD69, CD25 and / or CD71. Preferably such marker is CD40L. 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 15 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 of20 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 25 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. 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. Release of IL-1 and IL-6 may enhance the development of T helper cells (e.g. Th17 30 cells), which are known to play a considerably role in immunity against neoplastic and infectious diseases. Therefore, the presence of enhanced levels of Il-6 and IL-1 both at a neoplastic and / or infectious lesion and a lymph node may have beneficial effects on the immune response. CD25, CD69, CD71 and CD40L are well-known surface markers for T cell activation 35 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 known40 to support both APC and B cell activation and survival and proliferation. APR-P04602WO24 PCT Application (final).docx 168 In particular, an increase of IL-2, IFN-γ and / or TNF-α secretion, and / or CD40Lexpression 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. 5 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 10 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 15 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 dose- dependency 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 20 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 25 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. 30 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 35 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 40 antigens are recognized as non-self and thus, the patient's own immune system may APR-P04602WO24 PCT Application (final).docx 169 be re-activated to attack those tumor cells present in the patient, independently of the respective type of neoplastic and / or infectious disease. In the view of the above, in a further aspect, the present invention relates to the 5 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.Disclosed herein is a method of treating or preventing a neoplastic and / or infectious 10 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. 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 15 the compound, the pharmaceutical composition and the use thereof as a medicament) also apply mutatis mutandis. 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 20 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.), most25 preferably a human. 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 or30 more clinical symptom(s). 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 35 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). 40 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 APR-P04602WO24 PCT Application (final).docx 170 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 5 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. 10 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 15 International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) classes C00-D48. 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), 20 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),25 i.e., is malignant neoplasia (ICD-10 classes C00-C97). In a more preferred embodiment, the neoplastic disease is cancer. 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. 30 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). Subtypes of cancer may be classified in different ways such as by the location in the 35 body the main or only tumor bulk is found or by the tissue of origin the tumor(s) is / are derived from. 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 40 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 APR-P04602WO24 PCT Application (final).docx 171 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- 5 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)10 multiple sites (ICD-10 class C97). 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 15 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 20 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., 25 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., 30 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, 35 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). 40 APR-P04602WO24 PCT Application (final).docx 172 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, 5 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,10 adrenal cancer, brain cancer, and head-and-neck cancer. 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, 15 melanomas, lung cancer, rectal cancer, breast cancer, multiple myeloma, gastrointestinal cancer, non-small cell lung cancer (NSCLC). 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, Non- 20 Hodgkin lymphoma, AML (Acute Myeloid leukemia, DLBCL (Diffuse Large B-cell Lymphoma), and B-CLL (B-cell chronic lymphocytic lymphoma). 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 25 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 30 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 35 compounds produced or caused by such biological agent (e.g., toxins, semiochemicals, 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 40 as bacteria, nematodes such as roundworms and pinworms, arthropods (e.g., ticks, mites, fleas, and lice), fungi, ringworms, and tapeworms. Preferably, an infectious APR-P04602WO24 PCT Application (final).docx 173 disease according to the present invention is caused by viruses or bacteria, in particular is a virus infection. A viral infection in the context of the present invention may be an infection by any 5 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 10 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 15 virus, Machupo virus, Sabiá 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. 20 In the context of the present invention, those virus infections associated with a down- regulation 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)). 25 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. 30 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. 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 this35 context, inflammation may be characterized by an increase in the NF-κB activity, C- reactive protein (CRP) level, interferon-gamma (IFN-gamma) level, interleukin 1 (IL- 1) level and / or interleukin 8 (IL-8) level. In the context of a treatment or prevention of a neoplastic and / or infectious disease, 40 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 APR-P04602WO24 PCT Application (final).docx 174 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 5 agent, and / or an antibiotic. 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 10 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. The application of such combination therapy will depend on the pharmacokinetic and 15 pharmacodynamics properties of the chosen compounds and agents used in such combination therapy (adjunction). Optionally, the further agent may be administered concomitantly, previously, or subsequently with one or more compound(s) of the present invention. As used 20 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 25 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. 30 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 35 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. In a preferred embodiment, the compound or pharmaceutical composition of the 40 present invention is administered in combination with one or more further stimulating agent(s) activating immune cells. APR-P04602WO24 PCT Application (final).docx 175 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, 5 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. In a preferred embodiment, the immune cells are peripheral blood mononuclear cells (PBMCs). 10 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 15 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). In another preferred embodiment, the immune cells are selected from the group20 consisting of T cells, NK cells, monocytes and B cells. In a particularly preferred embodiment, the immune cells are T cells and / or NK cells. 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 25 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). 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 role30 in developing humoral immunity against neoplastic cells. 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, in35 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 40 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 APR-P04602WO24 PCT Application (final).docx 176 enhancing the effect of naturally developed humoral immunity against tumor antigens in the patient. 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 5 such cells. 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 10 costimulatory T cell surface receptors such as CD40L, CD69, OX40, GITR, CD137, CD27 and / or HVEM, and a combination of two or more thereof. A TCR / CD3 agonist may be any agent triggering CD3. It may be a peptide or non- peptide agonist binding to the extracellular side of TCR / CD3 in the context or 15 absence of MHC-dependent antigen presentation, may be an agonist binding to the intracellular side of TCR / CD3, or may be an agent activating the intracellular signal transduction pathway triggered by TCR / 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, a20 CD3 agonist is a tumor antigen presented by MHC I or MHC II. 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 25 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. 30 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 35 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. 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 40 antibody fragment may be a fragment antigen binding (Fab fragment), a truncated antibody comprising one or both complementarity determining region(s) (CDR(s)) or APR-P04602WO24 PCT Application (final).docx 177 the variable fragment (Fv) of an antibody. The antibody fragments may be of natural origin, of gene technologic origin and / or of synthetic origin. An antibody mimetic may be understood in the broadest sense as organic 5 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, 10 Triabodies, flexibodies and tandabs. The antibody mimetics may be of natural origin, of gene technologic origin and / or of synthetical origin. 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 15 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. 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 20 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, irrespective25 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. Additionally or alternatively, the immune cells may also be triggered by an antigen of 30 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 35 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. 40 Additionally or alternatively, the immune cells may also be triggered by antigen- loaded antigen-presenting cells (APCs). Then, the antigen-loaded APCs are APR-P04602WO24 PCT Application (final).docx 178 considered as a further stimulating agent. In this context, the antigens are also antigens of the neoplasm and / or infectious pathogen as mentioned before. Additionally or alternatively, the one or more further stimulating agent(s) may be 5 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., 10 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 against15 tumor antigens. 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 20 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, 25 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), 30 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, 35 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, 40 hydroxyurea, idarubicin, irinotecan, letrozole, leuprorelin, lomustine, mercaptopurine, miltefosine, mitomycins, mitosis inhibitors, mitoxantrone, nimustine, procarbazine, APR-P04602WO24 PCT Application (final).docx 179 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, 5 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 α-1, aclarubicin, fludarabine-5'-dihydrogen phosphate, 10 hydroxycarbamide, aldesleukin, pegaspargase, cepharanthine, epothilone A and B, azathioprine, mycophenolate mofetil, c-myc antisense, b-myc antisense, betulinic acid, camptothecin, melanocyte stimulating hormone (α-MSH), activated protein C, IL-1β inhibitor, fumaric acid and esters thereof, dermicidin, calcipotriol, taclacitol,lapachol, β-lapachone, podophyllotoxin, betulin, podophyllic acid 2-ethyl hydrazide, 15 sagramostim, (rhuGM-CSF), peginterferon α-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, 20 NO donors, pentaerythrityl tetranitrate, sydnonimines, S-nitroso derivatives, staurosporine, β-estradiol, α-estradiol, estriol, estrone, ethinyl estradiol, fosfestrol, medroxyprogesterone, estradiol cypionates, estradiot benzoates, tranilast, kamebakaurin, verapamil, ciclosporin A, paclitaxel and derivatives thereof such as 6- α-hydroxy paclitaxel, baccatin, taxotere, mofebutazone, acemetacin, diclofenac, 25 lonazolac, dapsone, o-carbamoyl-phenoxy-acetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, β- sitosterol, ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, elipticine, Calbiochem D-24851, colcemid, cytochalasin A-E, 30 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, 35 dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotics, argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, enoxaparin, GpIIb / IIIa platelet membrane receptor, antibodies to factor Xa inhibitor, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidole, trapidil, nitroprussides, PDGF antagonists, 40 triazolopyrimidine, seramin, ACE inhibitors, captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin,. vapiprost, interferon α, β and γ,APR-P04602WO24 PCT Application (final).docx 180 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, 5 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, 10 antimycotics, clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, terbinafine, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, barringtogenol-C21-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, 15 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-senecioyloxychaparrine, taxamairin A and B, regenilol, triptolide, cymarin, apocymarin, aristolochic acid, anopterin, 20 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, 25 isobutyrylmallotochromanol, marchantin A, maytansine, lycoridicin, margetine, pancratistatin, liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-All, periplocoside A, ghalakinoside, deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, chromones of spathelia, stizophyllin, akagerine, dihydrousambaraensine, hydroxyusambarine, 30 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 35 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, 40 Cartilage-Derived Angiogenesis Inhibitory Factor, matrix metalloproteinase inhibitors, 2-methoxyestradiol, Tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, APR-P04602WO24 PCT Application (final).docx 181 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, CXCL10prothrombin (kringle domain-2), antithrombin III fragment prolactin, VEGI, SPARC, osteopontin, maspin, proliferin-related protein, 5 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. Alternatively or additionally, the patient is suffering from or being at risk of developing 10 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-α, IFN-β, IFN-γ, IL-4, IL-12, IL-18, platelet factor-4, TNF-α). These cytokines, hormones or analogues thereof may further trigger the patient's immune system. As mentioned before, high doses of many of such agents 15 may provoke severe side effects. However, lower doses may optionally be used to support the treatment or prevention of the present invention. 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 20 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. 25 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 30 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). Further, a treatment or prevention according to the present invention may also be 35 combined with other means of treatment such as, e.g., radiation therapy (exemplarily based on x-ray radiation, ultraviolet (UV) radiation (e.g., UV-A, UV-B, and / or UV-C radiation), alpha radiation, beta radiation, gamma radiation, or cosmic radiation), and / or surgery. 40 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 APR-P04602WO24 PCT Application (final).docx 182 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. 5 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 10 provide activated DCs which may optionally be useful for DC vaccination approaches. In another aspect, the present invention refers to an in vitro or ex vivo method for theproduction of activated immune cells comprising the steps of:15 (i) providing immune cells;(ii) contacting the cells of step (i) with:(a) at least one compound or pharmaceutically acceptable salt thereof asdefined in any of claims 1 to 9, and optionally (b) one or more further stimulating agents activating said immune cells; and20 (iii) cultivating the cells of step (ii) under conditions suitable for maintaining theviability of said cells. In this aspect relating to such method, the definitions as laid out in detail above also apply mutatis mutandis.25 The method is conducted ex vivo and / or in vitro, i.e., is an ex vivo and / or in vitromethod. 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. Preferably, the immune cells (e.g., T cells and / or natural killer cells) are mature 30 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., 35 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 40 type-specific surface markers with metal bead-labelled antibodies followed by magnetic extraction of the desired cells. APR-P04602WO24 PCT Application (final).docx 183 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. 5 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. The immune cells are subsequently contacted with at least one compound of the 10 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. 15 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, for20 at least 12 h, for at least 1 day or longer. 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 25 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 30 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. 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. 35 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 40 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. APR-P04602WO24 PCT Application (final).docx 184 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). 5 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 10 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). Furthermore, a compound of the present invention may be further used as a research tool for investigating immune cell activation in more detail. 15 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 20 infraction, acute coronary syndrome, myocardial ischemia, ischemic cardiomyopathy, myocardial reperfusion injury, non-ischemic cardiomyopathy, or acute or chronic heart failure. 25 Description of Figures Figures 1 and 2 depict M21 cell growth upon stimulated T cell co-culture. M2130 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / CD28 and compounds 56 and 55 at different concentrations. EC50was calculated at 32 hours post anit-CD3 / CD28 and compound addition using GraphPad Prism.35 Figures 3A to 3P depict M21 cell growth upon stimulated T cell co-culture. M21melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / CD28 and compounds 56, 53, 52, 62, 60, 57, 55, 75, 73, 72, 70, 32, 29, 37, 35 or 34 at different concentrations. EC50 was calculated at 40 hours postanti-CD3 / CD28 and compound addition using GraphPad Prism.40 APR-P04602WO24 PCT Application (final).docx 185 Figures 4A to 4G depict M21 cell growth upon stimulated T cell co-culture. M21melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / CD28 and compounds 58, 55, 73, 70, 78, 79, or 77 at different5 concentrations. EC50 was calculated at 40 hours post anti-CD3 / CD28 and compound addition using GraphPad Prism. Figure 5 depicts the treatment schedule for compound 56 (racemate) in vivo efficacyexperiments with p.o. compound administration monitoring tumor volume and10 survival rate of mice. Arrows indicate p.o. drug treatment. Figure 6 depicts the treatment schedule for compound 55 in vivo efficacyexperiments with p.o. compound administration monitoring tumor volume and survival rate of mice. Arrows indicate p.o. drug treatment. 15 Figures 7A, 7B, 7C, and 7D depict the impact on in vivo tumor growth rate andsurvival and indicate the tumor volumes of individual mice receiving p.o. treatments as described in Figure 5.20 Figures 8A, 8B, 8C, and 8D depict the impact on in vivo tumor growth rate andsurvival and indicate the tumor volumes of individual mice receiving p.o. treatments as described in Figure 6. Figures 9A to 9D depict M21 cell growth upon stimulated T cell co-culture. M2125 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / CD28 and compounds 95, 248, 294, or 305, at differentconcentrations. EC50 was calculated at 40 or 44 hours post anti-CD3 / CD28 and compound addition using GraphPad Prism.30 Figure 10 depicts the treatment schedule for compounds 95 and 305 in vivo efficacyexperiments with p.o. compound administration monitoring tumor volume and survival rate of mice. Arrows indicate p.o. drug treatment. Figures 11A to 11I depict the impact on in vivo tumor growth rate and survival and35 indicate the tumor volumes of individual mice receiving p.o. treatments as described in Figure 10. APR-P04602WO24 PCT Application (final).docx 186 Preparative Examples General Information: 5All reactions involving air- or moisture-sensitive reagents or intermediates werecarried 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 Bruker DRX400 (400 MHz). Multiplicities are indicated as: br s (broadened singlet), s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet),10 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 C181.7um, 2.1x50mm. Flow: 0.5ml / min. Eluents: A: H2O with 0.05% formic acid and B: ACN with 0.05% TFA. All chemicals 15 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 further20 purifications. Abbreviations used in the description and in the Examples that follow are: mCPBA (meta-chloroperoxybenzoic acid), chx (cyclohexane), DAST (diethylaminosulfur trifluloride), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DCM 25 (dichloromethane), DIPEA (N,N-diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethylsulfoxide), LCMS (liquid chromatography mass spectroscopy), Ms (mesyl, methanesulfonyl), p-TSA (PTSA, p-toluenesulfonic acid), Pd(dppf)Cl2([1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride), SEM ([2-(trimethylsilyl)ethoxy]methyl), TBDMS (tert-Butyldimethysilyl), 30 TFA (trifluoroacetic acid), THF (tetrahydrofuran), TMAD (N,N,N',N'-tetramethylazodicarboxamide), TMB (1,3,5-trimethoxybenzene),TLC (thin layer chromatography), TPP (triphenyl phosphine), Tos (tosyl, p- toluenesulfonyl); ACK (Ammonium-Chloride-Potassium), CD (Cluster of differentiation), CCR (C-C35 motif receptor), DMEM (Dulbecco's Modified Eagle's Medium), FBS (Fetal BovineSerum), EDTA (Ethylene-Diamine-Tetra-Acetic acid), FACS (Fluorescence activatedcell sorting), HPbCD (2-Hydroxypropyl-ß-cyclodextrin), HPMC (Hydroxypropyl-methylcellulose), PEG400 (polyethylene glycol), Pen-Strep (Penicillin-Streptomycin),PBMCs (Peripheral blood mononuclear cells), PBS (Phosphate Buffered Saline).40 APR-P04602WO24 PCT Application (final).docx 187 General Information General procedures and synthetic routes to disclosed compounds In the following section some general procedures are described enabling persons 5 skilled in the art to synthesize many key intermediates and final compounds disclosed in this patent application. The synthetic approach is not limited to theoutlined synthetic routes and reactions. Substances described herein can also be obtained by other conditions or reaction sequences e.g. as published in the literature. Especially broronic acids or esters can be obtained from commercial sources or10 prepared e.g. similar to procedures described herein or in literature. Synthetic routes 15 Pathways 1 20 APR-P04602WO24 PCT Application (final).docx 188 Pathway 3 5 General procedures General Procedure A: Mitsunobu reaction 10 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 Å. 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.15 After completion of the reaction add Celite and evaporate solvent. Purify via normalphase column chromatography (silica, cyclohexane / ethyl acetate gradient). APR-P04602WO24 PCT Application (final).docx 189 General Procedure B: nucleophilic substitution 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 5 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. 10 General Procedure C: aryl-trimethoxyphenyl iodonium salts 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 15 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). 20 General Procedure D: O-arylation with aryl-trimethoxyphenyl iodonium salts 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 25 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. APR-P04602WO24 PCT Application (final).docx 190 General Procedure E: Miyaura borylation 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 5 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). 10 General Procedure F: Suzuki cross coupling Dissolve an hetaryl bromide (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 thereaction vessel and stir at 90°C overnight. After complete reaction add Celite and 15 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 or potassium trifluoroborate derivative. General-Procedure G: TBDMS deprotection of an alcohol 20 Dissolve a TBDMS-protected alcohol (1.0 eq.) in THF (0.1M). Add concentrated hydrochloric acid (15 eq.) and stir at room temperature overnight. An alternative approach uses 5 eq. CsF in EtOH / DMSO. After complete deprotection remove volatiles under reduced pressure. Dissolve the residue in DMSO and purify via25 reversed-phase HPLC (C18 column, water (0.1 %TFA) and ACN (0.1 %TFA)gradient). Desired fractions were lyophilized to give the desired compound. General Procedure H: Deoxofluorination of alcohols APR-P04602WO24 PCT Application (final).docx 191 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 5 normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). An alternative suitable reagent is DAST. General Procedure I: Deoxofluorination of aldehydes and ketones 10 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. 15 General Procedure J: Dess-Martin oxidation 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 20 and evaporate the volatiles. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). General Procedure K: Nucleophilic aromatic substitution APR-P04602WO24 PCT Application (final).docx 192 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 normalphase column chromatography (silica, cyclohexane / ethyl acetate gradient). An 5 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. General Procedure L: Nucleophilic aromatic substitution (pyridine) 10 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 normalphase column chromatography (silica, cyclohexane / ethyl acetate gradient). 15 Alternative suitable bases are Cs2CO3or 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. 20 General Procedure M: N-3 alkylation of 7-methylxanthine derivatives Dissolve a pyrimidine-2,4-dione 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 25 evaporate volatiles. Purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate methanol gradient). APR-P04602WO24 PCT Application (final).docx 193 EXAMPLES Intermediate 1: methyl 5-bromo-3-(3-(2,2,2-trichloroacetyl)ureido)thiophene-2- carboxylate 5 To a solution of methyl 3-amino-5-bromothiophene-2-carboxylate 1 (8 g, 33.9 mmol) in tetrahydrofuran (75 ml) at 0 °C was added 2,2,2-trichloroacetyl isocyanate 2 (4.65 ml, 37.3 mmol). The mixture was stirred and warmed to room temperature over 2 h. 10 Reaction mixture was diluted with water (200 ml), solid was filtered and dried under vacuum to get intermediate 4 (14.0 g, 97 %) as off white solid. ). LCMS (ESI+): found 425.5 [M+H]+, calculated 423.82 for C9H6BrCl3N2O4S. Intermediate 2: ethyl 2-bromo-5-(3-(2,2,2-trichloroacetyl)ureido)thiazole-4-15 carboxylate 2.5 g ethyl 5-amino-2-bromothiazole-4-carboxylate (9.9 mmol) were dissolved in 25 ml THF and cooled down to 0°C.2.25 g 2,2,2-trichloroacetyl isocyanate were added to the stirred solution and the mixture was allowed to warm to room temperature. 20 After complete consumption of stating material the reaction mixture was concentrated and purified via normal phase column chromatography (silica, cyclohexane / ethyl acetate to MeOH / ethyl acetate gradient) to afford ethyl 2-bromo-5-(3-(2,2,2- trichloroacetyl)ureido)thiazole-4-carboxylate. LCMS (ESI+): found 438.1 [M+H]+, calculated 436.8 for C9H7BrCl3N3O4S. 25 APR-P04602WO24 PCT Application (final).docx 194 Table 2: synthesis of (2,2,2-trichloroacetyl)ureas listed in this table can be achieved as described for intermediates 1 and 2. 5 Intermediate 4: methyl 5-bromo-3-ureidothiophene-2-carboxylate To a stirred solution of methyl 5-bromo-3-(3-(2,2,2-trichloroacetyl)ureido)thiophene-2- carboxylate (intermediate 4) (14 g, 32.98 mmol) in methanol (150 ml) at 0 °C ammonia gas was purged for 20 min. The reaction mixture was allowed to come to 10 room temperature for 1 h and then concentrated under reduced pressure. The crude was treated with methanol (50 ml), solid was filtered and dried under vacuum to get methyl 5-bromo-3-ureidothiophene-2-carboxylate 4 (8.2 g, 89 %) as off white solid. LCMS (ESI+): found 281.1 [M+H]+, calculated 279.9 for C7H7BrN2O3S. 15 Intermediate 5: ethyl 2-bromo-5-ureidothiazole-4-carboxylate Dissolve 4.1 g ethyl 2-bromo-5-(3-(2,2,2-trichloroacetyl)ureido)thiazole-4-carboxylate in cold 13.3 ml 7M ammonia in methanol and stir at room temperature until starting material disappeared. Precipitate is filtered off and washed with water and APR-P04602WO24 PCT Application (final).docx 195 cyclohexane to afford ethyl 2-bromo-5-ureidothiazole-4-carboxylate LCMS (ESI+): found 294.1 [M+H]+, calculated 292.9 for C7H8BrN3O3S. Table 3: synthesis of ureas listed in this table can be achieved as described for5 Intermediate int.7: 6-bromothieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 10 To a stirred solution of methyl 5-bromo-3-ureidothiophene-2-carboxylate 4 (12.5 g, 44.8 mmol) in N, N-dimethylformamide (200 ml) potassium tert-butoxide (15.0 g, 134 mmol) was added. Stirring was continued for 3 h at room temperature. The reaction mixture was concentrated under reduced pressure and acidified to pH ~ 1-3 with 50% of H2SO4 solution. Precipitated solid was filtered and dried under vacuum to get 6-15 bromothieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (9.0 g, 81 %) as off white solid. LCMS (ESI+): found 247.2 [M+H]+, calculated 245.91 for C6H3BrN2O2S. Intermediate int.8: 2-bromothiazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione 20 To an ice cold solution of 2.5 g ethyl 2-bromo-5-(3-(2,2,2- trichloroacetyl)ureido)thiazole-4-carboxylate in 40 ml THF 25.5 ml 1M KOH in methanol were added. The reaction mixture was warmed to 70°C. After complete APR-P04602WO24 PCT Application (final).docx 196 consumption of starting material the mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with mixture of brine and diluted sulfuric acid. The organic phase was dried over MgSO4 and volatiles were removed under reduced pressure to afford 2-bromothiazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione. 5 LCMS (ESI+): found 248.0 [M+H]+, calculated 246.9 for C5H2BrN3O2S. Table 4: synthesis of thieno- und thiazolopyrimidindiones listed in this table can beachieved as described for intermediates int.7 and int.8. 10 Int.10: 5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Methyl 2-amino-4-methylthiophene-3-carboxylate (20.0 g, 117 mmol) and urea (54.0 g, 899 mmol) were heated at 200 °C for 2 h. The reaction mixture was cooled, 20% NaOH solution (1050 ml) was added and refluxed at 100°C overnight. The reaction 15 was cooled to room temperature and filtered off to remove inorganic solids. The filtrate was neutralized with 2N HCl to pH~6 to form a precipitate which was filtered, washed and dried under the vacuum (13.3 g). LCMS (ESI+): found 183 [M+H]+,calculated 182.0 for C7H6N2O2S. 20 Int.11: 6-bromo-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione A vial was charged with5-methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione (2.0 g, 11.0 mmol) and DCM (15 ml). N-bromosuccinimide (1.95 g, 11.0 mmol) was added at 0°C and the reaction mixture was stirred at 0°C until starting material was consumed. APR-P04602WO24 PCT Application (final).docx 197 Formed solid was filtered off, washed and dried under vacuum to get 2.9 g of 6- bromo-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 261 [M+H]+, calculated 259.9 for C7H5BrN2O2S. 5 Int.12: 6-bromo-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione 5-methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione (6.00 g, 32.9 mmol), magnesium oxide (1.46 g, 36.2 mmol), tetrabutylammonium bromide (TBAB) (11.7 g, 36.2 mmol) in 7510 ml DMSO were stirred at 80 °C. 2-(Trifluoromethyl)oxirane (2.7 mL, 32.9 mmol) was diluted in 120 ml DMSO andadded through a droping funnel over the period of 4h. After 4h the mixture was cooled to room temperature and solids were filtered off. The filtrate was stirred with 2M Na2CO3 solution for 30 mins. Solids were filtered off and the filtrate was washed 15 twice with Et2Oto remove the dialkylated product. Afterwards, that filtrate was neutralized with 2N aqueous HCl solution and extracted with Et2O three times. The combined organic layer were dried over anhydrous MgSO4 and concentrated under reduced pressure to obtain 3.5 g crude, that was washed with water and dried under reduced pressure to obtain 3.2 g 6-bromo-5-methyl-1-(3,3,3-trifluoro-2- 20 hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 295 [M+H]+, calculated 294.0 for C10H9F3N2O3S. Int.13: 1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 25 470 mg of commercially available thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, 135 mg magnesium oxide and 1081 mg tetrabutylammonium bromide were dissolved in 15ml DMSO. The mixture was heated to 60°C and add 217 µl of 2-(trifluoromethyl)oxirane were added. The sealed reaction vessel was stirred at 60°C overnight.2 ml saturated NH4Cl were added. Purification via normal phase column chromatography (silica,30 cyclohexane / ethyl acetate to MeOH / ethyl acetat gradient) afforded 1-(3,3,3-trifluoro- 2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 281.2 [M+H]+, calculated 280.0 for C9H7F3N2O3S APR-P04602WO24 PCT Application (final).docx 198 Int. 14: 6-bromo-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione Dissolve 70 mg 1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)- 5 dione in 4 ml DMSO. Add 40 mg of 1-bromopyrrolidine-2,5-dione (NBS). Stir at room temperature for 1h. Add 1 ml saturated NH4Cl and purify via normal phase column chromatography (silica, cyclohexane / ethyl acetate to MeOH / ethyl acetate gradient) to afford 6-bromo-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione. LCMS (ESI+): found 358.1 [M+H]+, calculated 357.9 for10 C9H6BrF3N2O3S. Int. 15: 6-bromo-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione 15 To a solution of 5-methyl-1-(3,3,3-trifluoro-2-hydroxy-propyl)thieno[2,3-d]pyrimidine- 2,4-dione ( 3.20 g, 10.9 mmol) in 40 ml DMF N-bromosuccinimide (2.13 g) was added. The reaction mixture was stirred at 25 °C until starting material was consumed. The reaction mixture was quenched with water and the volume of the reaction mixture was reduced under reduced pressure. To that mixture, cold water 20 was added and stirred for 30 mins to obtain solid precipitate. Afterwards, the solid was filtered. The obtained solid was sonicated with warm water for 30 mins. The solid was filtered, washed and dried under reduced pressure to obtain 3.9 g titlecompound. LCMS (ESI+): found 372.9 [M+H]+, calculated 371.9 for C10H8BrF3N2O3S. 25 Int.16: (R)-6-bromo-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3- d]pyrimidine-2,4(1H,3H)-dione 5.7 g intermediate 11, 1.14 g magnesium oxide and 9.15 g tetrabutylammonium 30 bromide were dissolved in 100 ml DMSO. The mixture was heated to 60°C and 2.45 APR-P04602WO24 PCT Application (final).docx 199 g (R)-2-(trifluoromethyl)oxirane were added. The sealed reaction vessel was stirred at 60°C overnight. The reaction mixture was cooled and 200 ml water were added. Formed precipitate was filtered off and purification was achieved by reversed phase column chromatography (RP18, water / acetonitrile gradient) to afford 4.8 g (R)-6- 5 bromo-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione. LCMS (ESI+): found 373.1 [M+H]+, calculated 371.9 for C10H8BrF3N2O3S. Int. 17: 1-(3,3-difluoro-2-hydroxypropyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-10 dione 5-methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione (3.00 g, 14.8 mmol) 1,8- Diazabicyclo[5.4.0]undec-7-ene (2.6 ml, 17.8 mmol) and 3-bromo-1,1-difluoro-2- propanol (2.59 g, 14.8 mmol) were dissolved in 30 ml DMF. The reaction mixture was 15 stirred at 60 °C overnight. The reaction mixture was concentrated under reduced pressure. Ice cold water was added and the mixture was stirred for 1 hr to obtain precipitate. The solid was filtered off, washed and dried under reduced pressure to obtain 1.5 g 1-(3,3-difluoro-2-hydroxypropyl)-5-methylthieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione. LCMS (ESI+): found 277.0 [M+H]+, calculated 276.0 for20 C10H10F2N2O3S. Int.18: 6-bromo-1-(3,3-difluoro-2-hydroxypropyl)-5-methylthieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione 25 This compound was prepared as described for intermediate 15 starting with 2.19 g intermediate 17 to yield 1.9 g 6-bromo-1-(3,3-difluoro-2-hydroxypropyl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione after additional washing of 2.1g crude sold with acetonitrile. LCMS (ESI+): found 355 [M+H]+, calculated 353.9 for C10H9BrF2N2O3S. 30 Int.19: 6-bromo-1-(2-((tert-butyldim l)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione APR-P04602WO24 PCT Application (final).docx 200 To 6-bromo-1-(3,3-difluoro-2-hydroxy-propyl)-5-methyl-thieno[2,3-d]pyrimidine-2,4- dione (1.80 g, 5.07 mmol) in 30 ml DMF tert-butyldimethylsilyl chloride (3.06 g, 20.3 mmol) and imidazole (1.73 g, 25.3 mmol) were added. The mixture was stirred at 5 room temperature overnight. The reaction mixture was concentrated under reduced pressure. To that residue ice water was added and stirred for 1h. The precipitate was filtered and dried under reduced pressure to obtain 2.0 g crude, that was first purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give 1.7 g which were purified a second time by normal phase column10 chromatography (silica, DCM / MeOH gradient) to provide pure 6-bromo-1-(2-((tert- butyldimethylsilyl)oxy)-3,3-difluoropropyl)-5-methylthieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione. LCMS (ESI+): found 469 [M+H]+, calculated 468.0 for C16H23BrF2N2O3SSi. 15 propyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Alkylation of 6 g intermediate 10 with 1.2 eq. 1-bromo-2-propanol similar to thepreparation of intermediate 17 afforded 4.8 g 1-(2-hydroxypropyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 241 [M+H]+, calculated 240.120 for C10H12N2O3S. Int.21: 6-bromo-1-(2-hydroxypropyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 25 In analogy to bromination reactions described above 4.8 g intermediate 20 gave 3.7 g 6-bromo-1-(2-hydroxypropyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 319 [M+H]+, calculated 317.97 for C10H11BrN2O3S. Int.24: 6-bromo-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-30 dione APR-P04602WO24 PCT Application (final).docx 201 To a solution of 6-bromothieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (1.5 g, 6.07 mmol) in 15 ml DMSO were added magnesium oxide (0.294 g, 7.29 mmol), tetrabutylammonium bromide (0.979 g, 3.04 mmol) and 2-(trifluoromethyl)oxirane 5 (0.680 g, 6.07 mmol). The mixture was stirred at 100 °C for 1 h in a sealed tube. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water (2x150 ml). Phases were separated, the organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude product (1.2 g). This crude was purified by normal phase column chromatography (120 g silica, petroleum ether / ethyl 10 acetate gradient). Product containing fractions were collected and volatiles removed under reduced pressure. This second crude (4.0 g) was triturated with acetonitrile (20 ml) to get pure 6-bromo-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[3,2-d]pyrimidine- 2,4(1H,3H)-dione (0.31 g, 14 %) as off white solid. LCMS (ESI+): found 359.0 [M+H]+, calculated 357.92 for C9H6BrF3N2O3S. 1H NMR (400 MHz, DMSO-d6)15 δ:11.75 (s, 1H), 7.57(s, 1H), 6.12 (d, J = 6.4 Hz ,1 H), 4.34-4.32 (m, 1H), 4.20 (dd, J= 14.4, 3.2 Hz, 1H), 4.07-4.01 (m, 1H). Table 5: Building blocks disclosed in this table can be made e.g. in analogy to themethods described above e.g. for intermediates int.12, int.13, int.16 or int.24.20 APR-P04602WO24 PCT Application (final).docx 202 Int.26: (4-(trifluoromethoxy)phenyl)(2,4,6-trimethoxyphenyl)iodonium 4- methylbenzenesulfonate APR-P04602WO24 PCT Application (final).docx 203 20,0 g 1-iodo-4-(trifluoromethoxy)benzene were dissolved in 250 ml dry acetonitrile. 13.15 g pTSA and 26.0 g mCPBA were added and the reaction was stirred at 80 °C 5 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). LCMS10 (ESI+): found 454.8 [M]+, calculated 455.00 for C16H15F3IO4+. Int.27: (2-(trifluoromethoxy)phenyl)(2,4,6-trimethoxyphenyl)iodonium 4- methylbenzenesulfonate 15 150 mg 1-iodo-2-(trifluoromethoxy)benzene were dissolved in 3 ml dry acetonitrile. 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 wasabsorbed on Celite. Volatiles were removed under reduced pressure. Purification 20 was achieved via normal phase column chromatography (silica, DCM / methanol gradient). LCMS (ESI+): found 454.6 [M]+, calculated 455.0 for C16H15F3IO4+. Compounds in the following table 6 were synthesized as exemplified by25 intermediates int.26, int.27 or literature. Other iodonium salts also were commerciallyavailable. Table 6: APR-P04602WO24 PCT Application (final).docx 204 APR-P04602WO24 PCT Application (final).docx 205 APR-P04602WO24 PCT Application (final).docx 206 Int.43: 1-bromo-4-(4-(trifluoromethoxy)phenoxy)benzene 5 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 underreduced pressure and the residue was absorbed on Celite. Purification of intermediate 43 was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). GCMS (EI): m / z found 334.2 [M] +˙, calculated10 333.96 for C13H8BrF3O2 Int.44: 4-bromo-2-(trifluoromethoxy)-1-(4-(trifluoromethoxy)phenoxy)benzene 15 (trifluoromethoxy)phenol were dissolved in 100ml THF and cooled in an ice bath.2.5 g sodium hydride (60% in mineral oil) add 139 µl of 2-(trifluoromethyl)oxirane were added and the stirred mixture was heated to 60°C. After starting material was consumed, volatiles were removed under reduced pressure, 100 ml water were APR-P04602WO24 PCT Application (final).docx 207 added and the aqueous phase was extracted with ethyl acetate trice. Combined organic phases were dried with MgSO4 and the solvent was removed under rduced pressure to afford 4-bromo-2-(trifluoromethoxy)-1-(4- (trifluoromethoxy)phenoxy)benzene. LCMS (ESI+): found 415.8 [M+H]+, calculated 5 416.0 for C14H7BrF6O3. Int.88: 4,4,5,5-tetramethyl-2-(3-(trifluoromethoxy)-4-(4- (trifluoromethoxy)phenoxy)phenyl)-1,3,2-dioxaborolane 10 11.0 g 4-bromo-2-(trifluoromethoxy)-1-(4-(trifluoromethoxy)phenoxy)benzene, 10.5 g 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane), 10.4 g potassium acetate and 2.2 g [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct in 100 ml 1,4-dioxane were stirred at 90°C. The mixture was concentrated under reduced pressure, 100ml water were added and the 15 aqueous phase was extracted three times with ethyl acetate. Combined organic phases were dried over MgSO4and solvent was removed under reduced pressure to give 4,4,5,5-tetramethyl-2-(3-(trifluoromethoxy)-4-(4- (trifluoromethoxy)phenoxy)phenyl)-1,3,2-dioxaborolane. LCMS (ESI+): found 465.1 [M+H]+, calculated 464.1 for C20H19BF6O5. 20 Int.45: 1-(benzyloxy)-4-bromo-2-(trifluoromethoxy)benzene 300 mg 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene, 163 mg phenylmethanol and 320 mg potassium carbonate were dissolved in 3 ml DMSO and heated at 120°C 25 overnight. Purification via normal phase column chromatography (silica, cyclohexane / ethyl acetate to MeOH / ethyl acetat gradient) affored 1-(benzyloxy)-4- bromo-2-(trifluoromethoxy)benzene. GCMS: found 346, calculated 345.98 for C14H10BrF3O2 . 30 Int.106: 5-bromo-3-chloro-2-((4-methylbenzyl)oxy)pyridine APR-P04602WO24 PCT Application (final).docx 208 Dissolve 200 mg 5-bromo-3-chloro-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 reactionvessel and stir for 10 min at 120°C under microwave irradiation. Purify via normalphase column chromatography (silica, cyclohexane / ethyl acetate gradient) to yield 5- 5 bromo-3-chloro-2-((4-methylbenzyl)oxy)pyridine. LCMS (ESI+): found 312.5 [M+H]+, calculated 311.0 for C13H11BrClNO Int.106a: 5-bromo-2-(4-(trifluoromethyl)phenoxy)pyrimidine 10 A solution of 131 mg 5-bromo-2-fluoropyrimidine (1.25 eq.), 204 mg K2CO3(2.0 eq.) and 150 mg 4-(trifluoromethyl)phenol (1.25 eq.) in 2 ml DMSO (0.42 M) was stirred at80°C for 30 min under microwave irradiation. Purification was achieved via normalphase column chromatography (silica, cyclohexane / ethyl acetate to MeOH / ethyl acetate gradient) to afford 5-bromo-2-(4-(trifluoromethyl)phenoxy)pyrimidine. LCMS15 (ESI+): found 318.6 [M+H]+, calculated 318.0 for C11H6BrF3N2O. 5-bromo-2-fluoropyrimidine may be replaced with other 4-fluoro-bromodiazines and4-(trifluoromethyl)phenol may be replaced by other hydroxy aromatic or heteroaromatic cylic systems to obtain the related ethers.20 Int.106b: 2-bromo-5-(4-(trifluoromethyl)phenoxy)pyrazineThe intermediate 106b has been prepared according to the similar method forintermediate int.106a as described above. 25 Dissolve 150 mg 2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol30 (1.0 eq.) and 47 µl cyclobutanol (1.5 eq.) in 5 ml dry THF (0.1 M). Dry the solutionover molecular sieve 4 Å. Remove the molecular sieve, cool down to 0°C, add 241 APR-P04602WO24 PCT Application (final).docx 209 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 5 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. dioxaborolane 10 10 g intermediate 44, 11.4 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 15 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. Int.93: 1-(4-ch l)-2,2-difluoroethan-1-ol 20 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 reaction vessel. Stir at 40°C for 4h. After completion of the addition add 3.1 ml 1MTBAF solution (2.0 eq.). After completion of the reaction add Celite and evaporate25 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 Int.94: 1-(3,4-dic l)-2,2-difluoroethan-1-ol 30 APR-P04602WO24 PCT Application (final).docx 210 1-(3,4-dichlorophenyl)-2,2-difluoroethan-1-ol was prepared as exemplified for 1-(4- chlorophenyl)-2,2-difluoroethan-1-ol. GCMS (EI): found 226.2 [M]+, calculated 226.0 for C8H6Cl2F2O 5 Int.95: 1-(4-chloro-3-fluorophenyl)-2,2-difluoroethan-1-ol Int.96: 1-(4-chloro-3-fluorophenyl)-2,2-difluoroethan-1-ol was prepared as exemplified for 1-(4-chlorophenyl)-2,2-difluoroethan-1-ol. GCMS (EI): found 210.2 [M]+, calculated 210.0 for C8H6ClF3O 10 Int.97: 1-(3-chloro-4-methylphenyl)-2,2-difluoroethan-1-ol 1-(3-chloro-4-methylphenyl)-2,2-difluoroethan-1-ol was prepared as exemplified for 1- (4-chlorophenyl)-2,2-difluoroethan-1-ol. GCMS (EI): found 206.2[M]+, calculated15 206.0 for C9H9ClF2O Int.97: 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-ol Dissolve 1500 mg 2-(benzyloxy)-5-bromobenzaldehyde (1.0 eq.) in 20 ml dry DMF 20 (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 chromatography (silica, cyclohexane / ethyl acetate / methanol gradient) to obtain 1-(2- 25 (benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-ol. GCMS (EI): found 342.4[M]·+, calculated 342.0 for C15H10BrF5O3 Int.98: 1-(5-bromo-2-(4-(trifluoromethoxy)phenoxy)phenyl)-2,2-difluoroethan-1-ol APR-P04602WO24 PCT Application (final).docx 211 Prepared from 5-bromo-2-(4-(trifluoromethoxy)phenoxy)benzaldehyde similar as exemplified for 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-ol. GCMS (EI): found 412.2[M] ·+, calculated 412.0 for C15H13BrF2O25 Int.99: 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-one 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 10 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 (EI): found 340.0[M]·+, calculated 340.0 for C15H11BrF2O2. 15 Int.100: 1-(5-bromo-2-(4-(trifluoromethoxy)phenoxy)phenyl)-2,2-difluoroethan-1-one 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-1-20 one. GCMS (EI): found 410.0[M] ·+, calculated 410.0 for C15H8BrF5O3Int.101: 1-(benzyloxy)-4-bromo-2-(1,1,2,2-tetrafluoroethyl)benzene APR-P04602WO24 PCT Application (final).docx 212 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 µl Deoxofluor (50 wt% in toluene, 2.1 eq.) and seal the reaction vessel. Stir at 20°C for 2h. After completion of 5 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 (EI): found 361.9[M]·+, calculated 362.0 for C15H11BrF4O 10 Int.102: 1-(benzyloxy)-4-bromo-2-(difluoromethyl)benzene Prepared from 2-(benzyloxy)-5-bromobenzaldehyde similar as exemplified for 1- (benzyloxy)-4-bromo-2-(1,1,2,2-tetrafluoroethyl)benzene. GCMS (EI): found 312.0[M] ·+, calculated 312.0 for C14H11BrF2O 15 Int.103: 4-bromo-2-(difluoromethyl)-1-(4-(trifluoromethoxy)phenoxy)benzene Prepared from 5-bromo-2-(4-(trifluoromethoxy)phenoxy)benzaldehyde similar as exemplified for 1-(benzyloxy)-4-bromo-2-(1,1,2,2-tetrafluoroethyl)benzene. GCMS20 (EI): found 382.2[M] ·+, calculated 382.0 for C14H8BrF5O2Int.104: 4-bromo-2-(1,1,2,2-tetrafluoroethyl)-1-(4-(trifluoromethoxy)phenoxy)benzene APR-P04602WO24 PCT Application (final).docx 213 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 (EI): found 432.4[M] ·+, calculated 432.0 for5 C15H8BrF7O2 Int.105: 1-(benzyloxy)-4-bromo-2-(fluoromethyl)-benzene 10 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 µl 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- 15 (fluoromethyl)-benzene. GCMS (EI): found 294.0 [M]·+, calculated 294.0 for C14H12BrFO Int.47: 4-bromo-2-(difluoromethoxy)-1-((4-methylbenzyl)oxy)benzene 20 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 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+):25 found 343.4 [M+H]+, calculated 342.01 for C15H13BrF2O2. APR-P04602WO24 PCT Application (final).docx 214Table 6a : similar to the above described 4-bromo phenyl ether or 4-bromo hetarylether intermediates in this table can be synthesized from related stating materials APR-P04602WO24 PCT Application (final).docx 215 APR-P04602WO24 PCT Application (final).docx 216 Int.48: 2-(3-(difluoromethoxy)-4-((4-methylbenzyl)oxy)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane 5 85 mg intermediate 47, 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). 10 LCMS (ESI+): found 391.3 [M+H]+, calculated 390.18 for C21H25BF2O4. Int.49: 2-(4-((4-(difluoromethyl)benzyl)oxy)-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane 15 500 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 K2CO3 were 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 intermediate 49. LCMS (ESI+):20 found 379 [M+H]+, calculated 378.16 for C20H22BF3O3. Int.50: 2-(4-(benzyloxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 324 mg benzyl alcohol and 500 mg 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2- 25 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 bynormal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to 30 obtain intermediate 50. LCMS (ESI+): found 341 [M+H]+, calculated 340.18 for C20H25BO4. APR-P04602WO24 PCT Application (final).docx 217 Int.45: 1-(benzyloxy)-4-bromo-2-(trifluoromethoxy)benzene 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 5 mixture was absorbed on Celite, dried and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain intermediate 45. LCMS (ESI+): found 348.6 [M+H]+, calculated 347.98 for C14H10BrF3O2. Int. 52: 2-(4-(benzyloxy)-3-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-10 dioxaborolane 3.5 g bromo derivative int.45, 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 15 Celite and purified via normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to afford pure intermediate 52. LCMS (ESI+): found 395 [M+H]+, calculated 394.16 for C20H22BF3O4. Building blocks in the following table 7 were synthesized e.g. as exemplified for20 intermediates 46, 48, 49, 50 or 52. Related starting materials are either commercially available or can be synthesized as exemplified for intermediate bromides like 43, 44, 45 and others above or according to literature procedures. Table 7: APR-P04602WO24 PCT Application (final).docx 218 APR-P04602WO24 PCT Application (final).docx 219 APR-P04602WO24 PCT Application (final).docx 220 APR-P04602WO24 PCT Application (final).docx 221 APR-P04602WO24 PCT Application (final).docx 222 APR-P04602WO24 PCT Application (final).docx 223 APR-P04602WO24 PCT Application (final).docx 224 APR-P04602WO24 PCT Application (final).docx 225 APR-P04602WO24 PCT Application (final).docx 226 APR-P04602WO24 PCT Application (final).docx 227 APR-P04602WO24 PCT Application (final).docx 228 APR-P04602WO24 PCT Application (final).docx 229 APR-P04602WO24 PCT Application (final).docx 230 APR-P04602WO24 PCT Application (final).docx 231 Example 5: 6-(4-((R)-1-(2,4-dichlorophenyl)ethoxy)-3-(trifluoromethoxy)phenyl)-1-(3,3-difluoro-2-hydroxypropyl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (5)5 To 30 mg bromide int.19, 71 mg (R)-2-(4-(1-(2,4-dichlorophenyl)ethoxy)-3- (trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 41 mg K3PO4and 11 mg Pd(dppf)Cl2*DCM under nitrogen 0.5 ml 1,4-dioxane / water (5:1) were added and the mixturewas heated to 100 °C until starting material was consumed. The mixture was absorbed on 10 Celite, dried and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to obtain the TBDMS-protected intermediate. This was dissolved in 0.5 ml EtOH / DMSO (4:1) and 58 mg CsF were added and the mixture was stirred at room temperature. After complete deprotection the mixture was filtered and directly purified by reversed-phase HPLC (C18 column, water (0.1 %TFA) / acetonitrile (0.1 %TFA) gradient). 15 Desired fractions were lyophilized to yield pure 6-(4-((R)-1-(2,4-dichlorophenyl)ethoxy)-3- (trifluoromethoxy)phenyl)-1-(3,3-difluoro-2-hydroxypropyl)-5-methylthieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione. LCMS (ESI+): found 625.0 [M+H]+, calculated 624.0 for C25H19Cl2F5N2O5S.20 Example 6: (R)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4-(trifluoromethoxy)phenoxy) phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (55) 4.6 g (R)-6-bromo-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione (intermediate 16), 5.16 g 4,4,5,5-tetramethyl-2-(4-(4-(trifluoro- 25 methoxy)phenoxy)phenyl)-1,3,2-dioxaborolane, 0.71 g Pd(PPh3)4 and 7.9 g K3PO4 were APR-P04602WO24 PCT Application (final).docx 232 suspended under a nitrogen atmosphere in 100 ml 1,4-dioxane / water (4:1) and heated to100 °C until reaction was complete. After cooling to room temperature the reaction is poured onto 200ml water and is extracted with EtOAc. The organic phases are combined and the solvent is removed under reduced pressure. The residue is prepared with hydromatrix and 5 purified via normal phase column chromatography (330g silica, cyclohexane / ethyl acetate / methanol gradient) to give 3 g product that was recrystallized from 20ml EtOH to yield 2.4 g (R)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4-(trifluoromethoxy) phenoxy)-phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 547.3 [M-H]+, calculated 546.0 for C23H16F6N2O5S. 10 Example 6A: (R)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(4-(trifluoromethyl)phenoxy)pyridin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 1.0 g (R)-6-bromo-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4- 15 (1H,3H)dione (1.0 eq.), 1.71 g K3PO4 (3.0 eq.), 453 mg XPhos-Pd-G3 (0.2 eq.) and 1.02 g (6-(4-(trifluoromethyl)phenoxy)pyridin-3-yl)boronic acid (1.35 eq.) were dissolved in 20 ml dioxan / water 4:1 under a nitrogen atmosphere and stirred at 110 °C for 8 h. The reaction mixture was diluted with saturated aqueous NH4Cl solution and extracted trice with ethyl acetate. Combined organic phases were dried using MgSO4 and prepared with hydromatrix.20 Purification was achieved by column chromatography (C18, water / acetonitrile) to yield 667mg (R)-6-(6-fluoropyridin-3-yl)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione after product fractions were combined and lyophilized.LCMS (ESI+): found 532.2 [M+H]+, calculated 531.1 for C22H15F6N3O4S.1H NMR (400 MHz, DMSO-d6) δ: 11.57 (s, 1H), 8.32-8.24 (m, 1H), 8.01 (dd, J = 8.5, 2.6 Hz ,1 H), 7.81 (d,25 J = 8.6Hz 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.29 - 7.24 (m, 1H), 6.84 (s, 1H), 4.46 (s, 1H), 4.26(dd, J = 14.6, 3.3 Hz, 1H), 3,75 (dd, J = 14.6, 9.4 Hz, 1H), 2.42 (s, 3H) int.163:: (R)-5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoro-2- hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 30 2.2 g (R)-6-bromo-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione (1.0 eq.) were dissolved in 40 ml THF (0.11 M). The solution was dried using molecular sieves 3 Å. After filtering off the molsieves and cooling down the reaction in APR-P04602WO24 PCT Application (final).docx 233 an acetone / dry ice bath to -78°C, 8.25 ml of a 2.5M n-butyllithium solution in THF (3.5 eq.) were added. Stirring for 30 min at -78°C followed by the addition of 4.8 ml 2-isopropoxy- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.0 eq.). After stirring for additional 30 min at -78 °Cthe reaction was warmed room temperature. Addition of sat. aqueous NH4Cl3 solution was5 followed by extraction of the aqueous phase three times with ethyl acetate. Combinedorganic phases were dried using MgSO4 and volatiles were removed to afford 621 mg (R)-5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoro-2- hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 421.2 [M+H]+, calculated 420.1 for C16H20BF3N2O5S 10 Example 6B: (R)-6-(4-(4-acetylphenoxy)-3-(trifluoromethoxy)phenyl)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Asolution of 70 mg (R)-5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-15 trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.0 eq.), 63 mg K3PO4(3.0 eq.), 8.5mg XPhos-Pd-G3 (0.1 eq.) and 133 mg 1-(4-(4-bromo-2-(trifluoro-methoxy)phenoxy)phenyl)ethan-1-one (3.5 eq.) in 2 ml Dioxan / water 4:1 under nitrogen wasstirred at 110°C for 18h. Purification was achieved via preparative HPLC (C18, water / acetonitrile) to afford 4.6 mg (R)-6-(4-(4-acetylphenoxy)-3-(trifluoromethoxy)phenyl)-5-20 methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 589.1 [M+H]+, calculated 588.1 for C25H18F6N2O6S Table 8: Examples disclosed in this table can be synthesized by cross-coupling reactions25 e.g. as exemplified by examples 5 or 6 from intermediate bromides such as int.14, int.15,int.16, int.18, int.19, int.21, int.22, int.23, int.24 described above and others. Boronic acidsor esters were either commercially available or synthesized as disclosed above in table 6 or made in analogy to herein or in literature described methods. It is also possible to synthesize disclosed examples in this table by cross coupling reactions as described for compound 17830 wherein the boron species is a thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione derivative and the halide part of the ether moiety. APR-P04602WO24 PCT Application (final).docx 234 APR-P04602WO24 PCT Application (final).docx 235 APR-P04602WO24 PCT Application (final).docx 236 APR-P04602WO24 PCT Application (final).docx 237 APR-P04602WO24 PCT Application (final).docx 238 APR-P04602WO24 PCT Application (final).docx 239 APR-P04602WO24 PCT Application (final).docx 240 APR-P04602WO24 PCT Application (final).docx 241 APR-P04602WO24 PCT Application (final).docx 242 APR-P04602WO24 PCT Application (final).docx 243 APR-P04602WO24 PCT Application (final).docx 244 APR-P04602WO24 PCT Application (final).docx 245 APR-P04602WO24 PCT Application (final).docx 246 APR-P04602WO24 PCT Application (final).docx 247 APR-P04602WO24 PCT Application (final).docx 248 APR-P04602WO24 PCT Application (final).docx 249 APR-P04602WO24 PCT Application (final).docx 250 APR-P04602WO24 PCT Application (final).docx 251 APR-P04602WO24 PCT Application (final).docx 252 APR-P04602WO24 PCT Application (final).docx 253 APR-P04602WO24 PCT Application (final).docx 254 APR-P04602WO24 PCT Application (final).docx 255 APR-P04602WO24 PCT Application (final).docx 256 APR-P04602WO24 PCT Application (final).docx 257 APR-P04602WO24 PCT Application (final).docx 258 APR-P04602WO24 PCT Application (final).docx 259 APR-P04602WO24 PCT Application (final).docx 260 APR-P04602WO24 PCT Application (final).docx 261 APR-P04602WO24 PCT Application (final).docx 262 APR-P04602WO24 PCT Application (final).docx 263 APR-P04602WO24 PCT Application (final).docx 264 APR-P04602WO24 PCT Application (final).docx 265 APR-P04602WO24 PCT Application (final).docx 266 APR-P04602WO24 PCT Application (final).docx 267 APR-P04602WO24 PCT Application (final).docx 268 Intermediate int.164: (R)-6-(4-fluoro-3-(trifluoromethoxy)phenyl)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 5 To a stirred solution of 1.50 g (1.0 eq.) (R)-6-bromo-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, 1.5 g (1.1 eq.) 2-(4-fluoro-3-(trifluoromethoxy)-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 340 mg Pd(dppf)Cl2*DCM (0.1 eq.) and 2.6 g (3 eq.) K3PO4 in 15 ml dioxan / water 5:1 was10 sirred under a nitrogen atmosphere at 100 °C over the weekend. Purification wasachieved via column chromatography (C18, water / acetonitrile) to afford 794 mg(R)-6-(4-fluoro-3-(trifluoromethoxy)phenyl)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)- thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 473.2 [M+H]+, calculated 472.0 for C17H11F7N2O4S15 Intermediate int.165: 6-(6-fluoro-5-methylpyridin-3-yl)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 6-(6-fluoro-5-methylpyridin-3-yl)-5-methyl-1-(3,3,3-trifluoro-2- 20 hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione was obtained by a cross coupling reaction in analogy to above described intermediate int.164 above.LCMS (ESI+): found 404.3 [M+H]+, calculated 403.1 for C16H13F4N3O3S. APR-P04602WO24 PCT Application (final).docx 269 Intermediate int.166: (R)-6-(6-fluoropyridin-3-yl)-5-methyl-1-(3,3,3-trifluoro-2- hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 5.8 g (R)-6-bromo-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine- 5 2,4(1H,3H)-dione (1.0 eq.), 9.9 g K3PO4 (3.0 eq.), 1.3 g XPhos-Pd-G3 (0.1 eq.) and 4.7 g potassium trifluoro(6-fluoropyridin-3-yl)borate (3.5 eq.) were dissolved in 60 ml dioxan / water 4:1 (0.26 M) under a nitrogen atmosphere and stirred at 110 °C for 18h. Purification was achieved via column chromatography (C18, water / acetonitrile) toafford 1.7 g (R)-6-(6-fluoropyridin-3-yl)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)-10 thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 390.1 [M+H]+, calculated 389.0 for C15H11F4N3O3S Intermediate int.167: (R)-1-(3,3-difluoro-2-hydroxypropyl)-6-(6-fluoropyridin-3-yl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 15 (R)-1-(3,3-difluoro-2-hydroxypropyl)-6-(6-fluoropyridin-3-yl)-5-methylthieno[2,3- d]pyrimidine-2,4(1H,3H)-dione was obtained by a cross coupling reaction in analogyto above described intermediate int.166. LCMS (ESI+): found 372.1 [M+H]+, calculated 372.1 for C15H12F3N3O3S.20 Intermediate int.168: (S)-6-(6-fluoropyridin-3-yl)-1-(2-hydroxybutyl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 25 (S)-6-(6-fluoropyridin-3-yl)-1-(2-hydroxybutyl)-5-methylthieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione was obtained by a cross coupling reaction in analogy to above described intermediate int.166. APR-P04602WO24 PCT Application (final).docx 270 LCMS (ESI+): found 350.3 [M+H]+, calculated 349.1 for C16H16FN3O3SIntermediate int.169: 6-(5-chloro-6-fluoropyridin-3-yl)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 5 500 mg 6-bromo-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione (1.0 eq.), 212 mg K3PO4 (4.0 eq.), 50 mg (0.05 eq.) Pd(PPh3)4 and 10 380 mg 3-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.1 eq.) were dissolved in 15 ml dioxan / water 4:1under a nitrogen atmosphere and stirred at 110 °C for 1 h. Purification was achieved by column chromatography (C18,water / acetonitrile) to afford 195 mg 6-(5-chloro-6-fluoropyridin-3-yl)-5-methyl-1-(3,3,3- trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+):15 found 424.1 [M+H]+, calculated 423.0 for C15H10ClF4N3O3SIntermediate int.170: (R)-6-(5-(difluoromethyl)-6-fluoropyridin-3-yl)-5-methyl-1- (3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 20 993 mg (R)-6-bromo-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.0 eq.), 2.26 g K3PO4 (4.0 eq.), 50 mg (0.13 eq.)Pd(PPh3)4 and 800 mg 3-(difluoromethyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-25 dioxaborolan-2-yl)pyridine (1.1 eq.) were dissolved in 20 ml dioxan / water 4:1under anitrogen atmosphere and stirred at 90 °C for 1 h. Purification was achieved bycolumn chromatography (C18, water / acetonitrile) to afford 141 mg (R)-6-(5-(difluoromethyl)-6-fluoropyridin-3-yl)-5-methyl-1-(3,3,3-trifluoro-2- hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 440.230 [M+H]+, calculated 439.0 for C16H11F6N3O3S APR-P04602WO24 PCT Application (final).docx 271 Example 6C: (R)-5-methyl-6-(6-phenoxypyridin-3-yl)-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione 30 mg (R)-6-(6-fluoropyridin-3-yl)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno- 5 [2,3-d]pyrimidine-2,4(1H,3H)-dione and (1.0 eq.), 64 mg K3PO4(4.0 eq.) and 14 mg phenol (2.0eq.) in 1mL DMSO (0.08M) were stirred at 60 °C for 18 h. After purification via preparative HPLC (C18, water / acetonitrile, 0.1%TFA) and drying 14.1 mg (R)-5-methyl-6-(6-phenoxypyridin-3-yl)-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno- [2,3-d]-pyrimidine-2,4(1H,3H)-dione were obtained. LCMS (ESI+): found 464.110 [M+H]+, calculated 463.1 for C21H16F3N3O4S Other nucleophiles like thiophenols may be used instead of Phenols as well. Deactivated phenols require temperatures up to 140°C. If acid labile functional groups are present, purification without 0,1%TFA is performed.15 Example 6D: 6-(6-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl)-5-methyl-1-((R)-3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (265) To a stirred solution of 40 mg (R)-6-(6-fluoropyridin-3-yl)-5-methyl-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.0 eq.) and 39 mg 1-(2,4-20 dichlorophenyl)ethan-1-ol (2.0 eq.) in 1 ml THF (0.19 M) at room temperature 16 mgsodium hydride (60%in mineral oil, 4.0 eq.) were added. After 2 h purification viapreparative HPLC (C18, water / acetonitrile) afforded 30.5 mg 6-(6-(1-(2,4-dichlorophenyl)ethoxy)pyridin-3-yl)-5-methyl-1-((R)-3,3,3-trifluoro-2- hydroxypropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 559.925 [M+H]+, calculated 559.0 for C23H18Cl2F3N3O4S Table 8a: examples in this table can be made e.g. in analogy to examples 6C or 6Dabove by nucleophilic aromatic substitution reactions from e.g. intermediates int.164-170 described above or others.30 APR-P04602WO24 PCT Application (final).docx 272 APR-P04602WO24 PCT Application (final).docx 273 APR-P04602WO24 PCT Application (final).docx 274 APR-P04602WO24 PCT Application (final).docx 275 APR-P04602WO24 PCT Application (final).docx 276 APR-P04602WO24 PCT Application (final).docx 277 APR-P04602WO24 PCT Application (final).docx 278 APR-P04602WO24 PCT Application (final).docx 279 APR-P04602WO24 PCT Application (final).docx 280 APR-P04602WO24 PCT Application (final).docx 281 APR-P04602WO24 PCT Application (final).docx 282 Example 7: 5-chloro-1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4- (trifluoromethoxy)phenoxy)phenyl) thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (94) APR-P04602WO24 PCT Application (final).docx 283 10.0 mg of 1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4- (trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (example 54) were dissolved in 1.0 ml DMF. 10.0 mg 1-chloropyrrolidine-2,5-dione (4.0eq.) were added at room temperature. The reaction mixture was then stirred at 55°C until complete consumption of starting material. 5 The reaction is filtered and purified via preperative-HPLC (C18, acetonitrile / water gradient) to afford 5-chloro-1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4- (trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione LCMS (ESI+): found 567.3 [M+H]+, calculated 566.0 for C22H13ClF6N2O5S.10 Example 8: 7-chloro-1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl) thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (95) 10.0 mg of 1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl)15 thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (example 70) were dissolved in 1.0 ml DMF. 10.0mg 1-chloropyrrolidine-2,5-dione (4.0eq.) were added at room temperature. The reaction mixture was then stirred at 55°C until complete consumption of starting material. The reaction is filtered and purified via preperative-HPLC (C18, acetonitrile / water gradient) to afford 7-chloro-1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl) 20 thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione. LCMS (ESI+): found 567.3 [M+H]+, calculated 566.0 for C22H13ClF6N2O5S 1H NMR (400 MHz, DMSO) δ 12.00 (s, 1H), 7.73 – 7.67 (m, 3H), 7.49 – 7.42 (m, 3H),7.29 – 7.22 (m, 3H), 7.22 – 7.17 (m, 3H), 6.61 (d, J = 6.4 Hz, 1H), 4.98 (dd, J = 14.4,9.4 Hz, 2H), 4.45 (ddd, J = 20.1, 14.5, 6.1 Hz, 3H).25 Table 9: examples in this table can be made e.g. in analogy to examples 7 or 8 bychlorination reactions. Alternatively examples can be prepared by cross-coupling reactions from one the bornic esters disclosed in this application and a hetaryl30 bromide like 6-bromo-5-chloro-1-(3,3,3-trifluoro-2-hydroxypropyl)thieno[2,3- d]pyrimidine-2,4(1H,3H)-dione. Chloro or bromo derivatives in this table likecompound 312 can undergo cross coupling reaction to introduce small moieties like cyclo-propyl in compound 313. APR-P04602WO24 PCT Application (final).docx 284 APR-P04602WO24 PCT Application (final).docx 285 Example 8A: 5-bromo-1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (312) 5229 mg 1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.0eq.) in 4 ml DMF (0.1 M) and 77 mg of1-bromopyrrolidine-2,5-dione (1.0 eq.) were stirred at room temperature for 18 h. Thereaction mixture was diluted with 50 ml water and precipitate was collected.The solidwas washed twice with water and dried under vacuum to afford 241 mg 5-bromo-1-10 (3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl)thieno[2,3- d]pyrimidine-2,4-(1H,3H)-dione. LCMS (ESI+): found 611.0 [M+H]+, calculated 610.0for C22H13BrF6N2O5S Example 8B: 5-cyclopropyl-1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4-15 (trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (313)APR-P04602WO24 PCT Application (final).docx 286 Amixtures of 60 mg 5-bromo-1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4-(trifluoromethoxy)phenoxy)-phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.0 eq.), 63 mg K3PO4 (3.0 eq.), 8.0 mg Pd(dppf)Cl2*DCM (0.1 eq.) and 16 mg5 cyclopropylboronic acid (2.0 eq.) in 2 ml Dioxan / water 4:1 (0.1 M) was stirred undernitrogen at 120°C for 1h under microwave irradiation. Purification via preparativeHPLC (C18, water / acetonitrile) afforded 14.1 mg 5-cyclopropyl-1-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(4-(trifluoromethoxy)-phenoxy)phenyl)thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione. LCMS (ESI+): found 573.3 [M+H]+, calculated 572.1 for10 C25H18F6N2O5S Intermediate int.25: 5-methyl-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl)thieno[2,3- d]pyrimidine-2,4(1H,3H)-dione 15 500 mg 6-bromo-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, 873 mg 4,4,5,5- tetramethyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-1,3,2-dioxaborolane, 160 mg Pd(dppf)Cl2*DCM and 1.2 g K3PO4 were suspended under a nitrogen atmosphere in 8 ml 1,4-dioxane / water (5:1) and heated to 100 °C until reaction was complete. The reaction mixture was distributed between ethyl acetate / brine and acidified with diluted aqueous 20 H2SO4.(pH ~1). The organic phase was separated, dried over MgSO4 and volaties were removed under reduced pressure. The crude was first purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient), then by reversed phase column chromatography (RP18, water / acetonitrile gradient). LCMS (ESI+): found 435.2 [M-H]+, calculated 434.05 for C20H13F3N2O4S. 25 Example 9: 1-(2-hydroxybutyl)-5-methyl-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl) thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (80) 25 mg 5-methyl-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine- 30 2,4(1H,3H)-dione (1.0 eq.), 4.9 mg 2-ethyloxirane (1.2eq.), 3.0 mg MgO (1.3eq.) and 11.5 mg APR-P04602WO24 PCT Application (final).docx 287 TMAB (1.3eq.) were dissolved in 1 ml dry DMSO. Reaction vessel was sealed and stirred at100°C until reaction was finished. The reaction mixture was purified via preparative HPLC (C18, Water / Acetonitril with 0,1% TFA) to afford 1-(2-hydroxybutyl)-5-methyl-6-(4-(4- (trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. 5 Example 10: 1-(3-hydroxy-2,2-dimethylpropyl)-5-methyl-6-(4-(4- (trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 25 mg 5-methyl-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine- 10 2,4(1H,3H)-dione (1.0 eq.), 10.6 mg 3-bromo-2,2-dimethylpropan-1-ol (1.2 eq.) and DBU (2.5 eq.) were dissolved in 1 ml dry DMF. Reaction vessel was sealed andheated to 100°C until reaction was finished. The reaction mixture was purified via preparative HPLC (C18, Water / Acetonitril with 0,1% TFA) to afford 1-(3-hydroxy-2,2- dimethylpropyl)-5-methyl-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl)thieno[2,3- 15 d]pyrimidine-2,4(1H,3H)-dione. Int.171 : 3-benzyl-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 69.6 g ethyl 2-amino-4-methylthiophene-3-carboxylate (1.0 eq.) were dissolved in 20 500 ml toluene (0.7 M). 45.9 ml (isocyanatomethyl)benzene (1.0 eq.) were added while stirring at room temperature. Stirring was continued 11 days at room temperature until the reaction was complete. Volatiles were removed under reducedpressure and the remaining oil was dissolved in 450 ml 1 M KOH in methanol (1.2eq.). After stirring for 1 h at 50°C a yellow precipitate was filtered off and washed 25 twice with methanol. This crude was dissolved in 600 ml water and acidified to pH = 1 with 30 ml conc. HCl (1.05 eq.). A white precipitate was collected and washed twice with water and once with cyclohexane. After drying the yield was 80.4 g of 3-benzyl-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione LCMS (ESI+): found 273.1 [M+H]+, calculated 272.1 for C14H12N2O2S. 30 Int.172: 3-benzyl-6-bromo-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione APR-P04602WO24 PCT Application (final).docx 288 To a solution of 1.8 g 3-benzyl-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.0eq.) in 20 ml DMF (0.33 M) 940 mg of 1-bromopyrrolidine-2,5-dione (0.8 eq.) wereadded while stirring at room temperature. Stirring at room temperature was continuedfor 1 h. The mixture was poured into 100 ml water. The precipitate was collected,5 wash with water and cyclohexane and dried under vacuum to afford 1.81 g 3-benzyl-6-bromo-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione LCMS (ESI+): found 351.0 [M+H]+, calculated 350.0 for C14H11BrN2O2S.Int.173 : 3-benzyl-5-methyl-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl)thieno[2,3-10 d]pyrimidine-2,4(1H,3H)-dione A mixture of 1.2 g 3-benzyl-6-bromo-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)- dione (1.0 eq.), 2.2 g K3PO4(3.0eq.), 297 mg XPhos-Pd-G3 (0.1 eq.) and 1.4 g (4- (4-(trifluoromethoxy)phenoxy)phenyl)boronic acid (3.5 eq.) in 25 ml dioxan / water 5:1 15 was stirred under nitrogen at 110 °C for 17 h. Volatiles were removed under vacuum and the crude was purified via column chromatography (silica, cyclohexane / ethyl acetate) to afford 1.45 g 3-benzyl-5-methyl-6-(4-(4- (trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione LCMS (ESI+): found 525.2 [M+H]+, calculated 524.1 for C27H19F3N2O4S20 Int.174 : 3-benzyl-1-(3-hydroxy-2-methylpropyl)-5-methyl-6-(4-(4- (trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione To a mixture of 50 mg 3-benzyl-5-methyl-6-(4-(4-(trifluoromethoxy)phenoxy)-25 phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.0 eq.) and 52 mg K3PO4 (1.5eq.)in 1 ml DMSO (0.08 M) 14.2 µl 5-methyl-1,3,2-dioxathiane 2,2-dioxide (1.5 eq.) wereadded at. The sealed the reaction vessel was stirred at 60°C for 21h. 40µl conc.H2SO4 were added and stirring was continued for 2 h at 60°C. Additional 40 µl conc.H2SO4 (1.0 eq.) and stirring for 2 h at 60°C were required to complete the cleavage.30 The reaction mixture was poured in sat. NaHCO3 solution and the aqueous phasewas extracted three times with ethyl acetate. Combined organic phases were driedover MgSO4 and evaporated. Purification via normal phase column chromatography(silica, cyclohexane / ethyl acetate gradient) afforded 3-benzyl-1-(3-hydroxy-2-APR-P04602WO24 PCT Application (final).docx 289 methylpropyl)-5-methyl-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl)thieno[2,3- d]pyrimidine-2,4(1H,3H)-dione LCMS (ESI+): found 597.3 [M+H]+, calculated 596.2for C31H27F3N2O5S 5Example 11: 1-(3-hydroxy-2-methylpropyl)-5-methyl-6-(4-(4-(trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (103) 1-(3-hydroxy-2-methylpropyl)-5-methyl-6-(4-(4-(trifluoromethoxy)phenoxy)- phenyl)thieno-[2,3-d]pyrimidine-2,4(1H,3H)-dione from the reaction described above10 was dissolved in 1.0 ml trifluoromethanesulfonic acid and stirred at 50°C overnight.The reaction was diluted with sat. NaHCO3 solution and extract the aqueous phasewas extracted three times with ethyl acetate. Combined the organic phases weredried using MgSO4 and evaporated. Purification was achieved via preparative HPLC(C18, water / acetonitrile) to afford 2.4 mg 1-(3-hydroxy-2-methylpropyl)-5-methyl-6-(4-15 (4-(trifluoromethoxy)phenoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione LCMS (ESI+): found 507.3 [M+H]+, calculated 506.1 for C24H21F3N2O5S. Table 10: examples in this table can be made e.g. in analogy to examples 9,10 or 11by alkylation reactions with related epoxides, halides, cyclic phosphate esters20 APR-P04602WO24 PCT Application (final).docx 290 APR-P04602WO24 PCT Application (final).docx 291 APR-P04602WO24 PCT Application (final).docx 292 Biological Examples 51. Example B-1: Immunostimulation assays with CD4+ and CD8+ T-cellsIn 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. 10 1.1 Materials for Bioassay 1.2 Procedure / Description15 1.2.1 Collection of PBMCs from buffy CoatWhite 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 APR-P04602WO24 PCT Application (final).docx 293 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. 1.2.2 Isolation of CD4+ and CD8+ T-Cells5 10^7 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.10 1.2.3 Serial dilution of compounds of the invention10 mM compounds of the invention stocks were further diluted using DMSO andequal amounts transferred to T-cell containing 96-wells. Final concentrations tested were: 30 µM, 10 µM, 3 µM, 1 µM, 0.3 µM, 0.1 µM, 0.03 µM, 0.01 µM, 0.003 µMand 0.001 µM.15 1.2.4 Stimulation setup for EC50 testingFor the stimulation assays 80.000 purified CD4+ and CD8+ T-cells were seeded per 96-well and incubated with 1 µg / ml anti-CD3, 1 µg / ml anti-CD28 and compounds ofthe invention ranging from 0.001 µM to 30 µM. DMSO only wells served as control to20 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. 1.2.5 Determination of EC50 values for compounds of the invention by surface25 FACS 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 tostain viable cells. Staining was performed for 15 minutes and cells analyzed using a Fortessa flow cytometer and FlowJo Software. EC50s were calculated using30 GraphPad Prism® and a variable slope model (agonist vs. response - variableslope). The assay results are summarized in Table B-1. Table B-1 shows immunostimulation assay data. Immunostimulation of CD4+ and35 CD8+ T-cells are indicated as EC50 [nM] (“–“ = not measured). Compounds having anactivity designated as ”A+” provided an EC50 ≤30 nM; compounds having an activitydesignated as ”A” provided an 30 nM < EC50 ≤ 100 nM; compounds having anactivity designated as ”B” provided an 100 nM < EC50 ≤ 500 nM; compounds havingan activity designated as ”C” provided an 500 nM < EC50 ≤ 1000 nM; compounds40 having an activity designated as ”D” provided an 1000 nM < EC50 ≤ 5000 nM;compounds having an activity designated as ”E” provided an EC50 > 5000 nM.APR-P04602WO24 PCT Application (final).docx 294 APR-P04602WO24 PCT Application (final).docx 295 APR-P04602WO24 PCT Application (final).docx 296 APR-P04602WO24 PCT Application (final).docx 297 APR-P04602WO24 PCT Application (final).docx 298 APR-P04602WO24 PCT Application (final).docx 299 APR-P04602WO24 PCT Application (final).docx 300 2. Example B-2: In vitro killing potency Compounds 56, 53, 52, 62, 60, 58, 57, 55, 75, 73, 72, 70, 32, 29, 37, 35, 34, 78, 79, and 77 are tested for their potential to enhance PBMC or T cell mediated killing of 5 allogeneic M21 melanoma cells using impedance based methodology. 2.1 Materials for Bioassay 10 2.2 Procedure / Description2.2.1 Seeding of M21 melanoma cellsE-plates or CytoView-Z 96 were coated with 10 µg / 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. 15 M21 cells were grown in a humidified incubator at 37 °C and 5 % CO2and used for purified PBMCs or T cells co-culture 20-24 hours post seeding. 2.2.2 Collection of PBMCs from healthy donorsWhite blood cell enriched buffy coats were ordered from the Austrian red cross, 20 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 APR-P04602WO24 PCT Application (final).docx 301 counted. For dose response experiments with PBMC co-cultures 25000 cells were seeded per M21 containing E-plate 96-well (PBMC to M215:1). 2.2.3 Isolation of CD4+ and CD8+ T-Cells5 PBMCs were magnetically labeled with CD4 and CD8 microbeads according to manufacturer’s instructions and separated using autoMACS device or pan-T purified using human Pan T Cell Isolation Kit according to manufacturer’s instructions. For dose response experiments with fresh or frozen purified T-cell co-cultures 25000 cells were seeded per M21 containing E-plate 96-well or CytoView-Z 96 well (T cell10 to M215:1 or 7:1). 2.2.4 Serial dilution of compounds of the invention (LMW compounds)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 15 concentrations tested were: 10 µM, 3 µM, 1 µM, 0.3 µM, and 0.1 µM. 2.2.5 Xcelligence / Axion in vitro killing assayE-plates or CytoView-Z 96 well plates containing M21 cell layers and isolated PBMCs or T cells were incubated with 1 µg / ml anti-CD3, 1 µg / ml anti-CD28 and LMW 20 compounds ranging from 0.1 µM to 10 µM. 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 or CytoView-Z 96 well 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 Agilent Xcelligence RTCA SP or Axion Mastro25 TrayZ device. 2.2.6 Determination of EC50 values for compounds of the inventionXcelligence or Axion data were analysed using GraphPad Prism and EC50s calculated using a variable slope model (agonist vs. response - variable slope).30 2.3 Results2.3.1 In vitro killing assay using stimulated CD4+ and CD8+ T cellsStimulated CD4+ and CD8+ T cells from one donor were co-cultured with M21 melanoma cells upon compound 56 and compound 55 addition at different35 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 56 and 55 (Fig.1 and 2).EC50 were calculated 32 hours post compound addition and are also dedicated in Fig.1 and 2.40 APR-P04602WO24 PCT Application (final).docx 302 Fig.1 and 2 depict M21 cell growth upon stimulated T cell co-culture. M21 melanomacells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti- CD3 / CD28 and compounds 56 and 55 at different concentrations. EC50 was calculated at 32 hours post anit-CD3 / CD28 and compound addition using GraphPad 5 Prism. 2.3.2 In vitro killing assay using stimulated CD4+ and CD8+ T cellsStimulated CD4+ and CD8+ T cells from the same donor as above were co-cultured with M21 melanoma cells upon compounds 56, 53, 52, 62, 60, 57, 55, 75, 73, 72, 70,10 32, 29, 37, 35 or 34 addition and cell growth monitored for 40 hours. Purified T cellsshowed dose-dependent M21 killing upon anti-CD3 / CD28 stimulation and increasing concentrations of compounds 56, 53, 52, 62, 60, 57, 55, 75, 73, 72, 70, 32, 29, 37, 35 or 34 (Fig.3A to 3P).EC50 were calculated 40 hours post compound addition and are also indicated in Fig. 15 3A to 3P. Fig. 3A to 3P depict M21 cell growth upon stimulated T cell co-culture. M21melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / CD28 and compounds 56, 53, 52, 62, 60, 57, 55, 75, 73, 72, 70, 32, 29, 37, 35 or 34 at different concentrations. EC50 was calculated at 40 hours post20 anti-CD3 / CD28 and compound addition using GraphPad Prism. 2.3.3 In vitro killing assay using stimulated CD4+ and CD8+ T cellsStimulated CD4+ and CD8+ T cells from the same donor as above were co-cultured with M21 melanoma cells upon compounds 58, 55, 73, 70, 78, 79, or 77 addition and 25 cell growth monitored for 40 hours. Purified T cells showed dose-dependent M21 killing upon anti-CD3 / CD28 stimulation and increasing concentrations of compounds 58, 55, 73, 70, 78, 79, or 77 (Fig.4A to 4G).EC50s were calculated 40 hours post compound addition and are indicated in Fig. 4A to 4G.30 Fig. 4A to 4G depict M21 cell growth upon stimulated T cell co-culture. M21melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / CD28 and compounds 58, 55, 73, 70, 78, 79, or 77 at differentconcentrations. EC50 was calculated at 40 hours post anti-CD3 / CD28 and compound addition using GraphPad Prism. 35 2.3.4 In vitro killing assay using stimulated CD4+ and CD8+ T cellsStimulated CD4+ and CD8+ T cells from another donor were co-cultured with M21 melanoma cells upon compounds 3, 24, 35, 55, 60, 80, 81, 83, 93, 95, 158, 171, 174,177, 238, 241, 242, 243, 244, 248, 294, 296, or 305 addition and cell growth40 monitored for 40 or 44 hours. Purified T cells showed dose-dependent M21 killing upon anti-CD3 / CD28 stimulation and increasing concentrations of compounds 3, 24,APR-P04602WO24 PCT Application (final).docx 303 35, 55, 60, 80, 81, 83, 93, 95, 158, 171, 174, 177, 238, 241, 242, 243, 244, 248, 294,296, or 305 at different concentrations.EC50s were calculated 40 or 44 hours post anti-CD3 / CD28 and compound addition. All tested compounds enhance the cytotoxicity of primary human T cells and show 5potency below 1 µM. Compounds 95, 248, 294, or 305 are selected as examples todemonstrate the effect described above in Fig.9A to 9D.Fig. 9A to 9D depict M21 cell growth upon stimulated T cell co-culture. M21melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / 28 and compounds 95, 248, 294, or 305 at different concentrations.10 EC50 was calculated at 40 or 44 hours post anti-CD3 / 28 and compound addition using GraphPad Prism. 3Example B-3: Efficacy on B16-SIY melanomaCompounds 56 (racemate) and compound 55 (R enantiomer of compound 56) show15 preclinical efficacy in a murine B16-SIY melanoma model. 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.20 3.1 Materials for Bioassay APR-P04602WO24 PCT Application (final).docx 304 3.2 Procedure / Description3.2.1 Animals and EthicsEight-weeks-old C57BL / 6 mice were purchased from Charles River. All animal experiments were in accordance with institutional guidelines of the Research Institute 5 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 mm³ or humaneendpoints were reached.10 3.2.2 B16-SIY cell cultureB16-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 final15 concentration of 1x107B16-SIY cells / ml. 3.2.3 Tumor inoculation and compound treatment3.2.3.1 Efficacy Experiment 1: Compound 56 (racemate)C57BL / 6 mice were inoculated intradermally with 1x106B16-SIY cells and tumor 20 bearing mice randomly assigned to different groups 3 days post transplantation: Compound 56 (8 mice, 1 mg / kg QD), 56 (8 mice, 5 mg / kg QD), 56 (8 mice, 10 mg / kgQD) and vehicle control (8 mice, 100 µl QD) were administered p.o.3 days post B16- SIY inoculation and subsequent daily treatment for 18 days (Fig.5).Compound 56 (racemate) was diluted in in 20% transcutol, 20% TPGS, 0,6 % HPMC25 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 40- or 41-days treatment freeobservation period. Mice were sacrificed when the tumor volume was ≥ 1000 mm3 orhumane endpoints were reached. Mice surviving beyond day 61 or 62 were 30 rechallenged on day 62 or 63 with an additional intradermal B16-SIY cell inoculation as described above and terminated on day 80 or 82. Fig. 5 depicts the treatment schedule for compound 56 (racemate) in vivo efficacyexperiments with p.o. compound administration monitoring tumor volume and survival rate of mice. Arrows indicate p.o. drug treatment. 35 3.2.3.2 Efficacy Experiment 2: Compound 55 (R enantiomer of compound 56)C57BL / 6J mice were inoculated intradermally with 1x106B16-SIY cells and tumor bearing mice randomly assigned to different groups 3 days post transplantation: compound 55 (8 mice, 1.2 mg / kg QD), compound 55 (8 mice, 6 mg / kg QD), 40 compound 55 (8 mice, 10 mg / kg QD), and vehicle control (8 mice, 100µl QD) were APR-P04602WO24 PCT Application (final).docx 305 administered p.o. 3 days post B16-SIY inoculation and subsequent daily treatment for 18 days (Fig.6).Compound 55 was 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 5 control. Tumors were measured 3 times a week and mice treated 4 days to 21 days after B16-SIY inoculation followed by a several days treatment free observation period. Mice were sacrificed when the tumor volume was ≥ 1000 mm3 or humaneendpoints were reached. Experiment ongoing. Fig. 6 depicts the treatment schedule for compound 55 in vivo efficacy experiments10 with p.o. compound administration monitoring tumor volume and survival rate of mice. Arrows indicate p.o. drug treatment. 3.2.3.3 Efficacy Experiment 3: Compounds 95 and 305C57BL / 6J mice were inoculated intradermally with 1x106B16-SIY cells and tumor bearing mice randomly assigned to 9 different groups 3 days post transplantation:15 compound 95 (8 mice, 1 mg / kg Q3D), compound 95 (8 mice, 5 mg / kg Q3D),compound 95 (8 mice, 10 mg / kg Q3D), compound 95 (8 mice, 15 mg / kg Q3D),compound 305 (8 mice, 1 mg / kg Q3D), compound 305 (8 mice, 5 mg / kg Q3D),compound 305 (8 mice, 10 mg / kg Q3D), compound 305 (8 mice, 15 mg / kg Q3D) andvehicle control (8 mice, 100µl Q3D) (Fig.10).20 Compounds 95 or 305 were diluted in 20% transcutol, 20% TPGS, 0,6 % HPMC and59,4 % 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 19 days after B16-SIY inoculation followed by a 22 days treatment free observationperiod. Mice were sacrificed when the tumor volume was ≥ 1000 mm3 or humane25 endpoints were reached. Fig. 10 depicts the treatment schedules for compound 95 or 305 in vivo efficacyexperiments with p.o. compound administration monitoring tumor volume and survival rate of mice treated p.o. Arrows indicate p.o. drug treatment. 30 3.3Results 3.3.1 Efficacy Experiment 1: Compound 56 (racemate)C57BL / 6 mice were inoculated intradermally with B16-SIY cells and treated p.o. with 1mg / kg, 5 mg / kg, and 10 mg / kg compound 56 3 days post B16-SIY injection.Vehicle treated mice (100 µL / mouse) served as controls. Mice were subsequently 35 observed without treatment for 40 or 41 days. All compounds and treatment regimes resulted in significantly reduced tumor volumes and prolonged survival compared to vehicle control over the course of 61 or 62 days. All mice surviving beyond day 61 or 62 and were rechallenged on day 62 or 63 with an additional intradermal B16-SIY cell inoculation and terminated on day 82. 5 previously untreated mice without 40 primary tumor were inoculated intradermally with B16-SIY cells and served as control (Fig.7A, 7B, 7C, and 7D).APR-P04602WO24 PCT Application (final).docx 306 Zero mice of 2 mice previously receiving 1 mg / kg compound 56 started to showsecondary tumor growth over the course of 19 days (data not shown). 3of 4 mice previously receiving 5 mg / kg compound 56 and 1 of 1 previouslyuntreated mouse started to show secondary tumor growth over the course of 19 days 5 (data not shown). 2of 6 mice previously receiving 10 mg / kg compound 56 started to show secondarytumor growth over the course of 19 days (data not shown). Fig. 7A, 7B, 7C, and 7D depict the impact on in vivo tumor growth rate and survivaland indicate the tumor volumes of individual mice receiving p.o. treatments as10 described in Fig.5.3.3.2 Efficacy Experiment 2: Compound 55 (R enantiomer of compound 56)C57BL / 6J mice were inoculated intradermally with B16-SIY cells and treated p.o. with 1.2 mg / kg, 6 mg / kg and 10 mg / kg compound 55 (R enantiomer of compound 56)15 daily starting on day 4 post inoculation until day 21 post inoculation. Vehicle administered mice (100 µL / mouse QD) treated from 4 days post B16-SIY inoculation until 21 days served as controls. Mice were subsequently observed without treatment for several days. All compounds and treatment regimes resulted in significantly reduced tumor volumes and prolonged survival compared to vehicle control over the 20 course of at least 40 days (Fig.8A, 8B) and at least 20 days (Fig.8C, 8D). Higher concentrations of administered compound show side effects. Experiment ongoing. Fig. 8A, 8B, 8C, and 8D depict the impact on in vivo tumor growth rate and survivaland indicate the tumor volumes of individual mice receiving p.o. treatments as described in Fig.6.25 3.3.3 Efficacy Experiment 3: Compounds 95 and 305C57BL / 6J mice were inoculated intradermally with B16-SIY cells and 8 mice / group treated p.o. with 1 mg / kg, 5 mg / kg, 10 mg / kg and 15 mg / kg compound 95 or 305Q3D starting 4 days post B16-SIY inoculation until 19 days. Vehicle administered30 mice (100 µL / mouse Q3D) treated from 4 days post B16-SIY inoculation until 19 daysserved as controls (Fig. 11I). Following the treatment period (D4-D19) mice wereobserved without treatment for 22 days. All compounds and treatment regimens except for 1 mg / kg compound 95 Q3Dresulted in significantly reduced tumor volumes and prolonged survival compared to 35 vehicle control over the course of 41 days (Fig.11A to 11I).4 of 8 mice receiving 15 mg / kg compound 305 Q3D and 1 mouse treated with 10 mg / kg compound 305 Q3Dshowed 6-10 % body weight loss 24h post first compound application but regained weight before the second compound application 7 days post tumor cell inoculation (data not shown). Compound 305 application did not result in additional clinical signs40 during the p.o. administration period. Experiment ongoing.APR-P04602WO24 PCT Application (final).docx 307 Fig. 11A to 11I depict the impact on in vivo tumor growth rate and survival andindicate the tumor volumes of individual mice receiving p.o. treatment with compounds 95 and 305 or vehicle 4 to 19 days post B15_SIY inoculation asdescribed in Fig.10. 5 APR-P04602WO24 PCT Application (final).docx

Claims

1. 308 Claims 1. A compound of the formula (I) 5 ; , , , , B is –O–R3, –S–R3, –O–CHR3R3*, –O–CH2–CH2–R3, or –O–CH2–CH2–10 CH2–R3; R2, R2a, R2b, and R2crepresent independently of each other –H, –F, –Br, –Cl, ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3, 15 ^CH2CH2OCH3, ^CF2^CH3, ^CHF^CHF2, ^CHF^CF3, ^CF2^CF3; and R2ais not –H; or R2aand R2bform together APR-P04602WO24 PCT Application (final).docx 309 5 10 15 R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other –H, –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, APR-P04602WO24 PCT Application (final).docx 310 –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OC(CH3)3, –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, ^C2H4–OCH3, ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, 5 ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O–cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6– OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, ^CH2–OCH2^Ph, ^C2H4–OCH2^Ph, ^C3H6–OCH2^Ph, –SH, –SCH3, –SC2H5, 10 –SC3H7, –S–cyclo-C3H5, –SCH(CH3)2, –SC(CH3)3, –SF5, –F, –Cl, –Br, –I, –CN, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, –COCH3, –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, –COC(CH3)3, –COOH, –COOCH3, –COOC2H5, –COOC3H7, –COO–cyclo-C3H5, 15 –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)2, –CON(C2H5)2, –CON(C3H7)2, –CON(cyclo-C3H5)2, –CON[CH(CH3)2]2, –CON[C(CH3)3]2, 20 –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, –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, 25 –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, –SO2–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, 30 –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)C2H5, ^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, 35 –S(=O)(=NH)C(CH3)3, –P(=O)(CH3)2, –P(=O)(C2H5)2, –P(=O)(OH)2, –P(=O)(OH)(OCH3), –P(=O)(OH)(OC2H5), –P(=O)(OCH3)2, –P(=O)(OC2H5)2, ^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–C3H7, ^O–SO2–cyclo-C3H5, ^O–SO2–CH(CH3)2, APR-P04602WO24 PCT Application (final).docx 311 5 –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)–NHCH3, –NH–C(=NH)–NHC2H5, 10 –NH–C(=NH)–NHC3H7, –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)2, –NH–C(=NH)–N(C2H5)2, –NH–C(=NH)– N(C3H7)2, –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–NHCH3,15 –O–CO–NHC2H5, –O–CO–NH[C(CH3)3], –O–CO–N(CH3)2, –O–CO– N(C2H5)2, –O–CO–N(C3H7)2, –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, ^CF3, ^CH2^CH2F, ^CH2^CHF2, ^CH2^CF3, cyclo-C8H15, ^Ph, ^CH2^Ph, 20 25 30 35 APR-P04602WO24 PCT Application (final).docx 312 5 10 15 20 25 30 APR-P04602WO24 PCT Application (final).docx 313 Z1, Z2, Z3, Z4, Z5, and Z6represent indepenently of each other –H, –F, –Cl, –Br, –CN, –OH, ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OC2H5,^OCH2F, ^OCHF2, ^OCF3, ^CH2^CF3, or ^CF2^CF3; 5 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 10 ; 15 R2, R2a, R2b, and R2crepresent independently of each other –H, –F, –Br, –Cl, ^CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3, APR-P04602WO24 PCT Application (final).docx 314 ^CH2CH2OCH3, ^CF2^CH3, ^CHF^CHF2, ^CHF^CF3, ^CF2^CF3 ; and R2ais not –H; 5 10 15 R5, R6, R7, R8, R9, R10, R11, R12and R13represent independently of each other –H, –cyclo-C3H5, –cyclo-C4H7, –cyclo-C5H9, –cyclo-C6H11, –cyclo-C7H13, –cycloC3H5O, –OH, –OCH3, –OCD3, –OC2H5, –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OC(CH3)3, –OC4H9, ^OPh, ^OCH2^Ph, ^OCPh3, ^CH2–OCH3, ^C2H4–OCH3, 20 ^C3H6–OCH3, ^CH2–OC2H5, ^C2H4–OC2H5, ^C3H6–OC2H5, ^CH2–OC3H7, ^C2H4–OC3H7, ^C3H6–OC3H7, ^CH2–O–cyclo-C3H5, ^C2H4–O–cyclo-C3H5, ^C3H6–O–cyclo-C3H5, ^CH2–OCH(CH3)2, ^C2H4–OCH(CH3)2, ^C3H6– OCH(CH3)2, ^CH2–OC(CH3)3, ^C2H4–OC(CH3)3, ^C3H6–OC(CH3)3, ^CH2–OC4H9, ^C2H4–OC4H9, ^C3H6–OC4H9, ^CH2–OPh, ^C2H4–OPh, ^C3H6–OPh, 25 ^CH2–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, ^CH2–OH, ^C2H4–OH, ^C3H6–OH, ^CH(CH3)(CH2OH), ^C(CH3)2OH, ^CH(CH2OH)2, ^CH(CH3)(C2H4OH), ^C(CH3)2(CH2OH), ^C(CH3)(CH2OH)2, APR-P04602WO24 PCT Application (final).docx 315 –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, 5 10 15 20 25 30 35 –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)–NHCH3, –NH–C(=NH)–NHC2H5, –NH–C(=NH)–NHC3H7, –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)2, –NH–C(=NH)–N(C2H5)2, –NH–C(=NH)– APR-P04602WO24 PCT Application (final).docx 316 N(C3H7)2, –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)2, –O–CO– N(C2H5)2, –O–CO–N(C3H7)2, –O–CO–N(cyclo-C3H5)2, –O–CO–N[CH(CH3)2]2, 5 –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, ^CF3, ^CH2^CH2F, ^CH2^CHF2, ^CH2^CF3, cyclo-C8H15, ^Ph, ^CH2^Ph, 10 15 20 25 30 35 APR-P04602WO24 PCT Application (final).docx 317 5 10 15 20 or R5 and R6, R6 and R7, or R5 and R8 may form together the following 5- or 6-membered ring system: 25 APR-P04602WO24 PCT Application (final).docx 318 Z1, Z2, Z3, Z4, Z5, and Z6represent indepenently of each other –H, –F, –Cl, –Br, ^CH3, ^C2H5, ^CH2F, ^CHF2, ^CF3, ^OCH3, ^OC2H5, ^OCH2F, ^OCHF2, ^OCF3, ^CH2^CF3, or ^CF2^CF3; 5 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.

3. The compound according to claim 1, wherein R3 represents10 15 and R5, R6, R7, R8, R9, R10, R11, R12and R13have the same meanings as defined in claim 1.

4. The compound according to claim 1 or 3, wherein APR-P04602WO24 PCT Application (final).docx 319 R2arepresents –CH3, ^C2H5, ^CH(CH3)2, ^cyclo-C3H5, ^C(CH3)3, ^CD3, ^CH2F, ^CHF2, ^CF3, ^CH2^CF3, ^CHF^CH2F, ^CH2OH, ^CH2CH2OH, ^CH2OCH3 ; and R2band R2crepresent indepenently of each other –H or ^CH3; or R2a and R2b form together 5 Brepresents –O–R3, –S–R3, –O–CHR3R3*; –O–CH2–CH2–R3, or–O–CH2–CH2–CH2–R3; 10 15 APR-P04602WO24 PCT Application (final).docx 320 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, –Br, ^CH3, 5 10 and R5, R6, R7, R8, R9, R10, R11, R12, R13, Z1and Z2have the same meanings as defined in claim 1.

5. The compound according to any one of the claims 1, 3 – 4, wherein 15 R3, R3* and R4 have the same meanings as defined in any one of the claims 1 to3.

6. The compound according to any one of the claims 1, 3 – 5, wherein 20 R3represents , APR-P04602WO24 PCT Application (final).docx 321 as defined in any one of the claims 1 to 3. 5 7. The compound according to any one of the claims 1 – 6, wherein the compoundhas any one of the following formulae (II-1) to (II-6), (III-1) to (III-6), (IV-1) to (IV-6), (V-1) to (V-6), (VI-1) to (VI-4) and (VII-1) to (VII-6): APR-P04602WO24 PCT Application (final).docx 322 APR-P04602WO24 PCT Application (final).docx 323 APR-P04602WO24 PCT Application (final).docx 324 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 – 6.5 8. The compound according to any one of the claims 1, 3 – 7, wherein10 APR-P04602WO24 PCT Application (final).docx 325 5 10 15 20 APR-P04602WO24 PCT Application (final).docx 326 R5, R6, R7, R8 and R9 represent independently of each other–H, –F, –Cl, –CN, –CH3, ^C2H5, ^C3H7, ^CH(CH3)2, ^C(CH3)2CN, ^CH(CH3)(OH), ^CH(CF3)(OH), ^C(CH3)2(OH), ^C(CH3)(CF3)(OH), –cyclo-C3H5, –cyclo-C4H7, –CH2F, –CHF2, –CF3, –CH2CF3, –OCH3, –OCD3, –OC2H5, 5 –OC3H7, –O–cyclo-C3H5, –OCH(CH3)2, –OCHF2, –OCF3, –OCH2CF3, –CH2OCH3, –COCH3, –COC2H5, –COC3H7, –CO–cyclo-C3H5, –COCH(CH3)2, –CONH2, –CONHCH3, –CONHC2H5, –CONHC3H7, –CONH–cyclo-C3H5,–CON(CH3)2, –CON(C2H5)2,–NHCH3, –NHC2H5, –NHC3H7, –NH–cyclo-C3H5, –NHCH(CH3)2, –N(CH3)2, –N(C2H5)2, –N(C3H7)2, –SF5, –SOCH3, –SOC2H5,10 –SOC3H7, –SO–cyclo-C3H5, –SOCH(CH3)2, –SOC(CH3)3, –SO2CH3, –SO2C2H5, –SO2C3H7, –SO2CH(CH3)2, –SO2–cyclo-C3H5, –SO2NH2, 15 20 R11and R12represent independently of each other –H or –F.

9. The compound according to any one of claims 1, 3 – 8, wherein; APR-P04602WO24 PCT Application (final).docx 327 , Brepresents –O–R3, –S–R3, or –O–CHR3R3*;5 10 15 APR-P04602WO24 PCT Application (final).docx 328 5 10 15 , APR-P04602WO24 PCT Application (final).docx 329 5 10 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 compound selected from the group consisting of: APR-P04602WO24 PCT Application (final).docx 330 APR-P04602WO24 PCT Application (final).docx 331 APR-P04602WO24 PCT Application (final).docx 332 APR-P04602WO24 PCT Application (final).docx 333 APR-P04602WO24 PCT Application (final).docx 334 APR-P04602WO24 PCT Application (final).docx 335 APR-P04602WO24 PCT Application (final).docx 336 APR-P04602WO24 PCT Application (final).docx 337 APR-P04602WO24 PCT Application (final).docx 338 APR-P04602WO24 PCT Application (final).docx 339 APR-P04602WO24 PCT Application (final).docx 340 APR-P04602WO24 PCT Application (final).docx 341 APR-P04602WO24 PCT Application (final).docx 342 APR-P04602WO24 PCT Application (final).docx 343 APR-P04602WO24 PCT Application (final).docx 344 APR-P04602WO24 PCT Application (final).docx 345 APR-P04602WO24 PCT Application (final).docx 346 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. 5 11. A pharmaceutical composition comprising at least one compound according toany one of the claims 1 – 10 as an active ingredient, together with at least onepharmaceutically acceptable carrier, excipient and / or diluent.10 12. The pharmaceutical composition according to claim 11 further comprising atleast one stimulating agent for activating immune cells.

13. A compound according to any one of the claims 1 – 10, a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition according to claim 1115 or 12 for use as a medicament.

14. A compound according to any one of the claims 1 – 10 for use, apharmaceutically acceptable salt thereof for use, or the pharmaceutical APR-P04602WO24 PCT Application (final).docx 347 composition according to claim 11 or 12 for use in the prophylaxis or treatmentof a neoplastic and / or infectious disease.

15. The compound for use, the pharmaceutically acceptable salt thereof for use, or5 the pharmaceutical composition for use according to claim 14, 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.10 16. An in vitro or ex vivo method for the production of activated immune cellscomprising 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 as15 defined in any one of the claims 1 – 10, 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 theviability of said cells. APR-P04602WO24 PCT Application (final).docx

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