Substituted 3,7-dihydro-1H-purine-2,6-diones and uses thereof

Abstract

The present invention relates to 3,7,8-trisubstituted 3,7-dihydro-1H-purine-2,6-dione compounds, also known as 3,7,8-trisubstituted xanthine compounds, of general formula (I), or pharmaceutically acceptable salts thereof. The present invention further relates to pharmaceutical compositions containing the compounds, and to the use of the compounds or pharmaceutical compositions as medicaments, particularly in methods and in vitro methods for the treatment or prevention of neoplastic and / or infectious diseases. These compounds activate immune cells, particularly T cells, such as CD4+ and CD8+ cells. [Formula 1] TIFF2026502179000416.tif37170

Description

Detailed Description of the Invention

[0001] [Field of the Invention] The present invention relates to 3,7,8-trisubstituted 3,7-dihydro-1H-purine-2,6-dione compounds, also called 3,7,8-trisubstituted xanthine compounds, of general formula (I): or a pharmaceutically acceptable salt of said compound:

[0002] [ka]

[0003] The present invention further relates to pharmaceutical compositions containing said compounds and to their use as medicaments, in particular in methods for the treatment or prevention of neoplastic and / or infectious diseases, and in in vitro methods. These compounds activate immune cells, including NK cells, or T cells, such as CD4+ and CD8+ cells.

[0004] [Background of the invention] Malignant tumors (cancer) and infectious diseases are two of the leading causes of death worldwide. In an increasing number of cases, it is known that there is often interdependence between neoplastic diseases and infectious diseases, such as cervical tumors and herpes simplex virus infections. Although various compounds have been identified for the treatment and prevention of these diseases, it is well known that such compounds have serious drawbacks, such as causing serious side effects. Therefore, there remains an unmet need for new compounds for the treatment and prevention of neoplastic diseases and / or infectious diseases.

[0005] To overcome these shortcomings, therapeutic and preventive approaches based on modulating a patient's immune response are becoming increasingly important in today's medical care. A patient's immunological activity is often supported by drug therapy. In this context, immunological treatments for neoplastic and infectious diseases are particularly important. In this regard, it is well known that multiple types of immune cells, such as natural killer (NK) cells, T cells, B cells, dendritic cells, monocytes, and macrophages, are often involved in the inactivation and elimination of pathogens in the body. For example, with regard to tumors, each mature tumor is known to possess specific antigens and / or neoantigens (e.g., Sensi and Anichini, 2006, Clin Cancer Res. 12:5023-5032). This generally involves not only the innate immune system (e.g., natural killer (NK) cells), but also the adaptive immune system (e.g., T cells and / or The immune system in a healthy body is, in most cases, effective enough to prevent or cure the body from neoplastic and infectious diseases.

[0006] CD4+ and CD8+ T cells constitute the majority of T lymphocytes. After activation and differentiation into distinct effector subtypes, CD4+ T cells play a key role in mediating immune responses through the secretion of specific cytokines. CD4+ T cells perform diverse functions ranging from activating innate immune cells, B lymphocytes, cytotoxic T cells, and non-immune cells, and also play an important role in suppressing immune responses.

[0007] 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. + T cell metabolism is coupled to transcriptional, translational, and epigenetic changes triggered by extracellular metabolites and immune signals. These programs are driven by CD8+ It facilitates the adaptation of T cells to the diverse and dynamic metabolic environments they encounter in the circulatory system and in tissues.

[0008] However, the immune system may be unable to eliminate, for example, neoplastic or infectious diseases, and the condition may become chronic. In these cases, especially when the patient is suffering from a malignant tumor (cancer), the immune system is often downregulated. In a healthy body (i.e., in an environment without immunosuppression), appropriate expression of major histocompatibility complex I (MHCI), which presents antigens to immune cells such as cytotoxic CD8 T cells, is observed, whereas MHCI expression is downregulated in tumor cells. This can be countered by NK cells, which specifically recognize and destroy cells with reduced MHC-I surface expression. However, during tumor maturation (especially tumor progression), numerous immunosuppressive mechanisms leading to immune tolerance increase the likelihood that the maturing tumor will escape the immune system; i.e., tumor antigens are not recognized as non-self and the immune system is not activated. This mechanism is a general principle of tumor maturation and is not limited to specific tumors or dependent on specific tumor antigens. In particular, it has been shown that tumor-associated T cells and NK cells are present in most cancer patients, but due to various mechanisms of suppression, they do not produce sufficient amounts of many cytokines (e.g., IL-2 and IFN-γ) or exert cytotoxic activity against tumors, preventing an efficient antitumor immune response (De Paola et al., 2003, British Journal of Cancer 88:320-326; Ahmadzadeh et al., 2009, Blood 114:1537-1544, especially the section "PD-1+ TILs display an impaired effector function" on pages 1541-1542). This is clearly one of the reasons why tumor vaccines often fail.

[0009] Similarly, many infectious diseases, particularly viral infections, such as human immunodeficiency virus (HIV) or herpes simplex virus (HSV), are known to downregulate the immune system of patients, and in this context, cytokine production by T cells and other antiviral immune cells is abnormal.

[0010] There remains an unmet need for such compounds that have enhanced immunogenic activity and thereby allow for the treatment and / or prevention of neoplastic and / or infectious diseases.

[0011] The object of the present invention is to provide compounds and pharmaceutical compositions that activate immune cells, particularly T cells. These compounds can be used as pharmaceutically active agents, particularly for the prevention and / or treatment of tumor diseases and infectious diseases.

[0012] The present invention provides novel 3,7,8-trisubstituted xanthine compounds of general formula (I) that activate immune cells. The object of the present invention is therefore solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the drawings and the examples of the present application.

[0013] [Description of the Invention] Accordingly, the present invention relates to a compound of formula (I), or to an enantiomer, diastereomer, tautomer, mixture of enantiomers, mixture of diastereomers, mixture of tautomers, hydrate, solvate or pharmaceutically acceptable salt thereof of a compound of formula (I),

[0014] [ka]

[0015] During the ceremony, A is,

[0016] [ka] represents;

[0017] B is -OR 3 , -O-CHR 3 R 3* , -O-CH2-CH2-R 3 , or -O-CH2-CH2-CH2-R 3 and; R 1 teeth,

[0018] [ka] represents;

[0019] R 2a and R 2b represent, independently of one another, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3; where R 2a is - not H; R 3 teeth,

[0020] [ka] represents;

[0021] R 3* represents -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2-CF3; R 4 and R 4*are, independently of one another, -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, -CF2-CHF2, -CF2-CF3,

[0022] [ka] represents;

[0023] R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are, independently of each other, -H, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -cyclo-CH 13 , -cycloC3H5O, -OH, -OCH3, -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-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、-C2H 4-OPh、-C3H6-OPh、-CH2-OCH2-Ph、-C2H4-OCH2-Ph、-C3H6-OCH2-Ph、-SH、- SCH3、-SC2H5、-SC3H7、-S-シクロ-C3H5、-SCH(CH3)2、-SC(CH3)3、-F、-Cl、-Br 、-I、-CN、-COCH3、-COC2H5、-COC3H7、-CO-シクロ-C3H5、-COCH(CH3)2、-COC(C H3)3、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COO-シクロ-C3H5、-COOCH(CH3) 2-COOC(CH3)3-OOC-CH3-OOC-C2H5-OOC-C3H7-OOC-C3H5-OOC-CH(CH3)2-OOC-C(CH3)3-CONH2-CONHCH3-CONHC2H5-CONHC3H7-CONH -シクロ-C3H5、-CONH[CH(CH3)2]、-CONH[C(CH3)3]、-CON(CH3)2、-CON(C2H5) 2、-CON(C3H7)2、-CON(シクロ-C3H5)2、-CON[CH(CH3)2]2、-CON[C(CH3)3]2、- NHCOCH3、-NHCOC2H5、-NHCOC3H7、-NHCO-シクロ-C3H5、-NHCO-CH(CH3)2、-NHC O-C(CH3)3、-NHCO-OCH3、-NHCO-OC2H5、-NHCO-OC3H7、-NHCO-O-シクロ-C3H5、- NHCO-OCH(CH3)2、-NHCO-OC(CH3)3、-NH2、-NHCH3、-NHC2H5、-NHC3H7、-NH-シクロ-C3H5、-NHCH(CH3)2、-NHC(CH3)3、-N(CH3)2、-N(C2H5)2、-N(C3H7)2、- N(シクロ-C3H5)2、-N[CH(CH3)2]2、-N[C(CH3)3]2、-SOCH3、-SOC2H5、-SOC3H7 、-SO-シクロ-C3H5、-SOCH(CH3)2、-SOC(CH3)3、-SO2CH3、-SO2C2H5、-SO2C3H7、-SO2-CH3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-CH3H5, -SO3CH(CH3)2, -SO3C(CH3)3, -SO2NH2, -SO2N HCH3、-SO2NHC2H5、-SO2NHC3H7、-SO2NH-シクロ-C3H5、-SO2NHCH(CH3)2、-SO 2NHC(CH3)3、-SO2N(CH3)2、-SO2N(C2H5)2、-SO2N(C3H7)2、-SO2N(シクロ-C3H 5)2、-SO2N[CH(CH3)2]2、-SO2N[C(CH3)3]2、-OS(=O)CH3、-OS(=O)C2H5、- OS(=O)C3H7、-OS(=O)-シクロ-C3H5、-OS(=O)CH(CH3)2、-OS(=O)C(CH3)3、-S( =O)(=NH)CH3、-S(=O)(=NH)C2H5、-S(=O)(=NH)C3H7、-S(=O)(=NH)-シクロ-C3 H5、-S(=O)(=NH)CH(CH3)2、-S(=O)(=NH)C(CH3)3、-NH-SO2-CH3、-NH-SO2- C2H5, -NH-SO2-C3H7, -NH-SO2-CH(CH3)2, -NH-SO2-C(CH3)3, -O-SO2-CH3, -O-SO2-C2H5, -O-SO2-C3H7, -O-SO2-CH(CH3)3, -O-S O2-CH(CH3)2, -O-SO2-C(CH3)3, -OCH2F, -OCHF2, -OCF3, -CH2-OCF3, -C2H4-OCF3, -C3H6-OCF3, -CH2-OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -OC2F5, -C H2-OC2F5、-C2H4-OC2F5、-C3H6-OC2F5、-O-COOCH3、-O-COOC2H5、-O-COOC 3H7、-O-COO-シクロ-C3H5、-O-COOCH(CH3)2、-O-COOC(CH3)3、-NH-CO-NH2、-N H-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-シクロ-C3H5、-NH-CO-N(シクロ-C3H5)2、-NH-CO-N[CH(CH3)2]2、-NH-C(=NH)-NHCH3、-NH-C(=N H)-NHC2H5、-NH-C(=NH)-NHC3H7、-O-CO-NH-シクロ-C3H5、-NH-C(=NH)-NH-シクロ-C3H5、-NH-C(=NH)-NH[CH(CH) 3)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(シクロ-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(シクロ- 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-シクロ-C3H5、-O-CO-OCH(CH3)2、-O-CO-OC (CH3)3、-CH2F、-CHF2、-CF3、-CH2-CH2F、-CH2-CHF2、-CH2-CF3、シクロ-C8H 15 、-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、-C5H 11 、-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、-C6H 13 -C7H 15 -C8H 17、-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、-CH(CH3)-C(CH3)3、-CH=CH2、-CH2-CH=CH2、-C(CH3)=CH2、-CH=CH-CH3、-C2H4-CH=CH2、-CH2-CH=CH-CH3、-CH=CH-C2H5、-CH2-C(CH3)=CH2、-CH(CH3)-CH=CH、-CH=C(CH3)2、-C(CH3)=CH-CH3、-CH=CH-CH=CH2、-C3H6-CH=CH2、-C2H4-CH=CH-CH3、-CH2-CH=CH-C2H5、-CH=CH-C3H7、-CH=CH-CH=CH-CH3、-C2H4-C(CH3)=CH2、-CH2-CH(CH3)-CH=CH2、-CH(CH3)-CH2-CH=CH2、-CH2-CH=C(CH3)2、-CH2-C(CH3)=CH-CH3、-CH(CH3)-CH=CH-CH3、-CH=CH-CH(CH3)2、-CH=C(CH3)-C2H5、-C(CH3)=CH-C2H5、-C(CH3)=C(CH3)2、-C(CH3)2-CH=CH2、-CH(CH3)-C(CH3)=CH2、-C4H8-CH=CH2、-C3H6-CH=CH-CH3、-C2H4-CH=CH-C2H5、-CH2-CH=CH-C3H7、-CH=CH-C4H9、-C3H6-C(CH3)=CH2、-C2H4-CH(CH3)-CH=CH2、-CH2-CH(CH3)-CH2-CH=CH2、-C2H4-CH=C(CH3)2、-CH(CH3)-C2H4-CH=CH2、-C2H4-C(CH3)=CH-CH3、-CH2-CH(CH3)-CH=CH-CH3、-CH(CH3)-CH2-CH=CH-CH3、-CH2-CH=CH-CH(CH3)2、-CH2-CH=C(CH3)-C2H5、-CH2-C(CH3)=CH-C2H5、-CH(CH3)-CH=CH-C2H5、-CH=CH-CH2-CH(CH3)2、-CH=CH-CH(CH3)-C2H5、-CH=C(CH3)-C3H7、-C(CH3)=CH-C3H7、-CH2-CH(CH3)-C(CH3)=CH2、-C[C(CH3、 )3]=CH2、-CH(CH3)-CH2-C(CH3)=CH2、-CH(CH3)-CH(CH3)-CH=CH2、-CH=CH-C2H4-CH=CH2、-C(CH3)2-CH2-CH=CH2、-CH2-C(CH3)=C(CH3)2、-CH(CH3)-CH=C(CH3)2、-C(CH3)2-CH=CH-CH3、-CH=CH-CH2-CH=CH-CH3、-CH(CH3)-C(CH3)=CH-CH3、-CH=C(CH3)-CH(CH3)2、-C(CH3)=CH-CH(CH3)2、-C(CH3)=C(CH3)-C2H5、-CH=CH-C(CH3)3、-C(CH3)2-C(CH3)=CH2、-CH(C2H5)-C(CH3)=CH2、-C(CH3)(C2H5)-CH=CH2、-CH(CH3)-C(C2H5)=CH2、-CH2-C(C3H7)=CH2、-CH2-C(C2H5)=CH-CH3、-CH(C2H5)-CH=CH-CH3、-C(C4H9)=CH2、-C(C3H7)=CH-CH3、-C(C2H5)=CH-C2H5、-C(C2H5)=C(CH3)2、-C[CH(CH3)(C2H5)]=CH2、-C[CH2-CH(CH3)2]=CH2、-C2H4-CH=CH-CH=CH2、-CH2-CH=CH-CH2-CH=CH2、-C3H6-C≡C-CH3、-CH2-CH=CH-CH=CH-CH3、-CH=CH-CH=CH-C2H5、-CH(CH3)-CH2-C≡CH、-CH(CH3)-C≡C-CH3、-C2H4-CH(CH3)-C≡CH、-CH=CH-CH=C(CH3)2、-CH2-CH(CH3)-CH2-C≡CH、-CH=CH-C(CH3)=CH-CH3、-CH=C(CH3)-CH=CH-CH3、-CH2-CH(CH3)-C≡CH、-C(CH3)=CH-CH=CH-CH3、-C≡CH、-C≡C-CH3、-CH2-C≡CH、-C2H4-C≡CH、-CH2-C≡C-CH3、-C≡C-C2H5、-C3H6-C≡CH、-C2H4-C≡C-CH3、-CH2-C≡C-C2H5、-C≡C-C3H7、-CH(CH3)-C≡CH、-C4H8-C≡CH、-C2H4-C≡C-C2H5、-CH2-C≡C-C3H7、-C≡C-C4H9、-C≡C-CH2-CH(CH3)2、-CH(CH3)-C2H4-C≡CH、-CH2-CH(CH3)-C≡C-CH3, -C(CH3)(C2H5)-C≡CH, -CH(CH3)-CH2-C≡C-CH3, -CH(CH3)-C≡C-C2H5, -CH2-C≡C-CH(CH3)2, -C≡C-CH(C H3)-C2H5, -CH2-C≡CC≡C-CH3, -CH(C2H5)-C≡C-CH3, -C(CH3)2-C≡C-CH3, -CH(C2H5)-CH2-C≡CH, -CH2-CH(C2H5)-C≡CH, -C(CH3)2- CH2-C≡CH, -CH2-C(CH3)2-C≡CH, -CH(CH3)-CH(CH3)-C≡CH, -CH(C3H7)-C≡CH, -CH2-CH(C≡CH)2, -C≡CC≡CH, -CH2-C≡CC≡CH, -C≡CC ≡C-CH3, -CH(C≡CH)2, -C2H4-C≡CC≡CH, -CH2-C≡C-CH2-C≡CH, -C≡ C-C2H4-C≡CH, -C≡CC(CH3)3, -C≡C-CH2-C≡C-CH3, -C≡CC≡C-C2H5,

[0024] [ka] represents; or

[0025] R 5 and R 6 , or R 6 and R 7 may form, together with the two carbon atoms of the phenyl ring to which they are attached, a 4- to 8-membered ring system, which may be formed by R 10 , R 11 , R 12 , and R 13 may be optionally substituted with one or more substituents selected from:

[0026] Preferably, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, tautomer, mixture of enantiomers, mixture of diastereomers, mixture of tautomers, hydrate, solvate of a compound of formula (I), or a pharmaceutically acceptable salt thereof, During the ceremony, A is,

[0027] [ka] represents;

[0028] B is -OR 3 , -O-CH2-R 3 , -O-CH2-CH2-R 3 , -O-CH2-CH2-CH2-R 3 and; R 1 teeth,

[0029] [ka] represents;

[0030] R 2a and R 2b are, independently of each other, -H, or C 1~3 represents alkyl, and C 1~3 The alkyl is optionally substituted with 1 to 6 fluorine atoms or -OH; R 3 teeth,

[0031] [ka] represents;

[0032] R 4 -H, halogen, C 1~4 Alkyl, -OC 1~4 Alkyl, C 3~4 Cycloalkyl, -OC 3~4 cycloalkyl, C 1~4 Alkyl, -OC 1~4 Alkyl, -OC 3~4 Cycloalkyl, and C 3~4 The cycloalkyl may be optionally substituted with 1 to 6 fluorine atoms; R 5 , R 6 , R 7 , R 8 , R 9 , R10 , R 11 , R 12 and R 13 are, independently of each other, -H, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -cyclo-CH 13 , -cycloC3H5O, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OPh, -OCH2-Ph, -OCPh3, -CH2-OC H3, -C2H4-OCH3, -C3H6-OCH3, -CH2-OC2H5, -C2H4-OC2H5, -C3H6-OC2H5, -CH2-OC3H7, -C2H4-OC3H7, -C3H6-OC3H7, -CH2-O-cyclo-C3H5, -C2H4-O-cyclo-C3 H5, -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, -C2 H4-OC4H9, -C3H6-OC4H9, -CH2-OPh, -C2H4-OPh, -C3H6-OPh, -CH2-OCH2-Ph, -C2H4-OCH2-Ph, -C3H6-OCH2-Ph, -SH, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H 5, -SCH(CH3)2, -SC(CH3)3, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -C OOC3H7, -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, -C ONHCH3, -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 , -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(シクロ-C3H5)2、-N[CH(CH3)2]2、-N[C( CH3)3]2、-SOCH3、-SOC2H5、-SOC3H7、-SO-シクロ-C3H5、-SOCH(CH3)2、-SOC(C) H3)3, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO2-CH3-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-CH3-C3H5, -SO3CH(C H3)2, -SO3C(CH3)3, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NH-CH3H5, -SO2NHCH(CH3)2, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5 )2、-SO2N(C3H7)2、-SO2N(シクロ-C3H5)2、-SO2N[CH(CH3)2]2、-SO2N[C(CH3) 3]2、-OS(=O)CH3、-OS(=O)C2H5、-OS(=O)C3H7、-OS(=O)-シクロ-C3H5、-OS(=O) CH(CH3)2、-OS(=O)C(CH3)3、-S(=O)(=NH)CH3、-S(=O)(=NH)C2H5、-S(=O)( =NH)C3H7、-S(=O)(=NH)-シクロ-C3H5、-S(=O)(=NH)CH(CH3)2、-S(=O)(=NH)C (CH3)3, -NH-SO2-CH3, -NH-SO2-C2H5, -NH-SO2-C3H7, -NH-SO2-CH3H5, -NH-SO2-CH(CH3)2, -NH-SO2-C(CH3)3, -O-SO2-CH3, -O-SO2-C2H5, -O-SO2 -C3H7, -O-SO2-CH(CH3)2, -O-SO2-C(CH3)3, -OCH2F, -OCHF2, -OCF3, -CH2-OCF3, -C2H4-OCF3, -C3H6-OCF3, -CH2-OCHF2, -C2H4-OC HF2、-C3H6-OCHF2、-OC2F5、-CH2-OC2F5、-C2H4-OC2F5、-C3H6-OC2F5、-O-C OOCH3、-O-COOC2H5、-O-COOC3H7、-O-COO-シクロ-C3H5、-O-COOCH(CH3)2、-OC、 OOC(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-シクロ-C3H5, -NH-CO-N(シクロ-C3H5)2, - NH-CO-N[CH(CH3)2]2, -NH-C(=NH)-NHCH3, -NH-C(=NH)-NHC2H5, -NH-C(=NH)-NHC3H7, -O-CO-NH-シクロ-C3H5, -NH-C(=NH)-NH-シクロ-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(シクロ-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(シクロ-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-シクロ-C3H5、-O-CO-OCH(CH3)2、-O-CO-OC(CH3)3、-C H2F、-CHF2、-CF3、-CH2-CH2F、-CH2-CHF2、-CH2-CF3、シクロ-C8H 15 、-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、-C5H 11、-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、-C6H 13 、-C7H 15 、-C8H 17、-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、-CH(CH3)-C(CH3)3、-CH=CH2、-CH2-CH=CH2、-C(CH3)=CH2、-CH=CH-CH3、-C2H4-CH=CH2、-CH2-CH=CH-CH3、-CH=CH-C2H5、-CH2-C(CH3)=CH2、-CH(CH3)-CH=CH、-CH=C(CH3)2、-C(CH3)=CH-CH3、-CH=CH-CH=CH2、-C3H6-CH=CH2、-C2H4-CH=CH-CH3、-CH2-CH=CH-C2H5、-CH=CH-C3H7、-CH=CH-CH=CH-CH3、-C2H4-C(CH3)=CH2、-CH2-CH(CH3)-CH=CH2、-CH(CH3)-CH2-CH=CH2、-CH2-CH=C(CH3)2、-CH2-C(CH3)=CH-CH3、-CH(CH3)-CH=CH-CH3、-CH=CH-CH(CH3)2、-CH=C(CH3)-C2H5、-C(CH3)=CH-C2H5、-C(CH3)=C(CH3)2、-C(CH3)2-CH=CH2、-CH(CH3)-C(CH3)=CH2、-C4H8-CH=CH2、-C3H6-CH=CH-CH3、-C2H4-CH=CH-C2H5、-CH2-CH=CH-C3H7、-CH=CH-C4H9、-C3H6-C(CH3)=CH2、-C2H4-CH(CH3)-CH=CH2、-CH2-CH(CH3)-CH2-CH=CH2、-C2H4-CH=C(CH3)2、-CH(CH3)-C2H4-CH=CH2、-C2H4-C(CH3)=CH-CH3、-CH2-CH(CH3)-CH=CH-CH3、-CH(CH3)-CH2-CH=CH-CH3、-CH2-CH=CH-CH(CH3)2、-CH2 -CH=C(CH3)-C2H5、-CH2-C(CH3)=CH-C2H5、-CH(CH3)-CH=CH-C2H5、-CH=CH-CH2-CH(CH3)2、-CH=CH-CH(CH3)-C2H5、-CH=C(CH3)-C3H7、-C(CH3)=CH-C3H7、-CH2-CH(CH3)-C(CH3)=CH2、-C[C(CH3)3]=CH2、-CH(CH3)-CH2-C(CH3)=CH2、-CH(CH3)-CH(CH3)-CH=CH2、-CH=CH-C2H4-CH=CH2、-C(CH3)2-CH2-CH=CH2、-CH2-C(CH3)=C(CH3)2、-CH(CH3)-CH=C(CH3)2、-C(CH3)2-CH=CH-CH3、-CH=CH-CH2-CH=CH-CH3、-CH(CH3)-C(CH3)=CH-CH3、-CH=C(CH3)-CH(CH3)2、-C(CH3)=CH-CH(CH3)2、-C(CH3)=C(CH3)-C2H5、-CH=CH-C(CH3)3、-C(CH3)2-C(CH3)=CH2、-CH(C2H5)-C(CH3)=CH2、-C(CH3)(C2H5)-CH=CH2、-CH(CH3)-C(C2H5)=CH2、-CH2-C(C3H7)=CH2、-CH2-C(C2H5)=CH-CH3、-CH(C2H5)-CH=CH-CH3、-C(C4H9)=CH2、-C(C3H7)=CH-CH3、-C(C2H5)=CH-C2H5、-C(C2H5)=C(CH3)2、-C[CH(CH3)(C2H5)]=CH2、-C[CH2-CH(CH3)2]=CH2、-C2H4-CH=CH-CH=CH2、-CH2-CH=CH-CH2-CH=CH2、-C3H6-C≡C-CH3、-CH2-CH=CH-CH=CH-CH3、-CH=CH-CH=CH-C2H5、-CH(CH3)-CH2-C≡CH、-CH(CH3)-C≡C-CH3、-C2H4-CH(CH3)-C≡CH、-CH=CH-CH=C(CH3)2、-CH2-CH(CH3)-CH2-C≡CH、-CH=CH-C(CH3)=CH-CH3、-CH=C(CH3)-CH=CH-CH3、-CH2-CH(CH3)-C≡CH、-C(CH3)=CH-CH=CH-CH3、-C≡CH、-C≡C-CH3、-CH2-C≡CH、-C2H4-C≡CH、-CH2-C≡C-CH3、-C≡C-C2H5, -C3H6-C≡CH, -C2H4-C≡C-CH3, -CH2-C≡C-C2H5, -C≡C-C3H7, -CH(CH3)-C≡CH, -C4H8-C≡CH, -C2H4-C≡C-C2H5, -CH2-C≡C-C3H7, -C≡C-C4H9, -C≡C-CH2-CH(CH3)2, -CH(C H3)-C2H4-C≡CH, -CH2-CH(CH3)-C≡C-CH3, -C(CH3)(C2H5)-C≡CH, -CH(CH3)-CH2-C≡C-CH 3, -CH(CH3)-C≡C-C2H5, -CH2-C≡C-CH(CH3)2, -C≡C-CH(CH3)-C2H5, -CH2-C≡CC≡C-CH3, -C H(C2H5)-C≡C-CH3, -C(CH3)2-C≡C-CH3, -CH(C2H5)-CH2-C≡CH, -CH2-CH(C2H5)-C≡CH, -C (CH3)2-CH2-C≡CH, -CH2-C(CH3)2-C≡CH, -CH(CH3)-CH(CH3)-C≡CH, -CH(C3H7)-C≡CH, -C H2-CH(C≡CH)2, -C≡CC≡CH, -CH2-C≡CC≡CH, -C≡CC≡C-CH3, -CH(C≡CH)2, -C2H4-C≡CC≡CH, - CH2-C≡C-CH2-C≡CH, -C≡C-C2H4-C≡CH, -C≡CC(CH3)3, -C≡C-CH2-C≡C-CH3, -C≡CC≡C-C2H5,

[0033] [ka] represents; or

[0034] R 5 and R 6 , or R 6 and R 7 may form, together with the two carbon atoms of the phenyl ring to which they are attached, a 4- to 8-membered ring system, which may be formed by R 10 , R 11 , R 12 , and R 13 may be optionally substituted with one or more substituents selected from:

[0035] These compounds are suitable for increasing the levels of cytokines secreted by stimulated immune cells, thereby enhancing the local activity of immune cells in the vicinity of the stimulated immune cells. These findings indicate that the compounds of the present invention are useful for the treatment and / or prevention of neoplastic and / or infectious diseases.

[0036] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not abolish the biological activity and properties of the compound. The compounds of the present invention may form salts with organic acids or inorganic bases or organic acids or organic bases. Examples of acids suitable for forming such acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ... Examples of suitable salts include sulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, do-tolyltartaric acid, tartronic acid, (o,m,p)-toluic acid, naphthylaminesulfonic acid, trifluoroacetic acid, and other mineral or carboxylic acids known to those skilled in the art. The salts are prepared by contacting the free base form of the compound of formula (I) with a sufficient amount of the desired acid to produce the salt in a conventional manner known to those skilled in the art.

[0037] When the compound of the present invention has an acidic group, salts can also be formed using inorganic or organic bases.Examples of suitable inorganic or organic bases include, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine, etc.Salts can be prepared by conventional methods well known in the art, for example, by treating a solution of the compound of general formula (I) with a solution of an acid selected from the above group.

[0038] As used herein, the term "4- to 8-membered ring system" refers to a 4- to 8-membered aromatic ring, or a 4- to 8-membered heteroaromatic ring, a 4- to 8-membered carbohydryl group, or a 4- to 8-membered heterocyclic group. 5 and R 6 , or R 6 and R 7 form the 4- to 8-membered ring system, and in the 4- to 8-membered ring system, R 5 and R 6 , or R 6 and R 7 The two carbon atoms of the phenyl ring are substituted.

[0039] Preferably, the 4- to 8-membered aromatic ring refers to phenyl and naphthyl, where these phenyl and naphthyl are R 10 From R 13 However, the term "substitutable" does not mean that a hydrogen atom is substituted with one to four substituents selected from the substituents R 10 From R 13 It will be clear to one skilled in the art that the term "substituted" refers to the group "a" or "b" being substituted with any one of the following:

[0040] Preferably, the "4- to 8-membered heteroaromatic ring" contains at least one heteroatom, such as O, S, SO, SO, N, or NO, and one double bond, and these monovalent unsaturated 4-membered heterocyclic groups are represented by R 10 From R 13 The term "substitutable" means that a hydrogen atom can be substituted with 1 to 4 substituents selected from the substituents R 10 From R13 Noise It will be clear to one skilled in the art that the term "substituted" refers to a group having one of the following substituents:

[0041] Preferably, the "4- to 8-membered heterocyclic group" contains at least one heteroatom, such as O, S, SO, SO2, and N, and optionally one carbonyl (CO) bond, one or more double bonds, wherein the 4- to 8-membered heterocyclic group is R 10 From R 13 The term "substitutable" means that a hydrogen atom can be substituted with 1 to 4 substituents selected from the substituents R 10 From R 13 It will be clear to one skilled in the art that the term "substituted" refers to the group "a" or "b" being substituted with any one of the following:

[0042] Preferably, the "4- to 8-membered carbocyclyl group" may optionally contain one or more double bonds, and R 10 From R 13 The term "substitutable" means that a hydrogen atom can be substituted with 1 to 4 substituents selected from the substituents R 10 From R 13 It will be clear to one skilled in the art that the term "substituted" refers to the group "a" or "b" being substituted with any one of the following:

[0043] Preferably, in formula (I), R 5 and R 6 , or R 6 and R 7 may form the following 4- to 6-membered ring systems, wherein the 4- to 6-membered ring systems are 10 From R 13 It can be optionally substituted with 1 to 4 substituents selected from:

[0044] [ka] .

[0045] Thus, in formula (I), R 3 preferably represents the following bicyclic ring, and R3 In R 5 and R 6 , or R 6 and R 7 forms a 4- to 6-membered ring system fused to a phenyl ring, wherein the 4- to 6-membered ring system is 10 From R 13 It can be optionally substituted with 1 to 4 substituents selected from:

[0046] [ka] .

[0047] More preferably, in formula (I), R 5 and R 6 , or R 6 and R 7 may form the following 4- to 6-membered ring systems, wherein the 4- to 6-membered ring systems are 10 From R 13 It can be optionally substituted with 1 to 4 substituents selected from:

[0048] [ka] .

[0049] Thus, in formula (I), R 3 preferably represents the following bicyclic ring, and R 3 In R 5 and R 6 , or R 6 and R 7 forms a 4- to 6-membered ring system fused to a phenyl ring, wherein the 4- to 6-membered ring system is 10 From R 13 It can be optionally substituted with 1 to 4 substituents selected from:

[0050] [ka] .

[0051] Even more preferably, in formula (I), R 5 and R 6 , or R 6 and R 7 may form the following six-membered ring system, wherein the six-membered ring system is 10 From R 13 It can be optionally substituted with 1 to 4 substituents selected from:

[0052] [ka] .

[0053] More preferably, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, tautomer, mixture of enantiomers, mixture of diastereomers, mixture of tautomers, hydrate, solvate, or pharmaceutically acceptable salt thereof of a compound of formula (I):

[0054] [ka]

[0055] During the ceremony, A is,

[0056] [ka] represents;

[0057] B is -OR 3 , -O-CHR 3 R 3* , -O-CH2-CH2-R 3 , or -O-CH2-CH2-CH2-R 3 and; R 1 teeth,

[0058] [ka] represents;

[0059] R 2a and R 2b represent, independently of one another, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3; where R 2a is - not H; R 3 teeth,

[0060] [ka] or preferably

[0061] [ka] represents;

[0062] R 3* represents -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2-CF3; R 4 and R 4* are, independently of one another, -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, -CF2-CHF2, -CF2-CF3,

[0063] [ka] represents;

[0064] R 5 , R 6 , R 7 , R 8 , R 9 , R10 , R 11 , R 12 and R 13 are, independently of each other, -H, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -cyclo-CH 13, -cycloC3H5O, -OH, -OCH3, -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-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-OC4 H9, -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, -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, -CONHC2H 5, -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, -NHCO-OC3H7,-NHCO-O-C3H5, -NHCO-OCH(CH3)2, -NHCO-OC(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5, -SOC3H7, - SO-CH3H5, SOCH(CH3)2, SOCH(CH3)3, SO2CH3, SO2C2H5, SO2C3H7, SO2-CH3H5, SO2CH(CH3)2, SO2C(CH3)3, SO3H, SO3CH3, SO3C2H5, SO3C3H7, SO3-CH3H5, SO3CH(CH3)2, SO3C(CH3)3, SO2NH2, SO2NHCH3, SO2NHC2H5, SO2NHC 3H7、-SO2NH-シクロ-C3H5、-SO2NHCH(CH3)2、-SO2NHC(CH3)3、-S O2N(CH3)2、-SO2N(C2H5)2、-SO2N(C3H7)2、-SO2N(シクロ-C3H5)2 、-SO2N[CH(CH3)2]2、-SO2N[C(CH3)3]2、-OS(=O)CH3、-OS(=O)C2H5、-OS(=O)C3H7、-OS(=O)-シクロ-C3H5、-OS(=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)-CH3H5, -S(=O)(=NH)CH(CH3)2, -S(=O)(=NH)C(CH3)3, -NH-SO2-CH3, -NH-SO2-C2H5, -NH-SO2-C3H7, -NH-SO2-CH3H5, -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-OC F3, -CH2-OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -OC2F5, -CH2-OC2F5, -C2H4-OC2F5, -C3H6-OC2F5, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, cyclo-C8H 15 , -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, -C5H 11 , -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH,

[0065] [ka] represents;

[0066] Preferably, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are, independently of each other, -H, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -cyclo-CH 13, -cycloC3H5O, -OH, -OCH3, -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-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-OC4H 9, -CH2-OPh, -C2H4-OPh, -C3H6-OPh, -CH2-OCH2-Ph, -C2H4-OCH2-Ph, -C3H6-OCH2-Ph, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5 , -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], - CON(CH3)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, -NH2, -NHCH3,-NHC2H5、-NHC3H7、-NH-シクロ-C3H5、-NHCH(CH3)2、-NHC(CH3)3、 -N(CH3)2、-N(C2H5)2、-N(C3H7)2、-N(シクロ-C3H5)2、-N[CH(CH、 3)2]2、-N[C(CH3)3]2、-SOCH3、-SOC2H5、-SOC3H7、-SO-CHRO-C3H5、-SOCH(CH3)2、-SOC(CH3)3、-SO2CH3、-SO2C2H5、-SO2C3H7、-SO2-CHRO-C3H5、-SO2CH(CH3)2、-SO2C(CH3)3、-SO3H、-SO3CH3、-SO3C2H5、-SO3C3H7、-SO3-CHRO-C3H5、-SO3CH(CH3) 2、-SO3C(CH3)3、-SO2NH2、-SO2NHCH3、-SO2NHC2H5、-SO2NHC3H7、-SO2NH-シクロ-C3H5、-SO2NHCH(CH3)2、-SO2NHC(CH3)3、- SO2N(CH3)2、-SO2N(C2H5)2、-SO2N(C3H7)2、-SO2N(シクロ-C3H5)2、-SO2N[CH(CH3)2]2、-SO2N[C(CH3)3]2、-OS(=O)CH3、-O S(=O)C2H5, -OS(=O)C3H7, -OS(=O)-C3H5, -OS(=O)CH(CH3)2, -OS(=O)C(CH3)3, -O-SO2-CH3, -O-SO2-C2H5, -O-SO2-C3H7, -O-SO2-C3H5, -O-SO2-CH(CH3)2, -O-SO2-C(CH3)3, -OCH2F, -OCHF2, -OCF3, -CH2-OCF3, -C2H4-OCF3, -C3H6-O CF3、-CH2-OCHF2、-C2H4-OCHF2、-C3H6-OCHF2、-OC2F5、-CH2-OC2F5、-C2H4-OC2F5、-C3H6-OC2F5、-CH2F、-CHF2、-CF3、-C H2-CH2F、-CH2-CHF2、-CH2-CF3、-CH3、-C2H5、-C3H7、-CH(CH3)2、-C4H9、-CH2-CH(CH3)2、-CH(CH3)-C2H5、-C(CH3)3、-C5H 11, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH,

[0067] [ka] represents; or

[0068] R 5 and R 6 , or R 6 and R 7 may form, together with the two carbon atoms of the phenyl ring to which they are attached, a 4- to 8-membered ring system, which may be formed by R 10 , R 11 , R 12 , and R 13 is optionally substituted with one or more substituents selected from:

[0069] In all general formulae disclosed herein, B is preferably -OR 3 , -O-CHR 3 R 3* , or -O-CH2-CH2-R 3 Represents. Furthermore, B is -OR 3 It has been found that compounds of formula (I) having the formula (I) are able to penetrate the blood-brain barrier well. Consequently, for indications in which the ability to penetrate the blood-brain barrier is important, it is preferable that B is -OR 3 Particularly preferred are compounds of formula (I) which represent:

[0070] Thus, as disclosed herein, a class of compounds of formula (I) is claimed, wherein B is -OR to claim a class of compounds that can readily cross the blood-brain barrier. 3 Represents only.

[0071] As a result, B becomes -O-CHR 3 R 3* , or -O-CH2-CH2-R 3 , or -O-CH2-CH2-CH2-R3 The remaining compounds of formula (I) are claimed which represent:

[0072] Furthermore, the inventors have 1 We found that the residues R are particularly important for inhibitory activity. 1 The residue must have a hydroxy group (-OH) and, in addition, at least one substituent R different from hydrogen (-H). 2a and optionally a second substituent R 2b Must have stomach.

[0073] For all general formulae disclosed herein, the substituent R 2a and R 2b is defined below: R 2a and R 2b represent, independently of one another, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3; where R 2a is - not H; Or in other words, R 2a represents -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3; and R 2b represents -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3.

[0074] Therefore, R 2a is different from hydrogen (-H),2a and R 2b preferably denote, independently of one another, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3; More preferably, R 2a and R 2b represent, independently of one another, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CF2-CH3, -CHF-CHF2; More preferably, R 2a and R 2b represent, independently of each other, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3; More preferably, R 2a and R 2b represent, independently of each other, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3; More preferably, R 2a and R 2b represent, independently of one another, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CF2-CH3, -CHF-CHF2; More preferably, R 2a and R 2b represent, independently of one another, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CF2-CH3, -CHF-CHF2; More preferably, R2a and R 2b represent, independently of one another, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CF2-CH3, -CHF-CHF2; More preferably, R 2a and R 2b represent, independently of one another, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CF2-CH3, -CHF-CHF2; More preferably, R 2a and R 2b are, independently of each other, -H, -F, -CH3, - C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH (always R 2a is different from hydrogen).

[0075] Furthermore, R 2a and R 2b Also preferred are compounds in which both represent -CH3 or -C2H5, more preferably -CH3. More preferably, R 2b represents -H, and R 2a represents -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3; more preferably, R 2a is a compound representing -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3; more preferably, R 2a is a compound representing -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3; more preferably, R2a is a compound representing -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CF2-CH3, -CHF-CHF2; more preferably, R 2a is a compound representing -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CF2-CH3, -CHF-CHF2; more preferably, R 2a is a compound representing -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CF2-CH3, -CHF-CHF2; more preferably, R 2a is a compound representing -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CF2-CH3, -CHF-CHF2; more preferably, R 2a is a compound representing -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH; more preferably, R 2a is a compound representing -CH3, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH; more preferably, R 2a is a compound representing -CH3, -CH2F, -CHF2, -CF3, -CHF-CH2F, -CH2OH; more preferably, R 2a is a compound that represents -CH3, -CH2F, -CHF2, -CF3, -CH2OH.

[0076] R 2b preferably represents -H or -CH; more preferably, R 2a If represents -CH3, then R 2b represents -CH3, and R 2a If different from -CH3, R 2b represents -H.

[0077] More preferably, in formula (I), R3 teeth,

[0078] [ka] represents; and

[0079] Even more preferably, R 3 teeth,

[0080] [ka] represents;

[0081] and even more preferably, R 3 teeth,

[0082] [ka] represents; and

[0083] Even more preferably, R 3 teeth,

[0084] [ka] Represents.

[0085] Furthermore, in all general formulas disclosed herein, R 10 , R 11 , R 12 , and R 13 preferably represents hydrogen (-H). More preferred are compounds of general formula (I), R 2a represents -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, and R 2b represents -H or -CH; preferably, R 2a If represents -CH3, then R 2b represents -CH3, and R2a If different from -CH3, R 2b represents -H.

[0086] B is -OR 3 or -O-CHR 3 R 3* represents; R 3 teeth,

[0087] [ka] represents;

[0088] R 3* represents -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2-CF3; R 4 and R 4* are, independently of one another, -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, -CF2-CHF2, -CF2-CF3,

[0089] [ka] represents;

[0090] and A, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 has the same meaning as defined in claim 1 or as defined herein.

[0091] In all the general formulae disclosed herein, and in particular in the residue A, the substituent R 4 preferably represents -H, -F, -Cl, -Br, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, or -CF2-CF3; more preferably , -H, -F, -Cl, -Br, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, or -CF2-CF3; more preferably -H, -F, -Cl, -CH2F, -C represents -HF2, -CF3, -OCH3, -OC2H5, -OCH2F, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, or -CF2-CF3; more preferably -H, -F, -Cl, -CHF2, -CF3, -OCH3, -OC2H5, -OCHF 2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, or -CF2-CF3; even more preferably -H, -F, -Cl, -CHF2, -CF3, -OCH3, -OC2H5, -OCHF2, -OCF3, -CHF-CHF2, -CHF-CF3, -CF2- represents CH3, -CF2-CH2F, -CF2-CHF2, or -CF2-CF3; even more preferably, -H, -F, -Cl, -CHF2, -CF3, -OCH3, -OC2H5, -OCHF2, -OCF3, -CHF-CHF2, -CHF-CF3, -CF2-CHF2, or -CF2-CF3; even more preferably, -H, -F, -Cl, -CHF2, -CF3, represents -OCH3, -OC2H5, -OCHF2, -OCF3, -CF2-CHF2, or -CF2-CF3; even more preferably, represents -H, -F, -Cl, -CHF2, -CF3, -OCH3, -OC2H5, -OCHF2, or -OCF3; and even more preferably, represents -H, -F, -Cl, -CHF2, -CF3, -OCH3, -OCHF2, or -OCF3.

[0092] R 4 In combination with the preferred definitions of the substituent R 4* preferably represents -H, -F, -Cl, -CHF, -CHF, -CF, -OCHF, or -OCF, more preferably R 4*preferably represents -H, -F, -Cl, -CHF2, -CF3, -OCHF2, or -OCF3, even more preferably represents -H, -F, -Cl, -CHF2, -OCHF2, or -OCF3, even more preferably represents -H, -F, -Cl, -OCHF2, or -OCF3, even more preferably represents -H, -F, -Cl, or -OCF3, even more preferably represents -H, -F, or -OCF3, even more preferably represents -H or -F, and even more preferably represents -H.

[0093] In all general formulae disclosed herein, the substituent R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 , or a substituent R 5 , R 6 , R 7 , R 8 , and R 9 are preferably, independently of one another, -H, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11、-OH、-OCH3、-OC2H5、-OC3H7、-O-シクロ-C3H5、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-CH2-OCH3、-C2H4-OCH3、-CH2-O C2H5、-CH2-O-シクロ-C3H5、-CH2-OCH(CH3)2、-F、-Cl、-Br 、-I、-CN、-COCH3、-COC2H5、-COC3H7、-CO-シクロ-C3H5、-CO CH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COO-Siロ-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-Siロ-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -CONH2, -CONHCH3, -CONHC2H 5, -CONHC3H7, -CONH-シクロ-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(シクロ-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -NHCOCH3, -NHCOC2H5, -NHCOC3H7, -NHCO-シクロ-C3H5, - NHCO-CH(CH3)2、-NHCO-C(CH3)3、-NH2、-NHCH3、-NHC2H5、-NHC3H7、-NH-シクロ-C3H5、-NHCH(CH3)2、-NHC(CH3)3、 -N(CH3)2、-N(C2H5)2、-SOCH3、-SOC2H5、-SOC3H7、-SO-シクロ-C3H5、-SOCH(CH3)2、-SOC(CH3)3、-SO2CH3、-SO2C2H 5, -SO2C3H7, -SO2-cyclo-C3H5, -SO2CH(CH3)2, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -S O2NH-cyclo-C3H5, -SO2NHCH(CH3)2, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, - OS(=O)CH3, -OS(=O)C2H5, -OS(=O)C3H7, -OS(=O)-cyclo-C3H5, -OS(=O)CH(CH3)2, -O- SO2-CH3, -O-SO2-C2H5, -O-SO2-C3H7, -O-SO2-cyclo-C3H5, -O-SO2-CH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-OCF3, -C2H4-OCF3, -CH2-OCHF2, -C2H4-OCHF2, -C3H6-OCHF2 , -OC2F5, -CH2-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, -C5H 11 , -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, or R 5 and R 6 , or R 6 and R 7 may form, together with the two carbon atoms of the phenyl ring to which they are attached, a 6-membered aromatic ring system or a 6-membered N-heteroaromatic ring system, which may be formed by R 10 , R 11 , R 12 , and R 13 and preferably, the 6-membered aromatic ring system or the 6-membered N-heteroaromatic ring system is unsubstituted (R 10 =R 11 =R 12 =R 13 =-H).

[0094] Even more preferably, in all the general formulae disclosed herein, the substituent R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 , or a substituent R 5 , R 6 , R 7 , R 8 , and R 9 are preferably, independently of one another, -H, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11、 -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -CH2-OCH3, -C2H4-OCH3, -CH2-OC2H5, -CH2-O-cyclo-C3H5, -CH2-OCH(CH3)2, -F, -Cl, -Br, -I, -CN, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CON(CH3)2, -CON(C2H5)2, -NHCOCH3, -NHCOC2H5, -NHCOC3H7, -NHCO-cyclo-C3H5, -NHCO-CH(CH3)2, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO2-cyclo-C3H5, -SO2CH(CH3)2, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NH-cyclo-C3H5, -SO2N(CH3)2, -SO2N(C2H5)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-SO2-CH3, -O-SO2-C2H5, -O-SO2-C3H7, -O-SO2-cyclo-C3H5, -O-SO2-CH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-OCF3, -C2H4-OCF3, -CH2-OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -OC2F5, -CH2-OC2F5, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3 , -CH3, -C2H5, -C3H7, -CH(CH3)2, represents; or R5 and R 6 , or R 6 and R 7 may together with the two carbon atoms of the phenyl ring to which they are attached form a 6-membered aromatic ring system or a 6-membered N-heteroaromatic ring system containing one or two nitrogen atoms, and a 6-membered aromatic ring system or a 6-membered N-heteroaromatic ring system containing one or two nitrogen atoms can be formed by R 10 , R 11 , R 12 , and R 13 and preferably, the 6-membered aromatic ring system or 6-membered N-heteroaromatic ring system containing one or two nitrogen atoms is unsubstituted (R 10 =R 11 =R 12 =R 13 =-H).

[0095] Even more preferably, in all the general formulae disclosed herein, the substituent R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 , or a substituent R 5 , R 6 , R 7 , R 8 , and R 9are preferably, independently of one another, -H, -cyclo-C3H5, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -CH2-OCH3, -CH2-OC2H5, -F, -Cl, -Br, -CN, -COCH3, -COC2H5, -CONH2, -CONHCH3, -CONHC2H5, -CON( CH3)2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SO2CH3, -SO2C2H5, -SO2C3H7 , -SO2-cyclo-C3H5, -SO2CH(CH3)2, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3C H(CH3)2, -OS(=O)CH3, -OS(=O)C2H5, -OS(=O)C3H7, -OS(=O)-cyclo-C3H5, -OS(=O)CH(CH3)2, -O- SO2-CH3, -O-SO2-C2H5, -O-SO2-C3H7, -O-SO2-cyclo-C3H5, -O-SO2-CH(CH3)2, -OCH2F, -OCHF2, - OCF3, -CH2-OCF3, -C2H4-OCF3, -CH2-OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -OC2F5, -CH2-OC2F5, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH3, -C2H5, -C3H7, -CH(CH3)2; or R 5 and R 6 , or R 6 and R 7 may form, together with the two carbon atoms of the phenyl ring to which they are attached, a six-membered aromatic ring system or a six-membered N-heteroaromatic ring system containing one nitrogen atom, and the six-membered aromatic ring system or the six-membered N-heteroaromatic ring system containing one nitrogen atom may be formed by R 10 , R 11 , R 12 , and R 13 and preferably, the 6-membered aromatic ring system or 6-membered N-heteroaromatic ring system containing one nitrogen atom is unsubstituted (R 10 =R 11 =R 12=R 13 =-H).

[0096] Preferably, R 3 teeth,

[0097] [ka] where:

[0098] Substituent R 5 ~R 7 has the meaning disclosed on the two pages above, and even more preferably, R 5 ~R 7 are, independently of one another, -H, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -F, -Cl, -Br, -CN, -SO2CH3, -SO2C2H5, -OCH2F, -OCHF2, -OCF3, -CH2-OCF3, -CH2-OCHF2, -OC2F5, -CH2F, -CHF2, -CF3 , —CH2—CHF2, —CH2—CF3, —CH3, —C2H5, —C3H7, —CH(CH3)2; more preferably selected from —H, —OCH3, —OC2H5, —F, —Cl, —CN, —SO2CH3, —SO2C2H5, —OCH2F, —OCHF2, —OCF3, —CH2F, —CHF2, —CF3, —CH3, —C2H5; even more preferably selected from —H, —OCH3, —OC2H5, —F, —Cl, —CN, —SO2CH3, —SO2C2H5, —OCH2F, —OCHF2, —OCF3, —CH2F, —CHF2, —CF3, —CH3; and even more preferably selected from —H, —OCH3, —F, —Cl, —OCHF2, —OCF3, —CHF2, —CF3, —CH3.

[0099] Furthermore, the substituent R 5 ~R 7 Preferably, only one of R represents hydrogen and the other two are different from hydrogen. 5 is different from hydrogen, and R 6 represents hydrogen, or R 7 represents hydrogen, or R6 and R 7 represents hydrogen. Consequently, the residue R 3 Para substitution of is preferred.

[0100] In all general formulas disclosed herein, R 3 is preferably

[0101] [ka] Represents.

[0102] In some embodiments, the present invention relates to compounds of formula (I):

[0103] [ka]

[0104] During the ceremony, A is,

[0105] [ka] represents;

[0106] B is -OR 3 , -O-CHR 3 R 3* , -O-CH2-CH2-R 3 , or -O-CH2-CH2-CH2-R 3 and; R 1 teeth,

[0107] [ka] represents;

[0108] R 2a and R 2brepresent, independently of one another, -H, -F, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CF2-CH3, -CHF-CHF2, -CHF-CF3, -CF2-CF3; where R 2a is - not H; R 3 teeth,

[0109] [ka] represents;

[0110] R 3* are -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, - represents CH2F, -CHF2, -CF3, -CH2-CF3; R 4 and R 4* are, independently of one another, -H, -F, -Cl, -Br, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, -CF2-CF3,

[0111] [ka] represents;

[0112] Preferably, R 4 -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -CF2-CHF2,

[0113] [ka] more preferably, -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3,

[0114] Preferably, R 4* represents -H, -F, -Cl, -CHF, -CHF, -CF, -OCHF, or -OCF, and more preferably, R 4* represents -H or -F; and R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 has the same meaning as defined herein, and R 10 , R 11 , R 12 and R 13 preferably represents hydrogen.

[0115] Preferably, the present invention relates to compounds of formula (I): During the ceremony, A is,

[0116] [ka] represents;

[0117] B is -OR 3 , -O-CHR 3 R 3* , -O-CH2-CH2-R 3 , or -O-CH2-CH2-CH2-R 3 and preferably B is -OR 3 , -O-CHR 3 R 3* represents; R 1 teeth,

[0118] [ka] represents;

[0119] R 2a represents -CH3, -C2H5, -CH2F, -CHF2, -CF3, -CH2-CF3, -CHF-CH2F, -CH2OH, -CH2CH2OH, -CH2OCH3; and R 2b represents -H, or -CH; preferably, R 2a If represents -CH3, then R 2b represents -CH3, and R 2a If different from -CH3, R 2b represents -H.

[0120] R 3 teeth,

[0121] [ka] represents;

[0122] Preferably, R 3 teeth,

[0123] [ka] represents;

[0124] R 3* represents -H, -F, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2-CF3; R 4 and R 4* are, independently of one another, -H, -F, -Cl, -Br, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, -CF2-CF3,

[0125] [ka] represents;

[0126] Preferably, R 4 -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -CF2-CHF2,

[0127] [ka] represents;

[0128] Preferably, R 4* represents -H, -F, -Cl, -CHF, -CHF, -CF, -OCHF, or -OCF, and more preferably, R 4* represents -H or -F; and R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 has the same meaning as defined herein, and R 10 , R 11 , R 12 and R 13 preferably represents hydrogen.

[0129] Preferably, in the compounds of formula (I) as defined herein, R 1 teeth,

[0130] [ka] Represents.

[0131] More preferably, R 1 teeth,

[0132] [ka] Represents.

[0133] In some embodiments, the present invention relates to a compound of Formula (Ia) or Formula (Ib):

[0134] [ka]

[0135] During the ceremony, n is 0, 1, 2 or 3; preferably, n is 0, 1 or 2, more preferably, n is 0 or 1; R 1 , R 2a , R 2b , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 has the same meaning as defined above.

[0136] Preferably, the compound is of formula (Ia):

[0137] [ka]

[0138] During the ceremony, n is 0, 1 or 2, more preferably n is 0 or 1; R 1 teeth,

[0139] [ka] Represents.

[0140] R 4-H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -C H2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, -CF2-CF3,

[0141] [ka] represents;

[0142] Preferably, R 4 is -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -CF2-CH F2,

[0143] [ka] more preferably, R 4 represents -H, -F, -Cl, -CHF, -CHF, -CF, -OCHF, -OCF, -CF-CHF, and even more preferably R 4 represents -H, -F, -CH2F, -CHF2, -CF3, -OCHF2, -OCF3, -CF2-CHF2;

[0144] and R 5 From R 8 has the same meaning as defined above. More preferably, in formula (I), formula (Ia) or formula (Ib), R 1 teeth,

[0145] [ka] more preferably, R 1 teeth,

[0146] [ka] Represents.

[0147] In some embodiments, the present invention relates to a compound of any one of the following formulas (II-1) to (II-5), (III-1) to (III-6), (IV-1) to (IV-8), (V-1) to (V-5), (VI-1) to (VI-2), and (VII-1) to (VII-3):

[0148] [ka]

[0149] [ka]

[0150] [ka]

[0151] In the formula, R 1 , R 3* , R 4 , R 4* , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 13 has the same meaning as defined above. In some embodiments, the present invention relates to a compound of any one of the following formulas (II-1) to (II-5), (III-1) to (III-6), (IV-1) to (IV-6), and (V-1) to (V-3):

[0152] [ka]

[0153] [ka]

[0154] [ka]

[0155] In the formula, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 13 has the same meaning as defined above. Preferably, in any one of the compounds of the following formulae (II-1) to (II-5), (III-1) to (III-6), (IV-1) to (IV-6), (V-1) to (V-3), (II-1) to (II-5), (III-1) to (III-6), (IV-1) to (IV-8), (V-1) to (V-5), (VI-1) to (VI-2), and (VII-1) to (VII-3): R 1 teeth,

[0156] [ka] represents;

[0157] Preferably, R 1 teeth,

[0158] [ka] represents;

[0159] More preferably, R 1 teeth,

[0160] [ka] and even more preferably R 1 teeth,

[0161] [ka] Represents.

[0162] Preferably, in any one of the compounds of the following formulae (II-1) to (II-5), (III-1) to (III-6), (IV-1) to (IV-8), (V-1) to (V-5), (VI-1) to (VI-2), and (VII-1) to (VII-3): R 4 -H, -F, -Cl, -Br, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, -CF2-CF3,

[0163] [ka] represents;

[0164] Preferably, R 4 -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3 , -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, -CF2-CF3,

[0165] [ka] more preferably, R 4 -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -CF2-CHF2,

[0166] [ka] and even more preferably represents -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -CF2-CHF2.

[0167] Even more preferably, R 4 represents -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3, or -CF2-CHF2; even more preferably, represents -H, -F, -Cl, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3; most preferably, R 4 is -OCF3.

[0168] In a preferred embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, tautomer, mixture of enantiomers, mixture of diastereomers, mixture of tautomers, hydrate, solvate, or pharmaceutically acceptable salt thereof of a compound of formula (I):

[0169] [ka]

[0170] During the ceremony, A is,

[0171] [ka] represents;

[0172] B is -OR 3 , or -O-CH2-R 3 represents; R 1 teeth,

[0173] [ka] preferably R 1 teeth,

[0174] [ka] more preferably, R 1 teeth,

[0175] [ka] represents;

[0176] R 3 teeth,

[0177] [ka] represents;

[0178] R 4 represents -H, -F, -Cl, -CH3, -CF3, -OCH3, -OCHF2, or -OCF3; and R 5 , R 6 , R 7 , and R 8 represent, independently of one another, -H, -F, -Cl, -CN, -CH3, -CHF2, -CF3, -OCHF2, -OCF3, or -SO2CH3.

[0179] More preferably, the compound is any one of the compounds represented by the following formulae (III-1) to (III-2), (III-4) to (III-6), (IV-1) to (IV-2), and (IV-4) to (IV-6), or an enantiomer, diastereomer, tautomer, mixture of enantiomers, mixture of diastereomers, mixture of tautomers, hydrate of the above compounds. a compound, solvate, or pharmaceutically acceptable salt thereof:

[0180] [ka]

[0181] During the ceremony, R 1 teeth,

[0182] [ka] preferably R 1 teeth,

[0183] [ka] more preferably, R 1 teeth,

[0184] [ka] represents;

[0185] R 4 represents -F, -Cl, -Br, -CH3, -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -OCH3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CF3, or -OCF2CF3; preferably, R 4 represents -H, -F, -Cl, -CH3, -CF3, -OCH3, -OCHF2, or -OCF3; and R 5 , R 6 , R 7 , and R 8 represent, independently of one another, -H, -F, -Cl, -CN, -CH3, -CHF2, -CF3, -OCHF2, -OCF3, or -SO2CH3.

[0186] In some embodiments, the present invention relates to a compound of any one of the following formulas (I), (II-1) to (II-5), (III-1) to (III-6), (IV-1) to (IV-8), (V-1) to (V-5), (VI-1) to (VI-2), and (VII-1) to (VII-3), wherein R 3 teeth,

[0187] [ka] represents;

[0188] Preferably, R 3 teeth,

[0189] [ka] represents

[0190] More preferably, R 3 teeth,

[0191] [ka] represents

[0192] Even more preferably, R 3 teeth,

[0193] [ka] most preferably represents

[0194] [ka] Represents.

[0195] In a preferred embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, tautomer, mixture of enantiomers, mixture of diastereomers, mixture of tautomers, hydrate, solvate, or pharmaceutically acceptable salt thereof of a compound of formula (I):

[0196] [ka]

[0197] During the ceremony, A is,

[0198] [ka] represents;

[0199] B is -OR 3 , or -O-CH2-R 3 , or -O-CH2-R 3 R 3* Represents; R 1 teeth,

[0200] [ka] represents;

[0201] R 3 teeth,

[0202] [ka] represents

[0203] R 3* represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, or -CH2-CF3; R 4 and R 4* are, independently of one another, -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -CH2-CF3, -CHF-CH2F, -CHF-CHF2, -CHF-CF3, -CF2-CH3, -CF2-CH2F, -CF2-CHF2, -CF2-CF3,

[0204] [ka] represents;

[0205] Preferably, R 4 -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -CF2-CHF2,

[0206] [ka] more preferably, R 4 represents -H, -F, -Cl, -CHF, -CHF, -CF, -OCHF, -OCF, -CF-CHF, and even more preferably R 4 represents -H, -F, -CHF, -CHF, -CF, -OCHF, -OCF, -CF-CHF; preferably, R 4* represents -H, -F, -Cl, -CHF, -CHF, -CF, -OCHF, or -OCF, and more preferably, R 4* represents -H, or -F; and

[0207] R 5 , R 6 , R 7 , and R 8 represent, independently of one another, -H, -F, -Cl, -CN, -CH3, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3, or -SO2CH3.

[0208] In a preferred embodiment, the present invention relates to a compound of formula (I), or an enantiomer, diastereomer, tautomer, mixture of enantiomers, mixture of diastereomers, mixture of tautomers, hydrate, solvate, or pharmaceutically acceptable salt thereof of a compound of formula (I):

[0209] [ka]

[0210] During the ceremony, A is,

[0211] [ka] represents;

[0212] B is -OR3 , or -O-CH2-R 3 represents; R 1 teeth,

[0213] [ka] represents;

[0214] Preferably, R 1 teeth,

[0215] [ka] more preferably, R 1 teeth,

[0216] [ka] represents;

[0217] R 3 teeth,

[0218] [ka] represents;

[0219] Preferably, R 3 teeth,

[0220] [ka] represents;

[0221] R 4 represents -H, -F, -Cl, -CH3, -CF3, -OCH3, -OCHF2, or -OCF3. Particularly preferred compounds according to the present invention include the compounds set forth in Table 1, or enantiomers, diastereomers, tautomers, mixtures of enantiomers, mixtures of diastereomers, mixtures of tautomers, hydrates, solvates, or pharmaceutically acceptable salts thereof of the compounds set forth in Table 1. Table 1

[0222] [Table 1-1]

[0223] [Table 1-2]

[0224] [Table 1-3]

[0225] [Table 1-4]

[0226] [Table 1-5]

[0227] [Table 1-6]

[0228] [Table 1-7]

[0229] [Table 1-8]

[0230] [Table 1-9]

[0231] Table 1-10

[0232] Table 1-11

[0233] Table 1-12

[0234] Table 1-13

[0235] Table 1-14

[0236] Table 1-15

[0237] Table 1-16

[0238] Table 1-17

[0239] Table 1-18

[0240] Table 1-19

[0241] Table 1-20

[0242] Table 1-21

[0243] Table 1-22

[0244] Table 1-23

[0245] Table 1-24

[0246] Table 1-25

[0247] Table 1-26

[0248] Table 1-27

[0249] Table 1-28

[0250] Table 1-29

[0251] Table 1-30

[0252] Table 1-31

[0253] Table 1-32

[0254] Table 1-33

[0255] Table 1-34

[0256] Table 1-35

[0257] Table 1-36

[0258] Table 1-37

[0259] Table 1-38

[0260] Table 1-39

[0261] Table 1-40

[0262] Table 1-41

[0263] Table 1-42

[0264] Table 1-43

[0265] Table 1-44

[0266] Table 1-45

[0267] Table 1-46

[0268] Table 1-47

[0269] Table 1-48

[0270] Table 1-49

[0271] Table 1-50

[0272] Table 1-51

[0273] Table 1-52

[0274] Table 1-53

[0275] Table 1-54

[0276] Table 1-55

[0277] Table 1-56

[0278] Table 1-57

[0279] Table 1-58

[0280] Table 1-59

[0281] [Table 1-60]

[0282] [Table 1-61]

[0283] [Table 1-62]

[0284] [Table 1-63]

[0285] The most preferred compounds of the present invention include compounds 142, 156, 248, and 329, or enantiomers, diastereomers, tautomers, mixtures of enantiomers, mixtures of diastereomers, mixtures of tautomers, hydrates, solvates, or pharmaceutically acceptable salts thereof of compounds 142, 156, 248, and 329.

[0286] [ka]

[0287] Compound synthesis The compounds of formula (I) can be prepared by referring to the methods illustrated by the following reaction protocols. The compounds of formula (I) can be produced as outlined below by selecting appropriate reagents with appropriate substituents. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by one skilled in the art. Starting materials are commercially available. Other synthetic routes to prepare compounds of formula (I) can be applied by those skilled in the art in analogy to the methods disclosed in the literature.

[0288] Scheme 1

[0289] [ka]

[0290] The present invention further relates to a process for preparing a compound of formula (Ib),

[0291] [ka]

[0292] It includes the following steps: Step A) Compound (I-1 * ) to provide;

[0293] [ka] Step B1) B1a) Compound (I-4 * In order to obtain compound (I-1), * ) and (A 1* ) by C-C coupling reaction;

[0294] [ka] B1b) Compound (I-4) was reacted with HCl to obtain compound (Ib). * ) to the protecting group P 1 Removing;

[0295] [ka]

[0296] [ka]

[0297] During the ceremony, X represents a leaving group, preferably a halogen; P 1 represents a hydroxy protecting group; R' is hydrogen or C 1~3 represents alkyl; or two R' together form a pinacol moiety; n, R 2a , R 2b , R 4 , and R 5 From R 9 has the same meaning as defined in formula (Ib).

[0298] Alternatively, the process for preparing a compound of formula (Ib) comprises the following steps: Step A) Compound (I-1 * )

[0299] [ka] Step B2) B2a) Compound (I-2 * In order to obtain compound (I-1), * ) and (A2 * ) by C-C coupling reaction;

[0300] [ka]

[0301] [ka] B2b) Compound (I-2) * ) and (B * ) to carry out a coupling reaction with

[0302] [ka]

[0303] [ka]

[0304] During the ceremony, X represents a leaving group, preferably a halogen; P 1 represents a hydroxy protecting group; R' is hydrogen or C 1~3 represents alkyl; or two R' together form a pinacol moiety; n, R 2a , R 2b , R 4 , and R 5 From R 9 has the same meaning as defined in formula (Ib).

[0305] Alternatively, the process for preparing a compound of formula (Ib) comprises the following steps: Step A2) Compound (I-3 * )

[0306] [ka] Step B3) B2a) Compound (I-3) was reacted with HCl to obtain compound (Ib). * ) and (R 1* ) by coupling reaction with

[0307] [ka]

[0308] [ka]

[0309] During the ceremony, X represents a leaving group, preferably a halogen; n, R 2a , R 2b , R 4 , and R 5 From R 9has the same meaning as defined in formula (Ib).

[0310] In step B1a), the brominated compound (I-1 * ) and compound A1 as a boronic acid derivative * Suzuki coupling reaction with

[0311] [ka]

[0312] or step B2a), the brominated compound (I-1 * ) and the boronic acid derivative, compound A2 * Suzuki coupling reaction with

[0313] [ka] is carried out in the presence of a palladium catalyst and a base,

[0314] where R' is hydrogen or C 1~3 represents alkyl, or two R' together form a pinacol moiety; Preferably, the boronic acid derivative (A1 * ) or (A2 * ) can be a boronic acid (R' = -H) or an ester of a boronic acid, such as the isopropyl ester (R' = -CH(CH3)2), an ester of a boronic acid with a pinacol moiety (R'-R' = -C(CH3)2-C(CH3)2-), etc.

[0315] The palladium catalyst is a Pd(0) or Pd(II) catalyst. The Pd(0) catalyst may be tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] or tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3]. The Pd(II) catalyst may be dichlorobis(triphenylphosphine)palladium(II) [Pd(PPh3)2Cl2], palladium(II) acetate, and triphenylphosphine, or, more preferably, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2). The reaction is preferably carried out in a mixture of water and a solvent such as dioxane, DMF, DME, THF, or isopropanol in the presence of a base such as aqueous sodium bicarbonate or K3PO4.

[0316] P 1 is a hydroxy-protecting group, preferably a silicon-based protecting group selected from trimethylsilyl (TMS), triethylsilyl (TES), isopropyldimethylsilyl (IPMDS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), [2-(trimethylsilyl)ethoxy]methyl (SEM), 2-(trimethylsilyl)ethoxycarbonate (Teoc), more preferably tert-butyldimethylsilyl (TBS) or tert-butyldiphenylsilyl (TBDPS).

[0317] medical use Surprisingly, the compounds of the present invention have been found to effectively activate immune cells, particularly CD4+ cells and / or CD8+ cells, as well as natural killer (NK) cells in T cell receptor (TCR) signaling and NK cell receptor signaling, respectively, as shown in Table B-1. This allows for highly selective activation of the immune system via TCR cell receptors or NK cell receptors against mutated tissues or tissues infected with foreign pathogens. Therefore, by applying the present invention to a clinical setting, highly effective treatment can be achieved while minimizing the risk of serious side effects. This is due to the fact that the compounds of the present invention can be administered at subnanomolar EC 50This is further evidenced by the possibility of administering highly effective compounds based on the . Thus, the present invention opens up a wide dosing window to balance the gap between effective treatment for sustained tolerability over multiple treatment courses and toxic off-target effects.

[0318] As indicated above, the present invention also refers to the medicinal use of the compounds of the present invention in a pharmaceutical context.In this specification, a pharmaceutical context may be understood in the broadest sense as any means for improving the health status and / or wellness of a patient.The terms "pharmaceutical" and "therapeutic" may be understood interchangeably.

[0319] A further aspect of the present invention relates to a pharmaceutical composition comprising at least one compound of the present invention and at least one pharmaceutically acceptable carrier. Preferably, it is a pharmaceutical composition comprising at least one compound of the present invention and at least one pharmaceutically acceptable carrier, excipient, and / or diluent, more preferably, said pharmaceutical composition further comprising at least one stimulator for activating immune cells.

[0320] In this aspect relating to pharmaceutical compositions, the definitions detailed above also apply mutatis mutandis. The pharmaceutically acceptable carrier of the present invention may be any additive that is pharmaceutically acceptable, and therefore non-toxic to the patient. Typically, the pharmaceutically acceptable carrier may contain a solvent, such as water, dimethyl sulfoxide (DMSO), ethanol, vegetable oil, paraffin oil, or a combination thereof. Additionally, the carrier may contain one or more detergents, one or more foaming agents (e.g., sodium lauryl sulfate (SLS) / sodium dodecyl sulfate (SDS)), one or more colorants (e.g., TiO, food coloring), one or more vitamins, one or more salts (e.g., sodium salts, calcium carbonate), one or more phosphate-soluble compounds (e.g., phosphate-soluble compounds ... sodium salts, calcium salts, zinc salts), one or more humectants (e.g., sorbitol, glycerol, mannitol, propylene glycol, polydextrose), one or more enzymes, one or more preservatives (e.g., benzoic acid, methylparaben), one or more texturing agents (e.g., carboxymethylcellulose (CMC), polyethylene glycol (PEG), sorbitol), one or more emulsifiers, one or more fillers, one or more glazing agents, one or more separating agents, one or more antioxidants, one or more herbal and botanical extracts, one or more stabilizers, one or more polymers (e.g., hydroxypropyl methacrylamide (HPMA), polyethyleneimine (PEI), carboxymethylcellulose (CMC), polyethylene glycol (PEG)), one or more uptake mediators (e.g., polyethyleneimine (PEI), dimethyl sulfoxide (DMSO), cell penetrating peptides (CPPs), protein transduction domains (PTDs), antimicrobial peptides, etc.), one or more antibodies / antibodies, one or more sweeteners (e.g., sucrose, acesulfame K, saccharin Na, stevia), one or more counterstain dyes (e.g., fluorescein, fluorescein derivatives, Cy dyes, Alexa Fluor dyes, S dyes, rhodamine, quantum dots, etc.), one or more homeopathic ingredients, one or more taste substances and / or one or more flavorings.

[0321] Suitable diluents are usually substances that make up the majority of the composition or dosage form.Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn, rice, and potato, and celluloses such as microcrystalline cellulose.The amount of diluent in the composition can range from about 5% to about 95% by weight, preferably from about 25% to about 75% by weight, and more preferably from about 30% to about 60% by weight of the total composition.

[0322] Suitable excipients are binders, disintegrants, lubricants, glidants, and / or colorants. The term disintegrant refers to a material added to the composition to aid in the disintegration (disintegration) and release of the pharmaceutical active ingredients of the drug.Suitable disintegrants include starch, "cold water soluble" modified starch, 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 cellulose, and cross-linked microcrystalline cellulose, such as croscarmellose sodium, alginates, such as alginic acid and sodium alginate, clays, such as bentonite, and effervescent mixtures.The amount of disintegrant in the composition can range from about 2% to about 20% by weight of the composition, more preferably from about 5% to about 10% by weight.

[0323] Binders are substances that bind or "glue" powder particles together, clumping them together by forming granules, thus acting as an "adhesive" in the formulation. Binders add cohesive strength already provided by the diluent or filler. Suitable binders include sugars such as sucrose, starches derived from wheat, corn, rice, and potato, natural gums such as acacia, gelatin, and tragacanth, seaweed derivatives such as alginic acid, sodium alginate, and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2% to about 20% by weight of the composition, preferably from about 3% to about 10% by weight, and more preferably from about 3% to about 6% by weight.

[0324] Lubricants help tablet granules to fit into the mold after compression by reducing friction and wear. This refers to the type of substance added to a dosage form to remove it from the granules. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high-melting point waxes, and other water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol, and D,L-leucine. Because lubricants must be present on the surface of the granules, they are usually added at the very last stage before compression. The amount of lubricant in the composition may range from about 0.2% to about 5% by weight of the composition, preferably from about 0.5% to about 2% by weight of the composition, and more preferably from about 0.3% to about 1.5% by weight of the composition.

[0325] Glidants are materials that prevent the components of pharmaceutical compositions from solidifying and improve the flow properties of granules, thus making them flow smoothly and uniformly.Suitable glidants include silicon dioxide and talc.The amount of glidant in the composition can be in the range of about 0.1% to about 5% by weight, preferably about 0.5% to about 2% by weight of the final composition.

[0326] A colorant is an excipient that provides color to a composition or dosage form. Such excipients can include food-grade dyes adsorbed onto a suitable adsorbent, such as clay or aluminum oxide. The amount of colorant can vary from about 0.1% to about 5% by weight of the composition, preferably from about 0.1% to about 1% by weight.

[0327] A pharmaceutical composition of the present invention comprises at least one compound of the present invention. Optionally, the pharmaceutical composition may comprise more than one compound of the present invention, such as a combination of two, three, four, five, or more compounds of the present invention.

[0328] Optionally, the pharmaceutical composition may comprise one or more other pharmaceutically active agents, such as one or more additional stimulatory agents that activate immune cells, which may be other pharmaceutically active ingredients of the pharmaceutical composition other than the compound of the present invention. Examples of such additional stimulatory agents that activate immune cells are provided below.

[0329] The compounds of the present invention, and pharmaceutically acceptable salts of the compounds of the present invention, and pharmaceutical compositions of the present invention may be used as medicaments. Thus, another aspect of the present invention relates to a compound or pharmaceutical composition of the present invention for use as a medicament.

[0330] In this aspect of the pharmaceutical use, the definitions detailed above also apply mutatis mutandis. In the context of the present invention, the terms "medicament", "therapeutic", "medicine", "drug", "therapeutic agent", "pharmaceutical", "pharmaceutical The terms "prophylactic agent", "prophylactic agent" and the like can be understood in the broadest sense as any kind of compound suitable for use in a pharmaceutical context, i.e., for treating and / or preventing a medical condition.

[0331] The compound or pharmaceutical composition comprising the compound may be administered to a patient by any method known in the art, for example, orally, by injection, intranasally, transdermally / percutaneously, etc. Administration may be local (e.g., intratumorally, intranodally (i.e., into a lymph node), intrathecally, intracerebroventricularly (icv), topically, or intravitreal) or systemically (e.g., intravenously (iv), intraarterially (ia), intraperitoneally (ip), intramuscularly (im), subcutaneously (sc), orally, intranasally). Preferably, administration is oral, intravenous, subcutaneous, intratumoral, or intralymphatic, particularly oral or intravenous.

[0332] Administration may be a single administration ((acute) single administration) or repeated administration (e.g., repeated pulse administration or chronic administration). Repeated administration may be, for example, two, three, four, five, six, seven, eight, nine, ten, more than ten administrations, or even permanent administration. There may be a time interval of less than one hour, one hour or more, six hours or more, twelve hours or more, or 24 hours or more between two administrations. Administration may be daily, twice a day, three times a day, four times a day, every two days, every three days, weekly, biweekly, monthly, twice a year, or once a year. A clinically feasible administration schedule may be determined by one skilled in the art based on the balance between efficacy and toxicity.

[0333] Preferably, the medicament is suitable for treating or preventing a condition associated with an insufficient immune response. In other words, the present invention also relates to a medicament suitable for enhancing an immune response. The terms "activate," "enhance," "strengthen," "increase," "induce," "stimulate," etc., used in the context of the activity of the immune response, can be understood interchangeably in the broadest sense of providing increased activity in the immune response.

[0334] In the context of the present invention, an increase in the immune response is preferably a local increase in the immune response, i.e. an increase in the immune response in the vicinity of the antigen recognized by the immune cells responsible for the respective immune response.

[0335] More specifically, antigen-stimulated TCR-binding immune cells receiving the compounds of the present invention exhibit significantly increased secretion of various cytokines, such as IL-2, IFN-γ, and / or TNF-α, as well as increased proliferation and cytotoxicity, as indicated by increased expression of cytotoxic factors such as granzyme B, whereas corresponding unstimulated immune cells do not. This results in local secretion of cytokines and effective antigen-specific cytotoxicity in the vicinity of tumors and / or infectious pathogens, improving the local immune response against the tumors and / or infectious pathogens. More preferably, the compounds of the present invention provide therapeutic or prophylactic interventions that enhance the local effector efficiency of antitumor or antiviral T cells, B cells, and NK cells. However, in the absence of tumor- or pathogen-associated antigens, undesirable significant increases in systemic cytokine levels can be largely avoided. When an antigen is localized on the surface of, for example, tumor cells (e.g., cancer cells) and / or antigen-presenting cells (e.g., mature dendritic cells), the activity of immune cells, particularly T cells, that come into contact with the antigen can be increased. Immune cells stimulated by administration of the compounds of the present invention, particularly activated T cells contacted with their cognate antigens (e.g., tumor antigens and / or pathogen antigens), have been shown to exhibit increased local activation of the immune system in the tumor microenvironment and draining lymph nodes. Therefore, an enhanced immune response in the vicinity of the tumor can drive an increase in the physiological immune response that supports tumor cytotoxicity. This can further induce antigen spread and neoantigen presentation by APCs, leading to broader T cell-specific immunity. For example, when an antigen is localized on the surface of virus-infected cells (e.g., human papilloma (HPV)-infected cells or hepatitis C-infected cells), the activity of immune cells contacting the antigen can be increased.

[0336] In particular, in contrast to vaccination-based strategies (e.g., tumor vaccination), for their activity the compounds of the present invention do not necessarily require that immune cells be in contact with a specific tumor antigen, but stimulation of cells can also be achieved by other means, for example by stimulating the TCR / CD3 pathway and / or costimulatory pathways such as CD28. In the context of the present invention, an increased immune response is preferably characterized by an increase in the secretion of at least one cytokine, more preferably at least one cytokine selected from the group consisting of IL-2, IFN-γ, TNF-α, IL-1 and IL-6, even more preferably at least one cytokine selected from the group consisting of IL-2, IFN-γ and TNF-α. The increased immune response is characterized by increased secretion of cytokines. Particularly preferably, the increased immune response is characterized by increased secretion of at least two cytokines, particularly preferably IL-2 and IFN-γ, IL-2 and TNF-α, or IFN-γ and TNF-α. Even more highly preferred is an increase in at least three cytokines, such as IL-2, IFN-γ, and TNF-α. Additionally or alternatively, expression of further markers associated with immune activity may be increased, such as CD40 ligand (CD40L, also known as CD154), granzyme / perforin, CD69, CD25, and / or CD71. Preferably, the marker is CD40L.

[0337] As explained above, enhanced IL-2 and IFN-γ production by tumor-infiltrating lymphocytes (TILs), particularly T cells specific for tumor and / or infectious antigens, is known to be associated with improved immunity against tumor and / or infectious lesions. TNF-α also has a similar effect. IL-2 can directly activate CD8 cells and natural killer (NK) cells. Therefore, while IL-2 release may be beneficial in tumor and / or infectious lesions, it may also play a general role in promoting T cell survival. Therefore, IL-2 release during antigen-presenting cell (APC) stimulation of T cells (in lymph nodes) may also enhance immune responses.

[0338] Granzymes / perforins are considered as effector molecules and consequently markers for direct killing of neoplastic cells, especially tumor cells, and can be specifically released in the vicinity of or even within tumors. Similarly, IFN-γ and TNF-α can not only activate immune cells (e.g., NK cells and myeloid cells) but also directly upregulate apoptotic pathways in neoplastic cells.

[0339] IL-6 is a cytokine with pleiotropic effects, and is known to promote the survival of B cells in particular. Therefore, the release of IL-6 in lymph nodes may also promote the survival of B cells.

[0340] The release of IL-1 and IL-6 can enhance the development of T helper cells (e.g., Th17 cells, etc.), which are known to play an important role in immunity against neoplastic and infectious diseases. Therefore, the presence of elevated levels of IL-6 and IL-1 in both neoplastic and / or infectious lesions and lymph nodes may have a beneficial effect on the immune response.

[0341] CD25, CD69, CD71, and CD40L are well-known surface markers for T cell activation and are known to indicate the effect of compounds on individual T cell activation levels. CD69, in particular, is an early marker of T cell activation. CD25 is an IL-2 receptor, and high expression typically supports more rapid proliferation of activated T cells. CD71 is a transferrin receptor, typically supporting the supply of iron for T cell proliferation. CD40L is a receptor on T helper cells and is known to support the activation, survival, and proliferation of both APCs and B cells.

[0342] In particular, increased IL-2, IFN-γ, and / or TNF-α secretion, and / or increased CD40L expression are also exemplified in the following examples. All these markers are well-known factors in antitumor immune responses and demonstrate the antitumor (particularly antitumor) activity of the compounds of the present invention.

[0343] This increase in cytokine secretion by immune cells was observed in mice treated with the same stimulant and under comparable conditions. The increase may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 75%, at least 2-fold, at least 3-fold, at least 4-fold, or at least 5-fold, compared to the secretion of the corresponding cytokine by immune cells cultured in a culture medium but not administered a compound of the present invention. Those skilled in the art will recognize that the percentage increase will also typically depend on the amount of the compound of the present invention administered to each immune cell in a dose-dependent manner. Thus, the percentage increase will often also depend on the dosage of the compound of the present invention administered to the patient in a dose-dependent manner. Within the appropriate dosage range, a higher dosage will typically also result in a greater increase. Those skilled in the art will further understand that dose-dependence will also be related to the patient's body weight, the patient's fat and water content, the patient's individual metabolic rate for inactivation and / or elimination of the compound, the patient's individual immune status, etc. Thus, those skilled in the art may adjust the dosage accordingly.

[0344] Additionally or alternatively, the proliferation rate of immune cells, such as T cells, NK cells, B cells, and / or monocytes, may also be increased. Illustratively, the proliferation of CD4+ cells and / or CD8+ cells may be increased. Additionally or alternatively, the maintenance (i.e., survival rate, activity time, or survival time) of immune cells, such as T cells, NK cells, B cells, and / or monocytes (e.g., CD4+ cells and / or CD8+ cells), may also be increased.

[0345] In particular, the compounds of the present invention may enhance T cell reactivity to tumor antigens presented by MHC-I to CD8 T cells or tumor antigens presented by MHC-II to CD4 T cells, regardless of tumor type and tumor antigen. Furthermore, the compounds of the present invention may enhance the immune activity of a patient's NK cells to promote the destruction of tumor cells with reduced tumor antigen presentation via MHC-I. Furthermore, potent antigen-specific T cell responses may be further amplified by B cells and other immune cells and targeted by the compounds of the present invention. Thus, the compounds of the present invention may overcome immunological ignorance of tumorigenesis and / or infectious pathogens, thereby recognizing patient-specific tumor antigens as non-self and reactivating the patient's own immune system to attack tumor cells present in the patient, regardless of the type of neoplastic and / or infectious disease.

[0346] In light of the above, in a further aspect, the present invention relates to a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention for use in the treatment or prevention of a tumor disease and / or an infectious disease.

[0347] Disclosed herein are methods for treating or preventing a neoplastic and / or infectious disease in a patient, comprising administering to said patient a compound or pharmaceutical composition of the present invention in an amount sufficient to treat or prevent said neoplastic and / or infectious disease in said patient.

[0348] In this aspect relating to said medical uses and to methods of treatment or prevention, respectively, the definitions detailed above (in particular in the context of compounds, pharmaceutical compositions and their use as medicaments) also apply mutatis mutandis.

[0349] The term "patient" as used throughout the present invention can be understood in the broadest sense as any subject or individual who is prevented or treated by the compounds or pharmaceutical compositions of the present invention, particularly any subject or individual who has or is at risk of developing a neoplastic disease and / or an infectious disease, regardless of whether or not they have clinical symptoms. The patient can be any animal, including humans. Preferably, the patient is a mammal (e.g., human, mouse, rat, cow, pig, dog, cat, horse, donkey, goat, etc.), and most preferably a human.

[0350] In the context of the present invention, the term "disease" refers to any medical condition, whether or not it has clinical symptoms. The term "disease" can be understood in its broadest sense as a condition associated with a phenotype. Thus, a disease may be associated with a phenotype or may be subclinical. Preferably, a disease is a condition accompanied by one or more clinical symptoms.

[0351] A disease in the context of the present invention can be a chronic disease and / or an acute disease. Preferably, the disease is a chronic disease. A chronic disease is a disease whose effects are persistent or persist for a long period of time, even in another form. In the context of the present invention, a chronic disease also includes a disease with a relapsing course, i.e., a recurrent disease that repeatedly recurs with periods of remission. Therefore, as used herein, a chronic disease can be understood in the broadest sense as any disease that persists for at least one week, at least one month, at least three months, at least six months, at least one year, or even several years (with or without clinical symptoms). When the patient is human, a chronic disease is usually understood as a disease that persists for at least one month, or preferably at least three months. This understanding can also be applied to the present invention. In this context, it can be understood that, for example, a tumor typically grows for several months or even years before the first clinical symptoms appear, but this is not necessarily the case. However, a neoplastic disease is already present from the time of the first neoplastic cell occurrence and typically does not have any clinical symptoms. Thus, recognized neoplastic diseases are typically, but not necessarily, chronic diseases. Similarly, infectious diseases such as human immunodeficiency virus (HIV) infection are typically chronic diseases when they first begin to cause clinical symptoms and are first recognized.

[0352] As used herein, a neoplastic disease can be understood in the broadest sense as any tissue resulting from uncontrolled cell proliferation. In many cases, a tumor results in at least a large tissue mass, optionally vascularized. A tumor may or may not include the formation of one or more metastases. The neoplastic disease of the present invention can be any tumor classified by classes C00 to D48 of the International Statistical Classification of Diseases and Related Health Problems, 10th Edition (ICD-10).

[0353] Exemplarily, the neoplastic disease according to the present invention may be the presence of one or more malignant tumors (tumors) (ICD-10 classes C00 to C97), the presence of one or more in situ tumors (ICD-10 classes D00 to D09), the presence of one or more benign tumors (ICD-10 classes D10 to D36), or the presence of one or more tumors of indeterminate or unknown behavior (ICD-10 classes D37 to D48). Preferably, the neoplastic disease according to the present invention refers to the presence of one or more malignant tumors, i.e., malignant neoplasia (ICD-10 classes C00 to C97).

[0354] In a more preferred embodiment, the neoplastic disease is cancer. Cancer, in its broadest sense, can be understood as any malignant neoplastic disease, i.e., the presence of one or more malignant tumors in a patient. The cancer may be a solid malignant tumor or a hematological malignancy. Preferably, the cancer is amenable to at least one type of immunotherapy (e.g., including therapeutic antibodies targeted against tumor antigens and / or experimental approaches such as cancer vaccination).

[0355] Cancer subtypes may be classified in various ways, such as by the location in the body of the primary or only tumor mass, or by the tissue from which the tumor originates. Exemplarily, the malignant tumors according to the present invention are those on or in the surface of the lips, oral cavity, and pharynx (ICD-10 classes C00-C14), on or in the surface of the digestive tract (ICD-10 classes C15-C26), on or in the surface of the respiratory system and intrathoracic organs (ICD-10 classes C30-C39), on or in the surface of bone and articular cartilage (ICD-10 classes C40-C41), on or in the surface of the skin (ICD-10 classes C43-C44), on or in the surface of connective tissue (ICD-10 classes C40-C41), on or in the surface of the skin (ICD-10 classes C43-C44), on or in the surface of the ... They may be located on or in the tissues and soft tissues (ICD-10 classes C45-C49), on or in the breast and female genitalia (ICD-10 classes C50-C58), on or in the male genitalia (ICD-10 classes C60-C63), on or in the urinary tract (ICD-10 classes C64-C68), on or in the eye, brain, and central nervous system (ICD-10 classes C69-C72), on or in the endocrine glands and related tissues (ICD-10 classes C73-C75), may be secondary or poorly defined tumors (ICD-10 classes C76-C80), may be declared or presumed to be primary tumors of the lymphatic system, hematopoietic system, and related tissues (ICD-10 classes C81-C96), and / or may be isolated (primary) multisite tumors (ICD-10 class C97).

[0356] Exemplarily, cancer in the context of the present invention may be selected from the group consisting of carcinoma (i.e., cancer derived from epithelial cells; for example, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, large cell carcinoma, and small cell carcinoma), sarcoma (i.e., cancer derived from connective tissue; for example, Askin tumor, botryoid sarcoma, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, and soft tissue sarcoma), blood cancer, for example, lymphoma, leukemia, or myeloma, etc. Hematological cancers contemplated herein include lymphomas and leukemias (i.e., cancers derived from hematopoietic (blood-forming) cells; e.g., mature B-cell tumors, mature T-cell tumors and natural killer (NK) cell tumors, Hodgkin's lymphoma, immunodeficiency-associated lymphoproliferative disorders, lymphocytic leukemia, myeloid leukemia), germ cell tumors (i.e., cancers derived from pluripotent cells of the reproductive organs; e.g., germinomas (including dysgerminomas and seminomas), dysgerminomas, seminomas), blastomas (i.e., cancers derived from immature "precursor" cells or germinal tissue; e.g., hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuropulmonary blastoma, retinoblastoma, glioblastoma, etc.), and malignant melanoma and its precursor forms. These include, but are not limited to, adult (i.e., cancers derived from melanocytes; for example, lentigo maligna, superficial spreading melanoma, acral lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma, amelanotic melanoma, soft tissue melanoma, etc.), and non-melanoma skin cancers (i.e., non-melanoma cancers derived from the skin, such as basal cell carcinoma, squamous cell carcinoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, keratoacanthoma, spindle cell tumor, sebaceous gland carcinoma, microcystic adnexal carcinoma, Paget's disease of the breast, atypical fibroblastoma, leiomyosarcoma, angiosarcoma, etc.) and gliomas (i.e., cancers derived from brain or spinal cord cells, such as ependymoma, astroglioma, oligodendroglioma, brainstem glioma, optic glioma, mixed glioma).

[0357] In some embodiments of the present invention, the cancer is a non-hematological cancer, such as, for example, a sarcoma, a carcinoma, or a melanoma. Preferably, the non-hematological cancer may be the formation of one or more solid tumors selected from the group consisting of, for example, melanoma, neuroblastoma, lung cancer, non-small cell lung cancer, small cell lung cancer, renal cell carcinoma, epithelial squamous cell carcinoma, breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, testicular cancer, colon cancer, colorectal cancer, hepatocellular carcinoma, bladder cancer, gastric cancer, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, mesothelioma, thyroid cancer, adrenal cancer, brain cancer, and head and neck cancer.

[0358] More preferably, the compound of the present invention or the pharmaceutical composition of the present invention is useful for the prevention and / or treatment of cancer, wherein the cancer is interstitial fibrosis, prostate cancer, colon cancer, melanoma, lung cancer, rectal cancer, breast cancer, multiple myeloma, gastrointestinal cancer, non-small cell lung cancer (NSCLC).

[0359] Alternatively, the cancer may be the formation of one or more hematological tumors, such as, for example, selected from the group consisting of multiple myeloma, non-Hodgkin's lymphoma, AML (acute myeloid leukemia), DLBCL (diffuse large B-cell lymphoma), and B-CLL (B-cell chronic lymphocytic lymphoma).

[0360] In an alternative preferred embodiment, the disease may be an infectious disease. The term "infectious disease" as used in the context of the present invention can be understood in the broadest sense as any pathological condition caused by the invasion of a patient's body by one or more biological agents foreign to the body that are capable of inducing an immune response in the patient's body. An infectious disease may or may not be accompanied by an inflammatory response (inflammation). Preferably, an infectious disease in the context of the present invention is accompanied by an inflammatory response. Illustratively, the immune response in the patient's body is triggered, more specifically, by the biological agent itself (e.g., by the presence of its surface antigen), by antigens derived from the biological agent presented on the major histocompatibility complex I or II (MHC I or MHC II), by proliferation of the biological agent, by the reaction of host tissues to the biological agent, by compounds produced or triggered by the biological agent (e.g., toxins, semiochemicals, cytokines, etc.), or by the formation of antigens from haptens derived from the biological agent. The biological agent may be non-living or living. Illustratively, the infectious disease may be caused by a biological agent selected from the group consisting of a virus, a viroid, a prion, a microorganism such as a bacterium, a nematode such as a roundworm or a pinworm, an arthropod (e.g., a tick, a mites, a flea, and a lice), a fungus, a ringworm, and a tapeworm. Preferably, the infectious disease according to the present invention is caused by a virus or a bacterium, and in particular is a viral infection.

[0361] In the context of the present invention, a viral infection can be an infection by any virus. The viral infection can be an acute viral infection or a chronic viral infection. Preferably, the viral infection is a chronic viral infection. Non-limiting examples of clinically important viral families and species in the context of the present invention include adenovirus, herpes simplex type 1, herpes simplex type 2, varicella-zoster virus, Epstein-Barr virus, human cytomegalovirus, human herpesvirus type 8, human papillomavirus, BK virus, JC virus, smallpox, hepatitis B virus, human bocavirus, parvovirus B19, human astrovirus, Norwalk virus, coxsackievirus, hepatitis A virus, poliovirus, rhinovirus, severe acute respiratory syndrome virus, hepatitis C virus, yellow fever virus, These include rabies, dengue virus, West Nile virus, rubella virus, hepatitis E virus, human immunodeficiency virus, influenza virus, Guanarito virus, Junin virus, Lassa virus, Machupo virus, Sabia virus, Crimean-Congo hemorrhagic fever virus, Ebola virus, Marburg virus, measles virus, mumps virus, parainfluenza virus, respiratory syncytial virus, human metapneumovirus, Hendra virus, Nipah virus, rabies virus, hepatitis D virus, rotavirus, orbivirus, coltivirus, and bannavirus.

[0362] In the context of the present invention, those viral infections associated with a down-regulation of the immune response are, for example, asymptomatic or symptom-associated human immunodeficiency virus (HIV) infections (acquired immune deficiency syndrome (AIDS)) of particular interest.

[0363] Furthermore, of particular interest are viral infections associated with tumorigenesis, such as herpes simplex virus (HSV) type 1 or 2. In this case, the compounds or pharmaceutical compositions of the present invention may simultaneously have pharmacological activity against the viral infection and the tumor resulting from said viral infection.

[0364] Furthermore, those viral infections that have a long latency period and are therefore hidden from the immune system, such as, for example, HSV type 1 or HSV type 2, are of particular interest. Optionally, but not necessarily, infectious diseases, particularly chronic infectious diseases (e.g., chronic viral infections), may be associated with inflammation. In this context, inflammation is characterized by increased NF-κB activity, C-reactive protein (CRP) levels, interferon-gamma (IFN-gamma) levels, interleukin-1 (IL-1) levels, and / or interleukin-8 (IL-8). -8) May be characterized by elevated levels.

[0365] In the context of treating or preventing neoplastic and / or infectious diseases, the compounds of the present invention may be administered as the sole pharmacologically active agent or in combination with one or more other pharmacologically active agents. Illustratively, the other pharmacologically active agents may be stimulants that activate immune cells, antiproliferative agents (e.g., anti-cancer agents such as chemotherapeutic agents, antimetabolites, hormones, antibodies (Abs)), antiviral agents, and / or antibiotics.

[0366] Preferably, the other pharmacologically active agent is a biological compound, such as a therapeutic monoclonal antibody, that has been shown to be effective in treating tumors. Illustratively, the therapeutic monoclonal antibody targets PD-1, PD-L1, or other ligands of PD-1, CTLA-4, TIM3, LAG3, VISTA, or BTLA-4.

[0367] The application of the combination therapy will depend on the pharmacokinetic and pharmacodynamic properties of the selected compounds and agents used in the combination therapy (adjunctive component).

[0368] Optionally, the additional drug may be administered simultaneously with one or more compounds of the present invention, before one or more compounds of the present invention, or after one or more compounds of the present invention. As used herein, simultaneous administration may refer to administration in a single composition (e.g., mixed in the pharmaceutical composition of the present invention), or administration in two separate compositions, which may be administered via the same or different administration routes (e.g., via injection, oral administration, nasal administration, transdermal administration). As used herein, when the compound of the present invention is administered first or later, the time interval between the administration of the compound and the additional drug may be less than 1 hour, 1 hour or more, 3 hours or more, 6 hours or more, 12 hours or more, 24 hours or more, 2 days or more, or 1 week or more.

[0369] As mentioned in the context of the compounds of the present invention above, one or more additional agents may be administered once (single dose) or repeatedly, for example, two, three, four, five, six, seven, eight, nine, ten, ten or more times, or even permanently. There may be a time interval of less than one hour, one hour or more, six hours or more, twelve hours or more, or twenty-four hours or more between two doses. Administration may be daily, twice a day, three times a day, four times a day, every two days, every three days, weekly, biweekly, monthly, twice a year, or yearly.

[0370] In a preferred embodiment, the compounds or pharmaceutical compositions of the invention are administered in combination with one or more additional stimulatory agents that activate immune cells. The immune cells used in the context of the present invention may be any immune cells known in the art. The immune cells may be cells of the adaptive immune system (e.g., T cells or B cells, cells of the innate immune system (natural killer (NK) cells, macrophages, monocytes), and / or cells that may be included in both groups (e.g., dendritic cells (DCs), antigen-presenting cells (APCs))) and / or cells known for their phagocytic activity, such as, for example, basophils, neutrophils, or eosinophilic granulocytes.

[0371] In a preferred embodiment, the immune cells are peripheral blood mononuclear cells (PBMCs). In a preferred embodiment, the immune cells are selected from those having a T cell antigen receptor (TCR) and a CD4 coreceptor and / or a CD8 coreceptor on their cell surface. The immune cells having a CD4 coreceptor on their cell surface may be selected from the group consisting of helper T cells (Th cells), macrophages, and dendritic cells (DCs). The immune cells having a CD8 coreceptor on their cell surface may be selected from the group consisting of cytotoxic T cells, naive T cells, and leukocyte antigen receptors (LECs). The cells may be selected from the group consisting of: neural killer (NK) cells, cortical thymocytes, and dendritic cells (DCs).

[0372] In other preferred embodiments, the immune cells are selected from the group consisting of T cells, NK cells, monocytes, and B cells. In particularly preferred embodiments, the immune cells are T cells and / or NK cells.

[0373] T cells and NK cells are well known to have particular efficacy against tumorigenesis (especially antitumor immunity) and infectious diseases. NK cells are preferably lymphocytes that can be stimulated via Fc receptors (FcRs). This may provide some advantages in the context of the present invention (e.g., when therapeutic antibodies against tumor antigens and / or infectious antigens are administered alone or in combination), especially in the context of antibody-dependent cellular cytotoxicity (ADCC).

[0374] B cells are well known to play an important role in humoral responses to infectious pathogens. Furthermore, it is known in the art that B cells may also play a role in the development of humoral immunity against tumor cells.

[0375] Monocytes can be understood as a transient phenotype of myeloid cells present in large numbers in PBMCs. Furthermore, myeloid cells include dendritic cells (DCs). Macrophages can have both positive and suppressive effects on immunity, particularly in antitumor therapy. Particularly noteworthy macrophages include M1 macrophages. Myeloid cells can also include myeloid-derived suppressor cells (MDSCs), which have a negative effect on antitumor immune responses. Myeloid cells can be stimulated via FcRs. This may be beneficial in the context of the present invention (e.g., when therapeutic antibodies against tumor antigens and / or infectious antigens are administered alone or in combination), particularly in the context of antibody-dependent cellular cytotoxicity (ADCC). Furthermore, myeloid cells may enhance the effects of naturally occurring humoral immunity against tumor antigens in patients.

[0376] Activation of immune cells can be understood in the broadest sense as an increase in the immune activity of said cells and / or an increase in cell proliferation of said cells. In a more preferred embodiment, the additional stimulatory agent for activating immune cells is selected from the group consisting of one or more antigens of the tumor and / or infectious pathogen to be treated, one or more TCR or CD3 agonists, one or more CD28 agonists, one or more agonists for other costimulatory T cell surface receptors such as CD40L, CD69, OX40, GITR, CD137, CD27 and / or HVEM, and combinations of two or more thereof.

[0377] The TCR / CD3 agonist can be any agent that attracts CD3. The TCR / CD3 agonist can be a peptide or non-peptide agonist that binds to the extracellular side of TCR / CD3 regardless of whether or not MHC-dependent antigen presentation is present, an agonist that binds to the intracellular side of TCR / CD3, or an agent that activates an intracellular signaling pathway triggered by TCR / CD3 engagement. Preferably, the CD3 agonist can be an anti-CD3 antibody, a peptide antigen presented by MHC1 or MHCII, an anti-CD3 antibody fragment, or an anti-CD3 antibody mimic. Highly preferably, the CD3 agonist is a tumor antigen presented by MHC1 or MHCII.

[0378] The CD28 agonist may be any agent that attracts CD28. The CD28 agonist may be an agonist that binds to the extracellular side of CD28, an agonist that binds to the intracellular side of CD28, or an agonist that binds to the intracellular side of CD28. It may also be a drug that activates signal transduction pathway.Preferably, CD28 agonist can be anti-CD28 antibody, anti-CD28 antibody fragment, anti-CD28 antibody mimic, or protein that comprises the natural ligand for CD28, such as B7.1 or B7.2.Highly preferably, CD28 agonist is (agonistic) anti-CD28 antibody, or Ig fusion protein that comprises the natural ligand for CD28, such as B7.1 or B7.2.

[0379] In the context of the present invention, antibodies can be monoclonal or polyclonal antibodies of any species or origin. Antibodies can bind to any epitope, including post-translational modifications, within a polypeptide having its respective cognate antigen (e.g., CD3 or CD28). Cognate antigens can illustratively be linear epitopes, structural epitopes, primary epitopes, and / or secondary epitopes. Antibodies can be naturally derived, genetically engineered, and / or synthetic.

[0380] An antibody fragment, in the broadest sense, can be understood as any fragment of an antibody that still has binding affinity for the target polypeptide. Exemplarily, an antibody fragment can be an antigen-binding fragment (Fab fragment), a truncated antibody containing one or both complementarity-determining regions (CDRs), or an antibody variable fragment (Fv). Antibody fragments can be of natural, genetically engineered, and / or synthetic origin.

[0381] In the broadest sense, an antibody mimic can be understood as an organic compound that can specifically bind to an antigen in the same way as an antibody and typically has a molecular weight ranging from about 3 kDa to about 25 kDa. Antibody mimics can be, for example, affibody molecules (affibodies), affilins, affitins, anticalins, avimers, DARPins, finomers, Kunitz domain peptides, single domain antibodies (e.g., VHH antibodies or VNAR antibodies), monobodies, diabodies, triabodies, flexibodies, and tandems. Antibody mimics can be of natural, genetically engineered, and / or synthetic origin.

[0382] A peptide antigen can be understood in the broadest sense as an organic compound that specifically binds to an MHC1 or MHCII molecule and typically consists of 8 to 30 amino acids, preferably 9 to 25 amino acids. Peptides can be of natural, genetically engineered, and / or synthetic origin.

[0383] Preferably, the additional stimulatory agent for activating immune cells is a combination of one or more CD3 agonists and one or more CD28 agonists. Particularly preferably, the additional stimulatory agent for activating immune cells is a combination of at least one (agonistic) anti-CD3 antibody and at least one (agonistic) anti-CD28 antibody. As will be apparent from the examples shown below, stimulation of immune cells by contact with (agonistic) anti-CD3 antibodies and / or (agonistic) anti-CD28 antibodies mechanistically stimulates T cells, regardless of the specific antigen recognized by the individual TCR. Stimulation with (agonistic) anti-CD3 antibodies and (agonistic) anti-CD28 antibodies closely mimics T cell activation in vivo in a patient.

[0384] Additionally or alternatively, immune cells can be induced by tumor and / or infectious pathogen antigens (e.g., by vaccinating a patient with one or more antigens). The antigens are then considered stimulants. The tumor and / or infectious pathogen antigens can illustratively be vaccines containing one or more antigens of tumors and / or infectious pathogens, such as polypeptide-based vaccines, polynucleotide vaccines, oligosaccharide vaccines, or vaccines based on fragments of the same type of tumor or fragments of the same type of infectious pathogen. Commercial manufacturers know many ways to provide such vaccines. Several anti-tumor and anti-viral vaccines are also commercially available.

[0385] Additionally or alternatively, immune cells can also be triggered by antigen-carrying antigen-presenting cells (APCs).The antigen-carrying APCs are then considered as further stimulants.In this context, the antigen can also be an antigen of tumor and / or infectious pathogen, as described above.

[0386] Additionally or alternatively, the one or more further stimulatory agents may be selected from the group consisting of checkpoint inhibitor therapeutics (particularly T cell surface receptor-binding agents, e.g., binding to one or more selected from the group consisting of CTLA4, PD-1, PDL-1, TIM3, LAG3, BTLA, VISTA, and / or their ligands (e.g., anti-CTLA4 antibodies, anti-PD-1 antibodies, and / or anti-PDL-1 antibodies)), cytokines (e.g., IL-2, IL-15, and / or IL-7), APC activators (e.g., CD40 agonists), adoptive immune cell factors (particularly adoptive T cells (e.g., chimeric immunoreceptor T cell therapy, such as CART cell therapy), dendritic cell therapy (e.g., sipuleucel-T), and / or natural killer cell therapy), T cell function enhancers (e.g., lenalidomide and related agents), natural killer cell function enhancers (e.g., anti-KIR antibodies), and therapeutic antibodies against tumor antigens.

[0387] Optionally, particularly if the patient is suffering from a neoplastic disease, the patient may further be administered one or more chemotherapeutic agents, cytokines, and / or other anti-tumor agents in addition to one or more compounds of the present invention. Illustratively, the chemotherapeutic agents, cytokines, and anti-cancer agents include polyclonal or monoclonal antibodies (e.g., rituximab, trastuzumab, cetuximab, bevacizumab, basiliximab, daclizumab, etc.), antimetabolites (e.g., 5-fluorouracil, azathioprine, 6-mercaptopurine, mercaptopurine, pyrimidines, thioguanine, fludarabine, floxuridine, cytosine arabinoside (cytarabine), pemetrexed, raltitrexed, pralatrexate, methotrexate, etc.). oxalate, etc.), 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), cytoxans, topoisomerase inhibitors (e.g., camptothecins: irinotecan, topotecan, etoposide, etoposide phosphate) , teniposide), melphalan, antineoplastic agents (e.g., doxorubicin (adriamycin), doxorubicin lipoprotein, epirubicin, bleomycin), actinomycin D, aminoglutethimide, amsacrine, anastrozole, purine and pyrimidine base antagonists, anthracyclines, aromatase inhibitors, asparaginase, antiestrogens, bexarotene, buserelin, busulfan, camptothecin derivatives, capecitabine, carmustine, cladribine, cytarabine, cytosine arabinoside Do, alkylating cytostatics, dacarbazine, daunorubicin, docetaxel, epirubicin, estramustine, etoposide, exemestane, fludarabine, fluorouracil, folate antagonists, formestane, gemcitabine, glucocorticoids, goserelin, hormones and hormone antagonists, hycamtin, hydroxyurea, idarubicin, irinotecan, letrozole, leuprorelin, lomustine, mercaptopurine, miltefosine, mitomycin, mitotic inhibitors, mitoxantrone,Nimustine, procarbazine, tamoxifen, temozolomide, teniposide, testolactone, thiotepa, topoisomerase inhibitors, treosulfan, tretinoin, triptorelin, trofosfamide, antibiotics with cytostatic effects, everolimus, pimecrolimus, tacrolimus, azithromycin, spiramycin, sirolimus (rapamycin), roxithromycin, ascomycin, bafilomycin, erythromycin, mitomycin, Decamycin, josamycin, concancamycin, clarithromycin, troleandomycin, folimycin, tobramycin, mutamycin, dactinomycin, rebeccamycin, statins (e.g., cerivastatin, simvastatin, lovastatin, somatostatin, fluvastatin, nystatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, pentostatin), 4-hydroxyoxycyclophosphamide, bendamustine, thymosin alpha-1, aclarubicin, fludarabine-5'-dihydrate phosphate, 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 of fumaric acid, delmicidin, calcipotriol, taclacitol, lapachol, β-lapachone, podophyllotoxin, betulin, podophyllinic acid 2-ethylhydrazide, sagramostim (r huGM-CSF), peginterferon α-2b, lenograstim (r-HuG-CSF), filgrastim, macrogol, cephalomannine, selectins (cytokine antagonists), CETP inhibitors, cadherins, cytokinin inhibitors, COX inhibitors (COX-2 inhibitors or COX-3 inhibitors), angiopeptin, ciprofloxacin, fluroblastine, bFGF antagonists, probucol, prostaglandins, 1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one, scopoletin, colchicine , NO donors, pentaerythrityl tetranitrate, sydnonimine, S-nitroso derivatives, staurosporine, β-estradiol, α-estradiol, estriol, estrone, ethinylestradiol, fosfestrol, medroxyprogesterone, estradiol cypionate, estradiol benzoate, tranilast, camebacurin, verapamil, cyclosporine A, paclitaxel and paclitaxel derivatives such as 6-α-hydroxypaclitaxel, bacatin, taxotere, mofebutazone, acemetacin,Diclofenac, lonazolac, dapsone, o-carbamoyl-phenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium gold thiomalate, oxaceprol, celecoxib, β-sitosterol, ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, ellipticine, Calbiochem D-24851, colcemid, cytochalasin AE, indanocine, nocodazole, bacitra Synthins, vitronectin receptor antagonists, azelastine, free nucleic acids, nucleic acids incorporated into viral transmitters, DNA and RNA fragments, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotides, VEGF inhibitors, IGF-1, active agents of the antibiotic group such as cefadroxil, cefazolin, cefaclor, cefoxitin, gentamicin, penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotic agents, argatroban, aspirin, abciximab, synthetic antithrombotic agents thiamin, bivalirudin, coumadin, enoxaparin, antibodies to GpIIb / IIIa platelet membrane receptors, factor Xa inhibitors, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidol, trapidil, nitroprusside, PDGF antagonists, triazolopyrimidines, theramine, ACE inhibitors, captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, bapiprost, interferon alpha, β, and γ, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, NF-κB or Bcl-xL antisense oligonucleotides, halofuginone, nifedipine, tocopherol, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, boswellic acid and derivatives of boswellic acid, leflunomide, anakinra, etanercept, sulfasalazine, tetracycline, triamcinolone, procainimide, retinoic acid, quinidine, disopyramide, flecainide, propafenone,Sotaro, ol, amiodarone, naturally occurring and synthetically derived steroids such as bryophylline A, inotodiol, makiroside A, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, acyclovir, ganciclovir, zidovudine, antifungals, clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, terbinafine, chloroquine, mefloquine, quinine, natural terpenoids , hypocaesculin, barringtogenol-C21-angelate 14-dehydroagrostistatin, agroskerin, agrostistatin, 17-hydroxyagrostistatin, obatodiolide, 4,7-oxycycloanisomelic acid, baccarinoids B1, B2, B3, and B7, tubeimoside, bruceanol A, B, and C, bruceantinoside C, yadandiosides N and P, isodeoxyelephantopine, tomenphantopine A and B, coronarin A, B, C, and D, ursolic acid, hyptatic acid A, zeolin, ibuprofen Soylidogermanal, Maitenfoliol, Efsanthin A, Ecsisanin A and B, Longicaurin B, Scarponeatin C, Kamebaunin, Leucamenin A and B, 13,18-dehydro-6-alpha-senecioyloxychaparin, Taxamaylin A and B, Regenilol, Triptolide, Cymarin, Apocymarin, Aristolochic Acid, Anopterin, Hydroxyanopterin, Anemonin, Protoanemonin, Berberine, Keribrine Chloride, Cicutoxin, Sinococulin, Combrestatin A and B, Kudraisoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-beta-hydroxypregnadiene-3,20-dione bilobol, ginkol, ginkgolic acid, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, glycoside 1a, justicidin A and B, lareatin, malotelin, malottochromanol, isobutyrylmalotochromanol, marchantin A, maytansine, lycorizin, margetin, pancratistatin, liriodenine, bisparthenolidine, oxocinsunin, aristolactam-ol,Periplocoside A, galacchinoside, deoxypsorospermine, cycorbin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, spatheria chromone, styzophylline, akagerin, dihydrousambarensin, hydroxyusambarensin, strychnopentamine, strychnophilline, usambarensin, usambarensin, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferone, afromosone, acetylvismion B, desacetylvismion A, vismion A and B, radiation therapy (e.g., intensity-modulated radiation therapy (IMRT)), 3-dimensional conformal radiation therapy ( 3DCRT), stereotactic body radiotherapy (SBRT), stereotactic radiosurgery (SRS), image-guided radiotherapy (IGRT), particle therapy (e.g., proton therapy), brachytherapy, radioisotope therapy (RIT) (e.g., iodine-131, lutetium-177, strontium-89, and samarium (153Sm), lexidronam and / or yttrium-90), etc.), antiangiogenic therapy (e.g., carboxyamidotriazole, TNP-470, CM101, suramin, SU5416, thrombospondin, VEG FR antagonists, antiangiogenic steroids plus heparin, cartilage-derived angiogenesis inhibitors, matrix metalloproteinase inhibitors, 2-methoxyestradiol, tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, soluble VEGFR-1 and NRP-1, angiopoietin 2, angiostatin (e.g., TSP-1 and TSP-2 angiostatin), endostatin, vasostatin, canstatin, calreticulin, platelet factor-4, TIMPs and CDAI, methicillin- 1 and Meth-2, CXCL10 prothrombin (kringle domain-2), antithrombin III fragment prolactin, VEGI, SPARC, osteopontin, maspin, proliferin-related protein, restin, etc.), 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,may be selected from the group consisting of:

[0388] Alternatively, or in addition, if the patient is suffering from or at risk of developing a neoplastic disease and / or an infectious disease, the patient may further be administered one or more cytokines, hormones, or analogs thereof (e.g., selective estrogen receptor modulators tamoxifen, IL-2, IFN-α, IFN-β, IFN-γ, IL-4, IL-12, IL-18, platelet factor-4, TNF-α, etc.). These cytokines, hormones, or analogs thereof may further stimulate the patient's immune system. As mentioned above, many of these drugs can cause serious side effects when administered in high doses. However, lower doses may be used as needed to supplement the treatment or prevention of the present invention.

[0389] Optionally, particularly if the patient is suffering from a viral infection, the patient may further be administered, in addition to one or more compounds of the present invention, one or more antiviral compounds, which may illustratively be selected from the group consisting of entry or fusion inhibitors, nucleoside / nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors.

[0390] Optionally, particularly if the patient is suffering from a bacterial infection, the patient may further be administered one or more antibacterial antibiotics in addition to one or more compounds of the present invention, which may be selected from the group consisting of antibiotics that target bacterial cell walls (e.g., penicillins and cephalosporins) or cell membranes (e.g., polymyxins), antibiotics that interfere with essential bacterial enzymes (e.g., rifamycins, lipiarmycins, quinolones, and sulfonamides), and / or antibiotics that target polypeptide synthesis (e.g., macrolides, lincosamides, and tetracyclines).

[0391] Furthermore, the treatment or prevention according to the present invention may be combined with other therapeutic measures, such as, for example, radiation therapy (e.g., based on X-ray irradiation, ultraviolet (UV) irradiation (e.g., UV-A, UV-B, and / or UV-C irradiation), alpha-ray irradiation, beta-ray irradiation, gamma-ray irradiation, or cosmic ray irradiation), and / or surgery.

[0392] As mentioned above, it will be understood that the compounds of the present invention can be very well used in the treatment and / or prevention of tumor diseases and / or infectious diseases in patients in vivo.However, the compounds of the present invention can not only be used for in vivo applications, but also for any kind of ex vivo and / or in vitro applications.Exemplarily, they can also be used to activate immune cells in vivo, ex vivo, and in vitro.

[0393] Illustratively, the compounds of the present invention may be used in any method to support the generation and / or expansion of immune cells ex vivo and / or in vitro, particularly but not necessarily for further use in adoptive cell therapy (ACT). For ACT, antigen-specific T cells may preferably be used. The method may also provide activated DCs, which may optionally be useful in DC vaccination approaches.

[0394] In another aspect, the present invention relates to an in vitro or ex vivo method for the production of activated immune cells, comprising the steps of: (i) providing immune cells; (ii) contacting the cells of step (i) with: (a) at least one compound as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and optionally (b) one or more additional stimulatory agents that activate the immune cells; and (iii) culturing the cells of step (ii) under conditions suitable to maintain the viability of said cells.

[0395] In this aspect relating to the method, the definitions detailed above apply mutatis mutandis. The method may be performed ex vivo and / or in vitro, i.e., is an ex vivo and / or in vitro method. Thus, in the context of this embodiment relating to the method, the immune cells are preferably activated ex vivo, in particular outside the patient's body.

[0396] Preferably, the immune cells (e.g., T cells and / or natural killer cells) are mature immune cells. The cells (e.g., T cells) may be CD4+ cells and / or CD8+ cells. The immune cells may be obtained from any source suitable for this purpose. Alternatively, or additionally, the cells may be B cells, such as CD19+ B cells. Those skilled in the art are aware of various methods for obtaining such immune cells. Illustratively, mature immune cells may be obtained from a blood sample (e.g., stored blood or fresh blood). Peripheral blood mononuclear cells (PBMCs) may then be obtained, illustratively from the buffy coat after centrifugation of the blood sample, and optionally further isolated / purified, illustratively by labeling cell-type-specific surface markers with fluorescently labeled antibodies followed by fluorescence-activated cell sorting (flow cytometry) or by labeling cell-type-specific surface markers with metal bead-labeled antibodies followed by magnetic extraction of the desired cells.

[0397] Alternatively, mature immune cells may be obtained from cell culture. Methods for obtaining buffy coats, as well as methods for further isolating and purifying the cells, are exemplified in the Examples section below. (Mature) immune cells are commercially available.

[0398] Alternatively, immature immune cells or precursors of immature immune cells may be used and, at an intermediate step, matured by well-known methods supplemented with the respective cytokines and growth factors.

[0399] Subsequently, the immune cells are contacted with at least one compound of the present invention and, optionally, one or more additional stimulants that activate immune cells. Those skilled in the art will readily recognize that these compounds and stimulants can be added to cells in any type of solution or medium suitable for the cells. Illustratively, the solution or medium may contain the components defined in the context of the pharmaceutical composition above. The additional stimulant that activates immune killer cells may be understood in the broadest sense as defined above. Optionally, the additional stimulant may be administered simultaneously with, before, or after one or more compounds of the present invention. The cells may be contacted with the compound and / or stimulant for less than 30 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 5 hours, at least 12 hours, at least 1 day, or longer.

[0400] Following or simultaneously with contacting the cells with the compound and any agent (step (ii)), the cells are cultured under conditions suitable for maintaining the viability of the cells (step (iii)). Thus, step (ii) and step (iii) may be performed as one step (simultaneously), or as two separate steps (subsequently), or with partial temporal overlap. Typically, the cells are cultured in a suitable cell culture medium (e.g., XV) optimized to allow cell culture in the absence of FCS RPMI1640. The cells are cultured in 15% CO, optionally supplemented with fetal calf serum (FCS), at a temperature of 30° C. to 39° C., preferably (about) 37° C. Preferably, the cells are cultured for at least 1 hour, at least 2 hours, at least 5 hours, at least 12 hours, at least 1 day, or at least 3 days.

[0401] The methods of the invention may result in activated immune cells (eg, T cells and / or natural killer cells). These activated immune cells may optionally be isolated by any means known in the art (optional step (iv)). Optionally, as a further step (v), the activated immune cells may then 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 be stored and / or preserved (e.g., dispersed in a DMSO-containing medium and stored at -80°C). Alternatively, the isolated activated immune cells of step (iv) or the cells of step (iii) may be used for any other in vitro and / or in vivo purposes. Exemplarily, the activated immune cells may be used for research purposes aimed at further investigating activated immune cells (particularly activated T cells and / or natural killer cells).

[0402] Illustratively, activated immune cells (particularly activated T cells and / or natural killer cells) may be used to produce cytokines secreted by the cells. Then, a further step (iv) is to culture the cells until the level of the desired cytokine secreted into the culture medium reaches a desired level, followed by step (v) of isolating and optionally purifying the desired cytokine. Isolation and optional purification of the cytokine may be performed by any method known in the art, such as, for example, chromatography. Optionally, the cytokine may then be stored and / or preserved (e.g., frozen, dried, or freeze-dried).

[0403] Furthermore, the compounds of the present invention can further be used as research tools to investigate immune cell activation in more detail. In a further aspect, the present invention relates to a compound, or a pharmaceutically acceptable salt thereof for use, or a pharmaceutical composition thereof for use as a medicament in the prevention or treatment of neoplastic and / or infectious diseases, cardiovascular diseases, wherein the cardiovascular diseases are myocardial infarction, acute coronary syndrome, myocardial ischemia, ischemic cardiomyopathy, myocardial reperfusion injury, non-ischemic cardiomyopathy, or acute or chronic heart failure. [Brief explanation of the drawings]

[0404] [Figure 1] Treatment schedule for Compound 142 in an in vivo efficacy experiment using oral compound administration. Efficacy Experiment 1 treatment schedule for a POC study monitoring tumor volume and survival rate of orally administered mice. Arrow indicates oral administration of Compound 142. [Figure 2] The effect of Compound 142 on in vivo tumor growth rate. Mean tumor volume ± SEM in mice orally treated with Compound 142 d3: 30 mg / kg + QD: 10 mg / kg, or d3: 9 mg / kg + QD: 3 mg / kg. Statistically significant differences (p<0.05) between treatment groups and vehicle control groups were calculated using two-way ANOVA. [Figure 3A] M21 cell proliferation upon co-culture with stimulated PBMCs. M21 melanoma cells were incubated with isolated PBMCs and stimulated with anti-CD3 / 28 and compound 142 at five different concentrations. [Figure 3B] M21 cell proliferation upon co-culture with stimulated PBMCs. M21 melanoma cells were incubated with isolated PBMCs and stimulated with anti-CD3 / 28 and compound 142 at five different concentrations. [Figure 4A] Proliferation of M21 cells in response to co-culture with stimulated T cells. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / 28 and different concentrations of compound 142. EC50 was calculated using GraphPad Prism 32 hours after addition of anti-CD3 / 28 and compound 142. [Figure 4B] Proliferation of M21 cells in response to co-culture with stimulated T cells. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / 28 and different concentrations of compound 142. EC50 was calculated using GraphPad Prism 32 hours after addition of anti-CD3 / 28 and compound 142. [Figure 5A] Proliferation of M21 cells upon co-culture with stimulated T cells. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / 28 and compound 142 at different concentrations. [Figure 5B] Proliferation of M21 cells upon co-culture with stimulated T cells. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / 28 and compound 156 at different concentrations. [Figure 5C] Proliferation of M21 cells upon co-culture with stimulated T cells. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / 28 and compound 119 at different concentrations. [Figure 6] Proliferation of M21 cells in co-culture with unstimulated PBMCs and T cells. M21 melanoma cells were incubated with unstimulated PBMCs and 10 μM Compound 142 or with T cells and 10 μM Compound 142. [Figure 7] Treatment schedule for Compound 142 in an in vivo efficacy study using oral compound administration. Efficacy experiment 2 treatment schedule for a POC study monitoring tumor volume and survival rate of orally administered mice. Arrows indicate oral administration of Compound 142. Asterisks indicate Compound 142 treatment at 40 mg / kg every 48 hours, except for days 7 (30 mg / kg) and 9 (60 mg / kg). [Figure 8]Treatment schedule for Compound 142 in an in vivo efficacy study using oral compound administration. Efficacy experiment 3 treatment schedule for a POC study monitoring tumor volume and survival rate of orally administered mice. Arrow indicates oral administration of Compound 142. [Figure 9] Treatment schedule for Compound 142 or Compound 120 in an in vivo efficacy study using oral compound administration. Efficacy experiment 4 treatment schedule for a POC study monitoring tumor volume and survival rate of orally administered mice. Black arrows indicate daily oral administration of Compound 142 or Compound 120, and gray arrows indicate oral administration of Compound 142 every 3 days. [Figure 10] Treatment schedule for Compound 142, Compound 156, or Compound 119 in an in vivo efficacy study using oral compound administration. Efficacy Experiment 5 treatment schedule for a POC study monitoring tumor volume and survival rate of orally administered mice. Arrows indicate daily administration of Compound 142, Compound 156, or Compound 119. [Figure 11] Treatment schedule for Compound 142, Compound 156, or Compound 119 in an in vivo efficacy study using oral compound administration. Efficacy experiment 6 treatment schedule for a POC study monitoring tumor volume and survival rate of orally administered mice. Arrows indicate daily oral administration of Compound 142, Compound 156, or Compound 119. [Figure 12] The effect of Compound 142 on in vivo tumor growth rate. Mean tumor volume ± SEM in mice receiving oral administration treatment with Compound 142 60 mg / kg D3 + 40 mg / kg Q2D* or vehicle. Asterisks indicate Compound 142 treatment at 40 mg / kg every 48 hours, except for days 7 (30 mg / kg) and 9 (60 mg / kg). Statistically significant differences (p<0.05) between treatment groups and vehicle control groups were calculated using two-way ANOVA. [Figure 13]The effect of Compound 142 on in vivo tumor growth rate. Mean tumor volume ± SEM in mice orally administered Compound 142 30 mg / kg D4 + 10 mg / kg QD, 9 mg / kg D4 + 3 mg / kg QD, or vehicle. Statistical significance (p<0.05) between treatment groups and vehicle control group was calculated using two-way ANOVA. [Figure 14] The effect of Compound 142 and Compound 120 on in vivo tumor growth rate. Mean tumor volume ± SEM in mice orally treated with Compound 142 30 mg / kg D4 + 10 mg / kg QD, or 30 mg / kg Q3D. Statistically significant differences (p<0.05) between treatment groups and vehicle control groups were calculated using two-way ANOVA. [Figure 15A] The effects of Compound 142 and Compound 119 on in vivo tumor growth rate and survival rate. A: Mean tumor volume ± SEM of mice orally treated with Compound 142 30 mg / kg D4 + 10 mg / kg QD, Compound 156 20 mg / kg D4 + 10 mg / kg QD, Compound 119 10 mg / kg QD, or vehicle. Statistically significant differences (**p<0.01, ***p<0.01) between treatment groups and the vehicle control group were calculated using two-way analysis of variance. [Figure 15B] Effect of Compound 142 and Compound 119 on in vivo tumor growth rate and survival. B: Survival of mice receiving oral administration of Compound 142 30 mg / kg D4 + 10 mg / kg QD, Compound 156 20 mg / kg D4 + 10 mg / kg QD, Compound 119 10 mg / kg QD, or vehicle. [Figure 15C1] Effect of Compound 142 and Compound 119 on in vivo tumor growth rate and survival rate. C: Mean tumor volume ± SEM and tumor volume of individual mice receiving primary B16-SIY inoculation or secondary B16-SIY re-inoculation. [Figure 15C2]Effect of Compound 142 and Compound 119 on in vivo tumor growth rate and survival rate. C: Mean tumor volume ± SEM and tumor volume of individual mice receiving primary B16-SIY inoculation or secondary B16-SIY re-inoculation. [Figure 15C3] Effect of Compound 142 and Compound 119 on in vivo tumor growth rate and survival rate. C: Mean tumor volume ± SEM and tumor volume of individual mice receiving primary B16-SIY inoculation or secondary B16-SIY re-inoculation. [Figure 15C4] Effect of Compound 142 and Compound 119 on in vivo tumor growth rate and survival rate. C: Mean tumor volume ± SEM and tumor volume of individual mice receiving primary B16-SIY inoculation or secondary B16-SIY re-inoculation. [Figure 16A] The effect of Compound 142, Compound 156, and Compound 119 on in vivo tumor growth rate. A: Mean tumor volume ± SEM of mice orally treated with Compound 142, Compound 156, or Compound 119 from day 7 to day 21 after B16-SIY inoculation. Statistically significant differences (**p<0.01, ***p<0.01) between treatment groups and vehicle control groups were calculated using two-way ANOVA. [Figure 16B] Effect of Compound 142, Compound 156, and Compound 119 on in vivo tumor growth rate. B: Survival rate of mice orally treated with Compound 142, Compound 156, or Compound 119 from days 7 to 21 after B16-SIY inoculation. [Figure 17] Treatment schedule for Compound 142, Compound 156, or Compound 119 in an in vivo efficacy experiment using oral compound administration. Efficacy experiment treatment schedule for a POC study monitoring tumor volume and survival rate of orally administered mice. Arrows indicate oral drug treatment. [Figure 18A]The effect of Compound 142, Compound 156, and Compound 119 on tumor growth rate in vivo. A: Mean tumor volume ± SEM of mice orally treated with Compound 142, Compound 156, or Compound 119 from day 7 to day 21 after EO771 inoculation. Statistical significance (p<0.01) between the treatment group and the vehicle control group was calculated using two-way ANOVA. [Figure 18B] Effect of Compound 142, Compound 156, and Compound 119 on in vivo tumor growth rate. B: Survival rate of mice orally treated with Compound 142, Compound 156, or Compound 119 from days 7 to 21 after EO771 inoculation. [Figure 19]

[0023] Figure 1 shows the treatment schedule for Compound 142 in an in vivo efficacy study using oral compound administration. Efficacy experiment treatment schedule for a POC study monitoring tumor growth in orally dosed mice. Arrows indicate oral drug treatment. [Figure 20] Effect of Compound 142 on in vivo tumor growth rate. Mean tumor volume ± SEM in mice receiving oral administration from day 7 to day 21 after GL261-LUC2-iRFP inoculation. Statistically significant differences (p<0.0001) between treatment groups and vehicle control groups were calculated using two-way ANOVA. [Figure 21A] In vitro CD4+ or CD8+ T cell stimulation. Purified T cells were stimulated with anti-CD3, anti-CD3 / CD28, or CEFx viral peptides and eight different concentrations of Compound 142. [Figure 21B] In vitro CD4+ or CD8+ T cell stimulation. Purified T cells were stimulated with anti-CD3, anti-CD3 / CD28, or CEFx viral peptides and eight different concentrations of Compound 142. DETAILED DESCRIPTION OF THE INVENTION

[0405] [Preparation Example] General information: All reactions involving air- or moisture-sensitive reagents or intermediates were carried out in flame-dried glassware under an argon atmosphere. Commercially available dry solvents (THF, toluene, MeOH, DMF, DCM) were used. 1 H-NMR and 13 C-NMR was recorded on a Bruker DRX400 (400 MHz). Multiplicities are indicated as: brs (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m (multiplet), and coupling constants (J) are given in Hertz (Hz). HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Waters Acquity Performance Liquid Chromatography (UPLC) with an SQ3100 mass detector spectrometer. Column: Acquity UPLC BEH C18 1.7 μm, 2.1 × 50 mm. Flow rate: 0.5 ml / min. Eluents: A: HO with 0.05% formic acid, and B: ACN with 0.05% TFA. All chemicals and solvents were purchased from commercial sources such as Sigma-Aldrich, Fluka, TCI, Acros Organics, ABCR, Alfa Aesar, Enamine, VWR, Combi-Blocks, Apollo Scientific, Aquilla Pharmatech, Ark Pharm, DL Chiral Chemicals, ChemBridge, Renno Tech, Accela, KeyOrganics, Pharmablock, and Chem Impex. Unless otherwise noted, all commercially available compounds were used as received without further purification.

[0406] Abbreviations used in the description and examples are as follows: mCPBA (meta-chloroperoxybenzoic acid), chx (cyclohexane), DAST (diethylaminosulfur trifluoride), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DCM (dichloromethane), DIPEA (N,N-diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), LCMS (liquid chromatography mass spectrometry), 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-butyldimethylsilyl), TFA (trifluoroacetic acid), THF (tetrahydrofuran), T MAD (N,N,N',N'-tetramethylazodicarboxamide), TMB (1,3,5-trimethoxybenzene), TLC (thin layer chromatography), TPP (triphenylphosphine), Tos (tosyl, p-toluenesulfonyl); ACK (ammonium chloride-potassium chloride), CD (cluster of differentiation), CCR (CC motif receptor), DMEM (Dulbecco's modified Eagle's medium), FBS (fetal bovine serum), EDTA (ethylenediaminetetraacetic acid), FACS (fluorescence activated cell sorting), HPbCD (2-hydroxypropyl-β-cyclodextrin), HPMC (hydroxypropyl methylcellulose), PEG400 (polyethylene glycol), Pen-Strep (penicillin-streptomycin), PBMC (peripheral blood mononuclear cells), PBS (phosphate buffered saline).

[0407] General information General Procedures and Synthetic Routes for Disclosed Compounds The following sections describe some general procedures by which one skilled in the art can synthesize many of the key intermediates and final compounds disclosed in this patent. The synthetic approach is not limited to the synthetic routes and reactions outlined. The materials described herein can also be obtained by other conditions or reaction sequences published in the literature.

[0408] Synthetic Route Route 1

[0409] [ka]

[0410] Route 2

[0411] [ka]

[0412] Route 3

[0413] [ka]

[0414] General Procedure General Procedure A: Mitsunobu Reaction

[0415] [ka]

[0416] Dissolve phenol (1.0 eq.) and alcohol (1.5 eq.) in dry THF (0.1 M). Dry the solution with 4 Å molecular sieves. Remove the molecular sieves, cool to 0°C, add TPP (2.2 eq.), and seal the reaction vessel. Stir at 0°C for 30 minutes, then add TMAD (2.6 eq.) and stir for another 30 minutes at 0°C. Heat to 55°C and stir overnight. After the reaction is complete, add Celite and evaporate the solvent. Purify by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[0417] General Procedure B: Nucleophilic Substitution Reaction

[0418] [ka]

[0419] Dissolve phenol (1.0 eq.), halide (1.5 eq.), and K2CO3 (3.0 eq.) in dry acetonitrile (0.1 M). Stir the mixture overnight at 60 °C in a sealed vessel. After completion of the reaction, add Celite and remove volatiles under reduced pressure. Purify by 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 starting materials, the equivalents of phenol and halide can be reversed.

[0420] General Procedure C: Aryltrimethoxyphenyliodonium Salts

[0421] [ka]

[0422] Iodoarene (1.0 eq.) was dissolved in dry acetonitrile (0.15 M). The solution was acidified with pTSA (1.1 eq.). mCPBA (1.1 eq.) was then added and stirred at 80 °C for 1-2 h. Once the oxidation step was complete, 1,3,5-trimethoxybenzene (TMB) was added and stirred for an additional 30 min at 80 °C. After the reaction was complete, Celite was added and the volatiles were removed under reduced pressure. The product was purified by normal phase column chromatography (silica, DCM / methanol gradient).

[0423] General Procedure D: O-Arylation with Aryl-trimethoxyphenyliodonium Salts

[0424] [ka]

[0425] Suspend 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 by normal phase column chromatography (silica gel, cyclohexane / ethyl acetate gradient). To broaden the scope of the reaction, phenol and K2CO3 can be replaced by an aliphatic alcohol and NaH.

[0426] General Procedure E: Miyaura Borylation

[0427] [ka]

[0428] In dry 1,4-dioxane (0.1 M), aryl halide (1.0 eq.), bis(pinacolato)diboron (1.2 eq.), Pd(dppf)Cl2 * Dissolve DCM (0.1 eq.) and KOAc (3.0 eq.). Seal the reaction vessel and stir at 90 °C overnight. After completion of the reaction, add Celite and remove volatiles under reduced pressure. Purify by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[0429] General Procedure F: Suzuki Cross-Coupling

[0430] [ka]

[0431] In a 4:1 mixture of 1,4-dioxane and water (0.1 M), 8-bromoxanthine derivative (1.0 eq.), boronic acid ester (1.2 eq.), Pd(dppf)Cl2 * Dissolve DCM (0.1 eq.) and K3PO4 (3.0 eq.). Seal the reaction vessel and stir at 90 °C overnight. After completion of the reaction, add Celite and remove volatiles under reduced pressure. Purify by normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient). Boronic esters can be replaced by boronic acids.

[0432] General Procedure G: TBDMS deprotection of alcohols

[0433] [ka]

[0434] Dissolve TBDMS-protected alcohol (1.0 eq.) in THF (0.1 M). Add concentrated hydrochloric acid (15 eq.) and stir at room temperature overnight. After deprotection is complete, remove volatile components under reduced pressure. Dissolve the residue in DMSO and purify by reverse-phase HPLC (C18 column, water (0.1% TFA) and ACN (0.1% TFA) gradient). Lyophilize the desired fraction to give the final compound.

[0435] General Procedure H: SEM Protection

[0436] [ka]

[0437] The xanthine derivative (1.0 eq.) is dissolved in dry THF (0.2 M) and DIPEA (6.0 eq.). SEM-Cl (4.0 eq.) is added and stirring is continued at room temperature overnight. If the reaction is incomplete, additional DIPEA and SEM-Cl are added. After completion of the reaction, saturated NaHCO3 solution is added, the mixture is concentrated under reduced pressure, Celite is added, and the volatile components are removed under reduced pressure. Purification is carried out by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[0438] General Procedure I: TBDMS and SEM-Deprotection

[0439] [ka]

[0440] Dissolve the SEM and TBDMS protected compound (1.0 eq.) in THF (0.1 M). Add concentrated hydrochloric acid (15.0 eq.) and stir at room temperature overnight. Remove volatiles under reduced pressure and add a solution of ammonia in methanol (25.0 eq., 7 M). Stir at room temperature for 30 min. Remove volatiles under reduced pressure again, dissolve the residue in DMSO, and purify by reverse-phase HPLC (C18 column, water (0.1% TFA) / acetonitrile (0.1% TFA) gradient). Lyophilize the desired fraction to give the final compound.

[0441] General Procedure J: Deoxyfluorination of Alcohols

[0442] [ka]

[0443] Dissolve 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 for 2 hours at 20°C. After the reaction is complete, Celite is added and the solvent is evaporated. Purification can be achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). A suitable alternative reagent is DAST.

[0444] General Procedure K: Deoxyfluorination of Aldehydes and Ketones

[0445] [ka]

[0446] Dissolve the aldehyde or ketone (1.0 equiv.) in dry DCM (0.1 M) and cool 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 the volatiles. Purify by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). DAST can be used instead of deoxofluor.

[0447] General Procedure L: Dess-Martin oxidation

[0448] [ka]

[0449] Dissolve the alcohol (1.0 eq.) in dry DCM (0.1 M). Add Dess-Martin periodinane (2.0 eq.) and seal the reaction vessel. Stir at 60°C. After completion of the reaction, add Celite and evaporate the volatiles. Purify by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[0450] General Procedure M: Aromatic Nucleophilic Substitution

[0451] [ka]

[0452] Dissolve aryl fluoride (1.0 eq.), phenol (1.5 eq.), and K2CO3 (3.0 eq.) in dry DMSO (0.1 M). Stir the mixture at 110 °C for 3 h in a sealed reaction vessel. After completion of the reaction, add Celite and remove the volatiles under reduced pressure. Purify by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). An alternative suitable base is Cs2CO3. Depending on the availability of starting materials, the equivalents of phenol and halide can be reversed. The reaction can be carried out under microwave irradiation instead of conventional heating.

[0453] General Procedure N: Aromatic Nucleophilic Substitution Reactions (Pyridine)

[0454] [ka]

[0455] Aryl fluoride (1.0 eq.), phenol (1.5 eq.), and K2CO3 (3.0 eq.) are dissolved in dry DMF (0.1 M). The mixture is stirred in a sealed reaction vessel at 110 °C. After completion of the reaction, Celite is added and the volatile components are removed under reduced pressure. Purification is carried out by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Suitable alternative bases are Cs2CO3 or K3PO4. Depending on the availability of starting materials, the equivalents of phenol and halide can be reversed. An alcohol can also be used instead of the phenol. The reaction can be carried out under microwave irradiation instead of conventional heating.

[0456] General Procedure O: Telescopic SNAr / Suzuki Reaction

[0457] [ka]

[0458] Aryl fluoride (1.5 eq.), alcohol (1.5 eq.), and K3PO4 (4.0 eq.) are dissolved in dry 1,4-dioxane (0.1 M). The mixture is stirred at 100 °C in a sealed reaction vessel. After the first step is complete, (hetero)aryl bromide (1.0 eq.), Pd(dppf)Cl2 * Add DCM (0.1 eq.) and water to a 4:1 ratio of 1,4-dioxane:water. Stir at 100°C. After the second reaction is complete, add Celite and remove the volatiles under reduced pressure. Purify by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Depending on the availability of starting materials, the equivalents of boronic acid and halide can be reversed. Alcohols can also be used instead of phenols.

[0459] General Procedure P: N-3 Alkylation of 7-Methylxanthine Derivatives

[0460] [ka]

[0461] Dissolve 7-methylxanthine derivative (1.0 eq.), MgO (1.0 eq.), and TBAB (1.0 eq.) in dry DMSO (0.1 M) and heat to 100°C. Add epoxide (1.1 eq.) and seal the reaction vessel. Stir at 100°C. After completion of the reaction, add Celite and evaporate the volatiles. Purify by normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient).

[0462] General Procedure Q: TBDMS Deprotection

[0463] [ka]

[0464] Dissolve TBDMS-protected xanthine derivative (1.0 eq.) and CsF (5.0 eq.) in dry EtOH / DMSO 5 / 1 (0.1 M). The reaction vessel is sealed and stirred at 60 °C. After completion of the reaction, add Celite and evaporate the volatile components. Purify by normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient). The reaction can be carried out under microwave irradiation instead of conventional heating.

[0465] [Example] Preparation of 8-bromo-3-(2-hydroxypropyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione (1)

[0466] [ka]

[0467] To a stirred solution of 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione (5 g, 20.49 mmol) in DMF (50 mL) at room temperature, 1-bromo-2-propanol (4.24 g, 30.73 mmol) and DBU (3.1 g, 20.49 mmol) were added. The resulting reaction mixture was stirred at 90° C. for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The reaction mixture was diluted with DCM (100 mL), and the precipitated solid was collected. The crude product was dried under vacuum to obtain compound 1 (3.66 g, 59%) as an off-white solid. 1HNMR (400MHz, DMSO-d6) δ:11.16(brs,1H),4.80(d,J=5.2Hz,1H),4.06-4.00( m,1H),3.88-3.78(m,4H),3.69(dd,J=13.4,5.6Hz,1H),1.05(d,J=6.0Hz,3H). Actual value 303.1[M+H] + , LCMS(ESI+):C9H Calculated value for 11BrN4O3: 302.00.

[0468] Preparation of (R)-8-bromo-3-(3,3-difluoro-2-hydroxypropyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione (3b)

[0469] [ka]

[0470] To a mixture of 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione (3.13 g, 12.8 mmol), MgO (429 mg, 10.6 mmol), and tetrabutylammonium bromide (3.77 g, 11.7 mmol) in 60 mL of DMSO was added 1.0 g (10.6 mmol) of (R)-2-(difluoromethyl)oxirane at 60 °C. The reaction mixture was stirred overnight and filtered through Celite. The filtrate was concentrated under reduced pressure and purified by reverse-phase column chromatography (RP18, water / acetonitrile gradient) to give (R)-8-bromo-3-(3,3-difluoro-2-hydroxypropyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 3b. LCMS (ESI+): Found 339 / 341 (1:1) [M+H] + , calculated value for C9H9BrF2N4O3 338.0 / 340.0.

[0471] Preparation of 5-(difluoromethyl)-2,2-dimethyl-1,3-dioxane 69

[0472] [ka]

[0473] To a stirred solution of 2,2-dimethyl-1,3-dioxane-5-carbaldehyde (300 mg, 2.08 mmol) in DCM (6 mL) was added DAST (0.55 mL, 4.16 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The crude product was purified by column chromatography, and the compound was eluted in 10% EtOAc in petroleum ether. Fractions containing the compound were combined and evaporated to give 69 (0.2 g, 58%) as a brown liquid. H NMR (400 MHz, CDCl) δ ppm: 6.09 (td, J = 56.0, 7.2 Hz, 1H), 4.04-4.08 (m, 2H), 3.99-3.90 (m, 2H), 1.89-1.98 (m, 1H), 1.46 (s, 3H), 1.40 (s, 3H).

[0474] Preparation of 2-(difluoromethyl)propane-1,3-diol 70

[0475] [ka]

[0476] To a stirred solution of compound 69 (1.3 g, 7.82 mmol, 1.0 eq.) in MeOH:HO (3:1, 26 mL) was added p-TSA (1.61 g, 9.38 mmol, 1.2 eq.) at 0 °C, and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated to remove excess volatiles, diluted with ethyl acetate, and washed with water. The separated organic phase was dried over NaSO, filtered, and concentrated under reduced pressure to give compound 70 (400 mg, 41% yield) as a viscous, pale yellow syrup. H NMR (400 MHz, CDCl) δ ppm: 6.09 (td, J = 56.0, 5.2 Hz, 1H), 4.02-3.95 (m, 4H), 2.05-2.24 (m, 2H).

[0477] Preparation of 3,3-difluoro-2-(hydroxymethyl)propyl methanesulfonate 111

[0478] [ka]

[0479] To a stirred solution of compound 70 (200 mg, 1.58 mmol, 1.0 eq.) in DCM (4 mL) was added triethylamine (0.22 mL, 1.58 mmol, 1.0 eq.) and methanesulfonyl chloride (0.12 mL, 1.58 mmol, 1.0 eq.) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure to remove excess volatiles to give compound 111 (120 mg, 37%). The crude compound was used in the next step as a viscous, pale yellow syrup without further purification. 1HNMR (400MHz, CDCl3) δppm: 6.12-5.82 (m, 1H), 4.49-4.39 (m, 3H), 3.92-3.89 (m, 1H), 3.06-3.08 (m, 3H), 2.73-2.44 (m, 1H).

[0480] Preparation of 8-bromo-3-(3,3-difluoro-2-(hydroxymethyl)propyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 71

[0481] [ka]

[0482] To a stirred solution of compound 111 (100 mg, 0.49 mmol, 1.0 eq.) in DMF (1 mL) was added 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione (179 mg, 0.73 mmol, 1.5 eq.) and DBU (73 mg, 0.49 mmol, 1.0 eq.). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted with EtOAc (2 × 10 mL). The organic layer was washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography using 3% methanol in dichloromethane as the mobile phase to give compound 71 (100 mg, 58%) as a colorless solid. H NMR (400 MHz, CDCl) δ ppm: 11.31 (s, 1H), 6.11 (td, J = 56.0, 4 Hz, 1H), 4.84 (t, J = 5.2 Hz, 1H), 4.13 (dd, J = 14 Hz, 1H), 3.98 (dd, J = 14 Hz, 1H), 3.82 (s, 3H), 3.52 (t, J = 5.2 Hz, 2H). LCMS (ESI+): found 355.3 [M+H]+, calculated for C10H11BrF2N4O3: 354.0.

[0483] Preparation of 8-bromo-7-methyl-3-(3,3,3-trifluoro-2-(hydroxymethyl)propyl)-3,7-dihydro-1H-purine-2,6-dione 71a 2-((8-bromo-7-methyl-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)-3,3,3-trifluoropropanoic acid

[0484] [ka]

[0485] To a solution of 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione (2.5 g, 10.20 mmol, 1.0 equiv.) and 2-(trifluoromethyl)acrylic acid (1.43 g, 10.20 mmol, 1.0 equiv.) in DMF (50 ml) was added DBU (1.5 ml, 10.20 mmol, 1.0 equiv.) in a sealed microwave vial at room temperature under an argon atmosphere. The reaction mixture was then stirred at 80 °C under microwave irradiation for 30 min until LC-MS indicated complete consumption of the starting material. All volatiles were evaporated under reduced pressure to give the crude product (2.8 g), which was used in the next step without further purification. LC-MS: found 386.06 [M+H] + , calculated for CHBrFNO 383.97.

[0486] Methyl 2-((8-bromo-7-methyl-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)-3,3,3-trifluoropropanoate

[0487] [ka]

[0488] To a stirred solution of 2-((8-bromo-7-methyl-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)-3,3,3-trifluoropropanoic acid (2.8 g, 7.27 mmol, 1.0 equiv.) in methanol (28 ml) at 0 °C, sulfuric acid (143 mg, 1.45 mmol, 0.2 equiv.) was added under an argon atmosphere. The reaction mixture was then stirred at 70 °C for 16 h until the starting material was completely consumed. All volatile solvents were evaporated under reduced pressure to give the crude product, which was purified by column chromatography (230-400 mesh silica) using 58% ethyl acetate in petroleum ether as the eluent. The compound-containing fractions were concentrated and dried to give methyl 2-((8-bromo-7-methyl-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)-3,3,3-trifluoropropanoate as a colorless solid. LC-MS: found 399.12 [M+H], calculated for C11H10BrF3N4O4 397.98.

[0489] 8-Bromo-7-methyl-3-(3,3,3-trifluoro-2-(hydroxymethyl)propyl)-3,7-dihydro-1H-purine-2,6-dione 71a

[0490] [ka]

[0491] To a solution of methyl 2-((8-bromo-7-methyl-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl)-3,3,3-trifluoropropanoate (900 mg, 2.25 mmol, 1.0 equiv.) in THF (20 ml) at 0° C. was added LiBH (2 M in THF (2.3 ml, 4.5 mmol, 2 equiv.)) under an argon atmosphere. The reaction mixture was then stirred at room temperature for 5 hours. The progress of the reaction was monitored by LC-MS, which showed complete consumption of the starting material. The reaction mixture was quenched with ice-cold water (10 ml) and extracted with ethyl acetate (5×50 ml). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (230-400 mesh silica) using 75% ethyl acetate in petroleum ether as the eluent. Fractions containing the compound were concentrated and dried to give 8-bromo-7-methyl-3-(3,3,3-trifluoro-2-(hydroxymethyl)propyl)-3,7-dihydro-1H-purine-2,6-dione as a colorless solid. LC-MS: found 371.19 [M+H], calculated for C10H10BrF3N4O3 369.99. The components listed in Table A-1 can be used as derivatives, e.g. 1 , 3b , 71 ,or 71a can be prepared similarly to the method described for

[0492] [Table 2-1]

[0493] [Table 2-2]

[0494] [Table 2-3]

[0495] [Table 2-4]

[0496] 8-Bromo-3-(2-((tert-butyldimethylsilyl)oxy)propyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione ( 8 Preparation of

[0497] [ka]

[0498] Compound in DMF (35 mL) 1 To a stirred solution of (3.5 g, 11.55 mmol) at room temperature was added imidazole (5.2 g, 34.7 mmol) and TBDMSCl (2.36 g, 34.7 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by LC-MS), the reaction was cooled to room temperature. The reaction mixture was evaporated under reduced pressure. The crude product was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give HCl as a white solid. 8 (4.22 g, 87.5%). ¹H NMR (400 MHz, DMSO-d₆) δ: 11.28 (s, 1H), 4.22-4.19 (m, 1H), 3.95-3.90 (m, 1H), 3.81 (s, 3H), 3.70 (dd, J = 13.2, 4.0 Hz, 1H), 1.12 (d, J = 6 Hz, 3H), 0.70 (s, 9H), -0.05 (s, 3H), -0.25 (s, 3H). LCMS (ESI+): Found 417.3 [M+H] + Calculated value for C15H25BrN4O3Si: 416.1 8-Bromo-3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoropropyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 13 Preparation of

[0499] [ka]

[0500] Compound 1 in dry DMF (2 mL) 71 To a stirred solution of 1,2-dimethyl-3-(2,4-dichloro-2,6-dichloro-1,7-dione)-2-methyl-1,2-dichloro-2,4-dione (100 mg, 0.28 mmol, 1.0 equiv.), imidazole (39 mg, 0.57 mmol, 2.0 eq.) and TBDMS-Cl (86 mg, 0.57 mmol, 2.0 eq.) were added. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (2 x 10 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography using 3% methanol in dichloromethane to give compound (III). 13 (75 mg, 58%) was obtained as a colorless solid. LCMS (ESI+): Found 467.3 [M+H] + , Calculated value of C16H25BrF2N4O3Si 466.01.1HNMR(400MHz,DMSO-d6)δppm:11.30(s,1H),6.11(td,J=56.0,4.4Hz,1H),4.13 -4.04(m,2H),3.81(s,3H),3.72(d,J=4.8Hz,2H),2.67-2.51(m,1H),0.81(s,9H),-0.010(s,3H),-0.018(s,3H).

[0501] The components in Table A-2 below can be expressed as, for example, compounds 8 or 13 It can be synthesized as shown in

[0502] [Table 3-1]

[0503] [Table 3-2]

[0504] [Table 3-3]

[0505] [Table 3-4]

[0506] 8-(4-(benzyloxy)-3-methoxyphenyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 15 Preparation of

[0507] [ka]

[0508] 500 mg of 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione, 790 mg of (4-(benzyloxy)-3-methoxyphenyl)boronic acid, 170 mg of Pd(dppf)Cl * DCM and 423 mg of K2CO3 were suspended in 20 ml of 1,4-dioxane / water (1:1) under a nitrogen atmosphere and heated to 100 °C until the reaction was complete. After cooling to room temperature, 15 ml of water was added to precipitate the product, which was collected by filtration. The crude product was then triturated overnight with 30 ml of acetonitrile. The solid was collected, washed, and dried to give 680 mg of compound (III). 15 LCMS (ESI-): Found value 377 [MH] - , calculated value for C20H18N4O4: 378.13.

[0509] 8-(4-(benzyloxy)-3-fluorophenyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 15a Preparation of

[0510] [ka]

[0511] Anhydrous sodium carbonate (216 mg, 2.04 mmol, 2.0 equiv.) was added to a solution of 8-bromo-7-methyl-3,7-dihydro-1H-purine-2,6-dione (250 mg, 1.02 mmol, 1.0 equiv.) and (4-(benzyloxy)-3-fluorophenyl)boronic acid (276 mg, 1.12 mmol, 1.1 equiv.) in a mixed solvent (1,4-dioxane (6 mL) and HO (3 mL)) at room temperature under an argon atmosphere. The entire reaction mixture was degassed with argon for 15 minutes, after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (41.7 mg, 0.051 mmol, 0.05 equiv.) was added. The reaction was then stirred at 100° C. for 1 hour under microwave irradiation, H2O (20 ml) was added, and extracted with EtOAc (3×150 ml). The combined organic extracts were washed with brine (1×30 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified as follows: 18 Purification by reverse-phase column chromatography on silica gel using 50%-60% ACN in HO gave 8-(4-(benzyloxy)-3-fluorophenyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione (142 mg) as a colorless solid. LC-MS: Found 367.14 [M+H] + , calculated value for C19H15FN4O3: 366.1.

[0512] Preparation of 7-methyl-8-(3-(trifluoromethoxy)-4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1H-purine-2,6-dione 15b

[0513] [ka]

[0514] 7-Methyl-8-(3-(trifluoromethoxy)-4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1H-purine-2,6-dione was prepared analogously to 8-(4-(benzyloxy)-3-fluorophenyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione. LC-MS: found 503.2 [M+H], calculated for CHFNO 502.1.

[0515] 8-(4-(benzyloxy)-3-methoxyphenyl)-3-(2-hydroxypropyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 16 Preparation of

[0516] [ka]

[0517] 150mg of compound 15 , 0.051 ml of 1-bromo-2-propanol, and 46 mg of Na2CO3 were suspended in 3.9 ml of DMF under a nitrogen atmosphere and stirred at 50 °C for 72 hours. After cooling to room temperature, an appropriate amount of water was added to precipitate the product, which was then collected, washed, and dried. The pure compound 16 was obtained after purification by preparative TLC (DCM / MeOH, 15:1). LCMS (ESI+): Found 437 [M+H] + , calculated value for C23H24N4O5: 436.17.

[0518] 8-(4-(benzyloxy)-3-fluorophenyl)-3-(3,4-difluoro-2-hydroxybutyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 203 Preparation of 4,4-Dimethyl-3,5,8-trioxabicyclo[5.1.0]octane

[0519] [ka]

[0520] m-CPBA (26.84 g, 156.04 mmol, 2.0 equiv.) and NaHCO (13.1 g, 156.04 mmol, 2.0 equiv.) were added to a stirred solution of 2,2-dimethyl-4,7-dihydro-1,3-dioxepine (10 g, 78.02 mmol, 1.0 equiv.) in DCM (250 mL) at 0 °C under an inert atmosphere. The mixture was then stirred at room temperature for 16 h. The resulting solid was filtered through a filter paper and washed with excess DCM (3 × 100 mL). The combined filtrate was washed with saturated NaHCO3 (2 × 100 mL), brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel (100-200 mesh) column chromatography using 15-20% EtOAc in petroleum ether to give 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (7.5 g) as a colorless liquid. 1 HNMR (400MHz, CDCl3) δppm: 4.03 (qd, J=14.4Hz, 1.2Hz, 4H), 3.21-3.20 (m, 4H), 1.37 (s, 3H), 1.32 (s, 3H).

[0521] 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluoroethan-1-ol

[0522] [ka]

[0523] Triethylamine trihydrofluoride (97%) (83.86 g, 520.2 mmol, 3.0 equiv.) was added to a Teflon vial containing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (25 g, 173.4 mmol, 1.0 equiv.) at room temperature under an argon atmosphere. The vial was then tightly capped and stirred at 65 °C for 24 h. The reaction mixture was cooled to room temperature, poured into ice-cold saturated NaHCO solution (300 mL), stirred for 30 min, and then extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with saturated NaHCO solution (1 × 100 mL), brine (1 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel (230-400 mesh) column chromatography using 35% EtOAc in petroleum ether as the eluent to give 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluoroethan-1-ol (7.2 g) as a colorless liquid. 1 HNMR (400MHz, CDCl3) δppm:4.65-4.45(m,1H),4.36-4.27(m,1H),4.13-4.08(m,1H),3.95-3.82(m,3H),2.04(brs,1H),1.44(s,3H),1.38(s,3H).

[0524] 4-(1,2-difluoroethyl)-2,2-dimethyl-1,3-dioxolane

[0525] [ka]

[0526] DAST (8.84 mL, 67 mmol, 2.5 equiv.) was added to a stirred solution of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluoroethan-1-ol (4.4 g, 26.8 mmol, 1.0 equiv.) in toluene (60 mL) and stirred at room temperature under an argon atmosphere. After 5 minutes, pyridine (6.42 mL, 80.4 mmol, 3.0 equiv.) was added to the reaction at room temperature, followed by stirring at room temperature for 8 hours. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaHCO (1 × 50 mL), brine (1 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 4-(1,2-difluoroethyl)-2,2-dimethyl-1,3-dioxolane (0.8 g) as a pale yellow liquid, which was used in the next step without further purification. 1 HNMR(400MHz, CDCl3)δppm:4.75-4.53(m,3H),4.32-4.22(m,1H),4.13-4.08(m,1H),3.95(dd,J=8.4Hz,6.4Hz,1H),1.43(s,3H),1.37(s,3H).

[0527] 3,4-Difluorobutane-1,2-diol

[0528] [ka]

[0529] 4-(1,2-Difluoroethyl)-2,2-dimethyl-1,3-dioxolane (0.800 g, 4.81 mmol, 1.0 equiv.) was dissolved in methanol (10 ml) under an argon atmosphere and cooled to °C. p-Toluenesulfonic acid monohydrate (91.58 mg, 0.481 mmol, 0.1 equiv.) was then added, and the reaction was stirred at room temperature for 5 hours. All volatiles were removed under reduced pressure. The resulting residue was dissolved in EtOAc (100 ml), and the organic layer was washed with saturated NaHCO (3 × 20 ml), brine (2 × 20 ml). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The obtained crude product was purified by silica gel (230-400 mesh) column chromatography using 40% EtOAc in petroleum ether as eluent to give 3,4-difluorobutane-1,2-diol (170 mg) as a colorless liquid. 1 HNMR (400MHz, CDCl3) δppm:4.79-4.67(m,3H),4.01-3.92(m,1H),3.84-3.75(m,1H),2.45(d,J=5.2Hz,1H),1.94(t,J =5.6Hz,3H).

[0530] 3,4-Difluoro-2-hydroxybutyl trifluoromethanesulfonate

[0531] [ka]

[0532] To a solution of 3,4-difluorobutane-1,2-diol (20 mg, 0.159 mmol, 1 equiv.) in dry DCM (2 mL) was added triethylamine (99%, 24.1 mg, 0.238 mmol, 1.5 equiv.), followed by trifluoromethanesulfonic anhydride, 98% (53.697 mg, 0.190 mmol, 1.2 equiv.). All reagent additions were carried out at 0° C. and under an argon atmosphere. The reaction was then stirred at room temperature for 3 hours. The reaction progress was monitored by TLC, which showed complete consumption of SM (a solution of 50% EtOAc in petroleum ether, Rf =0.55, H2SO4). The reaction was quenched by the addition of ice-cold water (5 mL) and diluted with DCM (2 x 30 mL). The combined organic extracts were washed with 1N NaHCO3 (1 x 5 mL), brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used immediately in the next step.

[0533] 8-(4-(benzyloxy)-3-fluorophenyl)-3-(3,4-difluoro-2-hydroxybutyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 203

[0534] [ka]

[0535] Cesium carbonate (56.1 mg, 0.172 mmol, 2.0 equiv.) was added to a solution of 8-(4-(benzyloxy)phenyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione (30 mg, 0.086 mmol, 1 equiv.) in dry DMF (2 mL) at room temperature under an argon atmosphere and stirred for 30 minutes under an argon atmosphere. 3,4-Difluoro-2-hydroxybutyl trifluoromethanesulfonate (28.90 mg, 0.112 mmol, 1.3 equiv.) was then added to the reaction flask and the reaction was stirred at 60° C. for 30 hours. The progress of the reaction was monitored by LC-MS. HO (10 mL) was added and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with ice-cold water (3 x 20 ml), brine (3 x 20 ml), dried over anhydrous NaSO, filtered through cotton, and concentrated to give the crude product, which was first purified by reverse phase chromatography (C) using a solution of 30% ACN in water (0.01% acetic acid). 18Purification by column chromatography gave, after lyophilization, 8-(4-(benzyloxy)-3-fluorophenyl)-3-(3,4-difluoro-2-hydroxybutyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione as an off-white solid. 1 HNMR(400MHz,DMSO-d6)δppm:11.11(s,1H),7.71(dd,J=12.4Hz,2.0Hz,1H),7.60-7.58(m,1H),7.50-7.34(m 6H), 5.47 (brs, 1H), 5.28 (s, 2H), 4.84-4.58 (m, 3H), 4.23-4.12 (m, 2H), 4.05-4.00 (m, 1H), 3.98 (s, 3H). LC-MS: Actual value 475.3 [M+H] + ,Calculated value for C23H21F3N4O4: 474.15.

[0536] 7-methyl-3-(4,4,4-trifluoro-2-hydroxybutyl)-8-(3-(trifluoromethoxy)-4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1H-purine-2,6-dione 216 Preparation of

[0537] [ka]

[0538] Dissolve 30 mg of 7-methyl-8-(3-(trifluoromethoxy)-4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1H-purine-2,6-dione 15b (1.0 eq.), 2.6 mg of MgO (1.0 eq.), and 21.2 mg of TBAB (1.0 eq.) in 1 mL of dry DMSO (0.1 M) and heat to 100 °C. Add 6.4 μL of 2-(2,2,2-trifluoroethyl)oxirane (1.1 eq.) and seal the reaction vessel. Stir at 100 °C. After completion of the reaction, add Celite and evaporate the volatiles. Purification by normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient) gave 7-methyl-3-(4,4,4-trifluoro-2-hydroxybutyl)-8-(3-(trifluoromethoxy)-4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1H-purine-2,6-dione 216. LCMS (ESI+): Found 629.5 [M+H] + , calculated value for C24H17F9N4O6 628.1 The compounds in Table A-3 below can be used, for example, as compounds 16 , 203 ,or 216 was synthesized as exemplified by

[0539] [Table 4-1]

[0540] [Table 4-2]

[0541] [Table 4-3]

[0542] (4-(trifluoromethoxy)phenyl)(2,4,6-trimethoxyphenyl)iodonium 4-methylbenzenesulfonate 104 Preparation of

[0543] [ka]

[0544] 20.0 g of 1-iodo-4-(trifluoromethoxy)benzene was dissolved in 250 ml of dry acetonitrile. 13.15 g of pTSA and 26.0 mg of mCPBA were added, and the reaction was stirred at 80° C. for 2 hours. Once oxidation was complete, 12.8 g of 1,3,5-trimethoxybenzene was added, and stirring was continued for an additional 30 minutes at 80° C. The mixture was concentrated under reduced pressure, and the residue was absorbed onto Celite. Volatiles were removed under reduced pressure. Purification was achieved by normal phase column chromatography (silica, DCM / methanol gradient). LCMS (ESI+): Found 454.8 [M] + , C16H15F3IO4 + The calculated value is 455.00.

[0545] (2-(trifluoromethoxy)phenyl)(2,4,6-trimethoxyphenyl)iodonium 4-methylbenzenesulfonate 108 Preparation of

[0546] [ka]

[0547] 150 mg of 1-iodo-2-(trifluoromethoxy)benzene was dissolved in 3 ml of dry acetonitrile. 117 mg of pTSA and 167 mg of mCPBA were added, and the reaction was stirred at 55° C. for 1 hour. Once oxidation was complete, 96 mg of 1,3,5-trimethoxybenzene was added, and stirring was continued for an additional 30 minutes at 55° C. The mixture was adsorbed onto Celite. Volatiles were removed under reduced pressure. Purification was achieved by normal phase column chromatography (silica, DCM / methanol gradient). LCMS (ESI+): Found 454.6 [M] + , C16H15F3IO4 + The calculated value is 455.0.

[0548] The compounds in Table A-4 below are 104 , 108 or synthesized as exemplified in the literature. Other iodonium salts were commercially available.

[0549] [Table 5-1]

[0550] [Table 5-2]

[0551] [Table 5-3]

[0552] [Table 5-4]

[0553] [Table 5-5]

[0554] 1-Bromo-4-(4-(trifluoromethoxy)phenoxy)benzene 105 Preparation of

[0555] [ka]

[0556] 8.29 g of 4-bromophenol, iodonium tosylate in 250 ml of acetonitrile 104 A solution of 17.65 g of K2CO3 was heated at 55°C overnight. Part of the solvent was removed under reduced pressure and the residue was adsorbed onto Celite. 105Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). GCMS (EI): m / z found 334.2 [M] +· Calculated value for C13H8BrF3O2: 333.96 4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-1,3,2-dioxaborolane 106 Preparation of

[0557] [ka]

[0558] 10g bromide 105 11.43 g of bis(pinacolato)diborane, 1.22 g of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride in dichloromethane, and 11.91 g of potassium acetate were mixed in 200 ml of 1,4-dioxane. The reaction was stirred at 100° C. until the reaction was complete. A portion of the solvent was removed under reduced pressure, and the residue was adsorbed onto Celite. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). LCMS (ESI+): Found 381.2 [M+H] + , calculated value for C19H20BF3O4 380.14.

[0559] 4-Bromo-2-(difluoromethoxy)-1-((4-methylbenzyl)oxy)benzene 130 Preparation of

[0560] [ka]

[0561] 52 mg of p-tolylmethanol and 53 mg of KOtBu were added to 2 ml of ice-cold toluene under a nitrogen atmosphere. The mixture was allowed to warm to room temperature. 388 mg of iodonium salt 129was added and stirring was continued at room temperature for 1.5 hours. The reaction mixture was adsorbed onto Celite and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). LCMS (ESI+): Found 343.4 [M+H] + , calculated value for C15H13BrF2O2: 342.01.

[0562] 2-(3-(difluoromethoxy)-4-((4-methylbenzyl)oxy)phenyl )-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 131 Preparation of

[0563] [ka]

[0564] 85mg bromide 130 , 94 mg bis(pinacolato)diborane, 42 mg [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride in dichloromethane, and 49 mg potassium acetate were mixed in 1.5 mL of 1,4-dioxane. The reaction was stirred at 85 °C until completion and then directly absorbed onto Celite. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). LCMS (ESI+): Found 391.3 [M+H] + , calculated value for C21H25BF2O4: 390.18.

[0565] 2-(4-((4-(difluoromethyl)benzyl)oxy)-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 17 Preparation of

[0566] [ka]

[0567] 500 mg of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 603 mg (1.3 equivalents) of 1-(bromomethyl)-4-(difluoromethyl)benzene, and 138 mg of K2CO3 were heated to 60 °C in 10 ml of dry acetonitrile and stirred until the reaction was complete. The mixture was adsorbed onto Celite, dried, and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give compound (III). 17 LCMS (ESI+): Found 379 [M+H] + , calculated value for C20H22BF3O3: 378.16.

[0568] 2-(4-(benzyloxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 20 Preparation of

[0569] [ka]

[0570] A solution of 324 mg of benzyl alcohol and 500 mg of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol in 5 ml of THF was dried over 3 Å molecular sieves and then transferred to a solution of 1.15 g of triphenylphosphine in 5 ml of THF at 0 °C under nitrogen. 860 mg of TMAD was added. After 30 min, the reaction mixture was heated to 55 °C until the reaction was complete. The mixture was adsorbed onto Celite, dried, and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give compound (III). 20 LCMS (ESI+): Found 341 [M+H] + , calculated value for C20H25BO4: 340.18.

[0571] 1-(benzyloxy)-4-bromo-2-(trifluoromethoxy)benzene 23 Preparation of

[0572] [ka]

[0573] Benzyl bromide (4.16 g), 4-bromo-2-(trifluoromethoxy)phenol (2.5 g), and Cs2CO3 (9.5 g) were mixed in 30 ml of THF and stirred at 60 °C until the reaction was complete. The mixture was adsorbed onto Celite, dried, and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give compound (III). 23 LCMS (ESI+): Found 348.6 [M+H] + , C1 Calculated value for 4H10BrF3O2: 347.98.

[0574] 2-(4-(benzyloxy)-3-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 24 Preparation of

[0575] [ka]

[0576] 3.5 g of bromine derivative in 30 ml of 1,4-dioxane 23 , 0.411g Pd(dppf)Cl2 * A solution of DCM, 4.0 g of potassium acetate, and 3.84 g of bis(pinacolato)diboron was heated to 100° C. until the reaction was complete. Most of the solvent was evaporated, and the residue was adsorbed onto Celite and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give the pure compound. 24 LCMS (ESI+): Found 395 [M+H] + , calculated value for C20H22BF3O4: 394.16.

[0577] 4,4,5,5-tetramethyl-2-(3-(trifluoromethoxy)-4-(4-(trifluoromethoxy)phenoxy)phenyl)-1,3,2-dioxaborolane 337c Preparation of

[0578] [ka]

[0579] In 100 ml of 1,4-dioxane, 11.0 g of the bromine derivative 333f and 2.16 g of Pd(dppf)Cl2 * A solution of DCM, 10.4 g of potassium acetate, and 10.1 g of bis(pinacolato)diboron was heated to 90° C. until the reaction was complete. Most of the solvent was evaporated, and the residue was adsorbed onto Celite and purified by normal phase column chromatography (330 g of silica, cyclohexane / ethyl acetate gradient) to give pure boronic ester 337c. LCMS (ESI+): Found 465.3 [M+H] + , calculated value for C20H19BF6O5: 464.12.

[0580] 1-(4-chlorophenyl)-2,2-difluoroethan-1-ol 331a

[0581] [ka]

[0582] Dissolve 219 mg of 4-chlorobenzaldehyde (1.0 eq.) in 12 ml of dry DMF (0.1 M) and add 236 mg of CsF (1.0 eq.). Heat to 40 °C, add 400 μL of TMS-CF2H, and seal the reaction vessel. Stir at 40 °C for 4 hours. After the addition is complete, add 3.1 mL of 1 M TBAF solution (2.0 eq.). After the reaction is complete, add Celite and evaporate the volatiles. Purify by reverse-phase column chromatography (C18, acetonitrile / water) to obtain 1-(4-chlorophenyl)-2,2-difluoroethan-1-ol. GCMS (EI): Found 192.2 [M]·+ , calculated value for C8H7ClF2O: 192.0 1-(3,4-Dichlorophenyl)-2,2-difluoroethan-1-ol 331b

[0583] [ka]

[0584] 1-(3,4-Dichlorophenyl)-2,2-difluoroethan-1-ol was prepared as exemplified in 1-(4-chlorophenyl)-2,2-difluoroethan-1-ol 331a. GCMS (EI): Found 226.2 [M] + , calculated value for C8H6Cl2F2O: 226.0 1-(4-chloro-3-fluorophenyl)-2,2-difluoroethan-1-ol 331c

[0585] [ka]

[0586] 1-(4-Chloro-3-fluorophenyl)-2,2-difluoroethan-1-ol was prepared as exemplified in 1-(4-chlorophenyl)-2,2-difluoroethan-1-ol 331a. GCMS (EI): Found 210.2 [M]+, calculated for C8H6ClF3O 210.0 1-(3-chloro-4-methylphenyl)-2,2-difluoroethan-1-ol 331d

[0587] [ka]

[0588] 1-(3-Chloro-4-methylphenyl)-2,2-difluoroethan-1-ol was prepared as exemplified in 1-(4-chlorophenyl)-2,2-difluoroethan-1-ol 331a. GCMS (EI): Found 206.2 [M]+, calculated for C9H9ClF2O 206.0 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-ol 332a

[0589] [ka]

[0590] Dissolve 1500 mg of 2-(benzyloxy)-5-bromobenzaldehyde (1.0 eq.) in 20 ml of dry DMF (0.1 M) and add 782 mg of CsF (1.1 eq.). Heat to 40 °C, add 1.66 ml of TMS-CF2H (2.5 eq.) to the reaction, and seal the reaction vessel. Stir at 40 °C for 4 hours. After the addition is complete, add 10.3 mL of 1 M TBAF solution (2.0 eq.). After the reaction is complete, add Celite and evaporate the solvent. Purify by normal phase column chromatography (silica gel, cyclohexane / ethyl acetate / methanol gradient) to give 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-ol. GCMS (EI): Found 342.4 [M] ·+ , calculated value for C15H10BrF5O3: 342.0 1-(5-Bromo-2-(4-(trifluoromethoxy)phenoxy)phenyl)-2,2-difluoroethan-1-ol 333a

[0591] [ka]

[0592] Prepared from 5-bromo-2-(4-(trifluoromethoxy)phenoxy)benzaldehyde as exemplified for 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-ol. GCMS (EI): Found 412.2 [M] ·+ , calculated value for C15H13BrF2O2: 412.0 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-one 332b

[0593] [ka]

[0594] Dissolve 500 mg of 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-ol (1.0 eq.) in 4 ml of dry DCM. Add 1235 mg of Dess-Martin periodinane (2.0 eq.) and seal the reaction vessel. Stir at 60°C for 6 hours. After completion of the reaction, add Celite and evaporate the volatiles. Normal phase column Purification by column chromatography (silica, cyclohexane / ethyl acetate gradient) gave 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-one. GCMS (EI): Found 340.0 [M] ·+ , calculated value for C15H11BrF2O2: 340.0.

[0595] 1-(5-bromo-2-(4-(trifluoromethoxy)phenoxy)phenyl)-2,2-difluoroethan-1-one 333b

[0596] [ka]

[0597] Prepared from 1-(5-bromo-2-(4-(trifluoromethoxy)phenoxy)phenyl)-2,2-difluoroethan-1-ol as exemplified for 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-one. GCMS (EI): Found 410.0 [M] ·+ Calculated value for C15H8BrF5O3: 410.0 1-(benzyloxy)-4-bromo-2-(1,1,2,2-tetrafluoroethyl)benzene 332c

[0598] [ka]

[0599] Dissolve 150 mg of 1-(2-(benzyloxy)-5-bromophenyl)-2,2-difluoroethan-1-one (1.0 eq.) in 5 ml of dry DCM (0.1 M) and cool to 0°C. Add 322 μl of deoxofluor (50 wt% in toluene, 2.1 eq.) and seal the reaction vessel. Stir at 20°C for 2 hours. After completion of the reaction, add Celite and evaporate the volatiles. Purification by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) gave 1-(benzyloxy)-4-bromo-2-(1,1,2,2-tetrafluoroethyl)benzene. GCMS (EI): Found 361.9 [M] ·+ Calculated value for C15H11BrF4O: 362.0 1-(benzyloxy)-4-bromo-2-(difluoromethyl)benzene 332d

[0600] [ka]

[0601] Prepared from 2-(benzyloxy)-5-bromobenzaldehyde as exemplified for 1-(benzyloxy)-4-bromo-2-(1,1,2,2-tetrafluoroethyl)benzene. GCMS (EI): Found 312.0 [M] ·+ Calculated value for C14H11BrF2O: 312.0 4-Bromo-2-(difluoromethyl)-1-(4-(trifluoromethoxy)phenoxy)benzene 333d

[0602] [ka]

[0603] Prepared from 5-bromo-2-(4-(trifluoromethoxy)phenoxy)benzaldehyde as exemplified for 1-(benzyloxy)-4-bromo-2-(1,1,2,2-tetrafluoroethyl)benzene. GCMS (EI): Found 382.2 [M] ·+ Calculated value for C14H8BrF5O2: 382.0 4-Bromo-2-(1,1,2,2-tetrafluoroethyl)-1-(4-(trifluoromethoxy)phenoxy)benzene 333e

[0604] [ka]

[0605] Prepared from 1-(5-bromo-2-(4-(trifluoromethoxy)phenoxy)phenyl)-2,2-difluoroethan-1-one as exemplified by 1-(benzyloxy)-4-bromo-2-(1,1,2,2-tetrafluoroethyl)benzene. GCMS (EI): Found 432.4 [M] ·+ Calculated value for C15H8BrF7O2: 432.0 1-(benzyloxy)-4-bromo-2-(fluoromethyl)benzene 332e

[0606] [ka]

[0607] Dissolve 250 mg of (2-(benzyloxy)-5-bromophenyl)methanol (1.0 eq.) in 5 ml of dry DCM (0.1 M) and cool to 0°C. Add 314 μl of deoxofluor (50 wt% solution in toluene, 1.1 eq.) and seal the reaction vessel. Stir at 20°C for 2 hours. After completion of the reaction, add Celite and evaporate the solvent. Purify by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give 1-(benzyloxy)-4-bromo-2-(fluoromethyl)-benzene. GCMS (EI): Found 294.0 [M] ·+, calculated value for C14H12BrFO 294.0 4-Bromo-2-(trifluoromethoxy)-1-(4-(trifluoromethoxy)phenoxy)benzene 333f

[0608] [ka]

[0609] 5 g of 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene (1.0 eq.), 4.1 ml of 4-(trifluoromethoxy)-phenol (1.5 eq.), and 5.3 g of K2CO3 (3.0 eq.) were dissolved in 20 ml of dry DMSO (0.1 M). The mixture was stirred in a sealed reaction vessel at 110 °C for 3 h. After completion of the reaction, Celite was added and the volatiles were removed under reduced pressure. Purification by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) gave 4-bromo-2-(trifluoromethoxy)-1-(4-(trifluoromethoxy)phenoxy)benzene. GCMS (EI): Found 416.3 [M] ·+ , calculated value for C14H7BrF6O3: 415.9.

[0610] 5-Bromo-3-isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine 334a

[0611] [ka]

[0612] 200 mg of 5-bromo-2-fluoro-3-isopropoxypyridine (1.0 eq.), 259 μL of 4-(trifluoromethoxy)phenol (1.5 eq.), and 402 mg of K2CO3 (3.0 eq.) are dissolved in 2 mL of dry DMF (0.1 M). The mixture is stirred in a sealed reaction vessel at 110 °C for 3 h. After completion of the reaction, Celite is added and the volatiles are removed under reduced pressure. Purification by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) afforded 5-bromo-3-isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine. LCMS (ESI+): Found 392.1 [M+H] + , calculated value for C15H13BrF3NO3: 391.0.

[0613] 5-Bromo-3-methyl-2-(4-(trifluoromethoxy)phenoxy)pyridine 334b

[0614] [ka]

[0615] Prepared from 5-bromo-2-fluoro-3-methylpyridine as exemplified for 5-bromo-3-isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine. LCMS (ESI+): Found 348.0 [M+H] + , calculated value for C13H9BrF3NO2 347.0 5-Bromo-2-(4-(trifluoromethoxy)phenoxy)pyridine 334c

[0616] [ka]

[0617] Prepared from 5-bromo-2-fluoropyridine as exemplified for 5-bromo-3-isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine. LCMS (ESI+): Found 334.1 [M+H] +, calculated value for C12H7BrF3NO2 333.0 5-Bromo-3-(difluoromethyl)-2-(4-(trifluoromethoxy)phenoxy)pyridine 334d

[0618] [ka]

[0619] Prepared from 5-bromo-3-(difluoromethyl)-2-fluoropyridine as exemplified for 5-bromo-3-isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine. LCMS (ESI+): Found 383.0 [M+H] + Calculated value for C13H7BrF5NO2: 383.0 5-Bromo-3-methoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine 334e

[0620] [ka]

[0621] Prepared from 5-bromo-2-fluoro-3-methoxypyridine as exemplified in 5-bromo-3-isopropoxy-2-(4-(trifluoromethoxy)phenoxy)pyridine. LCMS (ESI+): Found 363.0 [M+H] + , calculated value for C13H9BrF3NO3 363.0 5-Bromo-3-chloro-2-((4-methylbenzyl)oxy)pyridine 334f

[0622] [ka]

[0623] 200 mg of 5-bromo-3-chloro-2-fluoropyridine (1.0 eq.), 151 mg of p-tolylmethanol (1.3 eq.), and 438 mg of K2CO3 (2.0 eq.) are dissolved in 6 ml of dry DMSO (0.15 M). The reaction vessel is sealed and stirred under microwave irradiation for 10 min at 120 °C. Purification by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) gave 5-bromo-3-chloro-2-((4-methylbenzyl)oxy)pyridine. LCMS (ESI+): Found 312.5 [M+H] + Calculated value for C13H11BrClNO: 311.0 Similar to 5-bromo-3-chloro-2-((4-methylbenzyl)oxy)pyridine 334f, other 5-bromo-2-alkoxypyridine derivatives were synthesized, for example, 5-bromo-3-chloro-2-(1-phenylethoxy)pyridine (LCMS (ESI+): found 312.1 [M+H] + , calculated for CHBrClNO 311.0) and 5-bromo-3-chloro-2-((4-(difluoromethyl)benzyl)oxy)pyridine (LCMS (ESI+): found 348.0 [M+H] + , calculated value for C14H13BrClNO 347.0). 2-(4-(benzyloxy)-3-cyclobutoxyphenyl)-4,4,5,5-tetrahydrofuran Preparation of tetramethyl-1,3,2-dioxaborolane 337i

[0624] [ka]

[0625] Dissolve 150 mg of 2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 eq.) and 47 μl of cyclobutanol (1.5 eq.) in 5 ml of dry THF (0.1 M). Dry the solution with 4 Å molecular sieves. Remove the molecular sieves, cool to 0 °C, add 241 mg of TPP (2.2 eq.), and seal the reaction vessel. Stir for 30 min at 0 °C, then add 187 mg of TMAD (2.6 eq.) and stir for another 30 min at 0 °C. Heat to 55 °C and stir overnight. After completion of the reaction, add Celite and evaporate the solvent. Purification by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) gave 2-(4-(benzyloxy)-3-cyclobutoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS (ESI+): Found 531.4 [M+H] + , calculated value for C23H29BO4: 530.2 The components of Table A-5 below are, for example, compounds 17 , 20 , 24 , 106 , 131 , 337c , 337i It was synthesized as exemplified in

[0626] [Table 6-1]

[0627] [Table 6-2]

[0628] [Table 6-3]

[0629] [Table 6-4]

[0630] Table 6-5

[0631] Table 6-6

[0632] Table 6-7

[0633] Table 6-8

[0634] Table 6-9

[0635] Table 6-10

[0636] Table 6-11

[0637] Table 6-12

[0638] Table 6-13

[0639] Table 6-14

[0640] Table 6-15

[0641] Table 6-16

[0642] Table 6-17

[0643] Table 6-18

[0644] Table 6-19

[0645] Table 6-20

[0646] Table 6-21

[0647] Table 6-22

[0648] Table 6-23

[0649] Table 6-24

[0650] Table 6-25

[0651] [Table 6-26]

[0652] [Table 6-27]

[0653] [Table 6-28]

[0654] [Table 6-29]

[0655] 8-(4-((4-(difluoromethyl)benzyl)oxy)-3-fluorophenyl)-7-methyl-3-(3,3,3-trifluoro-2-hydroxypropyl)-3,7-dihydro-1H-purine-2,6-dione 18 Synthesis of

[0656] [ka]

[0657] 730mg bromide 4 , 70 mg of boronic ester 17 100 mg of K3PO4, and 26.6 mg of Pd(dppf)Cl2 were added to 3 ml of 1,4-dioxane / water (5:1) under a nitrogen atmosphere, and the mixture was heated to 100 °C until the starting material disappeared. The mixture was adsorbed onto Celite, dried, and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give compound 18. LCMS (ESI+): Found 529.3 [M+H] + , calculated value for C23H18F6N4O4 528.12.

[0658] 8-(4-(benzyloxy)-3-methoxyphenyl)-3-(3,3-difluoro-2-hydroxypropyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 68 Preparation of

[0659] [ka]

[0660] 50mg bromide 10 , 66 mg of boronic ester 20 , 70 mg of K3PO4, and 18.7 mg of Pd(dppf)Cl2 were added to 3 ml of 1,4-dioxane / water (5:1) under a nitrogen atmosphere, and the mixture was heated to 100 °C until the starting material disappeared. The mixture was adsorbed onto Celite, dried, and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give the protected intermediate. The intermediate was dissolved in 1.5 ml of THF / 200 μl of 2 M hydrochloric acid, and the mixture was stirred at 60 °C overnight to remove the protecting group. The mixture was adsorbed onto Celite and purified by reverse phase column chromatography (RP18, water / acetonitrile gradient) to give compound 1. 68 LCMS (ESI+): Found 473.3 [M+H] + , calculated value for C23H22F2N4O5: 472.16.

[0661] 8-(4-(benzyloxy)-3-(trifluoromethoxy)phenyl)-3-(2-hydroxypropyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 120 Preparation of

[0662] [ka]

[0663] 150 mg of 8-(4-(benzyloxy)-3-(trifluoromethoxy)phenyl)-3-(2-((tert-butyldimethylsilyl)oxy)-propyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione (1.0 eq.) and 192 mg of CsF (5.0 eq.) are dissolved in 5 ml of dry EtOH / DMSO 9 / 1 (0.1 M). The reaction vessel is sealed and stirred overnight at 80°C. After completion of the reaction, Celite is added and the volatiles are evaporated. Purification by normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient) afforded 8-(4-(benzyloxy)-3-(trifluoromethoxy)phenyl)-3-(2-hydroxypropyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione. 120 LCMS (ESI+): Found 491.2 [M+H] + , calculated value for C23H21F3N4O5: 490.1.

[0664] 8-(5-chloro-6-((4-chloro-3-fluorobenzyl)oxy)pyridin-3-yl)-7-methyl-3-(3,3,3-trifluoro-2-hydroxypropyl)-3,7-dihydro-1H-purine-2,6-dione 299 Preparation of

[0665] [ka]

[0666] 150 mg of 3-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.5 eq.), (4-chloro-3-fluorophenyl)methanol (1.5 eq.), and K3PO4 (4.0 eq.) are dissolved in 3 ml of dry 1,4-dioxane (0.1 M). The mixture is stirred in a sealed reaction vessel at 100 °C for 5 h. After the initial reaction is complete, 35 mg of 8-bromo-7-methyl-3-(3,3,3-trifluoro-2-hydroxypropyl)-3,7-dihydro-1H-purine-2,6-dione (1.0 eq.), 5.9 mg of Pd(dppf)Cl2 are added.* Add DCM (0.05 eq.) and 750 μL of water. Stir at 100° C. for 2 hours. After the second reaction is complete, add Celite and remove volatiles under reduced pressure. Normal phase Purification by column chromatography (silica, cyclohexane / ethyl acetate gradient) gave 8-(5-chloro-6-((4-chloro-3-fluorobenzyl)oxy)pyridin-3-yl)-7-methyl-3-(3,3,3-trifluoro-2-hydroxypropyl)-3,7-dihydro-1H-purine-2,6-dione. LCMS (ESI+): found 548.4 [M+H]+, calculated for C21H15Cl2F4N5O4 547.0 The compounds in Table A-6 below, as exemplified by compounds 18, 68, 120, 299, etc., were synthesized using 8-bromoxanthine derivatives listed in Table A-1 or Table A-2 and commercially available boronic acids or boronic acid esters listed in Table A-5, or were synthesized according to procedures described herein or in the literature.

[0667] [Table 7-1]

[0668] [Table 7-2]

[0669] [Table 7-3]

[0670] [Table 7-4]

[0671] [Table 7-5]

[0672] Table 7-6

[0673] Table 7-7

[0674] Table 7-8

[0675] Table 7-9

[0676] Table 7-10

[0677] Table 7-11

[0678] Table 7-12

[0679] Table 7-13

[0680] Table 7-14

[0681] Table 7-15

[0682] Table 7-16

[0683] Table 7-17

[0684] Table 7-18

[0685] Table 7-19

[0686] Table 7-20

[0687] Table 7-21

[0688] Table 7-22

[0689] Table 7-23

[0690] Table 7-24

[0691] Table 7-25

[0692] Table 7-26

[0693] [Table 7-27]

[0694] [Table 7-28]

[0695] [Table 7-29]

[0696] [Table 7-30]

[0697] [Table 7-31]

[0698] [Table 7-32]

[0699] 8-Bromo-3-(2-((tert-butyldimethylsilyl)oxy)propyl)-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-1H-purine-2,6-dione 42 Preparation of

[0700] [ka]

[0701] 3.0 g of compound 8 and 3.74 ml of DIPEA were dissolved in 20 ml of THF. 2.55 ml of SEMCl was added at room temperature and the reaction mixture was stirred overnight. Additional SEMCl (0.5 ml) and DIPEA (1 ml) were added and the reaction was again stirred at room temperature overnight. Ethyl acetate was added and the organic layer was washed with saturated NaHCO3 solution, dried over MgSO4 and the volatiles were removed under reduced pressure. The crude product was pure enough to be used in the next reaction without further purification. LCMS (ESI+): Found 547.3 [M+H] + , calculated value for C21H39BrN4O4Si2: 546.17.

[0702] 3-(2-((tert-butyldimethylsilyl)oxy)propyl)-8-(3-fluoro-4-hydroxyphenyl)-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-3,7-dihydro-1H-purine-2,6-dione 43 Preparation of

[0703] [ka]

[0704] 2.5g bromide 42 , 1.3 g of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 0.39 g of Pd(dppf)Cl * DCM and 2.91 g of KPO were stirred overnight at 90 °C in 30 ml of 1,4-dioxane / water (4:1) under an inert atmosphere. The mixture was concentrated under reduced pressure and adsorbed onto Celite. Purification was carried out by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give the phenol. 43 LCMS (ESI+): Found 579.4 [M+H] + , calculated value for C27H43FN4O5Si2: 578.28.

[0705] 8-(4-(benzyloxy)-3-fluorophenyl)-3-(2-hydroxypropyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 44 Preparation of

[0706] [ka]

[0707] 30mg phenol 43 , and 12 mg of benzyl alcohol were dissolved in 1.5 ml of THF and dried over 4 Å molecular sieves. This solution was then transferred to a solution of 30 mg of triphenylphosphine in 0.5 ml of THF at 0 °C under a nitrogen atmosphere. After 30 min, TMAD was added, and after another 30 min at 0 °C, the mixture was heated at 55 °C overnight. The mixture was adsorbed onto Celite and purified by normal-phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient) to give the protected intermediate. To remove both protecting groups, the crude product was dissolved in 750 μl of THF and 750 μl of concentrated hydrochloric acid was added. After stirring at 30 °C, the volatiles were removed, and the crude product was dissolved in 2 ml of ammonia (0.5 M in dry 1,4-dioxane) at room temperature. After 5 min, the volatiles were again removed and the crude product was dissolved in DMSO and directly purified by reverse-phase HPLC (C18 column, water (0.1% TFA) / acetonitrile (0.1% TFA) gradient). The desired fractions were lyophilized to give the title compound. 44 LCMS (ESI+): Found 425.3 [M+H] + , calculated value for C22H21FN4O4 424.15.

[0708] 8-(4-(4-chlorophenoxy)-3-fluorophenyl)-3-(2-hydroxypropyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 197 Preparation of

[0709] [ka]

[0710] 130 mg of phenol in 4 ml of acetonitrile 43 , 218 mg of iodonium salt 159 A solution of 1,2-dimethyl-3-(2-methyl-2-propanol)-2,4-diol (2,2-dimethyl-2-propanol) and 62 mg of K2CO3 was stirred at 55 °C until the phenol was completely converted. The mixture was adsorbed onto Celite and purified by normal-phase column chromatography (silica, cyclohexane / ethyl acetate gradient). The protected intermediate was dissolved in 3 ml of DCM and 500 μl of TFA and stirred at 40 °C overnight. The volatiles were removed, and the crude product was dissolved in 3 ml of ammonia (7 M in methanol) at room temperature. After 5 min, the volatiles were removed again, and the crude product was dissolved in some DMSO and directly purified by reverse-phase HPLC (C18 column, water (0.1% TFA) / acetonitrile (0.1% TFA) gradient). The desired fractions were lyophilized to give the title compound. 197 LCMS (ESI+): Found 445.4 [M+H] + , calculated value for C21H18ClFN4O4 444.1.

[0711] 3-(2-((tert-butyldimethylsilyl)oxy)propyl)-8-(4-hydroxy-3-(trifluoromethyl)phenyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 154 Preparation of

[0712] [ka]

[0713] 100mg bromide 8 , 104 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenol, 30.4 mg of Pd(dppf)2Cl *DCM and 153 mg of KPO were mixed with 2.5 ml of 1,4-dioxane / water (4:1) under an inert atmosphere and stirred at 90 °C overnight. The mixture was concentrated under reduced pressure and adsorbed onto Celite. Purification was carried out by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give the phenol. 154 LCMS (ESI+): Found 499.2 [M+H] + , calculated value for C22H29F3N4O4Si: 498.19.

[0714] 3-(2-hydroxypropyl)-7-methyl-8-(3-(trifluoromethoxy)-4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1H-purine-2,6-dione 155 Preparation of

[0715] [ka]

[0716] 100 mg of phenol in 4 ml of acetonitrile 154 , 138 mg of iodonium salt 104 A solution of 111 mg of methylpropanol and 111 mg of K2CO3 was stirred at 55 °C until the phenol was completely converted. The mixture was adsorbed onto Celite and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient). The protected intermediate was dissolved in 2 ml of THF and 500 μl of concentrated hydrochloric acid and stirred overnight at 28 °C. Purification was achieved by reverse phase HPLC (C18 column, water (0.1% TFA) / acetonitrile (0.1% TFA) gradient). The desired fractions were lyophilized to give the title compound. 155 LCMS (ESI+): Found 545, calculated for C23H18F6N4O5 544.12.

[0717] 3-(2-((tert-butyldimethylsilyl)oxy)propyl)-8-(4-hydroxy-3-(trifluoromethyl)phenyl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione 157 Preparation of

[0718] [ka]

[0719] 100mg bromide 8 , 104 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenol, 30.4 mg of Pd(dppf)Cl * DCM and 153 mg of KPO were mixed with 2.5 ml of 1,4-dioxane / water (4:1) under an inert atmosphere and stirred at 90 °C overnight. The mixture was concentrated under reduced pressure and adsorbed onto Celite. Purification was performed by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give the phenol. 157 LCMS (ESI+): Found 515.5 [M+H] + , calculated value for C22H29F3N4OOSi 514.19.

[0720] 3-(2-hydroxypropyl)-7-methyl-8-(3-(trifluoromethoxy) -4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,7-dihydro-1H-purine-2,6-dione 156 Preparation of

[0721] [ka]

[0722] 100 mg of phenol in 4 ml of acetonitrile 157 , 138 mg of iodonium salt 104A solution of 111 mg of methylpropanol and 111 mg of K2CO3 was stirred at 55 °C until the phenol was completely converted. The mixture was adsorbed onto Celite and purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate / methanol gradient). The protected intermediate was dissolved in 2 ml of THF and 500 μl of concentrated hydrochloric acid and stirred overnight at 28 °C. Purification was achieved by reverse phase HPLC (C18 column, water (0.1% TFA) / acetonitrile (0.1% TFA) gradient). The desired fractions were lyophilized to give the title compound. 156 LCMS (ESI+): Found 561.1 [M+H] + , calculated value for C23H18F6N4O6 560.11.

[0723] The compounds in Table A-7 below are 44 , 155 , 156 , 197 It was synthesized as exemplified by others.

[0724] [Table 8-1]

[0725] [Table 8-2]

[0726] [Table 8-3]

[0727] [Table 8-4]

[0728] [Table 8-5]

[0729] [Table 8-6]

[0730] [Table 8-7]

[0731] [Table 8-8]

[0732] [Table 8-9]

[0733] [Table 8-10]

[0734] [Table 8-11]

[0735] Biological Examples 1. Example B-1: Immune stimulation assay using CD4+ T cells and CD8+ T cells In Example B-1, we demonstrate the principle of selecting potent compounds based on structure-activity relationship (SAR) using human anti-CD3 / 28 stimulated T cells. Enhanced activation in stimulated T cells is measured by CD69 expression by flow cytometry.

[0736] 1.1 Bioassay materials

[0737] [ka]

[0738] 1.2 Procedures / Instructions 1.2.1 Collection of PBMCs from buffy coat Leukocyte-enriched buffy coats were obtained from the Austrian Red Cross and diluted to a total volume of 480 mL with PBS. 30 mL was transferred to a 50 mL Falcon and 11 mL of LymphoPrep was added. The cell suspension was centrifuged for 20 minutes at 2200 rpm, and the PBMC-containing layer was removed, washed three times with PBS, and counted.

[0739] 1.2.2 Isolation of CD4+ and CD8+ T cells 10 7 PBMCs were magnetically labeled with CD4 and CD8 microbeads according to the manufacturer's instructions and separated using an autoMACS instrument. For dose-response experiments with purified CD4+CD8+ T cells, 80,000 cells were seeded per 96-well flat-bottom cell culture dish.

[0740] 1.2.3 Serial Dilutions of Compounds of the Invention 10 mM stocks of compounds of the invention were further diluted with DMSO and equal volumes were transferred to 96-well plates containing T cells. 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 μM, and 0.001 μM.

[0741] 1.2.4 Stimulus setup for EC50 testing For stimulation assays, purified CD4+ and CD8+ T cells were seeded at 80,000 cells per 96-well plate and incubated with 1 μg / ml anti-CD3, 1 μg / ml anti-CD28, and compounds of the invention ranging from 0.001 μM to 30 μM. DMSO-only wells served as controls to determine minimal T cell activation in response to stimulation, while CD3 / 28-conjugated Dynabeads were used to determine maximal T cell activation. Cells were cultured for 16 hours in a humidified incubator at 37°C and 5% CO2.

[0742] 1.2.5 Determination of EC50 values ​​for compounds of the invention by surface FACS T cells were stained for surface antigens (anti-CD4 and anti-CD8) and cell activation markers (anti-CD25 and anti-CD69). Additionally, fixable viability stains were used to stain live cells. Staining was performed for 15 minutes, and cells were analyzed using a Fortessa flow cytometer and FlowJo software. EC 50 was calculated using GraphPad Prism® and a variable slope model (agonist vs. response - variable slope).

[0743] The assay results are summarized in Table B-1. Table B-1 shows the data from the immune stimulation assay. The immune stimulation in CD4+ T cells and CD8+ T cells was measured using EC 50 The activity is expressed as [nM] ("-" indicates not determined). Compounds with activity indicated as "A" have an EC 50 compounds with an activity designated "B" have a saturation of 100 nM or less; <EC 50 compounds with an activity designated "C" have a saturation of 500 nM or less; <EC 50 compounds with an activity designated "D" have a saturation of 1000 nM <EC 50 Compounds with an activity designated "E" have an EC 50 It showed >5000nM.

[0744] [Table 9-1]

[0745] [Table 9-2]

[0746] [Table 9-3]

[0747] [Table 9-4]

[0748] [Table 9-5]

[0749] 2 Example B-2: In vitro killing activity Compounds 119, 142, 156, 120, 288, 248, 240, 238, 213, and 207 were tested for their potential to enhance PBMC or T cell-mediated killing activity in allogeneic M21 melanoma cells using Xcelligence-based methodology.

[0750] 2.1 Bioassay materials

[0751] [ka]

[0752] 2.2 Procedure / Overview 2.2.1 Seeding of M21 melanoma cells E-plates were coated with 10 μg / ml fibronectin for 1 hour at 37°C. Subconfluent M21 melanoma cells were trypsinized, counted, and 5,000 fibronectin-coated cells per 96-well plate were seeded in RPMI containing 10% FCS and 1% PenStrep. M21 cells were cultured at 37°C and 5% CO2 in a humidified incubator and used for coculture with purified PBMCs or purified T cells 20–24 hours after seeding.

[0753] 2.2.2 Collection of PBMCs from buffy coat Leukocyte-enriched buffy coats were obtained from the Austrian Red Cross and diluted to a total volume of 480 mL with PBS. 30 mL was transferred to a 50 mL Falcon and 11 mL of LymphoPrep was added. The cell suspension was centrifuged at 2200 rpm for 20 minutes, and the PBMC-containing layer was removed, washed three times with PBS, and counted. For dose-response experiments using PBMC coculture, 25,000 cells were seeded per 96-well E-Plate containing M21 (PBMC:M21 ratio 5:1).

[0754] 2.2.3 Isolation of CD4+ and CD8+ T cells 10 7 PBMCs were magnetically labeled with CD4 and CD8 microbeads according to the manufacturer's instructions and separated using an autoMACS instrument. For dose-response experiments with purified T cell cultures, 25,000 T cells were seeded per 96-well E-plate containing M21. (The ratio of T cells to M21 is 5:1).

[0755] 2.2.4 Serial Dilutions of Compounds of the Invention (LMW Compounds) 10 mM stocks of compounds of the invention were further diluted with DMSO and equal volumes were transferred to 96 wells containing M21 and PMBCs or 96 wells containing M21 and T cells. Final concentrations tested were: 10 μM, 3 μM, 1 μM, 0.3 μM, and 0.1 μM, or 10 μM, 3 μM, 1 μM, 0.3 μM, and 0.1 μM, 0.03 μM, 0.01 μM, or 0.003 μM.

[0756] 2.2.5 Xcelligence In Vitro Killing Assay E-plates containing M21 cell layers and isolated PBMCs, or M21 cell layers and isolated T cells, were incubated with 1 μg / ml anti-CD3, 1 μg / ml anti-CD28, and 0.1 μM to 10 μM LMW compounds. Wells containing DMSO alone, M21 alone (no effector cells), and unstimulated effector cells without anti-CD3 / 28 antibodies served as controls. E-plates were cultured for 40 hours in a humidified incubator at 37°C with 5% CO2, and M21 proliferation was monitored every 15 minutes using an Xcelligence instrument.

[0757] 2.2.6 Determination of EC50 Values ​​for Compounds of the Invention Using Xcelligence Xcelligence data were analyzed using GraphPad Prism and EC50s were calculated using a variable slope model (agonist vs. response - variable slope).

[0758] 2.3 Results 2.3.1 In vitro killing assay using stimulated PBMCs Stimulated PBMCs from two different donors were used to evaluate M21 melanoma cell killing over the course of 40 hours in the presence of five different concentrations of compound 142. PBMCs from both donors demonstrated efficient M21 killing in response to anti-CD3 / CD28 stimulation and the addition of compound 142 (+ / -), but not in a dose-dependent manner with increasing doses of compound 142 (Figures 3A and 3B).

[0759] Figures 3A and 3B show M21 cell proliferation in stimulated PBMC co-cultures. M21 melanoma cells were incubated with isolated PBMCs and stimulated with anti-CD3 / 28 and five concentrations of Compound 142.

[0760] 2.3.2 In vitro killing assays using stimulated CD4+ and CD8+ T cells Stimulated CD4+ and CD8+ T cells from one donor (donor 2) were co-cultured with M21 melanoma cells supplemented with compound 142, and cell proliferation was monitored for 40 hours. EC50 values ​​were calculated using GraphPad Prism 32 hours after addition of anti-CD3 / 28 antibody and compound 142. Purified T cells were , showed dose-dependent M21 killing in response to anti-CD3 / CD28 stimulation and increasing concentrations of compound 142, with an EC50 of 628 nM after 32 hours (Figures 4A and 4B).

[0761] Figures 4A and 4B show M21 cell proliferation in response to stimulated T cell co-culture. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / 28 and different concentrations of compound 142. EC50 values ​​were calculated using GraphPad Prism 32 hours after the addition of anti-CD3 / 28 and compound 142.

[0762] Stimulated CD4+ and CD8+ T cells from other donors were co-cultured with M21 melanoma cells with different concentrations of compound 142 (donor 3), compound 156 (donor 1), or compound 119 (donor 1), and cell proliferation was monitored for 40 hours. Purified T cells demonstrated dose-dependent M21 killing in response to anti-CD3 / CD28 stimulation and increasing concentrations of compound 142, 156, or 119 (Figure 5A-C).

[0763] Figures 5A-5C show the proliferation of M21 cells in stimulated T cell coculture. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / CD28 and different concentrations of Compound 142, Compound 156, or Compound 119.

[0764] Stimulated CD4+ and CD8+ T cells from the same donor as above were co-cultured with M21 melanoma cells with compound 142, compound 120, compound 156, compound 288, compound 119, compound 248, compound 240, compound 238, compound 213 (the active R enantiomer of compound 238), or compound 207 (the active R enantiomer of compound 240), and cell proliferation was monitored for 40 h. Purified T cells showed dose-dependent M21 killing with anti-CD3 / CD28 stimulation and increasing concentrations of compound 142, compound 120, compound 156, compound 288, compound 119, compound 248, compound 240, compound 238, compound 213, or compound 207 (Figure 5D-M). EC50 values ​​were calculated using GraphPad Prism 32 h after compound addition.

[0765] Figures 5D-5M show M21 cell proliferation in response to co-culture with stimulated T cells. M21 melanoma cells were incubated with purified CD4+ and CD8+ T cells and stimulated with anti-CD3 / 28 and different concentrations of Compound 142, Compound 120, Compound 156, Compound 288, Compound 119, Compound 248, Compound 240, Compound 238, Compound 213, or Compound 207.

[0766] 2.3.3 In vitro killing assays using unstimulated PBMCs and unstimulated T cells The killing efficiency of unstimulated PBMCs from one donor (donor 2) cocultured with M21 melanoma cells, and unstimulated CD4+ and CD8+ T cells from one donor (donor 2) cocultured with M21 melanoma cells, was evaluated in the presence of 10 μM compound 142. Unstimulated PBMCs cocultured with M21 cells showed efficient killing in response to compound 142 compared to DMSO controls, whereas coculture of purified T cells with M21 cells did not show enhanced killing even after 40 h (Figure 6).

[0767] Figure 6 shows M21 cell proliferation in co-culture with unstimulated PBMCs and unstimulated T cells. M21 melanoma cells were incubated with unstimulated PBMCs and 10 μM Compound 142, or with unstimulated T cells and 10 μM Compound 142.

[0768] 3 Example B-3: Efficacy against B16-SIY melanoma Compounds 142, 156, 120, 119, 288, 248, 240, 238, 213, 207, 260, 262, and 329 demonstrated preclinical efficacy in the murine B16-SIY melanoma model.

[0769] Individual compounds in the present invention were selected based on their potency, ADME and PK profiles and tested in immunocompetent C57BL / 6J mice implanted with B16-SIY melanoma cells.

[0770] 3.1 Bioassay materials

[0771] [ka]

[0772] [ka]

[0773] 3.2 Procedures / Instructions 3.2.1 Animals and Ethics Eight-week-old C57BL / 6 mice were purchased from Charles River. All animal experiments were conducted in accordance with the institutional guidelines of the Research Institute of Molecular Pathology (Austria) and approved in accordance with the European Community Animal Care Regulations under the permission of the Austrian Ministry of Science. Tumors with a volume of ≥1000 mm were excluded. 3 Mice were sacrificed when they reached the normal age or when a humane endpoint was reached.

[0774] 3.2.2 B16-SIY cell culture B16-SIY melanoma cells were cultured in DMEM containing 10% FCS, 1% PenStrep, and 1% glutamine in a humidified incubator at 37°C and 5% CO. For tumor inoculation, sub-confluent B16-SIY cells were trypsinized, washed, counted, and resuspended in PBS or a mixture of 50% PBS and 50% Matrigel at 1x10 7 The final concentration was B16-SIY cells / ml.

[0775] 3.2.3 Tumor inoculation and compound administration 3.2.3.1 Efficacy Experiment 1: Compound 142 1 × 10 in 30 C57BL / 6 mice 6 B16-SIY cells were inoculated intradermally, and 3 days after implantation, tumor-bearing mice were randomly assigned to three groups: one group (10 mice) received compound 142 at 30 mg / kg 3 days after B16-SIY inoculation followed by 10 mg / kg daily, one group (10 mice) received compound 142 at 9 mg / kg 3 days after B16-SIY inoculation followed by 3 mg / kg daily, or one group (10 mice) received vehicle control. Compound 142 was diluted in 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO and orally administered to mice on two dosing schedules: 30 mg / kg d3 + 10 mg / kg QD, or 9 mg / kg d3 + 3 mg / kg QD (Figure 1). 10% DMSO, 20% PEG400, and 21% HPbCD, 0.35% HPMC, and 48.65% HO served as vehicle controls. Tumors were measured daily, and mice were sacrificed on day 21 after B16-SIY inoculation (Figure 1).

[0776] 3.2.3.2 Efficacy Experiment 2: Compound 142 1 × 10 in 30 C57BL / 6 mice 6 B16-SIY cells were inoculated intradermally, and 3 days after implantation, tumor-bearing mice were randomly assigned to three different groups: Compound 142-treated group Mice were treated with either a 60 mg / kg D3 + 40 mg / kg Q2D (10 mice; 40 mg / kg was administered every 48 hours except on days 7 (30 mg / kg) and 9 (60 mg / kg) post-inoculation), a vehicle control group (10 mice; 100 μl QD), or an untreated group (10 mice). Compound 142 was diluted in 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO and orally administered to mice using different treatment regimens (Figure 7). Mice receiving compound 142 were treated with 60 mg / kg on day 3 post-inoculation with B16-SIY, followed by 40 mg / kg of compound 142 every 48 hours (60 mg / kg D3 + 40 mg / kg Q2D) except on days 7 (30 mg / kg) and 9 (60 mg / kg) post-inoculation. * Tumors were measured daily and mice were sacrificed 19 days after B16-SIY inoculation.

[0777] Figure 7 shows the dosing schedule for a POC study monitoring tumor volume and survival in mice in an in vivo efficacy experiment orally administered with compound 142. Arrows indicate oral drug treatment with compound 142. Asterisks indicate administration of 40 mg / kg of compound 142 every 48 hours, except on days 7 (30 mg / kg) and 9 (60 mg / kg).

[0778] 3.2.3.3 Efficacy Experiment 3: Compound 142 1 × 10 in 35 C57BL / 6 mice 6B16-SIY cells were inoculated intradermally, and 3 days after implantation, tumor-bearing mice were randomly assigned to three different groups: one group received 30 mg / kg of compound 142 4 days after B16-SIY inoculation, followed by 10 mg / kg daily (10 mice, 30 mg / kg D4 + 10 mg / kg QD); one group received 9 mg / kg of compound 142 4 days after B16-SIY inoculation, followed by 3 mg / kg daily (10 mice, 9 mg / kg D4 + 3 mg / kg QD); or a vehicle control group (10 mice, 100 μl QD). Compound 142 was diluted in 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO and orally administered to mice according to two different treatment schedules (Figure 8). 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO served as the control group. Tumors were measured daily, and mice were sacrificed on day 21 after B16-SIY inoculation.

[0779] 8 shows the treatment schedule for a POC study monitoring tumor volume and survival rate in mice in an in vivo efficacy experiment in which compound 142 was orally administered. The arrow indicates oral administration of compound 142.

[0780] 3.2.3.4 Efficacy Experiment 4: Compound 142 or Compound 120 1 × 10 in 40 C57BL / 6 mice 6B16-SIY cells were intradermally inoculated, and three days after implantation, tumor-bearing mice were randomly assigned to four different groups: Compound 142 treatment group (10 mice, 30 mg / kg D4 + 10 mg / kg QD), Compound 142 treatment group (10 mice, 30 mg / kg QD), Compound 120 treatment group (10 mice, 25 mg / kg QD), and vehicle control group (10 mice, 100 μl QD). Compound 142 and Compound 120 were diluted in 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO and orally administered to mice (Figure 9). 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO served as the vehicle control. Tumors were measured daily and mice were sacrificed 20 days after B16-SIY inoculation.

[0781] Figure 9 shows the treatment schedule for a POC study monitoring tumor volume and survival rate in mice in an in vivo efficacy study orally administered Compound 142 or Compound 120. Black arrows indicate daily oral administration of Compound 142 or Compound 120. The gray arrow indicates oral administration of Compound 142 every 3 days.

[0782] 3.2.3.5 Efficacy Test 5: Compound 142, Compound 156, or Compound 119 1 × 10 in 40 C57BL / 6 mice 6B16-SIY cells were intradermally inoculated, and 3 days after implantation, tumor-bearing mice were randomly assigned to four different groups: compound 142 treatment group (10 mice, 30 mg / kg D4 + 10 mg / kg QD), compound 156 treatment group (10 mice, 20 mg / kg D4 + 10 mg / kg QD), compound 119 treatment group (10 mice, 10 mg / kg QD), and vehicle control group (10 mice, 100 μl QD). Compounds 142, 155, and 119 were diluted in 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO and orally administered to mice (Figure 10). 10% DMSO, 20% PEG400, and 21% HPbCD, 0.35% HPMC, and 48.65% HO served as the control group. Tumors were measured daily, and mice were treated from days 4 to 21 after B16-SIY inoculation, followed by a 40-day treatment-free observation period. Tumors with a tumor volume of ≥1000 mm were treated. 3 Mice were sacrificed when they reached the humane endpoint or when they reached the normal age. Mice that survived beyond day 61 were re-inoculated intradermally with additional B16-SIY cells on day 62 as described above.

[0783] Figure 10 shows the treatment schedule for a POC study monitoring tumor volume and survival in mice orally administered with Compound 142, Compound 156, or Compound 119. Arrows indicate daily oral administration of Compound 142, Compound 156, or Compound 119.

[0784] 3.2.3.6 Efficacy Experiment 6: Compound 142, Compound 156, and Compound 119 1 × 10 in 55 C57BL / 6 mice 6 B16-SIY cells were inoculated intradermally, and 6 days after implantation, tumor-bearing mice were randomly assigned to five different groups, followed by daily administration on the 7th day: Compound 142 treatment group (10 mice, 30 mg / kg D7 + 10 mg / kg QD), Compound 156 treatment group (10 mice, 20 mg / kg D7 + 10 mg / kg QD), Compound 156 treatment group (10 mice, 6 mg / kg D7 + 3 mg / kg Mice were divided into three groups: a compound 142 group (10 mice, 10 mg / kg QD), a compound 119-treated group (10 mice, 10 mg / kg QD), and a vehicle control group (10 mice, 100 μl QD). Compound 142, compound 156, and compound 119 were diluted in 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO and orally administered to mice ( FIG. 11 ). 10% DMSO, 20% PEG400, and 21% HPbCD, 0.35% HPMC, and 48.65% HO served as the vehicle control. Tumors were measured daily, and tumor volumes of ≥1000 mm were evaluated. 3 Mice were sacrificed when they reached the humane endpoint or when they reached the normal age. Mice that survived beyond day 65 were reinoculated intradermally with additional B16-SIY cells on day 66 as described above and sacrificed on day 82.

[0785] Figure 11 shows the treatment schedule for a POC study monitoring tumor volume and survival in mice in an in vivo efficacy experiment orally administered with Compound 142, Compound 156, or Compound 119. Arrows indicate daily oral administration of Compound 142, Compound 156, or Compound 119.

[0786] 3.2.3.7 Efficacy Experiment 7: Compound 156 and Anti-PD1 1 × 10 in 41 C57BL / 6 mice 6 B16-SIY cells were inoculated intradermally, and 3 days after implantation, tumor-bearing mice were randomly assigned to four different groups (10 mice / group). Group 1 received Compound 156 (30 mg / kg D3 + 10 mg / kg QD) and a rat IgG2a isotype control antibody (BioXcell, clone 2A3; 10 mg / kg BIW), while Group 2 received Compound 156 (30 mg / kg D3 + 10 mg / kg QD). Group 1 received vehicle control (100 μl QD) and rat IgG2a isotype control antibody (BioXcell, clone 2A3; 10 mg / kg BIW), Group 2 received vehicle control (100 μl QD) and anti-PD1 antibody (BioXcell, clone RMP1-14; 10 mg / kg BIW), and Group 3 received vehicle control (100 μl QD) and rat IgG2a isotype control antibody (BioXcell, clone 2A3; 10 mg / kg BIW), and Group 4 received vehicle control (100 μl QD) and anti-PD1 antibody (BioXcell, clone RMP1-14; 10 mg / kg BIW). Compound 156 was diluted in 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, 48.65% HO and orally administered to mice (Figure 23). 10% DMSO, 20% PEG400, and 21% HPbCD, 0.35% HPMC, and 48.65% HO served as vehicle controls. Anti-PD1 antibodies and isotype control antibodies were diluted in PBS and administered intraperitoneally. Tumors in mice treated with B16-SIY were measured three times a week from day 3 to day 19 after inoculation. Mice were then cultured on day 19 or when tumor volumes were ≥ 2000 mm. 3 , or sacrificed when a humane endpoint was reached.

[0787] Figure 23 shows the treatment schedules for compound 156, isotype control, and anti-PD1 in an in vivo efficacy study with oral and intraperitoneal antibody administration. Black arrows indicate daily oral administration of compound 156, and gray arrows indicate twice-weekly intraperitoneal antibody treatment.

[0788] 3.2.3.8 Efficacy Experiment 8: Compound 156, Compound 238, Compound 213, Compound 207, and Compound 248 1 × 10 in 125 C57BL / 6 mice 6B16-SIY cells were inoculated intradermally, and 3 days after implantation, tumor-bearing mice were randomly assigned to 11 different groups: Compound 156 (10 mice, 10 mg / kg QD), two groups Compound 248 (20 mice, 20 mg / kg D4 + 10 mg / kg QD), Compound 238 (10 mice, 20 mg / kg D4 + 10 mg / kg QD), Compound 207 (10 mice, 20 mg / kg D4 + 10 mg / kg QD), Compound 213 (10 mice, 20 mg / kg D4 + 10 mg / kg QD), Compound 248 (10 mice, 20 mg / kg QD), Compound 248 (10 mice, 6 mg / kg D4 + 3 mg / kg QD), Compound 248 (10 mice, 2 mg / kg D4 + 1 mg / kg QD), and two groups Vehicle control (20 mice, 100 μl QD). Compound 156, compound 843, compound 207, and compound 213 were diluted with 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO. Compound 248 was diluted with 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO or with 20% Transcutol, 20% TPGS, 0.6% HPMC, and 59.4% HO. 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO or 20% Transcutol, 20% TPGS, 0.6% HPMC, and 59.4% HO served as vehicle controls. Tumors in mice treated with B16-SIY from day 4 to day 21 post-inoculation were measured three times weekly, followed by a 40-day treatment-free observation period (Figure 25). Tumor volumes >1000 mm were <1000 mm. 3 Mice were sacrificed when they reached the humane endpoint or when they reached the normal age. Mice that survived beyond day 61 were again inoculated intradermally with additional B16-SIY cells on day 62 as described above and sacrificed at an undetermined date (experiment ongoing).

[0789] Figure 25 shows the treatment schedule of Compound 156, Compound 238, Compound 213, Compound 207, and Compound 248 in Experiment 8 in an in vivo efficacy study by oral administration, and monitors tumor volume and mouse survival rate. Arrows indicate oral administration.

[0790] 3.2.3.9 Efficacy Experiment 9: Compound 156, Compound 329, Compound 213, and compound 262 1 × 10 C57BL / 6J mice 6 B16-SIY cells were inoculated intradermally, and 3 days after implantation, tumor-bearing mice were randomly assigned to 10 different groups: Compound 156 (8 mice, 10 mg / kg QD), Compound 329 (8 mice, 10 mg / kg QD), Compound 213 (8 mice, 10 mg / kg QD), Compound 213 (8 mice, 25 mg / kg QD), Compound 213 (8 mice, 60 mg / kg QD), Compound 262 (8 mice, 10 mg / kg QD), Compound 329 (7 mice, 20 mg / kg QD), and vehicle control (8 mice, 100 μl QD). Compound 156, Compound 329, Compound 213, or Compound 262 was diluted in 20% Transcutol, 20% TPGS, 0.6% HPMC, and 59.4% HO. 20% Transcutol, 20% TPGS, 0.6% HPMC, and 59.4% HO served as vehicle controls. Tumors in mice treated with B16-SIY from day 4 to day 21 post-inoculation were measured three times weekly, followed by a treatment-free observation period (Figure 27, ongoing experiment). Tumor volumes >1000 mm 3 Mice were sacrificed when they reached the normal age or humane endpoint.

[0791] Figure 27 shows the treatment schedules of Compound 156, Compound 329, Compound 213, and Compound 262 in an in vivo efficacy study with oral administration, monitoring tumor volume and mouse survival rate (data not shown, experiment ongoing). The arrow indicates oral administration.

[0792] 3.3 Results 3.3.1 Efficacy Experiment 1: Compound 142 C57BL / 6 mice were inoculated intradermally with B16-SIY cells and orally administered 30 mg / kg of compound 142 three days after B16-SIY inoculation, followed by 10 mg / kg daily (d3: 30 mg / kg + QD: 10 mg / kg), or 9 mg / kg of compound 142 three days after B16-SIY inoculation, followed by 3 mg / kg daily (d3: 9 mg / kg + QD: 3 mg / kg). Vehicle-treated mice served as controls. Tumor volumes in mice treated with both compound 142 regimens over 21 days were significantly reduced compared to the vehicle control group (Figure 2).

[0793] 3.3.2 Efficacy Experiment 2: Compound 142 C57BL / 6J mice were inoculated intradermally with B16-SIY cells and orally administered 60 mg / kg of compound 142 3 days after B16-SIY inoculation, followed by 40 mg / kg of compound 142 every 48 hours (60 mg / kg D3 + 40 mg / kg Q2D; 40 mg / kg was administered every 48 hours except on days 7 (30 mg / kg) and 9 (60 mg / kg) post-inoculation). Mice administered vehicle (100 μl QD) or untreated served as controls. Mice administered with compound 142 showed a significant reduction in tumor size over 19 days compared to all other treatment groups (Figure 12).

[0794] Figure 12 shows the effect of Compound 142 on in vivo tumor growth rate. Compound 142 60 mg / kg D3 + 40 mg / kg Q2D * Mean tumor volume ± SEM for mice orally dosed with 142 mg / kg or vehicle. Asterisks indicate Compound 142 treatment at 40 mg / kg every 48 hours, except on days 7 (30 mg / kg) and 9 (60 mg / kg). Statistical significance (p < 0.05) between treatment groups and the vehicle control group was calculated using two-way ANOVA.

[0795] 3.3.3 Efficacy Study 3: Compound 142 C57BL / 6J mice were inoculated intradermally with B16-SIY cells, and four days after B16-SIY inoculation, 30 mg / kg of Compound 142 was orally administered, followed by daily administration of 10 mg / kg (3 Mice were treated with either 0 mg / kg D4 or 10 mg / kg QD (9 mg / kg D4 + 3 mg / kg QD) or 9 mg / kg Compound 142 4 days after B16-SIY inoculation, followed by daily dosing at 3 mg / kg (9 mg / kg D4 + 3 mg / kg QD). Vehicle-treated mice (100 μl QD) were used as controls. Tumor volumes in mice treated with both dosing regimens of Compound 142 for 21 days were significantly reduced compared to the vehicle control group ( FIG. 13 ).

[0796] Figure 13 shows the effect on in vivo tumor growth rate. Compound 142 Mean tumor volume ± SEM for mice orally treated with 30 mg / kg D4 + 10 mg / kg QD, 9 mg / kg D4 + 3 mg / kg QD, or vehicle. Statistical significance (p<0.05) between treatment and vehicle control groups was calculated using two-way ANOVA.

[0797] 3.3.4 Efficacy Experiment 4: Compound 142 or Compound 120 C57BL / 6J mice were inoculated intradermally with B16-SIY cells and orally administered 30 mg / kg of compound 142 four days after B16-SIY inoculation, followed by 10 mg / kg daily (30 mg / kg D4 + 10 mg / kg QD), or 30 mg / kg of compound 142 four days after B16-SIY inoculation, followed by 30 mg / kg every three days (30 mg / kg Q3D). Compound 120 (25 mg / kg QD) was administered daily starting four days after B16-SIY inoculation, and vehicle-treated mice (100 μl QD) served as controls. The tumor volume of mice treated with the compound 142 regimen over a 20-day period was significantly reduced compared to the vehicle control group. Compound 120 administration did not affect tumor growth compared to the vehicle-treated control group (FIG. 14).

[0798] Figure 14 shows the effect of Compound 140 and Compound 120 on in vivo tumor growth rate. Mean tumor volumes ± SEM for mice orally dosed with Compound 142 30 mg / kg D4 + 10 mg / kg QD, or 30 mg / kg D4 + 30 mg / kg Q3D, Compound 120 25 mg / kg QD, or vehicle. Statistically significant differences ( ** p<0.01) was calculated using two-way analysis of variance.

[0799] 3.3.5 Efficacy Experiment 5: Compound 142, Compound 156, or Compound 119 C57BL / 6J mice were inoculated intradermally with B16-SIY cells and orally administered 30 mg / kg of compound 142 4 days after B16-SIY inoculation, followed by 10 mg / kg daily until day 21 (30 mg / kg D4 + 10 mg / kg QD), or 20 mg / kg of compound 156 4 days after B16-SIY inoculation, followed by 10 mg / kg daily until day 21 (20 mg / kg D4 + 10 mg / kg QD). Compound 119 (10 mg / kg QD) was administered daily from day 4 after B16-SIY inoculation until day 21. Vehicle-treated mice (100 μl QD) served as controls. Mice were then observed for 40 days without treatment. Mice treated with compound 142, compound 156, and compound 119 had significantly reduced tumor volume and prolonged survival compared to vehicle controls over a 61-day period (Figures 15A-C). Three mice receiving compound 156 from days 4 to 21 survived beyond day 61 and were again inoculated intradermally with additional B16-SIY cells on day 62. Three previously untreated mice without primary tumors were inoculated intradermally with B16-SIY cells and served as controls.

[0800] Figures 15A-C show the effects of Compound 142, Compound 156, and Compound 119 on in vivo tumor growth and survival rates. A: Mean tumor volume ± SEM for mice orally treated with Compound 142 30 mg / kg D4 + 10 mg / kg QD, Compound 156 20 mg / kg D4 + 10 mg / kg QD, Compound 119 10 mg / kg QD, or vehicle. Between treatment groups and vehicle control group. Statistically significant difference ( ** p<0.01, **** p<0.0001) was calculated using two-way ANOVA. B: Survival of mice orally treated with Compound 142 30 mg / kg D4 + 10 mg / kg QD, Compound 156 20 mg / kg D4 + 10 mg / kg QD, Compound 119 10 mg / kg QD, or vehicle. C: Mean tumor volume ± SEM and tumor volume of individual mice receiving primary B16-SIY administration or secondary B16-SIY re-administration.

[0801] 3.3.6 Efficacy Experiment 6: Compound 142, Compound 156, or Compound 119 C57BL / 6J mice were inoculated intradermally with B16-SIY cells and orally administered 30 mg / kg of compound 142 7 days after B16-SIY inoculation, followed by 10 mg / kg daily until day 21 (30 mg / kg D7 + 10 mg / kg QD). 20 mg / kg of compound 156 was administered 7 days after B16-SIY inoculation, followed by 10 mg / kg daily until day 21 (20 mg / kg D7 + 10 mg / kg QD), or 6 mg / kg of compound 156 was administered 7 days after B16-SIY inoculation, followed by 3 mg / kg daily until day 21 (6 mg / kg D7 + 3 mg / kg QD). Compound 119 (10 mg / kg QD) was administered daily from day 7 to day 21 after B16-SIY inoculation, and vehicle-treated mice (100 μl QD) served as controls. Mice were then observed without treatment for 44 days. Compound 156- and compound 119-treated mice showed significant reductions in tumor volume and extended survival compared to the vehicle control group over 65 days (Figure 16). One mouse administered compound 156 20 mg / kg D7 + 10 mg / kg QD between days 7 and 21 and one mouse administered compound 156 6 mg / kg D7 + 3 mg / kg QD survived beyond day 65 and were again inoculated intradermally with additional B16-SIY cells on day 66. Three previously untreated, age-matched mice without primary tumors were inoculated intradermally with B16-SIY cells and served as controls. Re-challenged mice showed no primary or secondary B16-SIY tumor growth compared to controls over a 16-day period and were sacrificed on day 82.

[0802] Figures 16A and 16B show the effects of Compound 142, Compound 156, and Compound 119 on in vivo tumor growth rates. A: Mean tumor volumes ± SEM of mice orally treated with Compound 142, Compound 156, or Compound 119 from day 7 to day 21 after B16-SIY inoculation. Statistically significant differences ( ** p<0.01, ***p<0.001) was calculated using two-way ANOVA. B: Survival rate of mice orally treated with compound 142, compound 156, or compound 119 from day 7 to day 21 after B16-SIY inoculation.

[0803] 3.3.7 Efficacy Experiment 7: Compound 156 and Anti-PD1 C57BL / 6J mice were inoculated intradermally with B16-SIY cells and orally administered 30 mg / kg of Compound 156 3 days after inoculation, followed by daily administration of 10 mg / kg until day 19 (30 mg / kg D3 + 10 mg / kg QD). Additionally, anti-PD1 antibody (10 mg / kg BIW) or rat IgG2a isotype control antibody (10 mg / kg BIW) was intraperitoneally injected twice a week from day 4 to day 19 after tumor cell inoculation. Vehicle-treated mice served as controls and were boosted twice weekly with 156 (BIW) from day 4 to day 19 after tumor cell inoculation. Mice treated with vehicle and anti-PD1, compound 156 and isotype control, and compound 156 and anti-PD1 showed significant reductions in tumor volume compared to the vehicle and isotype control group over the 19-day period. Combination treatment with compound 156 and anti-PD1 showed the best response in terms of tumor growth inhibition and tumor weight (Figures 24A-B).

[0804] Figures 24A and 24B show the monotherapy and combination therapy of compound 156 and an anti-PD1 antibody. The effect of treatment on in vivo tumor growth rates is shown. A: Mean tumor volume ± SEM in mice treated with oral administration of compound 156 or vehicle in combination with intraperitoneal administration of anti-PD1 or rat IgG2a isotype control antibody from days 3 to 19 after B16-SIY inoculation. Treatment groups were administered as follows: (gray) vehicle [QD] orally + isotype [10 mg / kg BIW] intraperitoneally; (yellow) vehicle [QD] orally + anti-PD-1 [10 mg / kg BIW] intraperitoneally; (purple) compound 156 [30 mg / kg D3 + 10 mg / kg QD] orally + isotype [10 mg / kg BIW] intraperitoneally; (teal) compound 156 [30 mg / kg D3 + 10 mg / kg QD] orally + anti-PD-1 [10 mg / kg BIW] intraperitoneally. Statistically significant differences between treatment groups and vehicle control group ( * p<0.5, **** p<0.0001) was calculated using two-way analysis of variance. B: Tumor weights of individual mice given oral and intraperitoneal administration as in A.

[0805] 3.3.8 Efficacy Experiment 8: Compound 156, Compound 238, Compound 213, Compound 207, and Compound 248 C57BL / 6J mice were inoculated intradermally with B16-SIY cells and orally administered 10 mg / kg of compound 156 daily (10 mg / kg QD) or, starting on day 4 after B16-SIY inoculation, 20 mg / kg of compound 248, compound 238, compound 207 (the R enantiomer of compound 240), or compound 213 (the R enantiomer of compound 238) followed by 10 mg / kg daily (20 mg / kg D4 + 10 mg / kg QD) until day 21. Compound 248 was further evaluated using the following dosing regimens: 20 mg / kg QD, 6 mg / kg D4 + 3 mg / kg QD, 2 mg / kg D4 + 1 mg / kg QD, and 20 mg / kg D4 + 10 mg / kg QD treatment schedules were compared in two different formulations. Mice administered vehicle (100 μL / mouse, QD) from day 4 to day 21 after B16-SIY inoculation served as controls. Mice were then observed without treatment for 40 days. Mice administered Compound 156, Compound 248, Compound 238, Compound 207, and Compound 213 exhibited significantly reduced tumor volume and prolonged survival compared to vehicle controls over a 61-day period (Figures 26A-D).

[0806] Four mice receiving compound 156, six mice receiving compound 248 at 20 mg / kg QD, six mice receiving compound 248 at 20 mg / kg D4 + 10 mg / kg QD, three mice receiving compound 248 at 6 mg / kg D4 + 3 mg / kg QD, five mice receiving compound 238, one mouse receiving compound 207, two mice receiving compound 213, and two mice receiving compound 248 at 20 mg / kg D4 + 10 mg / kg QD in different formulations between days 4 and 21 survived beyond day 61 and were again inoculated intradermally with additional B16-SIY cells on day 62. Five previously untreated mice without primary tumors were inoculated intradermally with B16-SIY cells and served as controls (ongoing experiments).

[0807] Figures 26A to 26D show the effects of Compound 156, Compound 238, Compound 213, Compound 207, and Compound 248 on in vivo tumor growth and survival rates. A: Mean tumor volume ± SEM of mice orally treated with Compound 156, Compound 248, or vehicle from day 4 to day 21 after B16-SIY inoculation. B: Survival rate of mice orally treated as in A. C: Mean tumor volume ± SEM of mice orally treated with Compound 156, Compound 238, Compound 213, Compound 207, and Compound 248, or vehicle from day 4 to day 21 after B16-SIY inoculation. D: Survival rate of mice orally treated as in C.

[0808] 3.3.9 Efficacy Experiment 9: Compound 156, Compound 329, Compound 213, and Compound 262 C57BL / 6J mice were inoculated intradermally with B16-SIY cells and administered 10 mg / kg of the compound. Compounds 156, 329 (the R enantiomer of compound 248), 213 (the R enantiomer of compound 238), and 262 were orally administered, with compound 213 being further evaluated at the following dosing schedules: 25 mg / kg QD and 60 mg / kg QD, starting on day 4 post-inoculation until day 21. Compound 329 was also evaluated at 20 mg / kg QD, starting on day 4 post-inoculation until day 21. Vehicle-treated mice (100 μL / mouse) served as controls. Mice were subsequently observed without treatment (during the duration of the experiment).

[0809] All compounds and treatment regimens resulted in significantly reduced tumor volume over several days and prolonged survival compared to the control group (Figure 28, experiment ongoing).

[0810] Figure 28 shows the effect of Compound 156, Compound 329, Compound 213, and Compound 262 on in vivo tumor growth rate. Mean tumor volume ± SEM for mice orally dosed with Compound 156, Compound 329, Compound 213, and Compound 262 or vehicle from day 4 to day 18 after B16-SIY inoculation.

[0811] 4 Example B-4: Efficacy of EO771 against breast cancer Compounds 156 and 119 were selected based on their potency, ADME, and PK profiles and were tested in immunocompetent C57BL / 6J mice implanted with EO771 breast cancer cells. Compound formulation and dosing for the proof-of-concept (POC) study were based on PK studies at LDC (Lead Discovery Center, Dortmund).

[0812] Compounds 156 and 119 demonstrate preclinical efficacy in the murine EO771 breast cancer model. 4.1 Bioassay materials

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[0815] 4.2 Procedures / Instructions 4.2.1 Animals and Ethics Eight-week-old C57BL / 6 mice were purchased from Charles River. All animal experiments were approved in accordance with the institutional guidelines of the Research Institute of Molecular Pathology (Austria) and in accordance with European Community animal care regulations under permission from the Austrian Ministry of Science.

[0816] 4.2.2 EO771 cell culture EO771 breast cancer cells were cultured in DMEM containing 10% FCS, 1% PenStrep, 1% sodium pyruvate, 1% non-essential amino acid solution, and 1% L-glutamine and incubated in a humidified incubator at 37°C and 5% CO. For tumor inoculation, subconfluent EO771 cells were trypsinized, washed, counted, and resuspended in a solution with 50% PBS and 50% Matrigel, and 20x10 6 A final concentration of EO771 cells / ml was achieved.

[0817] 4.2.3 Efficacy experiment 4.2.3.1 Tumor inoculation and compound administration Efficacy experiment 1, using a dosing schedule for POC testing, monitored tumor volume and survival rates in mice treated with oral drug administration.

[0818] 0.5 × 10 cells in the fourth mammary fat pad of 46 C57BL / 6J mice. 6 EO771 cells were inoculated into the tumor-bearing mice. Six days after implantation, the tumor-bearing mice were randomly assigned to four groups: Compound 142 (10 mice, 30 mg / kg D7 + 10 mg / kg QD), Compound 156 (10 mice, 20 mg / kg D7 + 10 mg / kg QD), Compound 119 (10 mice, 10 mg / kg QD), and vehicle control (10 mice, QD). Compound 142, Compound 156, and Compound 119 were diluted in a solution containing 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO and orally administered to the mice from days 7 to 21. A 100 μL solution with 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO served as a vehicle control. Tumors were measured daily and tumors with a volume of ≥700 mm were excluded. 3 Mice were sacrificed when they reached the normal age or humane endpoint.

[0819] 17 shows the dosing schedules for Compound 142, Compound 156, and Compound 119 in an in vivo efficacy experiment using oral compound administration. Arrows indicate oral drug administration.

[0820] 4.3 Results EO771 tumor-bearing C57BL / 6J mice received either 30 mg / kg of compound 142 7 days after EO771 inoculation, followed by 10 mg / kg daily (30 mg / kg D7 + 10 mg / kg QD) until day 21, or 20 mg / kg of compound 156 7 days after EO771 inoculation, followed by 10 mg / kg daily (20 mg / kg D7 + 10 mg / kg QD) until day 21. Compound 119 (10 mg / kg QD) was administered daily starting 7 days after EO771 inoculation until day 21, and vehicle-treated mice (100 μL / mouse QD) served as controls. Tumor volumes ≥ 700 mm 3 Mice were sacrificed when the tumor size reached 800 mg / kg or reached a humane endpoint. Subsequently, mice were observed without treatment for 40 days. Compound 156 treatment resulted in complete tumor elimination in 8 of 10 mice, and mice treated with compound 119 showed reduced tumor growth rates compared to vehicle controls even after treatment was discontinued. Mice treated with compound 156 and compound 119 showed extended survival times compared to vehicle controls even after treatment was discontinued. Compound 142 treatment did not affect tumor growth or survival compared to vehicle controls. Three mice treated with compound 142, eight mice treated with compound 156, four mice treated with compound 119, and two mice that received no treatment between days 7 and 21 survived beyond day 61 and were re-inoculated with additional EO771 cells on day 62. Eight previously untreated, age-matched mice without primary tumors were inoculated with EO771 cells and served as controls. Re-inoculated mice showed no primary or secondary EO771 tumor growth over 20 days compared to controls and were terminated on day 82 (Figure 18).

[0821] Figures 18A and 18B show the effect of compound 142, compound 156, or compound 119 on in vivo tumor growth rate. A: Mean tumor volume ± SEM of mice orally treated with compound 142, compound 156, or compound 119 from day 7 to day 21 after EO771 inoculation. Statistical significance (p<0.01) between the treatment group and the vehicle control group was calculated using two-way ANOVA. B: Survival rate of mice orally treated with compound 142, compound 156, or compound 119 from day 7 to day 21 after EO771 inoculation.

[0822] 5 Example B-5: Efficacy of GL261-LUC2-iRFP against glioma Compound 142 was preclinically demonstrated in the mouse GL261-LUC2-iRFP glioma model. Shows floor effectiveness.

[0823] 5.1 Bioassay materials

[0824] [ka]

[0825] [ka]

[0826] 5.2 Procedures / Instructions 5.2.1 Animals and Ethics Eight-week-old C57BL / 6J mice were purchased from Charles River, Inc. All animal experiments were approved in accordance with the institutional guidelines of the Research Institute of Molecular Pathology (Austria) and in accordance with European Community animal care regulations under permission from the Austrian Ministry of Science.

[0827] 5.2.2 GL261-LUC2-iRFP cell culture GL261-LUC2-iRFP glioma cells were cultured in DMEM containing 10% FCS, 1% PenStrep, and 1% L-glutamine and incubated in a humidified incubator at 37°C and 5% CO. For tumor inoculation, sub-confluent GL261-LUC2-iRFP cells were trypsinized, washed, counted, and resuspended in PBS at 50x10 6 The final concentration was GL261-LUC2-iRFP cells / ml.

[0828] 5.2.3 Efficacy Experiments 5.2.3.1 Tumor inoculation and compound administration 0.1 × 10 into the left hemisphere of 20 C57BL / 6J mice 6 GL261-LUC2-iRFP cells were inoculated, and 7 days after implantation, tumor-bearing mice were randomly assigned to the following two groups: Compound 142 treatment (10 mice, 30 mg / kg D7 + 10 mg / kg Compound 142 was diluted in a solution containing 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO and administered to mice from days 7 to 28. 100 μL of a solution containing 10% DMSO, 20% PEG400, 21% HPbCD, 0.35% HPMC, and 48.65% HO served as a vehicle control. Tumor growth was monitored using an IVIS® Spectrum in vivo imaging system on days 4, 10, 14, 17, 21, 24, 28, and 31 after GL261-LUC2-iRFP inoculation. Mice were sacrificed 31 days after GL261-LUC2-iRFP inoculation or when they reached a humane endpoint.

[0829] Figure 19 shows the dosing schedule for Compound 142 in an in vivo efficacy study using oral compound administration. The arrow indicates oral drug administration. 5.3 Results GL261-LUC2-iRFP tumor-bearing C57BL / 6J mice were administered 30 mg / kg of Compound 142 7 days after GL261-LUC2-iRFP administration, followed by 10 mg / kg daily until day 28 (30 mg / kg D7 + 10 mg / kg QD), with vehicle-treated mice (100 μl / mouse QD) serving as controls. Compound 142-treated mice showed reduced tumor volume compared to vehicle controls over 31 days ( FIG. 20 ).

[0830] Figure 20 shows the effect of compound 142 on in vivo tumor growth rate. Mean tumor volume ± SEM of mice orally administered GL261-LUC2-iRFP on days 7 to 28 after inoculation. Statistically significant differences (p<0.0001) between the treatment group and the vehicle control group were calculated using two-way analysis of variance.

[0831] 6 Example B-6: T cell stimulation ability against viral antigens in vitro Compound 142 was tested for its ability to enhance PBMC- or T-cell-mediated immunity to a viral peptide mix (CEFX) by measuring CD69 expression by flow cytometry.

[0832] 6.1 Bioassay Materials

[0833] [ka]

[0834] 6.2 Procedures / Instructions 6.2.1 Collection of PBMCs from buffy coat Leukocyte-enriched buffy coats were obtained from the Austrian Red Cross and diluted to a total volume of 480 mL with PBS. 30 mL was transferred to a 50 mL Falcon and 11 mL of LymphoPrep was added. The cell suspension was centrifuged for 20 minutes at 2200 rpm, and the PBMC-containing layer was removed, washed three times with PBS, and counted.

[0835] 6.2.2 Separation of CD4+ and CD8+ T cells 10 7 PBMCs were magnetically labeled with CD4 and CD8 microbeads according to the manufacturer's instructions and separated using an autoMACS instrument.

[0836] 6.2.3 Serial dilution of LMW compounds 10 mM LMW compound stocks were further diluted with DMSO and equal volumes were transferred to 96-well plates containing T cells. Final concentrations tested were 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, and 0.01 μM.

[0837] 6.2.4 Stimulus setup for EC50 testing For stimulation assays, purified CD4+ and CD8+ T cells were seeded at 80,000 cells per 96-well plate and incubated with 1 μg / mL anti-CD3, 1 μg / mL anti-CD3 and 1 μg / mL anti-CD28, or 0.5 μg / mL CEFx viral peptides and LMW compounds ranging from 0.01 μM to 30 μM. DMSO-only wells and wells without anti-CD3, anti-CD28, or CEFx served as controls. Stimulated and unstimulated cells were cultured in a humidified incubator at 37°C and 5% CO2 for up to 3 days.

[0838] 6.2.5 Determining EC50 Values ​​for LMW Compounds by Surface FACS T cells were stained with surface antigens (anti-CD4 and anti-CD8) and cell activation markers (anti-CD25 and anti-CD69). Additionally, fixable viability stains were used to stain live cells. Staining was performed for 15 minutes, and cells were analyzed using a Fortessa flow cytometer and FlowJo software. EC50 values ​​were calculated using GraphPad Prism® and a variable slope model (agonist vs. response—variable slope).

[0839] 6.3 Results 6.3.1 In vitro CD4+ and CD8+ T cell stimulation Extreme Assay Purified CD4+ and CD8+ T cells were incubated with anti-CD3, anti-CD3 / CD28, or CEFx viral peptides and compound 142, and T cell activation was monitored 24 and 72 hours after stimulation. Purified T cells showed a dose-dependent increase in CD25 and CD69 expression in response to anti-CD3, anti-CD3 / CD28, or CEFx stimulation and increasing concentrations of compound 142.

[0840] Compound 142 enhances virus-specific T cell activation in cells from healthy individuals (EC50 CD4+: 807 nm, EC50 CD8+: 504 nm). No antigen-specific, independent effect of Compound 142 on T cell activation was demonstrated.

[0841] Figures 21A and 21B show in vitro CD4+ and CD8+ T cell stimulation, respectively. Purified T cells were stimulated with anti-CD3, anti-CD3 / CD28, or CEFx viral peptides and eight different concentrations of Compound 142.

[0842] 7 Example B-7: In vitro phenotypic analysis in human tissues and disease settings Example B-7 demonstrates the characterization of compound 142 in the Eurofins BioMAP colorectal cancer (CRC) panel in human primary cell-based systems. These systems are designed to model complex human tissue and disease biology, evaluating the impact of small molecules in cell-based model systems in the immunosuppressed tumor microenvironment (TME), as well as the human vasculature, skin, lung, and inflamed tissues. Quantitative measurements of biomarker activity across this broad panel, along with comparative analysis of the biological activity of known bioactives in the BioMAP reference database, are used to predict the safety, efficacy, and function of investigational agents.

[0843] Compound 142 induces a lymphocyte activation biomarker pattern in in vitro cultures that mimics immune responses in human tissues and diseases. Compound 142 induces an inflammatory biomarker signature in human in vitro cell cultures that mimics immune responses in human tissues and diseases, particularly in the suppressive tumor microenvironment. Biomarker expression in compound 142-treated cancer cell lines, primary immune, and tissue cell cocultures was measured compared to vehicle control using the BioMAP assay. Compound 142 demonstrated activity in 17 annotated readouts and no cytotoxicity at the concentrations tested (10 μM and 3.3 μM). Compound 142 affects inflammation-related activity (increase in sTNFα, IP-10, MCP-1), matrix remodeling activity (decrease in collagen I, collagen III), angiogenesis-related activity (decrease in uPA, sVEGF), and immune-related activity (decrease in sIL-10, sIL-17A; increase in sIFNγ, sIL-2, sIL-6).

[0844] 8 Example B-8: Comparison of EC50 test with prior art compounds Example B-8 relates to a comparison of the compounds of the present invention with xanthine derivatives from the prior art. The xanthine derivatives from the prior art, Examples 103 and 104 of patent application WO2000 / 09507A1, show no or minimal T cell activation in vitro compared to the compound of the present invention, i.e., Compound 119.

[0845] Compound 119 and two xanthine derivatives from patent application WO2000 / 09507A1 were tested for their potential to enhance CD3 / 28 stimulated T cell activation. The activation of stimulated human CD4+ and CD8+ T cells was measured by flow cytometry. Compound 119 induced an increase in T cell activation at concentrations below 1 μM, while the xanthine derivatives from patent application WO 2000 / 09507 A1, Examples 103 and 104, showed no or only slight T cell activation at 10 μM.

[0846] 1.1 Bioassay materials

[0847] [ka]

[0848] 1.2 Procedures / Instructions 1.2.1 Collection of PBMCs from buffy coat Leukocyte-enriched buffy coats were obtained from the Austrian Red Cross and diluted to a total volume of 480 mL with PBS. 30 mL was transferred to a 50 mL Falcon and 11 mL of LymphoPrep was added. The cell suspension was centrifuged at 2200 rpm for 20 minutes, and the PBMC-containing layer was removed, washed three times with PBS, and counted.

[0849] 1.2.2 Separation of CD4+ and CD8+ T cells 10 7PBMCs were magnetically labeled with CD4 and CD8 microbeads according to the manufacturer's instructions and separated using an autoMACS instrument. For dose-response experiments with purified CD4+CD8+ T cells, 80,000 cells were seeded per 96-well flat-bottom cell culture dish.

[0850] 1.2.3 Serial dilution of LMW compounds 10 mM LMW compound stocks were further diluted with DMSO and equal volumes were transferred to 96-well plates containing T cells. 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 μM, and 0.001 μM.

[0851] 1.2.4 Stimulus setup for EC50 testing For stimulation assays, purified CD4+ and CD8+ T cells were seeded at 80,000 cells per 96-well plate and incubated with 1 μg / mL anti-CD3, 1 μg / mL anti-CD28, and LMW compounds ranging from 0.001 μM to 30 μM. DMSO-only wells served as controls to determine minimal T cell activation upon stimulation, while CD3 / 28-conjugated Dynabeads were used to determine maximal T cell activation. Cells were cultured for 16 hours in a humidified incubator at 37°C and 5% CO2.

[0852] 1.2.5 EC for LMW compounds by surface FACS 50 Measurement of values T cells were stained for surface antigens (anti-CD4 and anti-CD8) and cell activation markers (anti-CD69). Additionally, live cells were stained using a fixable viability stain. Staining was performed for 15 minutes, and cells were analyzed using a Fortessa flow cytometer and FlowJo software. EC 50 was calculated using GraphPad Prism® and a variable slope model (agonist vs. response - variable slope).

[0853] 1.3 Results 1.3.1 EC 50 Measurement of Stimulated CD4+ and CD8+ T cells from two donors were incubated with increasing concentrations of Compound 142, Examples 103 and 104 of Patent Application WO2000 / 09507A1, and T cell activation was measured 16 hours after stimulation. 2 showed a dose-dependent increase in human T cell activation in response to anti-CD3 / CD28 stimulation, and EC 50 The xanthine derivatives in Examples 103 and 104 of patent application WO2000 / 09507A1 showed limited T cell activation at 10 μM, and the EC 50 exceeded 1 μM (donor 1) (FIGS. 22A to 22B, Table B-2).

[0854] [Table 10]

[0855] CD4+ and CD8+ T cells from another donor (donor 2) showed no or dose-dependently reduced T cell activation in Examples 103 and 104 of patent application WO2000 / 09507A1 (Figures 22C-D, Table B-3).

[0856] [Table 11]

Claims

1. Compounds of formula (I) 【Chemistry 1】 During the ceremony, A is, 【Chemistry 2】 represents; B is -O-R ３ , —O—CHR ３ R ３＊ , —O—CH ２ -CH ２ -R ３ , or —O—CH ２ -CH ２ -CH ２ -R ３ and R １ teeth, 【Transformation 3】 represents; R ２ａ and R ２ｂ are each independently —H, —F, or —CH ３ , -C ２ H ５ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ -CF ３ , -CHF-CH ２ F, -CH ２ OH, -CH ２ CH ２ OH, -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CF ２ -CH ３ , -CHF-CHF ２ , -CHF-CF ３ , -CF ２ -CF ３ where R ２ａ is - not H; R ３ teeth, 【Chemistry 4】 represents; R ３＊ is -H, -F, -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ -CF ３ represents; R ４ and R ４＊ are each independently —H, —F, —Cl, —Br, —CH ３ , -C ２ H ５ , -CH ２ F, -CHF ２ , -CF ３ , -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OCH(CH ３ ) ２ , -OCH ２ F, -OCHF ２ , -OCF ３ , -CH ２ -CF ３ , -CHF-CH ２ F, -CHF-CHF ２ , -CHF-CF ３ , -CF ２ -CH ３ ,- CF ２ -CH ２ F、-CF ２ -CHF ２ 、-CF ２ -CF ３ 、 【Transformation 5】 represents; R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ are each independently —H, -cyclo-C ３ H ５ , -cyclo-C ４ H ７ , -cyclo-C ５ H ９ , -cyclo-C ６ H １１ , -cyclo-C ７ H １３ , -cyclo C ３ H ５ O, -OH, -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , —O-cyclo-C ３ H ５ , -OCH(CH ３ ) ２ , -OC(CH ３ ) ３ , -OC ４ H ９ , -OPh, -OCH ２ -Ph, -OCPh ３ , -CH ２ -OCH ３ , -C ２ H ４ -OCH ３ , -C ３ H ６ -OCH ３ , -CH ２ -OC ２ H ５ , -C ２ H ４ -OC ２ H ５ , -C ３ H ６ -OC ２ H ５ , -CH ２ -OC ３ H ７ , -C ２ H ４ -OC ３ H ７ 、-C ３ H ６ -OC ３ H ７ 、-CH ２ -O-シクロ-C ３ H ５ 、-C ２ H ４ -O-シクロ-C ３ H ５ 、-C ３ H ６ -O-シクロ-C ３ H ５ 、-CH ２ -OCH(CH) ３ ) ２ 、-C ２ H ４ -OCH(CH ３ ) ２ 、-C ３ H ６ -OCH(CH ３ ) ２ 、-CH ２ -OC(EH ３ ) ３ 、-C ２ H ４ -OC(EH ３ ) ３ 、-C ３ H ６ -OC(EH ３ ) ３ 、-CH ２ -OC ４ H ９ 、-C ２ H ４ -OC ４ H ９ 、-C ３ H ６ -OC ４ H ９ 、-CH ２ -OPh、-C ２ H ４ -OPh、-C ３ H ６ -OPh、-EH ２ -OCH ２ -Ph、-C ２ H ４ -OCH ２ -Ph、-C ３ H ６ -OCH ２ ___、____________________________ ３ 、+C ２ _ ５ 、+C ３ _ ７ 、｢+++B ３ _ ５ 、!\HHH ３ ) ２ 、.((H ３ ) ３ The ３ 、!C ２ _ ５ 、!C ３ _ ７ 、!!Q@B ３ _ ５ 、!CH(CH ３ ) ２ 、!CCH ３ ) ３ 、!CCH ３ 、!!C ２ _ ５ 、!!C ３ _ ７ 、!!Q@QC ３ _ ５ 、!CCH(H ３ ) ２ 、!CCCH ３ ) ３ 、!﯁CH ３ 、﯁!C ２ _ ５ 、﯁!C ３ _ ７ 、!C@BQC ３ _ ５ 、. ３ ) ２ 、!﯁CCCH ３ ) ３ 、!!H ２ 、!!\H ３ 、!!\| ２ _ ５ 、!!\| ３ _ ７ 、!HQ｢｢ｭ| ３ _ ５ 、!!\\\HH ３ ) ２ ]、-CONH[C(CH ３ ) ３ ]、-CON(CH ３ ) ２ 、-CON(C) ２ H ５ ) ２ 、-CON(C) ３ H ７ ) ２ 、-CON(シクロ-C ３ H ５ ) ２ 、-CON[CH(CH) ３ ) ２ ] ２ 、-CON[C(CH) ３ ) ３ ] ２ 、-NHCOCH ３ 、-NHCOC ２ H ５ 、-NHCOC ３ H ７ 、-NHCO-シクロ-C ３ H ５ 、-NHCO-CH(CH ３ ) ２ 、-NHCO-C(CH ３ ) ３ 、-NHCO-OCH ３ 、-NHCO-OC ２ H ５ 、-NHCO-OC ３ H ７ 、-NHCO-O-シクロ-C ３ H ５ 、-NHCO-OCH(CH ３ ) ２ 、-NHCO-OC(CH ３ ) ３ 、-NH ２ 、-NHCH ３ ,-NHC ２ H ５ 、-NHC ３ H ７ 、-NH-シクロ-C ３ H ５ 、-NHCH(CH ３ ) ２ 、-NHC(CH) ３ ) ３ 、-N(CH ３ ) ２ 、-N(C ２ H ５ ) ２ , -N (C) ３ H ７ ) ２ 、-N (シクロ-C ３ H ５ ) ２ , -N[CH(CH ３ ) ２ ] ２ , -N[C(CH ３ ) ３ ] ２ ,-SOC ３ ,-SOC ２ H ５ ,-SOC ３ H ７ 、-SO-シクロ-C ３ H ５ , - SOC (CH) ３ ) ２ , - SOC (CH) ３ ) ３ ,-SO ２ CH ３ ,-E ２ C ２ H ５ ,-SO ２ C ３ H ７ ,-SO ２ -シクロ-C ３ H ５ ,-SO ２ CH (CH) ３ ) ２ ,-E ２ C (CH) ３ ) ３ ,-E ３ H, -SO ３ CH ３ ,-SO ３ C ２ H ５ ,-E ３ C ３ H ７ ,-SO ３ -シクロ-C ３ H ５ ,-E ３ CH (CH) ３ ) ２ ,-SO ３ C (CH) ３ ) ３ ,-E ２ NH ２ ,-E ２ NHCHH ３ ,-E ２ NH ２ H ５ ,-E ２ NH ３ H ７ ,-E ２ NH-シクロ-C ３ H ５ ,-E ２ NHCH (CH) ３ ) ２ ,-E ２ NH (CH) ３ ) ３ ,-E ２ N (CH) ３ ) ２ ,-E ２ N (C) ２ H ５ ) ２ ,-E ２ N (C) ３ H ７ ) ２ ,-E ２ N (シロロ-C ３ H ５ ) ２ ,-E ２ N[CH(CH ３ ) ２ ] ２ ,-E ２ N[C(CH) ３ ) ３ ] ２ 、-O-S(=O)CH ３ 、-O-S(=O)C ２ H ５ 、-O-S(=O)C ３ H ７ 、-O-S(=O)-シクロ-C ３ H ５ 、-O-S(=O)CH (CH ３ ) ２ 、-O-S(=O)C (CH ３ ) ３ 、-S(=O)(=NH)CH ３ 、-S(=O)(=NH)C ２ H ５ 、-S(=O)(=NH)C ３ H ７ 、-S(=O)(=NH)-シクロ-C ３ H ５ 、-S(=O)(=NH)CH(CH ３ ) ２ 、-S(=O)(=NH)C(CH ３ ) ３ 、-NH-SO ２ -CH ３ 、-NH-SO ２ -C ２ H ５ 、-NH-SO ２ -C ３ H ７ 、-NH-SO ２ -シクロ-C ３ H ５ 、-NH-SO ２ -CH(CH ３ ) ２ 、-NH-SO ２ -C(CH ３ ) ３ 、-O-SO ２ -CH ３ 、-O-SO ２ -C ２ H ５ 、-O-SO ２ -C ３ H ７ 、-O-SO ２ -シクロ-C ３ H ５ 、-O-SO ２ -CH(CH ３ ) ２ 、-O-SO ２ -C(CH ３ ) ３ 、-OCH ２ F、-OCHF ２ 、-OCF ３ 、-CH ２ -OCF ３ 、-C ２ H ４ -OCF ３ 、-C ３ H ６ -OCF ３ 、-CH ２ -OCHF ２ ,-C ２ H ４ -OCHF ２ ,-C ３ H ６ -OCHF ２ 、-OC ２ F ５ 、-CH ２ -OC ２ F ５ ,-C ２ H ４ -OC ２ F ５ ,-C ３ H ６ -OC ２ F ５ 、-O-COOCH ３ 、-O-COOC ２ H ５ 、-O-COOC ３ H ７ 、-O-COO-シクロ-C ３ H ５ 、-O-COOCH(CH ３ ) ２ 、-O-COOC(CH ３ ) ３ 、-NH-CO-NH ２ 、-NH-CO-NHCH ３ 、-NH-CO-NHC ２ H ５ 、-NH-CO-NHC ３ H ７ 、-NH-C(=NH)-NH ２ 、-NH-CO-N(C ３ H ７ ) ２ 、-NH-CO-NH[CH(CH ３ ) ２ ]、-NH-CO-NH[C(CH ３ ) ３ ]、-NH-CO-N(CH ３ ) ２ 、-NH-CO-N(C ２ H ５ ) ２ 、-NH-CO-NH-シクロ-C ３ H ５ 、-NH-CO-N(シクロ-C ３ H ５ ) ２ 、-NH-CO-N[CH(CH ３ ) ２ ] ２ 、-NH-C(=NH)-NHCH ３ 、-NH-C(=NH)-NHC ２ H ５ 、-NH-C(=NH)-NHC ３ H ７ 、-O-CO-NH-シクロ-C ３ H ５ 、-NH-C(=NH)-NH-シクロ-C ３ H ５ 、-NHH-C(=NHH)-NHH[CH(CH ３ ) ２ ]、-O-CO-NH[CH(CH ３ ) ２ ]、-NHH-C(=NHH)-NH[C(CH) ３ ) ３ ]、-NHH-C(=NHH)-N(CH ３ ) ２ 、-NH-C(=NH)-N(C ２ H ５ ) ２ 、-NH-C(=NH)-N(C ３ H ７ ) ２ 、-NH-C(=NH)-N(シクロ-C ３ H ５ ) ２ 、-O-CO-NHC ３ H ７ 、-NH-C(=NH)-N[CH(CH ３ ) ２ ] ２ 、-NH-C(=NH)-N[C(CH ３ ) ３ ] ２ 、-O-CO-NH ２ 、-O-CO-NHCH ３ 、-O-CO-NHC ２ H ５ 、-O-CO-NH[C(CH ３ ) ３ ]、-O-CO-N(CH ３ ) ２ 、-O-CO-N(C ２ H ５ ) ２ 、-O-CO-N(C ３ H ７ ) ２ 、-O-CO-N(シクロ-C ３ H ５ ) ２ 、-O-CO-N[CH(CH ３ ) ２ ] ２ 、-O-CO-N[C(CH ３ ) ３ ] ２ 、-O-CO-OCH ３ 、-O-CO-OC ２ H ５ 、-O-CO-OC ３ H ７ 、-O-CO-O-シクロ-C ３ H ５ 、-O-CO-OCH(CH ３ ) ２ 、-O-CO-OC(CH ３ ) ３ 、-CH ２ F、-CHF ２ 、-CF ３ 、-CH ２ -CH ２ F、-CH ２ -CHF ２ 、-CH ２ -CF ３ 、シクロ-C ８ H １５ 、-Ph、-CH ２ -Ph、-CH ２ -CH ２ -Ph、-CH=CH-Ph、-CPh ３ 、-CH ３ 、-C ２ H ５ 、-C ３ H ７ 、-CH(CH ３ ) ２ 、-C ４ H ９ 、-CH ２ -CH(CH ３ ) ２ 、-CH(CH ３ )-C ２ H ５ 、-C(CH ３ ) ３ 、-C ５ H １１ 、-CH(CH ３ )-C ３ H ７ 、-CH ２ -CH(CH ３ )-C ２ H ５ 、-CH(CH ３ )-CH(CH ３ ) ２ 、-C(CH ３ ) ２ -C ２ H ５ 、-CH ２ -C(CH ３ ) ３ 、-CH(C ２ H ５ ) ２ 、-C ２ H ４ -CH(CH ３ ) ２ 、-C ６ H １３ 、-C ７ H １５ 、-C ８ H １７ 、-C ３ H ６ -CH(CH ３ ) ２ 、-C ２ H ４ -CH(CH ３ )-C ２ H ５ 、-CH(CH ３ )-C ４ H ９ 、-CH ２ -CH(CH ３ )-C ３ H ７ 、-CH(CH ３ )-CH ２ -CH(CH ３ ) ２ 、-CH(CH ３ )-CH(CH ３ )-C ２ H ５ 、-CH ２ -CH(CH ３ )-CH(CH ３ ) ２ 、-CH ２ -C(CH) ３ ) ２ -C ２ H ５ 、-C(CH ３ ) ２ -C ３ H ７ 、-CC(CH ３ ) ２ -CH(CH ３ ) ２ ,-C ２ H ４ -C(CH) ３ ) ３ 、-CH(CH ３ )-C(CH ３ ) ３ 、-CH=CH ２ 、-CH ２ -CH=CH ２ 、-CC(CH ３ )=CH ２ 、-CH=CH-CH ３ ,-C ２ H ４ -CH=CH ２ 、-CH ２ -CH=CH-CH ３ 、-CH=CH-C ２ H ５ 、-CH ２ -C(CH) ３ )=CH ２ 、-CH(CH ３ )-CH=CH、-CH=C(CH ３ ) ２ 、-C(CH ３ )=CH-CH ３ 、-CH=CH-CH=CH ２ ,-C ３ H ６ -CH=CH ２ ,-C ２ H ４ -CH=CH-CH ３ 、-CH ２ -CH=CH-C ２ H ５ 、-CH=CH-C ３ H ７ 、-CH=CH-CH=CH -CH ３ 、-C ２ H ４ -C(CH ３ )=CH ２ 、-CH ２ -CH(CH ３ )-CH=CH ２ 、-CH(CH ３ )-CH ２ -CH=CH ２ 、-CH ２ -CH=C(CH ３ ) ２ 、-CH ２ -C(CH ３ )=CH-CH ３ 、-CH(CH ３ )-CH=CH-CH ３ 、-CH=CH-CH(CH ３ ) ２ 、-CH=C(CH ３ )-C ２ H ５ 、-C(CH ３ )=CH-C ２ H ５ 、-C(CH ３ )=C(CH ３ ) ２ 、-C(CH ３ ) ２ -CH=CH ２ 、-CH(CH ３ )-C(CH ３ )=CH ２ 、-C ４ H ８ -CH=CH ２ 、-C ３ H ６ -CH=CH-CH ３ 、-C ２ H ４ -CH=CH-C ２ H ５ 、-CH ２ -CH=CH-C ３ H ７ 、-CH=CH-C ４ H ９ 、-C ３ H ６ -C(CH ３ )=CH ２ 、-C ２ H ４ -CH(CH ３ )-CH=CH ２ 、-CH ２ -CH(CH ３ )-CH ２ -CH=CH ２ ,-C ２ H ４ -CH=C(CH ３ ) ２ 、-CH(CH ３ )-C ２ H ４ -CH=CH ２ ,-C ２ H ４ -C(CH) ３ )=CH-CH ３ 、-CH ２ -CH(CH ３ )-CH=CH-CH ３ 、-CH(CH ３ )-CH ２ -CH=CH-CH ３ 、-CH ２ -CH=CH-CH(CH ３ ) ２ 、-CH ２ -CH=C(CH ３ )-C ２ H ５ 、-CH ２ -C(CH) ３ )=CH-C ２ H ５ 、-CH(CH ３ )-CH=CH-C ２ H ５ 、-CH=CH-CH ２ -CH(CH ３ ) ２ 、-CH=CH-CH(CH ３ )-C ２ H ５ 、-CH=C(CH ３ )-C ３ H ７ 、-C(CH ３ )=CH-C ３ H ７ 、-CH ２ -CH(CH ３ )-C(CH ３ )=CH ２ 、-C[C(CH ３ ) ３ =CH ２ 、-CH(CH ３ )-CH ２ -C(CH) ３ )=CH ２ 、-CH(CH ３ )-CH(CH ３ )-CH=CH ２ 、-CH=CH-C ２ H ４ -CH=CH ２ 、-C(CH ３ ) ２ -CH ２ -CH=CH ２ 、-CH ２ -C(CH) ３ )=C(CH ３ ) ２ 、-CH(CH ３ )-CH=C(CH ３ ) ２ 、-C(CH ３ ) ２ -CH=CH-CH ３ 、-CH=CH-CH ２ -CH=CH-CH ３ 、-CH(CH ３ )-C(CH ３ )=CH-CH ３ 、-CH=C(CH ３ )-CH(CH ３ ) ２ 、-C(CH ３ )=CH-CH(CH ３ ) ２ 、-C(CH ３ )=C(CH ３ )-C ２ H ５ 、-CH=CH-C(CH ３ ) ３ 、-C(CH ３ ) ２ -C(CH) ３ )=CH ２ 、-CH(C ２ H ５ )-C(CH ３ )=CH ２ 、-C(CH ３ (C) ２ H ５ )-CH=CH ２ 、-CH(CH ３ )-C(C ２ H ５ )=CH ２ 、-CH ２ -C(C ３ H ７ )=CH ２ 、-CH ２ -C(C ２ H ５ )=CH-CH ３ 、-CH(C ２ H ５ )-CH=CH-CH ３ 、-C(C ４ H ９ )=CH ２ 、-C(C ３ H ７ )=CH-CH ３ 、-C(C ２ H ５ )=CH-C ２ H ５ 、-C(C ２ H ５ )=C(CH ３ ) ２ 、-C[CH(CH ３ )(C ２ H ５ )]=CH ２ 、-C[CH ２ -CH(CH ３ ) ２ ]=CH ２ 、-C ２ H ４ -CH=CH-CH=CH ２ 、-CH ２ -CH=CH-CH ２ -CH=CH ２ 、-C ３ H ６ -C≡C-CH ３ 、-CH ２ -CH=CH-CH=CH-CH ３ 、-CH=CH-CH=CH-C ２ H ５ 、-CH(CH ３ )-CH ２ -C≡CH、-CH(CH ３ )-C≡C-CH ３ 、-C ２ H ４ -CH(CH ３ )-C≡CH、-CH=CH-CH=C(CH ３ ) ２ 、-CH ２ -CH(CH ３ )-CH ２ -C≡CH、-CH=CH-C(CH ３ )=CH-CH ３ 、-CH=C(CH ３ )-CH=CH-CH ３ 、-CH ２ -CH(CH ３ )-C≡CH、-C(CH ３ )=CH-CH=CH-CH ３ 、-C≡CH、-C≡C-CH ３ 、-CH ２ -C≡CH、-C ２ H ４ -C≡CH、-CH ２ -C≡C-CH ３ 、-C≡C-C ２ H ５ 、-C ３ H ６ -C≡CH、-C ２ H ４ -C≡C-CH ３ 、-CH ２ -C≡C-C ２ H ５ 、-C≡C-C ３ H ７ 、-CH(CH ３ )-C≡CH、-C ４ H ８ -C≡CH、-C ２ H ４ -C≡C-C ２ H ５ 、-CH ２ -C≡C-C ３ H ７ 、-C≡C-C ４ H ９ 、-C≡C-CH ２ -CH(CH ３ ) ２ 、-CH(CH ３ )-C ２ H ４ -C≡CH、-CH ２ -CH(CH ３ )-C≡C-CH ３ 、-C(CH ３ (C) ２ H ５ )-C≡CH、-CH(CH ３ )-CH ２ -C≡C-CH ３ 、-CH(CH ３ )-C≡C-C ２ H ５ 、-CH ２ -C≡C-CH(CH ３ ) ２ 、-C≡C-CH(CH ３ )-C ２ H ５ 、-CH ２ -C≡C-C≡C-CH ３ 、-CH(C ２ H ５ )-C≡C-CH ３ 、-C(CH ３ ) ２ -C≡C-CH ３ 、-CH(C ２ H ５ )-CH ２ -C≡CH, -CH ２ -CH(C) ２ H ５ )-C≡CH、-C(CH ３ ) ２ -CH ２ -C≡CH, -CH ２ -C(CH) ３ ) ２ -C≡CH、-CH(CH ３ )-CH(CH ３ )-C≡CH、-CH(C ３ H ７ )-C≡CH、-CH ２ -CH(C≡CH) ２ 、-C≡C-C≡CH、-CH ２ -C≡C-C≡CH、-C≡C-C≡C-CH ３ 、-CH (C≡CH) ２ 、-C ２ H ４ -C≡C-C≡CH、-CH ２ -C≡C-CH ２ -C≡CH、-C≡C-C ２ H ４ -C≡CH、-C≡C-C(CH ３ ) ３ 、-C≡C-CH ２ -C≡C-CH ３ 、-C≡C-C≡C-C ２ H ５ 、 【Transformation 6】 represents; or R ５ and R ６ , or R ６ and R ７ may form, together with the two carbon atoms of the phenyl ring to which they are attached, a 4- to 8-membered ring system, which may be formed by R １０ , R １１ , R １２ , and R １３ may be optionally substituted with one or more substituents selected from A compound of formula (I), or an enantiomer, diastereomer, tautomer, mixture of enantiomers, mixture of diastereomers, mixture of tautomers, hydrate, solvate, or pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein: R ３ teeth, 【Transformation 7】 represents; and R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ has the same meaning as defined in claim 1, compound.

3. 3. A compound according to claim 1 or claim 2, wherein: R ２ａ is -CH ３ , -C ２ H ５ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ -CF ３ , -CHF-CH ２ F, -CH ２ OH, -CH ２ CH ２ OH, -CH ２ OCH ３ represents; R ２ｂ is -H or -CH ３ represents; B is -O-R ３ or —O—CHR ３ R ３＊ represents; R ３ teeth, 【Transformation 8】 represents; R ３＊ is -H, -F, -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ -CF ３ represents; R ４ and R ４＊ are each independently —H, —F, —Cl, —Br, —CH ３ , -C ２ H ５ , -CH ２ F, -CHF ２ , -CF ３ , -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OCH(CH ３ ) ２ , -OCH ２ F, -OCHF ２ , -OCF ３ , -CH ２ -CF ３ , -CHF-CH ２ F, -CHF-CHF ２ , -CHF-CF ３ , -CF ２ -CH ３ , -CF ２ -CH ２ F, -CF ２ -CHF ２ , -CF ２ -CF ３ , 【Chemistry 9】 represents; and R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ has the same meaning as defined in claim 1, compound.

4. 3. The compound of claim 1 or claim 2, wherein B is —O—CHR ３ R ３＊ , —O—CH ２ -CH ２ -R ３ , or —O—CH ２ -CH ２ -CH ２ -R ３ represents; R ３ and R ３＊ has the same meaning as defined in claim 1, compound.

5. 4. The compound of claim 1, wherein B is —O—R ３ represents; R ３ has the same meaning as defined in claim 1, compound.

6. 10. The compound according to claim 1, wherein the compound has the following formulae (II-1) to (II-5), (III-1) to (III-6), (IV-1) to (IV-8), (V-1) to (V-5), (VI-1) to (VI-2), and (VII-1) to (VII-3): 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 and Here, R １ , R ３＊ , R ４ , R ４＊ , R ５ , R ６ , R ７ , R ８ , R １０ , R １１ , R １２ , and R １３ has the same meaning as defined in any one of claims 1 to 5, compound.

7. The compound according to any one of claims 1 to 6, 【Chemistry 11】 During the ceremony, A is, 【Chemistry 12】 represents; B is -O-R ３ , —O—CH ２ -R ３ or —O—CHR ３ R ３＊ represents; R １ teeth, 【Chemistry 13】 represents; R ３ teeth, 【Chemistry 14】 represents R ３＊ is -H, -F, -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ -CF ３ represents; R ４ and R ４＊ are each independently —H, —F, —Cl, —CH ３ , -CH ２ F, -CHF ２ , -CF ３ , -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OCH(CH ３ ) ２ , -OCH ２ F, -OCHF ２ , -OCF ３ , -CH ２ -CF ３ , -CHF-CH ２ F, -CHF-CHF ２ , -CHF-CF ３ , -CF ２ -CH ３ , -CF ２ -CH ２ F, -CF ２ -CHF ２ , -CF ２ -CF ３ , 【Chemistry 15】 represents; R ５ , R ６ , R ７ , and R ８ are each independently —H, —F, —Cl, —CN, or —CH ３ , -CHF ２ , -CF ３ , -OCH ３ , -OCHF ２ , -OCF ３ , or -SO ２ CH ３ Represents compound.

8. A compound according to any one of claims 1 to 7, wherein R ３ teeth 【Chemistry 16】 Represents a compound.

9. The compound of claim 1 selected from the group consisting of: 【Chemistry 17-1】 【Chemistry 17-2】 【Chemistry 17-3】 【Chemistry 17-4】 【Chemistry 17-5】 【Chemistry 17-6】 【Chemistry 17-7】 【Chemistry 17-8】 【Chemistry 17-9】 【Chemistry 17-10】 【Chemistry 17-11】 [Chemistry 17-12] [Chemistry 17-13] [Chemistry 17-14] 【Chemistry 17-15】 [Chemistry 17-16] 【Chemistry 17-17】 [Chemistry 17-18] [Chemistry 17-19] [Chemistry 17-20] [Chemistry 17-21] [Chemistry 17-22] [Chemistry 17-23] [Chemistry 17-24] [Chemistry 17-25] [Chemistry 17-26] [Chemistry 17-27] [Chemistry 17-28] [Chemistry 17-29] [Chemistry 17-30] [Chemistry 17-31] Or, an enantiomer, diastereomer, tautomer, mixture of enantiomers, mixture of diastereomers, mixture of tautomers, hydrate, solvate of the above compound, or a pharmaceutically acceptable salt thereof.

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

11. 11. The method of claim 10, further comprising at least one stimulatory agent for activating immune cells. Pharmaceutical composition.

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

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

14. 14. The compound for use, a pharmaceutically acceptable salt of the compound for use, or a pharmaceutical composition for use according to claim 13, wherein the compound, a pharmaceutically acceptable salt of the compound, or the pharmaceutical composition is administered in combination with one or more additional stimulatory agents that activate immune cells.

15. 1. An in vitro or ex vivo method for the production of activated immune cells, comprising the steps of: (i) providing immune cells; (ii) subjecting the cells of step (i) to: (a) at least one compound as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and optionally (b) one or more additional stimulatory agents that activate the immune cells; and contacting; and (iii) culturing the cells of step (ii) under conditions suitable to maintain the viability of the cells; A method comprising:

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